Bortezomib and Fludarabine With or Without Rituximab in Treating Patients With Relapsed or Refractory Indolent Non-Hodgkin's Lymphoma or Chronic Lymphocytic Leukemia

ClinicalTrials.gov

2013-09-27

Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Hematopoietic/Lymphoid Cancer; Nodal Marginal Zone B-cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Splenic Marginal Zone Lymphoma; Waldenström Macroglobulinemia

Obatoclax and Bortezomib in Treating Patients With Aggressive Relapsed or Recurrent Non-Hodgkin Lymphoma

ClinicalTrials.gov

2015-12-03

Adult Non-Hodgkin Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Small Lymphocytic Lymphoma

A Phase 1 Study of CC-486 as a Single Agent and in Combination With Carboplatin or ABI-007 in Subjects With Relapsed or Refractory Solid Tumors

ClinicalTrials.gov

2016-03-23

Urinary Bladder Neoplasms; Carcinoma, Transitional Cell; Ovarian Neoplasms; Fallopian Tube Neoplasms; Peritoneal Neoplasms; Carcinoma, Non-Small-Cell Lung; Carcinoma, Pancreatic Ductal; Tumor Virus Infections

A review of a novel, Bruton's tyrosine kinase inhibitor, ibrutinib.

PubMed

Lee, Chung-Shien; Rattu, Mohammad A; Kim, Sara S

2016-02-01

Ibrutinib, a Bruton's kinase inhibitor, was granted an accelerated approval by the US Food and Drug Administration in November, 2013, for the treatment of relapsed or refractory mantle cell lymphoma and subsequently for the treatment of relapsed refractory chronic lymphocytic leukemia in February, 2014. In the pivotal phase 2 study of 111 patients with relapsed or refractory mantle cell lymphoma, the overall response rate in patients who received ibrutinib 560 mg daily was 68%. The median progression-free survival was 13.9 months, and the overall survival was 58% at 18 months. In a recently published phase 3 trial (RESONATE) that compared ibrutinib and ofatumumab for the treatment of relapsed and refractory chronic lymphocytic leukemia or small lymphocytic lymphoma, ibrutinib at the daily dosage of 420 mg demonstrated a significantly higher overall response rate (43% in ibrutinib vs. 4% in ofatumumab) and a significantly improved overall survival at 12 months (90% ibrutinib vs. 81% ofatumumab). Similar clinical benefits were shown regardless of del (17 p). Ibrutinib was well tolerated, and dose-limiting toxicity was not observed. Ibrutinib has shown durable remission, improved progression-free survival and overall survival, and favorable safety profile in indolent B-cell lymphoid malignancies. Ibrutinib, as a monotherapy, is an effective treatment modality as a salvage therapy for treatment of mantle cell lymphoma and chronic lymphocytic leukemia / small lymphocytic lymphoma, particularly in older patients (age ≥70 years) who are not a candidate for intensive chemotherapy and/or those with del (17 p). In patients with chronic lymphocytic leukemia and del (17 p), the current practice guideline recommends ibrutinib as an upfront treatment option. Current on-going trials will further define its role as upfront therapy and/or as a combination therapy in indolent B-cell lymphoid malignancies. © The Author(s) 2014.

Yttrium Y 90 Ibritumomab Tiuxetan, Fludarabine, Radiation Therapy, and Donor Stem Cell Transplant in Treating Patients With Relapsed or Refractory Non-Hodgkin's Lymphoma

ClinicalTrials.gov

2017-04-17

B-cell Chronic Lymphocytic Leukemia; Nodal Marginal Zone B-cell Lymphoma; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Small Lymphocytic Lymphoma; Splenic Marginal Zone Lymphoma; Waldenström Macroglobulinemia

Acid ceramidase in prostate cancer radiation therapy resistance and relapse

NASA Astrophysics Data System (ADS)

Cheng, Joseph C.

Prostate tumor cell escape from ionizing radiation (IR)-induced killing can lead to disease progression and relapse. Sphingolipids such as ceramide and sphingosine 1-phosphate influence signal transduction pathways that regulate stress response in cancer cells. In particular, metabolism of apoptotic ceramide constitutes an important survival adaptation. Assessments of enzyme activity, mRNA, and protein demonstrated preferential upregulation of the ceramide deacylating enzyme acid ceramidase (AC) in irradiated cancer cells. Promoter-reporter and ChIP-qPCR assays revealed AC transcription by activator protein 1 (AP-1) is sensitive to pharmacological inhibition of de novo ceramide biosynthesis, identifying a protective feedback mechanism that mitigates the effects of IR-induced ceramide. Deregulation of c-Jun, in particular, induced marked radiosensitization in vitro and in vivo, which was rescued by ectopic AC over-expression. AC over-expression in prostate cancer clonogens surviving 80 Gray fractionated irradiation was associated with increased radioresistance and proliferation, suggesting a role in radiotherapy failure and relapse. Indeed, immunohistochemical analysis of human prostate cancer tissues revealed higher levels of AC after radiotherapy failure than therapy-naive adenocarcinoma, PIN, or benign tissues. By genetically downregulating AC with small interfering RNA (siRNA), we observed radiosensitization of cells using clonogenic and cytotoxicity assays. Finally, treatment with lysosomotropic small molecule inhibitors of AC, LCL385 or LCL521, induced prostate cancer xenograft radiosensitization and long-term suppression, suggesting AC is a tractable target for adjuvant radiotherapy.

Genetically Engineered Lymphocytes, Cyclophosphamide, and Aldesleukin in Treating Patients With Relapsed or Refractory Mantle Cell Lymphoma or Indolent B-Cell Non-Hodgkin Lymphoma

ClinicalTrials.gov

2014-08-04

B-cell Chronic Lymphocytic Leukemia; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Nodal Marginal Zone B-cell Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Splenic Marginal Zone Lymphoma; Waldenström Macroglobulinemia

CAR-T cells and allogeneic hematopoietic stem cell transplantation for relapsed/refractory B-cell acute lymphoblastic leukemia.

PubMed

Liu, Jun; Zhang, Xi; Zhong, Jiang F; Zhang, Cheng

2017-10-01

Relapsed/refractory acute lymphoblastic leukemia (ALL) has a low remission rate after chemotherapy, a high relapse rate and poor long-term survival even when allogeneic hematopoietic stem cell transplantation (allo-HSCT) is performed. Chimeric antigen receptors redirected T cells (CAR-T cells) can enhance disease remission with a favorable outcome for relapsed/refractory ALL, though some cases quickly relapsed after CAR-T cell treatment. Thus, treatment with CAR-T cells followed by allo-HSCT may be the best way to treat relapsed/refractory ALL. In this review, we first discuss the different types of CAR-T cells. We then discuss the treatment of relapsed/refractory ALL using only CAR-T cells. Finally, we discuss the use of CAR-T cells, followed by allo-HSCT, for the treatment of relapsed/refractory ALL.

Relapse of nephrotic syndrome during post-rituximab peripheral blood B-lymphocyte depletion.

PubMed

Sato, Mai; Kamei, Koichi; Ogura, Masao; Ishikura, Kenji; Ito, Shuichi

2018-02-01

Rituximab is effective against complicated childhood steroid-dependent nephrotic syndrome (SDNS). Peripheral blood B-lymphocyte (B-cell) depletion is strongly correlated with persistent remission, relapse rarely occurring during B-cell depletion; however, we have encountered several such patients. We retrospectively analyzed the characteristics and clinical course of 82 patients with SDNS treated with rituximab from January 2007 to December 2012 in our institution. Six of 82 patients (7.3%) had relapses during B-cell depletion after receiving rituximab (relapsed group). The remaining 76 patients did not have relapses during B-cell depletion (non-relapsed group). The median time to initial relapse during B-cell depletion was 85 days after receiving rituximab, which is significantly shorter than in the non-relapsed group (410 days, p = 0.0003). The median annual numbers of relapses after receiving rituximab were 2.5 and 0.9 in the relapsed and non-relapsed groups, respectively (p < 0.0001). Five patients in the relapsed group also had a total of 10 relapses after B-cell recovery; their median time from B-cell recovery to initial relapse was significantly shorter than in the non-relapsed group (31 vs. 161 days, p = 0.014). Number of relapses before rituximab, history of steroid resistance, onset age, previous treatment, time to ceasing steroids after rituximab, and duration of B-cell depletion did not differ between the two groups. Relapse during B-cell depletion after receiving rituximab suggests that various pathophysiological mechanisms play a part in childhood nephrotic syndrome.

Imatinib Mesylate in Treating Patients With Relapsed or Refractory Solid Tumors of Childhood

ClinicalTrials.gov

2015-04-14

Childhood Desmoplastic Small Round Cell Tumor; Childhood Synovial Sarcoma; Gastrointestinal Stromal Tumor; Lung Metastases; Recurrent Childhood Soft Tissue Sarcoma; Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Recurrent Neuroblastoma; Recurrent Osteosarcoma

Lenalidomide and Blinatumomab in Treating Patients With Relapsed Non-Hodgkin Lymphoma

ClinicalTrials.gov

2018-06-11

CD19 Positive; Mediastinal Lymphoma; Recurrent B-Cell Lymphoma, Unclassifiable, With Features Intermediate Between Diffuse Large B-Cell Lymphoma and Classic Hodgkin Lymphoma; Recurrent Burkitt Lymphoma; Recurrent Diffuse Large B-Cell Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Non-Hodgkin Lymphoma; Recurrent Small Lymphocytic Lymphoma; Refractory B-Cell Lymphoma, Unclassifiable, With Features Intermediate Between Diffuse Large B-Cell Lymphoma and Classic Hodgkin Lymphoma; Refractory Burkitt Lymphoma; Refractory Diffuse Large B-Cell Lymphoma; Refractory Follicular Lymphoma; Refractory Mantle Cell Lymphoma; Refractory Small Lymphocytic Lymphoma

Axicabtagene Ciloleucel Expanded Access Study

ClinicalTrials.gov

2018-05-29

Relapsed/Refractory Diffuse Large B Cell Lymphoma; Relapsed/Refractory Primary Mediastinal B Cell Lymphoma; Relapsed/Refractory Transformed Follicular Lymphoma; Relapsed/Refractory High-Grade B-Cell Lymphoma

Ibrutinib in Treating Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma in Patients With HIV Infection

ClinicalTrials.gov

2015-08-18

Adult B Acute Lymphoblastic Leukemia; Chronic Lymphocytic Leukemia; Cutaneous B-Cell Non-Hodgkin Lymphoma; Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue; HIV Infection; Intraocular Lymphoma; Multicentric Angiofollicular Lymphoid Hyperplasia; Nodal Marginal Zone Lymphoma; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Immunoblastic Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Refractory Plasma Cell Myeloma; Small Intestinal Lymphoma; Splenic Marginal Zone Lymphoma; Testicular Lymphoma; Waldenstrom Macroglobulinemia

CPI-613, Bendamustine Hydrochloride, and Rituximab in Treating Patients With Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma

ClinicalTrials.gov

2017-05-25

B-cell Adult Acute Lymphoblastic Leukemia; B-cell Chronic Lymphocytic Leukemia; Cutaneous B-cell Non-Hodgkin Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Intraocular Lymphoma; Nodal Marginal Zone B-cell Lymphoma; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; Testicular Lymphoma; Waldenström Macroglobulinemia

Targeted therapy with apatinib in a patient with relapsed small cell lung cancer

PubMed Central

Zhao, Jun; Zhang, Xiaoling; Gong, Chaojie; Zhang, Jialei

2017-01-01

Abstract Rationale: Small cell lung cancer (SCLC) is a lethal malignancy. Once relapsed, the disease is irreversible and most of the patients will die of cancer aggravation in 1 to 2 months. In the past several decades, little progress has been made in the systemic treatment of SCLC. Apatinib, as a novel small-molecule tyrosine kinase inhibitor specifically targeting the vascular endothelial growth factor receptor 2 (VEGFR2), has achieved progress in treatment of a variety of cancers. However, there has been no report of the targeted therapy with apatinib in SCLC yet. Patient concerns: A 63-year-old man, an ex-smoker, presented with a slight hoarseness and cough. The patient was admitted to our department with a primary diagnosis of SCLC at an extensive stage (ES-SCLC). After 17 months of successful first-, second-, and third-line chemotherapy, the disease eventually became relapsed. Then, apatinib treatment started promptly on demand by the patient and his family. Intervention: After presenting an informed consent, the patient received apatinib treatment immediately at a dose of 250 mg/day orally. Outcomes: (1) On the 28th day of apatinib therapy, the symptoms of dyspnea and poor appetite of the patient were notably improved. (2) The CT scan taken on the 70th day showed that the pleural effusion in the left lung almost disappeared. (3) The elevated serum neuron-specific enolase (NSE) level was decreased. The patient died of acute respiratory failure on the 172nd day of apatinib treatment. Importantly, the tumor mass did not enlarge obviously during apatinib treatment. Lessons: Here, we presented a case with relapsed SCLC who unexpectedly responded to single-agent apatinib treatment. Therefore, this report will shed light on future studies of targeted therapy with apatinib in SCLC at different stages. PMID:29390367

Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia.

PubMed

Byrd, John C; Furman, Richard R; Coutre, Steven E; Flinn, Ian W; Burger, Jan A; Blum, Kristie A; Grant, Barbara; Sharman, Jeff P; Coleman, Morton; Wierda, William G; Jones, Jeffrey A; Zhao, Weiqiang; Heerema, Nyla A; Johnson, Amy J; Sukbuntherng, Juthamas; Chang, Betty Y; Clow, Fong; Hedrick, Eric; Buggy, Joseph J; James, Danelle F; O'Brien, Susan

2013-07-04

The treatment of relapsed chronic lymphocytic leukemia (CLL) has resulted in few durable remissions. Bruton's tyrosine kinase (BTK), an essential component of B-cell-receptor signaling, mediates interactions with the tumor microenvironment and promotes the survival and proliferation of CLL cells. We conducted a phase 1b-2 multicenter study to assess the safety, efficacy, pharmacokinetics, and pharmacodynamics of ibrutinib (PCI-32765), a first-in-class, oral covalent inhibitor of BTK designed for treatment of B-cell cancers, in patients with relapsed or refractory CLL or small lymphocytic lymphoma. A total of 85 patients, the majority of whom were considered to have high-risk disease, received ibrutinib orally once daily; 51 received 420 mg, and 34 received 840 mg. Toxic effects were predominantly grade 1 or 2 and included transient diarrhea, fatigue, and upper respiratory tract infection; thus, patients could receive extended treatment with minimal hematologic toxic effects. The overall response rate was the same in the group that received 420 mg and the group that received 840 mg (71%), and an additional 20% and 15% of patients in the respective groups had a partial response with lymphocytosis. The response was independent of clinical and genomic risk factors present before treatment, including advanced-stage disease, the number of previous therapies, and the 17p13.1 deletion. At 26 months, the estimated progression-free survival rate was 75% and the rate of overall survival was 83%. Ibrutinib was associated with a high frequency of durable remissions in patients with relapsed or refractory CLL and small lymphocytic lymphoma, including patients with high-risk genetic lesions. (Funded by Pharmacyclics and others; ClinicalTrials.gov number, NCT01105247.).

Tracing the origins of relapse in acute myeloid leukaemia to stem cells.

PubMed

Shlush, Liran I; Mitchell, Amanda; Heisler, Lawrence; Abelson, Sagi; Ng, Stanley W K; Trotman-Grant, Aaron; Medeiros, Jessie J F; Rao-Bhatia, Abilasha; Jaciw-Zurakowsky, Ivana; Marke, Rene; McLeod, Jessica L; Doedens, Monica; Bader, Gary; Voisin, Veronique; Xu, ChangJiang; McPherson, John D; Hudson, Thomas J; Wang, Jean C Y; Minden, Mark D; Dick, John E

2017-07-06

In acute myeloid leukaemia, long-term survival is poor as most patients relapse despite achieving remission. Historically, the failure of therapy has been thought to be due to mutations that produce drug resistance, possibly arising as a consequence of the mutagenic properties of chemotherapy drugs. However, other lines of evidence have pointed to the pre-existence of drug-resistant cells. For example, deep sequencing of paired diagnosis and relapse acute myeloid leukaemia samples has provided direct evidence that relapse in some cases is generated from minor genetic subclones present at diagnosis that survive chemotherapy, suggesting that resistant cells are generated by evolutionary processes before treatment and are selected by therapy. Nevertheless, the mechanisms of therapy failure and capacity for leukaemic regeneration remain obscure, as sequence analysis alone does not provide insight into the cell types that are fated to drive relapse. Although leukaemia stem cells have been linked to relapse owing to their dormancy and self-renewal properties, and leukaemia stem cell gene expression signatures are highly predictive of therapy failure, experimental studies have been primarily correlative and a role for leukaemia stem cells in acute myeloid leukaemia relapse has not been directly proved. Here, through combined genetic and functional analysis of purified subpopulations and xenografts from paired diagnosis/relapse samples, we identify therapy-resistant cells already present at diagnosis and two major patterns of relapse. In some cases, relapse originated from rare leukaemia stem cells with a haematopoietic stem/progenitor cell phenotype, while in other instances relapse developed from larger subclones of immunophenotypically committed leukaemia cells that retained strong stemness transcriptional signatures. The identification of distinct patterns of relapse should lead to improved methods for disease management and monitoring in acute myeloid leukaemia. Moreover, the shared functional and transcriptional stemness properties that underlie both cellular origins of relapse emphasize the importance of developing new therapeutic approaches that target stemness to prevent relapse.

Radiolabeled Monoclonal Antibody Plus Rituximab With and Without Filgrastim and Interleukin-11 in Treating Patients With Relapsed or Refractory Non-Hodgkin's Lymphoma

ClinicalTrials.gov

2015-11-04

Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Nodal Marginal Zone B-cell Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Small Lymphocytic Lymphoma; Splenic Marginal Zone Lymphoma; Waldenström Macroglobulinemia

Pembrolizumab and its role in relapsed/refractory classical Hodgkin's lymphoma: evidence to date and clinical utility.

PubMed

Shindiapina, Polina; Alinari, Lapo

2018-04-01

Immune evasion is a critical mechanism of malignant cell survival, and relies in part on molecular signaling through the programmed cell death 1 (PD-1)/PD-1 ligand (PD-L1) axis that contributes to T cell exhaustion. Immune modulatory therapy with monoclonal antibodies against PD-1 designed to enhance antitumor immune response have shown promise in the treatment of advanced solid tumors and hematologic malignancies. Classical Hodgkin's lymphoma (cHL), a unique B cell malignancy characterized by an extensive but ineffective immune cell infiltrate surrounding a small number of tumor cells, has shown significant response to anti-PD-1 directed therapy. The anti-PD-1 monoclonal antibodies nivolumab and pembrolizumab have shown similarly remarkable activity in relapsed/refractory cHL and have been approved by the Food and Drug Administration for treatment of this disease. In this article we review the rationale of targeting the PD-1/PD-L1 axis in cHL and the pharmacology of pembrolizumab, and summarize the data on activity and safety profile of this agent in the treatment of relapsed/refractory cHL. We also discuss the potential benefits and pitfalls of using PD-1 blockade in the setting of allogeneic stem-cell transplantation, and summarize ongoing prospective trials of single-agent pembrolizumab and combination strategies as well as future directions.

Pembrolizumab and its role in relapsed/refractory classical Hodgkin’s lymphoma: evidence to date and clinical utility

PubMed Central

Shindiapina, Polina; Alinari, Lapo

2018-01-01

Immune evasion is a critical mechanism of malignant cell survival, and relies in part on molecular signaling through the programmed cell death 1 (PD-1)/PD-1 ligand (PD-L1) axis that contributes to T cell exhaustion. Immune modulatory therapy with monoclonal antibodies against PD-1 designed to enhance antitumor immune response have shown promise in the treatment of advanced solid tumors and hematologic malignancies. Classical Hodgkin’s lymphoma (cHL), a unique B cell malignancy characterized by an extensive but ineffective immune cell infiltrate surrounding a small number of tumor cells, has shown significant response to anti-PD-1 directed therapy. The anti-PD-1 monoclonal antibodies nivolumab and pembrolizumab have shown similarly remarkable activity in relapsed/refractory cHL and have been approved by the Food and Drug Administration for treatment of this disease. In this article we review the rationale of targeting the PD-1/PD-L1 axis in cHL and the pharmacology of pembrolizumab, and summarize the data on activity and safety profile of this agent in the treatment of relapsed/refractory cHL. We also discuss the potential benefits and pitfalls of using PD-1 blockade in the setting of allogeneic stem-cell transplantation, and summarize ongoing prospective trials of single-agent pembrolizumab and combination strategies as well as future directions. PMID:29623180

Natural killer-cell counts are associated with molecular relapse-free survival after imatinib discontinuation in chronic myeloid leukemia: the IMMUNOSTIM study.

PubMed

Rea, Delphine; Henry, Guylaine; Khaznadar, Zena; Etienne, Gabriel; Guilhot, François; Nicolini, Franck; Guilhot, Joelle; Rousselot, Philippe; Huguet, Françoise; Legros, Laurence; Gardembas, Martine; Dubruille, Viviane; Guerci-Bresler, Agnès; Charbonnier, Aude; Maloisel, Frédéric; Ianotto, Jean-Christophe; Villemagne, Bruno; Mahon, François-Xavier; Moins-Teisserenc, Hélène; Dulphy, Nicolas; Toubert, Antoine

2017-08-01

Despite persistence of leukemic stem cells, patients with chronic myeloid leukemia who achieve and maintain deep molecular responses may successfully stop the tyrosine kinase inhibitor imatinib. However, questions remain unanswered regarding the biological basis of molecular relapse after imatinib cessation. In IMMUNOSTIM, we monitored 51 patients from the French Stop IMatinib trial for peripheral blood T cells and natural killer cells. Molecular relapse-free survival at 24 months was 45.1% (95% CI: 31.44%-58.75%). At the time of imatinib discontinuation, non-relapsing patients had significantly higher numbers of natural killer cells of the cytotoxic CD56 dim subset than had relapsing patients, while CD56 bright natural killer cells, T cells and their subsets did not differ significantly. Furthermore, the CD56 dim natural killer-cell count was an independent prognostic factor of molecular-relapse free survival in a multivariate analysis. However, expression of natural killer-cell activating receptors, BCR-ABL1 + leukemia cell line K562-specific degranulation and cytokine-induced interferon-gamma secretion were decreased in non-relapsing and relapsing patients as compared with healthy individuals. After imatinib cessation, the natural killer-cell count increased significantly and stayed higher in non-relapsing patients than in relapsing patients, while receptor expression and functional properties remained unchanged. Altogether, our results suggest that natural killer cells may play a role in controlling leukemia-initiating cells at the origin of relapse after imatinib cessation, provided that these cells are numerous enough to compensate for their functional defects. Further research will decipher mechanisms underlying functional differences between natural killer cells from patients and healthy individuals and evaluate the potential interest of immunostimulatory approaches in tyrosine kinase inhibitor discontinuation strategies. (ClinicalTrial.gov Identifier NCT00478985) . Copyright© 2017 Ferrata Storti Foundation.

Phylogenetic ctDNA analysis depicts early stage lung cancer evolution

PubMed Central

Abbosh, Christopher; Birkbak, Nicolai J.; Wilson, Gareth A.; Jamal-Hanjani, Mariam; Constantin, Tudor; Salari, Raheleh; Le Quesne, John; Moore, David A; Veeriah, Selvaraju; Rosenthal, Rachel; Marafioti, Teresa; Kirkizlar, Eser; Watkins, Thomas B K; McGranahan, Nicholas; Ward, Sophia; Martinson, Luke; Riley, Joan; Fraioli, Francesco; Al Bakir, Maise; Grönroos, Eva; Zambrana, Francisco; Endozo, Raymondo; Bi, Wenya Linda; Fennessy, Fiona M.; Sponer, Nicole; Johnson, Diana; Laycock, Joanne; Shafi, Seema; Czyzewska-Khan, Justyna; Rowan, Andrew; Chambers, Tim; Matthews, Nik; Turajlic, Samra; Hiley, Crispin; Lee, Siow Ming; Forster, Martin D.; Ahmad, Tanya; Falzon, Mary; Borg, Elaine; Lawrence, David; Hayward, Martin; Kolvekar, Shyam; Panagiotopoulos, Nikolaos; Janes, Sam M; Thakrar, Ricky; Ahmed, Asia; Blackhall, Fiona; Summers, Yvonne; Hafez, Dina; Naik, Ashwini; Ganguly, Apratim; Kareht, Stephanie; Shah, Rajesh; Joseph, Leena; Quinn, Anne Marie; Crosbie, Phil; Naidu, Babu; Middleton, Gary; Langman, Gerald; Trotter, Simon; Nicolson, Marianne; Remmen, Hardy; Kerr, Keith; Chetty, Mahendran; Gomersall, Lesley; Fennell, Dean; Nakas, Apostolos; Rathinam, Sridhar; Anand, Girija; Khan, Sajid; Russell, Peter; Ezhil, Veni; Ismail, Babikir; Irvin-sellers, Melanie; Prakash, Vineet; Lester, Jason; Kornaszewska, Malgorzata; Attanoos, Richard; Adams, Haydn; Davies, Helen; Oukrif, Dahmane; Akarca, Ayse U; Hartley, John A; Lowe, Helen L; Lock, Sara; Iles, Natasha; Bell, Harriet; Ngai, Yenting; Elgar, Greg; Szallasi, Zoltan; Schwarz, Roland F; Herrero, Javier; Stewart, Aengus; Quezada, Sergio A; Peggs, Karl S.; Van Loo, Peter; Dive, Caroline; Lin, Jimmy; Rabinowitz, Matthew; Aerts, Hugo JWL; Hackshaw, Allan; Shaw, Jacqui A; Zimmermann, Bernhard G.; Swanton, Charles

2017-01-01

Summary The early detection of relapse following primary surgery for non-small cell lung cancer and the characterization of emerging subclones seeding metastatic sites might offer new therapeutic approaches to limit tumor recurrence. The potential to non-invasively track tumor evolutionary dynamics in ctDNA of early-stage lung cancer is not established. Here we conduct a tumour-specific phylogenetic approach to ctDNA profiling in the first 100 TRACERx (TRAcking non-small cell lung Cancer Evolution through therapy (Rx)) study participants, including one patient co-recruited to the PEACE (Posthumous Evaluation of Advanced Cancer Environment) post-mortem study. We identify independent predictors of ctDNA release and perform tumor volume limit of detection analyses. Through blinded profiling of post-operative plasma, we observe evidence of adjuvant chemotherapy resistance and identify patients destined to experience recurrence of their lung cancer. Finally, we show that phylogenetic ctDNA profiling tracks the subclonal nature of lung cancer relapse and metastases, providing a new approach for ctDNA driven therapeutic studies PMID:28445469

Lenalidomide With or Without Rituximab in Treating Patients With Progressive or Relapsed Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma, Prolymphocytic Leukemia, or Non-Hodgkin Lymphoma Previously Treated With Donor Stem Cell Transplant

ClinicalTrials.gov

2017-07-24

Adult Nasal Type Extranodal NK/T-cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Cutaneous B-cell Non-Hodgkin Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Hepatosplenic T-cell Lymphoma; Intraocular Lymphoma; Nodal Marginal Zone B-cell Lymphoma; Noncutaneous Extranodal Lymphoma; Peripheral T-cell Lymphoma; Prolymphocytic Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; T-cell Large Granular Lymphocyte Leukemia; Testicular Lymphoma; Waldenström Macroglobulinemia

Monoclonal Antibody Therapy Before Stem Cell Transplant in Treating Patients With Relapsed or Refractory Lymphoid Malignancies

ClinicalTrials.gov

2017-10-10

Adult Nasal Type Extranodal NK/T-cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Cutaneous B-cell Non-Hodgkin Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Hepatosplenic T-cell Lymphoma; Intraocular Lymphoma; Nodal Marginal Zone B-cell Lymphoma; Noncutaneous Extranodal Lymphoma; Peripheral T-cell Lymphoma; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Refractory Hairy Cell Leukemia; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; T-cell Large Granular Lymphocyte Leukemia; Testicular Lymphoma; Waldenström Macroglobulinemia

A meta-analysis of patient outcomes with subcentimeter disease after chemotherapy for metastatic non-seminomatous germ cell tumor

PubMed Central

Ravi, P.; Gray, K. P.; O'Donnell, E. K.; Sweeney, C. J.

2014-01-01

Background Approximately a quarter of men with metastatic non-seminomatous germ cell tumor (NSGCT) have a residual mass, typically in the retroperitoneum, after chemotherapy. The management of small residual masses (≤1 cm) is controversial, with good outcomes seen with either post-chemotherapy retroperitoneal lymph node dissection (PC-RPLND) or surveillance. We sought to review our experience of surveillance and synthesize the cumulative findings with the current literature in the form of a meta-analysis. Patients and methods We searched PubMed, EMBASE and abstracts from ASCO and AUA to identify relevant, English-language studies for the meta-analysis. The DFCI (Dana Farber Cancer Institute) database was constructed from a database of men undergoing cisplatin-based chemotherapy for metastatic NSGCT. The outcomes of interest were the proportion with necrosis, teratoma or active cancer on histology at PC-RPLND (literature) and the total number of relapses, RP-only relapses and overall survival in men undergoing surveillance (literature and DFCI cohort). Results Three of 47 men undergoing post-chemotherapy surveillance at our institution relapsed over a median follow-up of 5.4 years. All three were alive at a median of 4.2 years after relapse. On meta-analysis, the pooled estimates of necrosis, teratoma and active cancer in the 588 men who underwent PC-RPLND were 71, 24 and 4%, respectively. Of the combined 455 men who underwent surveillance, the pooled estimate of the relapse rate was 5%, with an RP-only relapse rate of 3%. Of the 15 men who suffered an RP-only relapse on surveillance, two died of disease. Conclusion Surveillance is a reasonable strategy for men with minimal residual RP disease after chemotherapy and avoids an RPLND in ∼97% of men who are cured with chemotherapy alone. PMID:24276027

Ibrutinib efficacy and tolerability in patients with relapsed chronic lymphocytic leukemia following allogeneic HCT.

PubMed

Ryan, Christine E; Sahaf, Bita; Logan, Aaron C; O'Brien, Susan; Byrd, John C; Hillmen, Peter; Brown, Jennifer R; Dyer, Martin J S; Mato, Anthony R; Keating, Michael J; Jaglowski, Samantha; Clow, Fong; Rezvani, Andrew R; Styles, Lori; Coutre, Steven E; Miklos, David B

2016-12-22

Ibrutinib, a potent and irreversible small-molecule inhibitor of both Bruton's tyrosine kinase and interleukin-2 inducible kinase (ITK), has been used to treat relapsed/refractory chronic lymphocytic leukemia (CLL) with prolongation of progression-free and overall survival. Here, we present 27 patients with relapsed CLL following allogeneic hematopoietic cell transplant (HCT) who subsequently received ibrutinib salvage therapy. Sixteen of these patients were part of multi-institutional clinical trials and achieved an overall response rate of 87.5%. An additional 11 patients were treated at Stanford University following US Food and Drug Administration approval of ibrutinib; 7 (64%) achieved a complete response, and 3 (27%) achieved a partial response. Of the 9 patients treated at Stanford who had mixed chimerism-associated CLL relapse, 4 (44%) converted to full donor chimerism following ibrutinib initiation, in association with disease response. Four of 11 (36%) patients evaluated by ClonoSeq achieved minimal residual disease negativity with CLL <1/10 000 white blood cells, which persisted even after ibrutinib was discontinued, in 1 case even after 26 months. None of the 27 patients developed graft-versus-host-disease (GVHD) following ibrutinib initiation. We postulate that ibrutinib augments the graft-versus-leukemia (GVL) benefit through a T-cell-mediated effect, most likely due to ITK inhibition. To investigate the immune modulatory effects of ibrutinib, we completed comprehensive immune phenotype characterization of peripheral B and T cells from treated patients. Our results show that ibrutinib selectively targets pre-germinal B cells and depletes Th2 helper cells. Furthermore, these effects persisted after drug discontinuation. In total, our results provide evidence that ibrutinib effectively augments GVL without causing GVHD. © 2016 by The American Society of Hematology.

Strategies to eradicate minimal residual disease in small cell lung cancer: high-dose chemotherapy with autologous bone marrow transplantation, matrix metalloproteinase inhibitors, and BEC2 plus BCG vaccination.

PubMed

Krug, L M; Grant, S C; Miller, V A; Ng, K K; Kris, M G

1999-10-01

In the last 25 years, treatment for small cell lung cancer (SCLC) has improved with advances in chemotherapy and radiotherapy. Standard chemotherapy regimens can yield 80% to 90% response rates and some cures when combined with thoracic irradiation in limited-stage patients. Nonetheless, small cell lung cancer has a high relapse rate due to drug resistance; this has resulted in poor survival for most patients. Attacking this problem requires a unique approach to eliminate resistant disease remaining after induction therapy. This review will focus on three potential strategies: high-dose chemotherapy with autologous bone marrow transplantation, matrix metalloproteinase inhibitors, and BEC2 plus BCG vaccination.

Targeted therapy with apatinib in a patient with relapsed small cell lung cancer: A case report and literature review.

PubMed

Zhao, Jun; Zhang, Xiaoling; Gong, Chaojie; Zhang, Jialei

2017-12-01

Small cell lung cancer (SCLC) is a lethal malignancy. Once relapsed, the disease is irreversible and most of the patients will die of cancer aggravation in 1 to 2 months. In the past several decades, little progress has been made in the systemic treatment of SCLC. Apatinib, as a novel small-molecule tyrosine kinase inhibitor specifically targeting the vascular endothelial growth factor receptor 2 (VEGFR2), has achieved progress in treatment of a variety of cancers. However, there has been no report of the targeted therapy with apatinib in SCLC yet. A 63-year-old man, an ex-smoker, presented with a slight hoarseness and cough. The patient was admitted to our department with a primary diagnosis of SCLC at an extensive stage (ES-SCLC). After 17 months of successful first-, second-, and third-line chemotherapy, the disease eventually became relapsed. Then, apatinib treatment started promptly on demand by the patient and his family. After presenting an informed consent, the patient received apatinib treatment immediately at a dose of 250 mg/day orally. (1) On the 28th day of apatinib therapy, the symptoms of dyspnea and poor appetite of the patient were notably improved. (2) The CT scan taken on the 70th day showed that the pleural effusion in the left lung almost disappeared. (3) The elevated serum neuron-specific enolase (NSE) level was decreased. The patient died of acute respiratory failure on the 172nd day of apatinib treatment. Importantly, the tumor mass did not enlarge obviously during apatinib treatment. Here, we presented a case with relapsed SCLC who unexpectedly responded to single-agent apatinib treatment. Therefore, this report will shed light on future studies of targeted therapy with apatinib in SCLC at different stages. Copyright © 2017 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.

Antiminor Histocompatibility Complex (MiHA) T Cells for Patients With Relapsed Hematologic Malignancies Following Matched HSCT (Guided Lymphocyte Immunopeptide Derived Expansion)

ClinicalTrials.gov

2017-12-04

Hematologic Cancer; Relapse Leukemia; Relapsed Adult ALL; Relapsed Adult AML; Relapsed CLL; Relapsed Non Hodgkin Lymphoma; Relapsed Hodgkin's Lymphoma; Relapsed Myelodysplastic Syndromes; Relapsed Multiple Myeloma

Therapies targeting cancer stem cells: Current trends and future challenges

PubMed Central

Dragu, Denisa L; Necula, Laura G; Bleotu, Coralia; Diaconu, Carmen C; Chivu-Economescu, Mihaela

2015-01-01

Traditional therapies against cancer, chemo- and radiotherapy, have multiple limitations that lead to treatment failure and cancer recurrence. These limitations are related to systemic and local toxicity, while treatment failure and cancer relapse are due to drug resistance and self-renewal, properties of a small population of tumor cells called cancer stem cells (CSCs). These cells are involved in cancer initiation, maintenance, metastasis and recurrence. Therefore, in order to develop efficient treatments that can induce a long-lasting clinical response preventing tumor relapse it is important to develop drugs that can specifically target and eliminate CSCs. Recent identification of surface markers and understanding of molecular feature associated with CSC phenotype helped with the design of effective treatments. In this review we discuss targeting surface biomarkers, signaling pathways that regulate CSCs self-renewal and differentiation, drug-efflux pumps involved in apoptosis resistance, microenvironmental signals that sustain CSCs growth, manipulation of miRNA expression, and induction of CSCs apoptosis and differentiation, with specific aim to hamper CSCs regeneration and cancer relapse. Some of these agents are under evaluation in preclinical and clinical studies, most of them for using in combination with traditional therapies. The combined therapy using conventional anticancer drugs with CSCs-targeting agents, may offer a promising strategy for management and eradication of different types of cancers. PMID:26516409

A nomogram to predict brain metastasis as the first relapse in curatively resected non-small cell lung cancer patients.

PubMed

Won, Young-Woong; Joo, Jungnam; Yun, Tak; Lee, Geon-Kook; Han, Ji-Youn; Kim, Heung Tae; Lee, Jin Soo; Kim, Moon Soo; Lee, Jong Mog; Lee, Hyun-Sung; Zo, Jae Ill; Kim, Sohee

2015-05-01

Development of brain metastasis results in a significant reduction in overall survival. However, there is no an effective tool to predict brain metastasis in non-small cell lung cancer (NSCLC) patients. We conducted this study to develop a feasible nomogram that can predict metastasis to the brain as the first relapse site in patients with curatively resected NSCLC. A retrospective review of NSCLC patients who had received curative surgery at National Cancer Center (Goyang, South Korea) between 2001 and 2008 was performed. We chose metastasis to the brain as the first relapse site after curative surgery as the primary endpoint of the study. A nomogram was modeled using logistic regression. Among 1218 patients, brain metastasis as the first relapse developed in 87 patients (7.14%) during the median follow-up of 43.6 months. Occurrence rates of brain metastasis were higher in patients with adenocarcinoma or those with a high pT and pN stage. Younger age appeared to be associated with brain metastasis, but this result was not statistically significant. The final prediction model included histology, smoking status, pT stage, and the interaction between adenocarcinoma and pN stage. The model showed fairly good discriminatory ability with a C-statistic of 69.3% and 69.8% for predicting brain metastasis within 2 years and 5 years, respectively. Internal validation using 2000 bootstrap samples resulted in C-statistics of 67.0% and 67.4% which still indicated good discriminatory performances. The nomogram presented here provides the individual risk estimate of developing metastasis to the brain as the first relapse site in patients with NSCLC who have undergone curative surgery. Surveillance programs or preventive treatment strategies for brain metastasis could be established based on this nomogram. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Comparison of mediastinal lymph node status and relapse pattern in clinical stage IIIA non-small cell lung cancer patients treated with neoadjuvant chemotherapy versus upfront surgery: A single center experience.

PubMed

Savic, Milan; Kontic, Milica; Ercegovac, Maja; Stojsic, Jelena; Bascarevic, Slavisa; Moskovljevic, Dejan; Kostic, Marko; Vesovic, Radomir; Popevic, Spasoje; Laban, Marija; Markovic, Jelena; Jovanovic, Dragana

2017-09-01

In spite of the progress made in neoadjuvant therapy for operable non small-cell lung cancer (NSCLC), many issues remain unsolved, especially in locally advanced stage IIIA. Retrospective data of 163 patients diagnosed with stage IIIA NSCLC after surgery was analyzed. The patients were divided into two groups: a preoperative chemotherapy group including 59 patients who received platinum-etoposide doublet treatment before surgery, and an upfront surgery group including 104 patients for whom surgical resection was the first treatment step. Adjuvant chemotherapy or/and radiotherapy was administered to 139 patients (85.3%), while 24 patients (14.7%) were followed-up only. The rate of N2 disease was significantly higher in the upfront surgery group ( P  < 0.001). The one-year relapse rate was 49.5% in the preoperative chemotherapy group compared to 65.4% in the upfront surgery group. There was a significant difference in relapse rate in relation to adjuvant chemotheraphy treatment ( P  = 0.007). The probability of relapse was equal whether radiotherapy was applied or not ( P  = 0.142). There was no statistically significant difference in two-year mortality ( P  = 0.577). The median survival duration after two years of follow-up was 19.6 months in the preoperative chemotherapy group versus 18.8 months in the upfront surgery group ( P  = 0.608 > 0.05). There was significant difference in preoperative chemotherapy group regarding relapse rate and treatment outcomes related to the lymph node status comparing to the upfront surgery group. Neoadjuvant/adjuvant chemo-therapy is a part of treatment for patients with stage IIIA NSCLC, but further investigation is required to determine optimal treatment. © 2017 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.

Pembrolizumab in Treating Patients With HIV and Relapsed, Refractory, or Disseminated Malignant Neoplasms

ClinicalTrials.gov

2018-03-22

AIDS-Related Non-Hodgkin Lymphoma; Classical Hodgkin Lymphoma; HIV Infection; Locally Advanced Malignant Neoplasm; Metastatic Malignant Neoplasm; Recurrent Hepatocellular Carcinoma; Recurrent Hodgkin Lymphoma; Recurrent Kaposi Sarcoma; Recurrent Malignant Neoplasm; Recurrent Melanoma of the Skin; Recurrent Non-Hodgkin Lymphoma; Recurrent Non-Small Cell Lung Carcinoma; Refractory Hodgkin Lymphoma; Refractory Malignant Neoplasm; Solid Neoplasm; Stage IIIA Cutaneous Melanoma AJCC v7; Stage IIIA Hepatocellular Carcinoma AJCC v7; Stage IIIA Non-Small Cell Lung Cancer AJCC v7; Stage IIIB Cutaneous Melanoma AJCC v7; Stage IIIB Hepatocellular Carcinoma AJCC v7; Stage IIIB Non-Small Cell Lung Cancer AJCC v7; Stage IIIC Cutaneous Melanoma AJCC v7; Stage IIIC Hepatocellular Carcinoma AJCC v7; Stage IV Cutaneous Melanoma AJCC v6 and v7; Stage IV Non-Small Cell Lung Cancer AJCC v7; Stage IVA Hepatocellular Carcinoma AJCC v7; Stage IVB Hepatocellular Carcinoma AJCC v7

A Phase 1-2 Multi-Center Study Evaluating Axicabtagene Ciloleucel in Subjects With Refractory Aggressive Non-Hodgkin Lymphoma (ZUMA-1)

ClinicalTrials.gov

2018-06-18

Refractory Diffuse Large B Cell Lymphoma; Refractory Primary Mediastinal B Cell Lymphoma; Refractory Transformed Follicular Lymphoma; Relapsed/Refractory Transplant Ineligible Diffuse Large B Cell Lymphoma; Relapsed/Refractory Transplant Ineligible Primary Mediastinal B Cell Lymphoma; Relapsed/Refractory Transplant Ineligible Transformed Follicular Lymphoma; Relapsed/Refractory Large B Cell Lymphoma Including DLBCL, PMBCL, TFL and HGBCL After Two Systemic Lines of Therapy" in Phase 2 Expanded Cohorts

Extensive disease small cell carcinoma of the lung; trial of non-cross resistant chemotherapy and consolidation radiotherapy. [X ray

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dillman, R.O., Taelle, R., Segren, S.; Royston, I.; Koziol, J.

1982-05-15

Twenty-nine patients with extensive disease, small-cell carcinoma of the lung, were treated with two cycles of intensive combination chemotherapy: HexaVAC (hexamethylmelamine, vincristine, Adriamycin, cyclophosphamide). Responders received prophylactic cranial radiation (2000 rad/10 fractions) and non cross resistant chemotherapy via a schedule of alternating cycles of CMV (cyclophosphamide, methotrexate, VP-16-213) and AMV (Adriamycin, methotrexate, VP-16-213). Whenever a complete response was achieved, consolidation radiotherapy was given to the lung primary (4000 rad/20 fractions, split dose) and abdominal metastases (2000 rad/10 fractions) synchronous with CMV therapy. The complete response rate was 14% with HexaVAC, but increased to 38% during CMV/AMV. Total response rate (completemore » and partial) was 59% and median survival was 42 weeks. Prophylactic brain radiation prevented clinical relapse in the brain in all 14 patients who received it. However, consolidation radiotherapy failed to prevent clinical relapse in the lung and/or liver, and therapeutic brain radiation (3000 rad) failed to prevent relapse in that site. The simultaneous administration of radiotherapy and chemotherapy was well-tolerated although two patients with poor performance status died of infectious complications while leukopenic. In spite of the high response rate, durable remissions with prolonged disease free survival were rare. Further evaluation of induction, consolidation, and maintenance modes of therapy are indicated.« less

Efficacy and safety of platinum combination chemotherapy re-challenge for relapsed patients with non-small-cell lung cancer after postoperative adjuvant chemotherapy of cisplatin plus vinorelbine.

PubMed

Imai, Hisao; Shukuya, Takehito; Yoshino, Reiko; Muraki, Keiko; Mori, Keita; Ono, Akira; Akamatsu, Hiroaki; Taira, Tetsuhiko; Kenmotsu, Hirotsugu; Naito, Tateaki; Murakami, Haruyasu; Tomizawa, Yoshio; Takahashi, Toshiaki; Takahashi, Kazuhisa; Saito, Ryusei; Yamamoto, Nobuyuki

2013-01-01

There is no standard therapy for relapsed patients who have received postoperative platinum-based adjuvant chemotherapy for resected non-small-cell lung cancer (NSCLC). We investigated the efficacy and safety of platinum combination chemotherapy re-challenge for such patients. Medical records from 3 institutes from April 2005 to July 2012 were retrospectively reviewed. Patients who underwent complete surgical resection were eligible if they received postoperative adjuvant chemotherapy consisting of cisplatin plus vinorelbine once and then re-challenge with platinum combination chemotherapy. Sixteen patients were enrolled in this study. After re-challenge with platinum combination chemotherapy, we observed an overall response rate of 31.2% (5/16) and a disease control rate of 81.2% (13/16). Median progression-free survival and overall survival from the start of the re-administration of platinum combination chemotherapy were 6.5 and 28.0 months, respectively. Frequently observed severe adverse events (≥grade 3) included neutropenia (31.2%), thrombocytopenia (31.2%), leukopenia (12.5%) and hyponatremia (12.5%). Frequently observed non-hematological toxicities (≥grade 2) were anorexia (37.5%) and nausea (37.5%). Re-challenge with platinum combination chemotherapy was effective and safe; therefore, this therapy should be considered as a treatment option for relapsed patients after postoperative cisplatin-based adjuvant chemotherapy for resected NSCLC. © 2014 S. Karger AG, Basel.

Ibrutinib efficacy and tolerability in patients with relapsed chronic lymphocytic leukemia following allogeneic HCT

PubMed Central

Ryan, Christine E.; Sahaf, Bita; Logan, Aaron C.; O’Brien, Susan; Byrd, John C.; Hillmen, Peter; Brown, Jennifer R.; Dyer, Martin J. S.; Mato, Anthony R.; Keating, Michael J.; Jaglowski, Samantha; Clow, Fong; Rezvani, Andrew R.; Styles, Lori; Coutre, Steven E.

2016-01-01

Ibrutinib, a potent and irreversible small-molecule inhibitor of both Bruton’s tyrosine kinase and interleukin-2 inducible kinase (ITK), has been used to treat relapsed/refractory chronic lymphocytic leukemia (CLL) with prolongation of progression-free and overall survival. Here, we present 27 patients with relapsed CLL following allogeneic hematopoietic cell transplant (HCT) who subsequently received ibrutinib salvage therapy. Sixteen of these patients were part of multi-institutional clinical trials and achieved an overall response rate of 87.5%. An additional 11 patients were treated at Stanford University following US Food and Drug Administration approval of ibrutinib; 7 (64%) achieved a complete response, and 3 (27%) achieved a partial response. Of the 9 patients treated at Stanford who had mixed chimerism–associated CLL relapse, 4 (44%) converted to full donor chimerism following ibrutinib initiation, in association with disease response. Four of 11 (36%) patients evaluated by ClonoSeq achieved minimal residual disease negativity with CLL <1/10 000 white blood cells, which persisted even after ibrutinib was discontinued, in 1 case even after 26 months. None of the 27 patients developed graft-versus-host-disease (GVHD) following ibrutinib initiation. We postulate that ibrutinib augments the graft-versus-leukemia (GVL) benefit through a T-cell–mediated effect, most likely due to ITK inhibition. To investigate the immune modulatory effects of ibrutinib, we completed comprehensive immune phenotype characterization of peripheral B and T cells from treated patients. Our results show that ibrutinib selectively targets pre–germinal B cells and depletes Th2 helper cells. Furthermore, these effects persisted after drug discontinuation. In total, our results provide evidence that ibrutinib effectively augments GVL without causing GVHD. PMID:27802969

Tumor cell dormancy: implications for the biology and treatment of breast cancer.

PubMed

Fehm, T; Mueller, V; Marches, R; Klein, G; Gueckel, B; Neubauer, H; Solomayer, E; Becker, S

2008-01-01

Despite progress made in the therapy of solid tumors such as breast cancer, the prognosis of patients even with small primary tumors is still limited by metastatic relapse often long after removal of the primary tumor. Therefore, it has been hypothesized that primary tumors shed tumor cells already at an early stage into the blood circulation. A subset of these disseminated tumor cells may persist in a state of so-called "dormancy". Based on cell culture and animal models, dormancy can occur at two different stages. Single dormant cells are defined as cells with a lack of proliferation and apoptosis with the cells undergoing cell cycle arrest. The micrometastasis model defines tumor cell dormancy as a state of balanced apoptosis and proliferation of micrometastasis resulting in no net increase of tumor mass. Mechanisms leading to a growth activation of dormant tumor cells and the outgrowth of manifest metastases are not completely understood. Genetic predisposition of the dormant cells as well as immunological and angiogenetic influences of the surrounding environment may contribute to this phenomenon. In this review, we summarize findings on different factors for tumor cell dormancy and potential therapeutic implications that should help to reduce metastatic relapse in cancer patients.

Proceedings from the National Cancer Institute's Second International Workshop on the Biology, Prevention, and Treatment of Relapse after Hematopoietic Stem Cell Transplantation: Part I. Biology of relapse after transplantation.

PubMed

Gress, Ronald E; Miller, Jeffrey S; Battiwalla, Minoo; Bishop, Michael R; Giralt, Sergio A; Hardy, Nancy M; Kröger, Nicolaus; Wayne, Alan S; Landau, Dan A; Wu, Catherine J

2013-11-01

In the National Cancer Institute's Second Workshop on the Biology, Prevention, and Treatment of Relapse after Hematopoietic Stem Cell Transplantation, the Scientific/Educational Session on the Biology of Relapse discussed recent advances in understanding some of the host-, disease-, and transplantation-related contributions to relapse, emphasizing concepts with potential therapeutic implications. Relapse after hematopoietic stem cell transplantation (HSCT) represents tumor escape, from the cytotoxic effects of the conditioning regimen and from immunologic control mediated by reconstituted lymphocyte populations. Factors influencing the biology of the therapeutic graft-versus-malignancy (GVM) effect-and relapse-include conditioning regimen effects on lymphocyte populations and homeostasis, immunologic niches, and the tumor microenvironment; reconstitution of lymphocyte populations and establishment of functional immune competence; and genetic heterogeneity within the malignancy defining potential for clonal escape. Recent developments in T cell and natural killer cell homeostasis and reconstitution are reviewed, with implications for prevention and treatment of relapse, as is the application of modern genome sequencing to defining the biologic basis of GVM, clonal escape, and relapse after HSCT. Published by Elsevier Inc.

Targeting BTK with Ibrutinib in Relapsed Chronic Lymphocytic Leukemia

PubMed Central

Byrd, John C.; Furman, Richard R.; Coutre, Steven E.; Flinn, Ian W.; Burger, Jan A.; Blum, Kristie A.; Grant, Barbara; Sharman, Jeff P.; Coleman, Morton; Wierda, William G.; Jones, Jeffrey A.; Zhao, Weiqiang; Heerema, Nyla A.; Johnson, Amy J.; Sukbuntherng, Juthamas; Chang, Betty Y.; Clow, Fong; Hedrick, Eric; Buggy, Joseph J.; James, Danelle F.; O'Brien, Susan

2013-01-01

BACKGROUND The treatment of relapsed chronic lymphocytic leukemia (CLL) has resulted in few durable remissions. Bruton's tyrosine kinase (BTK), an essential component of B-cell–receptor signaling, mediates interactions with the tumor microenvironment and promotes the survival and proliferation of CLL cells. METHODS We conducted a phase 1b–2 multicenter study to assess the safety, efficacy, pharmacokinetics, and pharmacodynamics of ibrutinib (PCI-32765), a first-in-class, oral covalent inhibitor of BTK designed for treatment of B-cell cancers, in patients with relapsed or refractory CLL or small lymphocytic lymphoma. A total of 85 patients, the majority of whom were considered to have high-risk disease, received ibrutinib orally once daily; 51 received 420 mg, and 34 received 840 mg. RESULTS Toxic effects were predominantly grade 1 or 2 and included transient diarrhea, fatigue, and upper respiratory tract infection; thus, patients could receive extended treatment with minimal hematologic toxic effects. The overall response rate was the same in the group that received 420 mg and the group that received 840 mg (71%), and an additional 20% and 15% of patients in the respective groups had a partial response with lymphocytosis. The response was independent of clinical and genomic risk factors present before treatment, including advanced-stage disease, the number of previous therapies, and the 17p13.1 deletion. At 26 months, the estimated progression-free survival rate was 75% and the rate of overall survival was 83%. CONCLUSIONS Ibrutinib was associated with a high frequency of durable remissions in patients with relapsed or refractory CLL and small lymphocytic lymphoma, including patients with high-risk genetic lesions. (Funded by Pharmacyclics and others; ClinicalTrials.gov number, NCT01105247.) PMID:23782158

Lungscape: resected non-small-cell lung cancer outcome by clinical and pathological parameters.

PubMed

Peters, Solange; Weder, Walter; Dafni, Urania; Kerr, Keith M; Bubendorf, Lukas; Meldgaard, Peter; O'Byrne, Kenneth J; Wrona, Anna; Vansteenkiste, Johan; Felip, Enriqueta; Marchetti, Antonio; Savic, Spasenija; Lu, Shun; Smit, Egbert; Dingemans, Anne-Marie; Blackhall, Fiona H; Baas, Paul; Camps, Carlos; Rosell, Rafael; Stahel, Rolf A

2014-11-01

The Lungscape project was designed to address the impact of clinical, pathological, and molecular characteristics on outcome in resected non-small- cell lung cancer (NSCLC). A decentralized biobank with fully annotated tissue samples was established. Selection criteria for participating centers included sufficient number of cases, tissue microarray building capability, and documented ethical approval. Patient selection was based on availability of comprehensive clinical data, radical resection between 2003 and 2009 with adequate follow-up, and adequate quantity and quality of formalin-fixed tissue. Fifteen centers contributed 2449 cases. The 5-year overall survival (OS) was 69.6% and 63.6% for stages IA and IB, 51.6% and 47.7% for stages IIA and IIB, and 29.0% and 13.0% for stages IIIA and IIIB, respectively (p < 0.001). Median and 5-year relapse-free survival (RFS) were 52.8 months and 47.3%, respectively. Distant relapse was recorded for 44.4%, local for 26.0%, and both for 16.9% of patients. Based on multivariate analysis for the OS, RFS, and time to relapse, the factors significantly associated with all of them are performance status and pathological stage. The aim of this report is to present the results from Lungscape, the first large series reporting on NSCLC surgical outcome measured not only by OS but also by RFS and time to relapse and including multivariate analysis by significant clinical and pathological prognostic parameters. As tissue from all patients is preserved locally and is available for detailed molecular investigations, Lungscape provides an excellent basis to evaluate the influence of molecular parameters on the disease outcome after radical resection, besides providing an overview of the molecular landscape of stage I to III NSCLC.

Iodine I 131 Tositumomab and Fludarabine Phosphate in Treating Older Patients Who Are Undergoing an Autologous or Syngeneic Stem Cell Transplant for Relapsed or Refractory Non-Hodgkin's Lymphoma

ClinicalTrials.gov

2014-08-04

Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Nodal Marginal Zone B-cell Lymphoma; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Splenic Marginal Zone Lymphoma; Waldenström Macroglobulinemia

Rituximab in Treating Patients Undergoing Donor Peripheral Blood Stem Cell Transplant for Relapsed or Refractory B-cell Lymphoma

ClinicalTrials.gov

2017-12-05

B-cell Adult Acute Lymphoblastic Leukemia; B-cell Childhood Acute Lymphoblastic Leukemia; B-cell Chronic Lymphocytic Leukemia; Childhood Burkitt Lymphoma; Childhood Diffuse Large Cell Lymphoma; Childhood Immunoblastic Large Cell Lymphoma; Cutaneous B-cell Non-Hodgkin Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Intraocular Lymphoma; Nodal Marginal Zone B-cell Lymphoma; Post-transplant Lymphoproliferative Disorder; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Grade III Lymphomatoid Granulomatosis; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Small Noncleaved Cell Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Small Lymphocytic Lymphoma; Recurrent/Refractory Childhood Hodgkin Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; Testicular Lymphoma; Waldenström Macroglobulinemia

Study of Akt Inhibitor MK2206 in Patients With Relapsed Lymphoma

ClinicalTrials.gov

2015-10-09

Adult Nasal Type Extranodal NK/T-cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; B-cell Adult Acute Lymphoblastic Leukemia; B-cell Chronic Lymphocytic Leukemia; Cutaneous B-cell Non-Hodgkin Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Hepatosplenic T-cell Lymphoma; Intraocular Lymphoma; Nodal Marginal Zone B-cell Lymphoma; Noncutaneous Extranodal Lymphoma; Peripheral T-cell Lymphoma; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Refractory Hairy Cell Leukemia; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; T-cell Adult Acute Lymphoblastic Leukemia; T-cell Large Granular Lymphocyte Leukemia; Testicular Lymphoma; Waldenström Macroglobulinemia

Depletion of CD20 B cells fails to inhibit relapsing mouse experimental autoimmune encephalomyelitis.

PubMed

Sefia, Eseberuo; Pryce, Gareth; Meier, Ute-Christiane; Giovannoni, Gavin; Baker, David

2017-05-01

Multiple sclerosis (MS) is often considered to be a CD4, T cell-mediated disease. This is largely based on the capacity of CD4 T cells to induce relapsing experimental autoimmune encephalomyelitis (EAE) in rodents. However, CD4-depletion using a monoclonal antibody was considered unsuccessful and relapsing MS responds well to B cell depletion via CD20 B cell depleting antibodies. The influence of CD20 B cell depletion in relapsing EAE was assessed. Relapsing EAE was induced in Biozzi ABH mice. These were treated with CD20-specific (18B12) antibody and the influence on CD45RA-B220 B cell depletion and clinical course was analysed. Relapsing EAE in Biozzi ABH failed to respond to the marked B cell depletion induced with a CD20-specific antibody. In contrast to CD20 and CD8-specific antibodies, CD4 T cell depletion inhibited EAE. Spinal cord antigen-induced disease in ABH mice is CD4 T cell-dependent. The lack of influence of CD20 B cell depletion in relapsing EAE, coupled with the relatively marginal and inconsistent results obtained in other mouse studies, suggests that rodents may have limited value in understanding the mechanism occurring following CD20 B cell depletion in humans. Copyright © 2017 Elsevier B.V. All rights reserved.

Concise Review: Emerging Drugs Targeting Epithelial Cancer Stem-Like Cells.

PubMed

Ahmed, Mehreen; Chaudhari, Kritika; Babaei-Jadidi, Roya; Dekker, Lodewijk V; Shams Nateri, Abdolrahman

2017-04-01

Increasing evidence suggests that cancer cell populations contain a small proportion of cells that display stem-like cell properties and which may be responsible for overall tumor maintenance. These cancer stem-like cells (CSCs) appear to have unique tumor-initiating ability and innate survival mechanisms that allow them to resist cancer therapies, consequently promoting relapses. Selective targeting of CSCs may provide therapeutic benefit and several recent reports have indicated this may be possible. In this article, we review drugs targeting CSCs, in selected epithelial cell-derived cancers. Stem Cells 2017;35:839-850. © 2017 AlphaMed Press.

Copy number profiling of adult relapsed B-cell precursor acute lymphoblastic leukemia reveals potential leukemia progression mechanisms.

PubMed

Ribera, Jordi; Zamora, Lurdes; Morgades, Mireia; Mallo, Mar; Solanes, Neus; Batlle, Montserrat; Vives, Susana; Granada, Isabel; Juncà, Jordi; Malinverni, Roberto; Genescà, Eulàlia; Guàrdia, Ramon; Mercadal, Santiago; Escoda, Lourdes; Martinez-Lopez, Joaquín; Tormo, Mar; Esteve, Jordi; Pratcorona, Marta; Martinez-Losada, Carmen; Solé, Francesc; Feliu, Evarist; Ribera, Josep-Maria

2017-11-01

The outcome of relapsed adult acute lymphoblastic leukemia (ALL) remains dismal despite new therapeutic approaches. Previous studies analyzing relapse samples have shown a high degree of heterogeneity regarding gene alterations without an evident relapse signature. Bone marrow or peripheral blood samples from 31 adult B-cell precursor ALL patients at first relapse, and 21 paired diagnostic samples were analyzed by multiplex ligation probe-dependent amplification (MLPA). Nineteen paired diagnostic and relapse samples of these 21 patients were also analyzed by SNP arrays. A trend to acquire homozygous CDKN2A/B deletions and a significant increase in the number of copy number alterations (CNA) was observed from diagnosis to first relapse. Evolution from an ancestral clone was the main pattern of clonal evolution. Relapse samples were extremely heterogeneous regarding CNA frequencies. However, CDKN2A/B, PAX5, ETV6, ATM, IKZF1, VPREB1, and TP53 deletions and duplications of 1q, 8q, 17q, 21, X/Y PAR1, and Xp were frequently detected at relapse. Duplications of genes involved in cell proliferation, drug resistance and stem cell homeostasis regulation, as well as deletions of KDM6A and STAG2 genes emerged as specific alterations at relapse. Genomics of relapsed adult B-cell precursor ALL is highly heterogeneous, although some recurrent lesions involved in essential pathways deregulation were frequently observed. Selective and simultaneous targeting of these deregulated pathways may improve the results of current salvage therapies. © 2017 Wiley Periodicals, Inc.

Rituximab monitoring and redosing in pediatric neuromyelitis optica spectrum disorder

PubMed Central

Nosadini, Margherita; Alper, Gulay; Riney, Catherine J.; Benson, Leslie A.; Mohammad, Shekeeb S.; Ramanathan, Sudarshini; Nolan, Melinda; Appleton, Richard; Leventer, Richard J.; Deiva, Kumaran; Brilot, Fabienne; Gorman, Mark P.; Waldman, Amy T.; Banwell, Brenda

2016-01-01

Objective: To study rituximab in pediatric neuromyelitis optica (NMO)/NMO spectrum disorders (NMOSD) and the relationship between rituximab, B cell repopulation, and relapses in order to improve rituximab monitoring and redosing. Methods: Multicenter retrospective study of 16 children with NMO/NMOSD receiving ≥2 rituximab courses. According to CD19 counts, events during rituximab were categorized as “repopulation,” “depletion,” or “depletion failure” relapses (repopulation threshold CD19 ≥10 × 106 cells/L). Results: The 16 patients (14 girls; mean age 9.6 years, range 1.8–15.3) had a mean of 6.1 events (range 1–11) during a mean follow-up of 6.1 years (range 1.6–13.6) and received a total of 76 rituximab courses (mean 4.7, range 2–9) in 42.6-year cohort treatment. Before rituximab, 62.5% had received azathioprine, mycophenolate mofetil, or cyclophosphamide. Mean time from rituximab to last documented B cell depletion and first repopulation was 4.5 and 6.8 months, respectively, with large interpatient variability. Earliest repopulations occurred with the lowest doses. Significant reduction between pre- and post-rituximab annualized relapse rate (ARR) was observed (p = 0.003). During rituximab, 6 patients were relapse-free, although 21 relapses occurred in 10 patients, including 13 “repopulation,” 3 “depletion,” and 4 “depletion failure” relapses. Of the 13 “repopulation” relapses, 4 had CD19 10–50 × 106 cells/L, 10 had inadequate monitoring (≤1 CD19 in the 4 months before relapses), and 5 had delayed redosing after repopulation detection. Conclusion: Rituximab is effective in relapse prevention, but B cell repopulation creates a risk of relapse. Redosing before B cell repopulation could reduce the relapse risk further. Classification of evidence: This study provides Class IV evidence that rituximab significantly reduces ARR in pediatric NMO/NMOSD. This study also demonstrates a relationship between B cell repopulation and relapses. PMID:26819962

Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution.

PubMed

Abbosh, Christopher; Birkbak, Nicolai J; Wilson, Gareth A; Jamal-Hanjani, Mariam; Constantin, Tudor; Salari, Raheleh; Le Quesne, John; Moore, David A; Veeriah, Selvaraju; Rosenthal, Rachel; Marafioti, Teresa; Kirkizlar, Eser; Watkins, Thomas B K; McGranahan, Nicholas; Ward, Sophia; Martinson, Luke; Riley, Joan; Fraioli, Francesco; Al Bakir, Maise; Grönroos, Eva; Zambrana, Francisco; Endozo, Raymondo; Bi, Wenya Linda; Fennessy, Fiona M; Sponer, Nicole; Johnson, Diana; Laycock, Joanne; Shafi, Seema; Czyzewska-Khan, Justyna; Rowan, Andrew; Chambers, Tim; Matthews, Nik; Turajlic, Samra; Hiley, Crispin; Lee, Siow Ming; Forster, Martin D; Ahmad, Tanya; Falzon, Mary; Borg, Elaine; Lawrence, David; Hayward, Martin; Kolvekar, Shyam; Panagiotopoulos, Nikolaos; Janes, Sam M; Thakrar, Ricky; Ahmed, Asia; Blackhall, Fiona; Summers, Yvonne; Hafez, Dina; Naik, Ashwini; Ganguly, Apratim; Kareht, Stephanie; Shah, Rajesh; Joseph, Leena; Marie Quinn, Anne; Crosbie, Phil A; Naidu, Babu; Middleton, Gary; Langman, Gerald; Trotter, Simon; Nicolson, Marianne; Remmen, Hardy; Kerr, Keith; Chetty, Mahendran; Gomersall, Lesley; Fennell, Dean A; Nakas, Apostolos; Rathinam, Sridhar; Anand, Girija; Khan, Sajid; Russell, Peter; Ezhil, Veni; Ismail, Babikir; Irvin-Sellers, Melanie; Prakash, Vineet; Lester, Jason F; Kornaszewska, Malgorzata; Attanoos, Richard; Adams, Haydn; Davies, Helen; Oukrif, Dahmane; Akarca, Ayse U; Hartley, John A; Lowe, Helen L; Lock, Sara; Iles, Natasha; Bell, Harriet; Ngai, Yenting; Elgar, Greg; Szallasi, Zoltan; Schwarz, Roland F; Herrero, Javier; Stewart, Aengus; Quezada, Sergio A; Peggs, Karl S; Van Loo, Peter; Dive, Caroline; Lin, C Jimmy; Rabinowitz, Matthew; Aerts, Hugo J W L; Hackshaw, Allan; Shaw, Jacqui A; Zimmermann, Bernhard G; Swanton, Charles

2017-04-26

The early detection of relapse following primary surgery for non-small-cell lung cancer and the characterization of emerging subclones, which seed metastatic sites, might offer new therapeutic approaches for limiting tumour recurrence. The ability to track the evolutionary dynamics of early-stage lung cancer non-invasively in circulating tumour DNA (ctDNA) has not yet been demonstrated. Here we use a tumour-specific phylogenetic approach to profile the ctDNA of the first 100 TRACERx (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy (Rx)) study participants, including one patient who was also recruited to the PEACE (Posthumous Evaluation of Advanced Cancer Environment) post-mortem study. We identify independent predictors of ctDNA release and analyse the tumour-volume detection limit. Through blinded profiling of postoperative plasma, we observe evidence of adjuvant chemotherapy resistance and identify patients who are very likely to experience recurrence of their lung cancer. Finally, we show that phylogenetic ctDNA profiling tracks the subclonal nature of lung cancer relapse and metastasis, providing a new approach for ctDNA-driven therapeutic studies.

Prevention and treatment of relapse after stem cell transplantation by cellular therapies.

PubMed

Falkenburg, Fred; Ruggiero, Eliana; Bonini, Chaira; Porter, David; Miller, Jeff; Malard, Floran; Mohty, Mohamad; Kröger, Nicolaus; Kolb, Hans Jochem

2018-05-24

Despite recent advances in reducing therapy-related mortality after allogeneic stem cell transplantation (alloSCT) relapse remains the major cause of treatment failure and little progress has been achieved in the last decades. At the 3rd International Workshop on Biology, Prevention, and Treatment of Relapse held in Hamburg/Germany in November 2016 international experts presented and discussed recent developments in the field. Here, the potential of cellular therapies including unspecific and specific T cells, genetically modified T cells, CAR-T cells, NK-cells, and second allografting in prevention and treatment of relapse after alloSCT are summarized.

Presumed primary immune-mediated neutropenia in 35 dogs: a retrospective study.

PubMed

Devine, L; Armstrong, P J; Whittemore, J C; Sharkey, L; Bailiff, N; Huang, A; Rishniw, M

2017-06-01

To describe, in a cohort of dogs with presumed primary immune-mediated neutropenia, the presenting clinical characteristics, haematology results, bone marrow characteristics, therapies used (drugs and doses), clinical response to treatment, relapse and outcome at six months and one year. Multi-institutional recruited retrospective descriptive case series with voluntary submissions. Presumed immune-mediated neutropenia was diagnosed based on a neutrophil concentration <1·5×10 9 cells/L on a minimum of two complete blood counts, exclusion of other causes of neutropenia based on a diagnostic bone marrow aspirate or biopsy, and exclusion of secondary immune-mediated neutropenia. Dogs meeting these diagnostic criteria between 2006 and 2013, and that had a haematocrit of ≥29% and minimum of two complete blood clounts performed after initiation of therapy, were included. Information on 35 dogs was included. Neutropenia was less than 0·5×10 9 cells/L in most cases (21 dogs), 0·5 to ·99×10 9 cells/L in 11, and 1.0 to 1·49×10 9 cells/L in three. Eight dogs had thrombocytopenia, which was severe (<49·9×10 9 cells/L) in three. [Correction added on 23 May 2017, after first online publication: the cell numbers were incorrect due to errors in the conversion of cell measurements to international units. The numbers have been corrected throughout the article and Table 2.] Twenty-three dogs had myeloid hyperplasia, 10 dogs had myeloid hypoplasia and two dogs had normal myelopoiesis. Neutropenia resolved in 32 of 33 dogs within two weeks of starting corticosteroid therapy and in all dogs within one month. Relapse of neutropenia occurred in 12 cases within one year. Initial response of presumed primary immune-mediated neutropenia cases to corticosteroid therapy can be excellent. Long-term monitoring for relapse is warranted because 34% of cases relapsed during or after taper of immunosuppressive medications. © 2017 British Small Animal Veterinary Association.

Donor Chimerism of B Cells and Nature Killer Cells Provides Useful Information to Predict Hematologic Relapse following Allogeneic Hematopoietic Stem Cell Transplantation.

PubMed

Jiang, Ying; Wan, Liping; Qin, Youwen; Wang, Xiaorui; Yan, Shike; Xie, Kuangcheng; Wang, Chun

2015-01-01

In this study we investigated the correlation between donor chimerism status and disease relapse following allogeneic hematopoietic stem cell transplantation (allo-HSCT). The chimerism of Fluorescence-activated cell sorter (FACS) sorted CD3+T lymphocytes of 153 cases, CD56+CD16+NK lymphocytes of 153 cases and CD19+B lymphocytes of 31 cases with acute B lymphoblastic leukemia (B-ALL) was analyzed post-transplant utilizing polymerase chain reaction amplification of short tandem repeats (PCR-STR). A total of 33 patients (33/153, 21.6%) had recurrent disease. The positive predictive values of declining donor chimerism for hematologic and isolated extramedullary relapse were 58.8% and 10% (P=0.018, Chi-Square). The positive predictive values of declining donor chimerism in BMB, BMT, BMNK and PBB for hematologic relapse were 11.6%, 0%, 0% and 0% under close monitoring in patients with B-ALL. Only the donor chimerism in BMB significantly decreased in the group with hematologic relapse as compared with the group without hematologic relapse (P=0.00, Independent-samples T test) in patients with B-ALL. The median drop of donor chimerism in PBT, BMT, PBNK and BMNK were 0%, 0%, 5.9% and 2.8% one or two weeks prior to hematologic relapse in patients with non-B-ALL. The donor chimerism in PBNK significantly decreased prior to hematologic relapse in the group with hematologic relapse as compared with the group without hematologic relapse (P=0.022, Independent-samples T test).These data suggest donor chimerism of BMB can be used to predict the occurrence of hematologic relapse in patients with B-ALL. Donor chimerism decrease in PBNK was associated with a somewhat increased risk of hematologic relapse in patients with non-B-ALL. Therefore, our results reveal a more effective path to individually predict for hematologic relapse by dynamic monitoring different cell lineages in different disease.

Iodine I 131 Tositumomab, Etoposide and Cyclophosphamide Followed by Autologous Stem Cell Transplant in Treating Patients With Relapsed or Refractory Non-Hodgkin's Lymphoma

ClinicalTrials.gov

2017-07-21

Anaplastic Large Cell Lymphoma; Cutaneous B-cell Non-Hodgkin Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Nodal Marginal Zone B-cell Lymphoma; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Splenic Marginal Zone Lymphoma; Waldenström Macroglobulinemia

Flavopiridol in Treating Patients With Relapsed or Refractory Lymphoma or Multiple Myeloma

ClinicalTrials.gov

2016-06-27

Adult Lymphocyte Depletion Hodgkin Lymphoma; Adult Lymphocyte Predominant Hodgkin Lymphoma; Adult Mixed Cellularity Hodgkin Lymphoma; Adult Nodular Sclerosis Hodgkin Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Nodal Marginal Zone B-cell Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Refractory Multiple Myeloma; Splenic Marginal Zone Lymphoma; Stage I Multiple Myeloma; Stage II Multiple Myeloma; Stage III Multiple Myeloma; Waldenström Macroglobulinemia

NCI First International Workshop on the Biology, Prevention and Treatment of Relapse after Allogeneic Hematopoietic Stem Cell Transplantation: Report from the Committee on Treatment of Relapse after Allogeneic Hematopoietic Stem Cell Transplantation

PubMed Central

Porter, David L.; Alyea, Edwin P.; Antin, Joseph H.; DeLima, Marcos; Estey, Eli; Falkenburg, J.H. Frederik; Hardy, Nancy; Kroeger, Nicolaus; Leis, Jose; Levine, John; Maloney, David G.; Peggs, Karl; Rowe, Jacob M.; Wayne, Alan S.; Giralt, Sergio; Bishop, Michael R.; van Besien, Koen

2010-01-01

Relapse is a major cause of treatment failure after allogeneic hematopoietic stem cell transplantation (alloHSCT). Treatment options for relapse have been inadequate and the majority of patients ultimately die of their disease. There is no standard approach to treating relapse after alloHSCT. Withdrawal of immune suppression and donor lymphocyte infusions (DLI) are commonly used for all diseases; although these interventions are remarkably effective for relapsed CML, they have limited efficacy in other hematologic malignancies. Conventional and novel chemotherapy, monoclonal antibody therapy, targeted therapies, and second transplants have been utilized in a variety of relapsed diseases, but reports on these therapies are generally anecdotal and retrospective. As such there is an immediate need for well designed, disease-specific trials for treatment of relapse after alloHSCT. This report summarizes current treatment options under investigation for relapse after alloHSCT in a disease-specific manner. In addition, recommendations are provided for specific areas of research necessary in the treatment of relapse after alloHSCT. PMID:20699125

Low dose elective brain irradiation in small cell carcinoma of the lung

DOE Office of Scientific and Technical Information (OSTI.GOV)

Beiler, D.D.; Kane, R.C.; Bernath, A.M.

Elective brain irradiation (EBI) in a dosage of 3000 rad (midplane) in 2 weeks (nominal standard dose (NSD) = 1314 ret) has proven highly effective in preventing initial brain relapse in small cell lung carcinoma. However, the optimal radiation dose for EBI is unknown. 55 patients (31 with regional disease, 24 with extensive disease) without brain metastases were treated with a 4 drug chemotherapy program, (lomustine (CCNU), methotrexate, cyclophosphamide, vincristine) plus radiotherapy (R.T.), 3000 rad in 2 weeks to the primary chest lesion and were randomized to EBI or a control group. The EBI consisted of 2400 rad whole brain,more » midplane, in 8 fractions, 10 days (NSD = 1130 ret) given at the same time as the R.T. to the primary (3 weeks post-initial chemotherapy). Though all 54 evaluable patients received CCNU 50 mg/M/sup 2/q. 6 weeks, there were 5 initial brain relapses among 31 control patients (16%) vs none in the 23 EBI patients. The time at risk for recurrence was similar in the two groups, i.e. 31 weeks median in the EBI and 32 weeks in the no-EBI patients. Brain relapses occurred in 2/17 with limited disease and 3/14 with extensive disease. It appears that 2400 rad in 8 fractions is as effective for EBI as larger doses. Toxicity was limited to alopecia. Survival was not significantly affected by EBI, though there is a suggestion of improvement in the regional group.« less

IMPACT OF PRETRANSPLANT CONDITIONING REGIMENS ON OUTCOMES OF ALLOGENEIC TRANSPLANTATION FOR CHEMOTHERAPY-UNRESPONSISVE DIFFUSE LARGE B-CELL LYMPHOMA AND GRADE-III FOLLICULAR LYMPHOMA

PubMed Central

Hamadani, Mehdi; Saber, Wael; Ahn, Kwang Woo; Carreras, Jeanette; Cairo, Mitchell S.; Fenske, Timothy S.; Gale, Robert Peter; Gibson, John; Hale, Gregory A.; Hari, Parameswaran N.; Hsu, Jack W.; Inwards, David J.; Kamble, Rammurti T.; Klein, Anderas; Maharaj, Dipnarine; Marks, David I.; Rizzieri, David A.; Savani, Bipin N.; Schouten, Harry C.; Waller, Edmund K.; Wirk, Baldeep; Laport, Ginna G.; Montoto, Silvia; Maloney, David G.; Lazarus, Hillard M.

2013-01-01

Patients with chemorefractory non-Hodgkin lymphomas (NHL) generally have a poor prognosis. We used the observational database of the CIBMTR to study the outcome of 533 patients with refractory diffuse large B-cell lymphoma (DLBCL) or grade-III follicular lymphoma (FL-III) who underwent allogeneic transplantation (allo-HCT) using either myeloablative (MA; N=307) or reduced intensity/non-myeloablative conditioning (RIC/NST; N=226), between 1998-2010. We analyzed non-relapse mortality (NRM), relapse/progression, progression-free survival (PFS), and overall survival (OS). Only 45% of the patients at transplant had a Karnofsky performance score of ≥90%. Median follow-up of surviving patients after MA and RIC/NST allo-HCT is 35 months and 30 months, respectively. At 3years, MA allo-HCT was associated with a higher NRM compared to RIC/NST (53% vs. 42%; p=0.03), similar PFS (19% vs. 23%; p=0.40), and lower OS (19% vs. 28%; p=0.02), respectively. On multivariate analysis, FL-III histology was associated with lower NRM (relative-risk [RR]=0.52), reduced risk of relapse/progression (RR=0.42), superior PFS (RR=0.51) and OS (RR=0.53), while MA conditioning was associated with reduced risk of relapse/progression (RR=0.66). Despite a refractory state, a small subset of DLBCL and FL-III patients can attain durable remissions after allo-HCT. Conditioning regimen intensity was not associated with PFS and OS despite a higher risk of relapse/progression with RIC/NST allo-HCT. PMID:23380340

[Chimeric antigen receptors T cells in treatment of a relapsed pediatric acute lymphoblastic leukemia, relapse after allogenetic hematopoietic stem cell transplantation: case report and review of literature review].

PubMed

Zuo, Yingxi; Wang, Jingbo; Lu, Aidong; Jia, Yueping; Wu, Jun; Dong, Lujia; Chang, Lungji; Zhang, Leping

2016-02-01

To evaluate the safety and efficacy of chimeric antigen receptors T cells (CAR-T) in childhood acute B lymphoblastic leukemia (B-ALL). A relapsed B-ALL child after allogeneic hematopoietic stem cell transplantation (allo-HSCT) was treated with CAR-T, and the related literatures were reviewed. An 11-year-old girl with TEL-AML1 fusion gene positive BALL who suffered a bone marrow relapse 28 months after remission from conventional chemotherapy. During the second remission, the patient received haploidentical allo-HSCT. She relapsed with detectable TEL-AML1 fusion gene even after chemotherapy and donor leukocyte infusions. She received an experimental donor-derived fourth generation CD19 CAR-T therapy. After infusion of 1 × 10(6)/kg CAR-T cells, she experienced only mild or moderate cytokine-release syndrome and the minimal residual disease turned negative. Then three maintenance of CAR-T cell infusions [(0.83-1.65)×10(6)/kg] was administered, and the disease-free survival had lasted for 10 months. However, the TEL-AML1 copies in her blood still increased and she died with leukemia relapse after additional CAR-T cell infusion. Treatment of relapsed B-ALL with the fourth generation CAR-T cells directed against CD19 was effective and safe. CAR-T therapy is a novel therapeutic approach that could be useful for patients with relapsed and refractory B-ALL who have failed all other treatment options.

Hematopoietic stem cell transplantation for non-Hodgkin lymphoma.

PubMed

Bhatt, Vijaya Raj; Vose, Julie M

2014-12-01

Up-front rituximab-based chemotherapy has improved outcomes in non-Hodgkin lymphoma (NHL); refractory or relapsed NHL still accounts for approximately 18,000 deaths in the United States. Autologous hematopoietic stem cell transplantation (SCT) can improve survival in primary refractory or relapsed aggressive NHL and mantle cell lymphoma and in relapsed follicular or peripheral T-cell lymphoma. Autologous SCT as a consolidation therapy after first complete or partial remission in high-risk aggressive NHL, mantle cell lymphoma, and peripheral T-cell lymphoma may improve progression-free survival. Allogeneic SCT offers a lower relapse rate but a higher nonrelapse mortality resulting in overall survival similar to autologous SCT. Copyright © 2014 Elsevier Inc. All rights reserved.

Enhanced gamma interferon responses of mouse spleen cells following immunotherapy for tuberculosis relapse.

PubMed

Gil, Olga; Vilaplana, Cristina; Guirado, Evelyn; Díaz, Jorge; Cáceres, Neus; Singh, Mahavir; Cardona, Pere-Joan

2008-11-01

Gamma interferon responses of spleen cells in mice were examined during postchemotherapy relapse of intraperitoneally induced latent tuberculous infection. The mycobacterial extract RUTI, which prevented the relapse, significantly enhanced the immune responses to secreted and structural recombinant mycobacterial antigens, suggesting that RUTI-mediated protection was mediated by activated T cells.

Pharmacological targets of breast cancer stem cells: a review.

PubMed

Pindiprolu, Sai Kiran S S; Krishnamurthy, Praveen T; Chintamaneni, Pavan Kumar

2018-05-01

Breast cancers contain small population of tumor-initiating cells called breast cancer stem cells (BCSCs), which are spared even after chemotherapy. Recently, BCSCs are implicated to be a cause of metastasis, tumor relapse, and therapy resistance in breast cancer. BCSCs have unique molecular mechanisms, which can be targeted to eliminate them. These include surface biomarkers, proteins involved in self-renewal pathways, drug efflux transporters, apoptotic/antiapoptotic proteins, autophagy, metabolism, and microenvironment regulation. The complex molecular mechanisms behind the survival of BCSCs and pharmacological targets for elimination of BCSCs are described in this review.

Auranofin Induces Lethal Oxidative and Endoplasmic Reticulum Stress and Exerts Potent Preclinical Activity against Chronic Lymphocytic Leukemia

PubMed Central

Fiskus, Warren; Saba, Nakhle; Shen, Min; Ghias, Mondana; Liu, Jinyun; Gupta, Soumyasri Das; Chauhan, Lata; Rao, Rekha; Gunewardena, Sumedha; Schorno, Kevin; Austin, Christopher P.; Maddocks, Kami; Byrd, John; Melnick, Ari; Huang, Peng; Wiestner, Adrian; Bhalla, Kapil N.

2014-01-01

Chronic lymphocytic leukemia (CLL) exhibits high remission rates after initial chemoimmunotherapy, but with relapses with treatment, refractory disease is the most common outcome, especially in CLL with the deletion of chromosome 11q or 17p. In addressing the need of treatments for relapsed disease, we report the identification of an existing U.S. Food and Drug Administration-approved small-molecule drug to repurpose for CLL treatment. Auranofin (Ridaura) is approved for use in treating rheumatoid arthritis, but it exhibited preclinical efficacy in CLL cells. By inhibiting thioredoxin reductase activity and increasing intracellular reactive oxygen species levels, auranofin induced a lethal endoplasmic reticulum stress response in cultured and primary CLL cells. In addition, auranofin displayed synergistic lethality with heme oxygenase-1 and glutamate-cysteine ligase inhibitors against CLL cells. Auranofin overcame apoptosis resistance mediated by protective stromal cells, and it also killed primary CLL cells with deletion of chromosome 11q or 17p. In TCL-1 transgenic mice, an in vivo model of CLL, auranofin treatment markedly reduced tumor cell burden and improved mouse survival. Our results provide a rationale to reposition the approved drug auranofin for clinical evaluation in the therapy of CLL. PMID:24599128

Vorinostat With or Without Isotretinoin in Treating Young Patients With Recurrent or Refractory Solid Tumors, Lymphoma, or Leukemia

ClinicalTrials.gov

2014-06-16

Childhood Acute Promyelocytic Leukemia (M3); Childhood Atypical Teratoid/Rhabdoid Tumor; Childhood Burkitt Lymphoma; Childhood Chronic Myelogenous Leukemia; Childhood Diffuse Large Cell Lymphoma; Childhood Immunoblastic Large Cell Lymphoma; Juvenile Myelomonocytic Leukemia; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Childhood Grade III Lymphomatoid Granulomatosis; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Medulloblastoma; Recurrent Childhood Small Noncleaved Cell Lymphoma; Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumor; Recurrent Neuroblastoma; Recurrent/Refractory Childhood Hodgkin Lymphoma; Relapsing Chronic Myelogenous Leukemia; Unspecified Childhood Solid Tumor, Protocol Specific

Impact of Routine Surveillance Imaging on Outcomes of Patients With Diffuse Large B-Cell Lymphoma After Autologous Hematopoietic Cell Transplantation.

PubMed

Epperla, Narendranath; Shah, Namrata; Hamadani, Mehdi; Richardson, Kristin; Kapke, Jonathan T; Patel, Asmita; Teegavarapu, Sravanthi P; Carrum, George; Hari, Parameswaran N; Pingali, Sai R; Karmali, Reem; Fenske, Timothy S

2016-12-01

For patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), autologous hematopoietic cell transplantation (auto-HCT) is commonly used. After auto-HCT, DLBCL patients are often monitored with surveillance imaging. However, there is little evidence to support this practice. We performed a multicenter retrospective study of DLBCL patients who underwent auto-HCT (n = 160), who experienced complete remission after transplantation, and who then underwent surveillance imaging. Of these, only 45 patients experienced relapse after day +100 after auto-HCT, with relapse detected by routine imaging in 32 (71%) and relapse detected clinically in 13 (29%). Baseline patient characteristics were similar between the 2 groups. Comparing the radiographic and clinically detected relapse groups, the median time from diagnosis to auto-HCT (389 days vs. 621 days, P = .06) and the median follow-up after auto-HCT (2464 days vs. 1593 days P = .60) were similar. The median time to relapse after auto-HCT was 191 days in radiographically detected relapses compared to 492 days in clinically detected relapses (P = .35), and median postrelapse survival was 359 days in such patients compared to 123 days in patients with clinically detected relapse (P = .36). However, the median posttransplantation overall survival was not significantly different for patients with relapse detected by routine imaging versus relapse detected clinically (643 vs. 586 days, P = .68). A majority (71%) of DLBCL relapses after auto-HCT are detected by routine surveillance imaging. Overall, there appears to be limited utility for routine imaging after auto-HCT except in select cases where earlier detection and salvage therapy with allogeneic HCT is a potential option. Copyright © 2016 Elsevier Inc. All rights reserved.

Influence of Cranial Radiotherapy on Outcome in Children With Acute Lymphoblastic Leukemia Treated With Contemporary Therapy

PubMed Central

Andreano, Anita; Pui, Ching-Hon; Hunger, Stephen P.; Schrappe, Martin; Moericke, Anja; Biondi, Andrea; Escherich, Gabriele; Silverman, Lewis B.; Goulden, Nicholas; Taskinen, Mervi; Pieters, Rob; Horibe, Keizo; Devidas, Meenakshi; Locatelli, Franco; Valsecchi, Maria Grazia

2016-01-01

Purpose We sought to determine whether cranial radiotherapy (CRT) is necessary to prevent relapse in any subgroup of children with acute lymphoblastic leukemia (ALL). Patients and Methods We obtained aggregate data on relapse and survival outcomes for 16,623 patients age 1 to 18 years old with newly diagnosed ALL treated between 1996 and 2007 by 10 cooperative study groups from around the world. The proportion of patients eligible for prophylactic CRT varied from 0% to 33% by trial and was not related to the proportion eligible for allogeneic stem-cell transplantation in first complete remission. Using a random effects model, with CRT as a dichotomous covariate, we performed a single-arm meta-analysis to compare event-free survival and cumulative incidence of isolated or any CNS relapse and isolated bone marrow relapse in high-risk subgroups of patients who either did or did not receive CRT. Results Although there was significant heterogeneity in all outcome end points according to trial, CRT was associated with a reduced risk of relapse only in the small subgroup of patients with overt CNS disease at diagnosis, who had a significantly lower risk of isolated CNS relapse (4% with CRT v 17% without CRT; P = .02) and a trend toward lower risk of any CNS relapse (7% with CRT v 17% without CRT; P = .09). However, this group had a relatively high rate of events regardless of whether or not they received CRT (32% [95% CI, 26% to 39%] v 34% [95% CI, 19% to 54%]; P = .8). Conclusion CRT does not have an impact on the risk of relapse in children with ALL treated on contemporary protocols. PMID:26755523

Response to rituximab and timeframe to relapse in rheumatoid arthritis patients: association with B-cell markers.

PubMed

Pyrpasopoulou, Athina; Douma, Stella; Triantafyllou, Areti; Simoulidou, Elisavet; Samara, Magda; Parapanisiou, Efthymia; Aslanidis, Spyros

2010-02-01

Rituximab is used to deplete B cells and control disease activity, mainly in patients with rheumatoid arthritis (RA) who have not responded to anti-tumor necrosis factor (TNF) therapy. Response rates and time to relapse vary significantly among treated individuals. The objective of this study was to monitor the response of seropositive and seronegative RA patients to rituximab and correlate relapse with B-cell markers in the two groups. Seventeen RA patients (eight seropositive for rheumatoid factor [RF+] and nine seronegative [RF-]) were treated with two cycles of rituximab. After treatment, all patients were re-evaluated at the outpatient clinic, and rituximab was readministered when disease relapse was confirmed by clinical-laboratory measures (Disease Activity Score [DAS]-28). CD20+ cells and CD20 receptor expression levels were estimated at initiation, relapse, and re-evaluation timepoints, and were compared between the two groups. Seropositive patients responded favorably to treatment compared with the seronegative group. The mean time to relapse was 337.5 +/- 127.0 days for the RF+ patients versus 233.3 +/- 59.6 days for the RF- patients (p = 0.043), despite more aggressive concomitant treatment in the seronegative group. The DAS28 decrease 3 months after treatment was 1.695 +/- 1.076 in seropositive patients versus 0.94 +/- 1.62 in seronegative patients. At relapse, CD20 receptor expression (molecules/cell) was higher in RF+ patients than in their RF- counterparts, despite a significantly lower percentage of CD20+ cells. Rituximab treatment is efficient in both seropositive and seronegative RA. However, seropositive RA patients tend to respond favorably compared with seronegative patients. The differential CD20 receptor expression in the two groups at relapse potentially suggests a different pathogenetic mechanism of relapse and merits further investigation.

Coccidioidomycosis, immunoglobulin deficiency: safety challenges with CAR T cells therapy for relapsed lymphoma.

PubMed

Zahid, Umar; Shaukat, Al-Aman; Hassan, Nida; Anwer, Faiz

2017-10-01

Treatment of patients with relapsed or refractory lymphoma may require allogenic hematopoietic stem cell transplant (HSCT), but treatment of post-transplant relapse disease remains very challenging. Donor lymphocyte infusion and blinatumomab have been used with limited success for the treatment of relapse. Initial data on donor-derived CAR T cells has shown this modality to be safe and highly effective in various hematological malignancies. We present a case of a patient with highly refractory, transformed follicular lymphoma who failed both autologous and allogenic HSCT. Patient achieved long-lasting complete remission with the use of donor origin CD19 CAR T-cell therapy, without any evidence of graft-versus-host disease flare. Our patient later developed disseminated coccidioidomycosis and persistent hypogammaglobulinemia. Immunotherapy using CD19 CAR T cells can be a highly effective salvage modality, especially in cases of focal lymphoma relapse. Long-term immunosuppression secondary to B cell lymphopenia, hypogammaglobulinemia, immunoglobulin subclass deficiency, fungal infections and other infectious complications need to be monitored and promptly treated as indicated.

Bruton’s tyrosine kinase inhibitors and their clinical potential in the treatment of B-cell malignancies: focus on ibrutinib

PubMed Central

Aalipour, Amin

2014-01-01

Aberrant signaling of the B-cell receptor pathway has been linked to the development and maintenance of B-cell malignancies. Bruton’s tyrosine kinase (BTK), a protein early in this pathway, has emerged as a new therapeutic target in a variety of such malignancies. Ibrutinib, the most clinically advanced small molecule inhibitor of BTK, has demonstrated impressive tolerability and activity in a range of B-cell lymphomas which led to its recent approval for relapsed mantle cell lymphoma and chronic lymphocytic leukemia. This review focuses on the preclinical and clinical development of ibrutinib and discusses its therapeutic potential. PMID:25360238

Rituximab in the treatment of refractory or relapsing eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome).

PubMed

Thiel, Jens; Hässler, Fabian; Salzer, Ulrich; Voll, Reinhard E; Venhoff, Nils

2013-09-24

Eosinophilic granulomatosis with polyangiitis (EGPA) is part of antineutrophil cytoplasmic antibodies (ANCAs)-associated vasculitides. In EGPA small-vessel vasculitis is associated with eosinophilia and asthma. About 40% of EGPA patients are ANCA-positive, suggesting a role for B cells in the pathogenesis of EGPA. B cell-depleting therapy with rituximab (RTX) can be effective in ANCA-positive EGPA, but very few patients have been published to date. The role of RTX in the treatment of ANCA-negative EGPA is unclear. We report a single-center cohort of patients with eosinophilic granulomatosis with polyangiitis. Of these patients, nine (six ANCA-positive, three ANCA-negative) had been treated with RTX for relapsing or refractory disease on standard immunosuppressive treatment. In a retrospective analysis, data on treatment response, frequency of relapses, adverse events, and peripheral B-cell reconstitution were evaluated. Furthermore, serum immunoglobulin concentrations, ANCA status, and peripheral B cell subpopulations were assessed after RTX treatment. All patients had high disease activity before RTX treatment. At presentation 3 months after RTX therapy, all ANCA-positive and ANCA-negative patients had responded to RTX, with one patient being in complete remission, and eight patients being in partial remission. After a mean follow-up of 9 months, C-reactive protein concentrations had normalized, eosinophils had significantly decreased, and prednisone had been tapered in all patients. In all patients, RTX therapy was combined with a standard immunosuppressive therapy. Within the 9-month observation period, no relapse was recorded. Three patients were preemptively retreated with RTX, and during the median follow-up time of 3 years, no relapse occurred in these patients. During the follow-up of 13 patient-years, five minor but no major infections were recorded. In our analysis on nine patients with EGPA resistant to standard therapy, rituximab proved to be an efficient and safe treatment for ANCA-positive and ANCA-negative patients. Preemptive retreatment with RTX, combined with standard maintenance immunosuppressants, resulted in a sustained treatment response. Prospective, randomized trials evaluating the use of RTX in EGPA are warranted.

Small sizes and indolent evolutionary dynamics challenge the potential role of P2RY8-CRLF2–harboring clones as main relapse-driving force in childhood ALL

PubMed Central

Morak, Maria; Attarbaschi, Andishe; Fischer, Susanna; Nassimbeni, Christine; Grausenburger, Reinhard; Bastelberger, Stephan; Krentz, Stefanie; Cario, Gunnar; Kasper, David; Schmitt, Klaus; Russell, Lisa J.; Pötschger, Ulrike; Stanulla, Martin; Eckert, Conny; Mann, Georg; Haas, Oskar A.; Panzer-Grümayer, Renate

2014-01-01

The P2RY8-CRLF2 fusion defines a particular relapse-prone subset of childhood acute lymphoblastic leukemia (ALL) in Italian Association of Pediatric Hematology and Oncology Berlin-Frankfurt-Münster (AIEOP-BFM) 2000 protocols. To investigate whether and to what extent different clone sizes influence disease and relapse development, we quantified the genomic P2RY8-CRLF2 fusion product and correlated it with the corresponding CRLF2 expression levels in patients enrolled in the BFM-ALL 2000 protocol in Austria. Of 268 cases without recurrent chromosomal translocations and high hyperdiploidy, representing approximately 50% of all cases, 67 (25%) were P2RY8-CRLF2 positive. The respective clone sizes were ≥ 20% in 27% and < 20% in 73% of them. The cumulative incidence of relapse of the entire fusion-positive group was clone size independent and significantly higher than that of the fusion-negative group (35% ± 8% vs 13% ± 3%, P = .008) and primarily confined to the non–high-risk group. Of 22 P2RY8-CRLF2–positive diagnosis/relapse pairs, only 4/8 had the fusion-positive dominant clone conserved at relapse, whereas none of the original 14 fusion-positive small clones reappeared as the dominant relapse clone. We conclude that the majority of P2RY8-CRLF2–positive clones are small at diagnosis and virtually never generate a dominant relapse clone. Our findings therefore suggest that P2RY8-CRLF2–positive clones do not have the necessary proliferative or selective advantage to evolve into a disease-relevant relapse clone. PMID:23091296

Study of Bortezomib and Panobinostat in Treating Patients With Relapsed/Refractory Peripheral T-cell Lymphoma or NK/T-cell Lymphoma

ClinicalTrials.gov

2014-06-26

Peripheral T-cell Lymphoma (Not Otherwise Specified); Angioimmunoblastic T-cell Lymphoma; Extranodal NK/T-cell Lymphoma Nasal Type; Enteropathy- Type T-cell Lymphoma; Hepatosplenic T-cell Lymphoma; Anaplastic Large Cell Lymphoma (ALCL) (ALK-1 Negative); Relapsed ALCL (ALK-1 Positive) Post Autologous Transplant

Mutations in epigenetic regulators are involved in acute lymphoblastic leukemia relapse following allogeneic hematopoietic stem cell transplantation.

PubMed

Xiao, Haowen; Wang, Li-Mengmeng; Luo, Yi; Lai, Xiaoyu; Li, Caihua; Shi, Jimin; Tan, Yamin; Fu, Shan; Wang, Yebo; Zhu, Ni; He, Jingsong; Zheng, Weiyan; Yu, Xiaohong; Cai, Zhen; Huang, He

2016-01-19

Although steady improvements to chemotherapeutic treatments has helped cure 80% of childhood acute lymphoblastic leukemia (ALL) cases, chemotherapy has proven to be less effective in treating the majority of adult patients, leaving allogeneic hematopoietic stem cell transplantation (allo-HSCT) as the primary adult treatment option. Nevertheless relapse are the leading cause of death following allo-HSCT. The genetic pathogenesis of relapse following allo-HSCT in Philadelphia chromosome- negative ALL (Ph- ALL) remains unexplored. We performed longitudinal whole-exome sequencing analysis in three adult patients with Ph- B-cell ALL (Ph- B-ALL) on samples collected from diagnosis to relapse after allo-HSCT. Based on these data, we performed target gene sequencing on 23 selected genes in 58 adult patients undergoing allo-HSCT with Ph- B-ALL. Our results revealed a significant enrichment of mutations in epigenetic regulators from relapsed samples, with recurrent somatic mutations in SETD2, CREBBP, KDM6A and NR3C1. The relapsed samples were also enriched in signaling factor mutations, including KRAS, PTPN21, MYC and USP54. Furthermore, we are the first to reveal the clonal evolution patterns during leukemia relapse after allo-HSCT. Cells present in relapsed specimens were genetically related to the diagnosed tumor, these cells therefore arose from either an existing subclone that was not eradicated by allo-HSCT therapy, or from the same progenitor that acquired new mutations. In some cases, however, it is possible that leukemia recurrence following allo-HSCT could result from a secondary malignancy with a distinct set of mutations. We identified novel genetic causes of leukemia relapse after allo-HSCT using the largest generated data set to date from adult patients with Ph- B-ALL.

Mutations in epigenetic regulators are involved in acute lymphoblastic leukemia relapse following allogeneic hematopoietic stem cell transplantation

PubMed Central

Lai, Xiaoyu; Li, Caihua; Shi, Jimin; Tan, Yamin; Fu, Shan; Wang, Yebo; Zhu, Ni; He, Jingsong; Zheng, Weiyan; Yu, Xiaohong; Cai, Zhen; Huang, He

2016-01-01

Although steady improvements to chemotherapeutic treatments has helped cure 80% of childhood acute lymphoblastic leukemia (ALL) cases, chemotherapy has proven to be less effective in treating the majority of adult patients, leaving allogeneic hematopoietic stem cell transplantation (allo-HSCT) as the primary adult treatment option. Nevertheless relapse are the leading cause of death following allo-HSCT. The genetic pathogenesis of relapse following allo-HSCT in Philadelphia chromosome- negative ALL (Ph− ALL) remains unexplored. We performed longitudinal whole-exome sequencing analysis in three adult patients with Ph− B-cell ALL (Ph− B-ALL) on samples collected from diagnosis to relapse after allo-HSCT. Based on these data, we performed target gene sequencing on 23 selected genes in 58 adult patients undergoing allo-HSCT with Ph− B-ALL. Our results revealed a significant enrichment of mutations in epigenetic regulators from relapsed samples, with recurrent somatic mutations in SETD2, CREBBP, KDM6A and NR3C1. The relapsed samples were also enriched in signaling factor mutations, including KRAS, PTPN21, MYC and USP54. Furthermore, we are the first to reveal the clonal evolution patterns during leukemia relapse after allo-HSCT. Cells present in relapsed specimens were genetically related to the diagnosed tumor, these cells therefore arose from either an existing subclone that was not eradicated by allo-HSCT therapy, or from the same progenitor that acquired new mutations. In some cases, however, it is possible that leukemia recurrence following allo-HSCT could result from a secondary malignancy with a distinct set of mutations. We identified novel genetic causes of leukemia relapse after allo-HSCT using the largest generated data set to date from adult patients with Ph− B-ALL. PMID:26527318

Clinical heterogeneity of diffuse large B cell lymphoma following failure of front-line immunochemotherapy.

PubMed

Farooq, Umar; Maurer, Matthew J; Thompson, Carrie A; Thanarajasingam, Gita; Inwards, David J; Micallef, Ivana; Macon, William; Syrbu, Sergei; Lin, Tasha; Lin, Yi; Ansell, Stephen M; Nowakowski, Grzegorz S; Habermann, Thomas M; Cerhan, James R; Link, Brian K

2017-10-01

This study aimed to describe the patterns of care and outcomes of diffuse large B cell lymphoma (DLBCL) after failure of front line anthracycline-based immunochemotherapy (IC). Patients with newly diagnosed lymphoma were prospectively enrolled in Molecular Epidemiology Resource (MER) of the University of Iowa/Mayo Clinic Lymphoma Specialized Program of Research Excellzence. All DLBCL and primary mediastinal B-cell lymphoma (PMBL) patients treated with front-line anthracycline-based IC were followed for relapse. Patients with relapse on follow-up and subsequently retreated were included in this analysis. 1039 patients received anthracycline-based IC between 2002 and 2012, of which 244 relapsed and were subsequently retreated. Across all therapies, overall survival at 4 years (OS4) from relapse was 28% and 103 patients ultimately underwent autologous haematopoietic cell transplant (autoHCT) with OS4 from autoHCT of 51%. Patients relapsing after 12 months from initial diagnosis had OS4 of 47% but those with a transient or no response to initial therapy had OS4 of only 13%. Outcomes of relapsed or refractory DLBCL differ substantially when categorized by response to initial therapy, timing of relapse and opportunity to undergo autoHCT. The design and interpretation of uncontrolled trials should account for this heterogeneity in patients with relapsed DLBCL. © 2017 John Wiley & Sons Ltd.

CRYAB modulates the activation of CD4+ T cells from relapsing-remitting multiple sclerosis patients.

PubMed

Quach, Que Lan; Metz, Luanne M; Thomas, Jenna C; Rothbard, Jonathan B; Steinman, Lawrence; Ousman, Shalina S

2013-12-01

Suppression of activation of pathogenic CD4(+) T cells is a potential therapeutic intervention in multiple sclerosis (MS). We previously showed that a small heat shock protein, CRYAB, reduced T cell proliferation, pro-inflammatory cytokine production and clinical signs of experimental allergic encephalomyelitis, a model of MS. We assessed whether the ability of CRYAB to reduce the activation of T cells translated to the human disease. CD4(+) T cells from healthy controls and volunteers with MS were activated in vitro in the presence or absence of a CRYAB peptide (residues 73-92). Parameters of activation (proliferation rate, cytokine secretion) and tolerance (anergy, activation-induced cell death, microRNAs) were evaluated. The secretion of pro-inflammatory cytokines by CD4(+) T cells was decreased in the presence of CRYAB in a subset of relapsing-remitting multiple sclerosis (RRMS) participants with mild disease severity while no changes were observed in healthy controls. Further, there was a correlation for higher levels of miR181a microRNA, a marker upregulated in tolerant CD8(+) T cells, in CD4(+) T cells of MS patients that displayed suppressed cytokine production (responders). CRYAB may be capable of suppressing the activation of CD4(+) T cells from a subset of RRMS patients who appear to have less disability but similar age and disease duration.

What causes relapses of autoimmune diseases? The etiological role of autoreactive T cells.

PubMed

Wildner, Gerhild; Kaufmann, Ulrike

2013-09-01

Most human autoimmune diseases have a relapsing-remitting or a chronic progressive course, while animal models are usually acute and monophasic. In our experimental animal model the disease can be either monophasic or remitting, depending on the autoantigen used for induction, and it appears to lie in the effector phenotype of the elicited T helper cell response. Since both, monophasic and relapsing courses of disease are induced by immunization as well as by adoptive transfer of peptide-specific, CD4(+) T cells, we were able to directly compare the transcriptomes of pathogenic T cell lines by gene array analysis and qPCR as well as protein expression. Upregulated genes were only determined in T cells inducing relapsing uveitis and belong to certain pathways of antigen presentation, activation, inflammation, migration and survival, comprising WNT, Hedgehog, MAP-kinase and JAK/STAT-pathways. These pathways are partially interacting with each other, and the central molecule upregulated in T cells causing relapsing disease was found to be IFN-γ. Here the course of the autoimmune diseases strictly depends on the characteristics of the autoreactive T cells, which are already determined at their early stage of antigen-specific activation. Our rat models of experimental autoimmune uveitis could help elucidating the immune mechanisms behind relapsing autoimmunity in order to develop better therapeutic strategies. Copyright © 2013 Elsevier B.V. All rights reserved.

Cytomegalovirus reactivation is associated with a lower rate of early relapse in myeloid malignancies independent of in-vivo T cell depletion strategy.

PubMed

Hilal, Talal; Slone, Stacey; Peterson, Shawn; Bodine, Charles; Gul, Zartash

2017-06-01

The association between cytomegalovirus (CMV) reactivation and relapse risk has not been evaluated in relation to T cell depletion strategies. We evaluated 93 patients who underwent allogeneic hematopoietic stem cell transplantation (HSCT) and analyzed the association between T cell depletion strategies with the cumulative incidence of relapse and CMV reactivation. A total of 33% of patients who received ATG vs. 34% who received alemtuzumab developed CMV reactivation. The cumulative incidence of relapse was 3% at 1year and 20% at 3 years in patients with CMV reactivation vs. 30% at 1year and 38% at 3 years in patients without CMV reactivation (p=0.02). When analyzed separately, this effect persisted in the myeloid, but not the lymphoid group. There was a numerical trend towards increased non-relapse mortality (NRM) in patients with CMV reactivation, especially in the myeloid group. The choice of T cell depleting agent and the rate of CMV reactivation were not associated with different overall survival (OS) rates. These results suggest that the choice of T cell depletion strategy may have similar effects on rates of CMV reactivation, disease relapse, and survival. Further studies examining these variables in patients not exposed to in-vivo T cell depleting agents may be of interest. Copyright © 2017 Elsevier Ltd. All rights reserved.

Allogeneic stem cell transplantation using lymphoablative rather than myeloablative conditioning regimen for relapsed or refractory lymphomas.

PubMed

Yoon, Jae-Ho; Jeon, Young-Woo; Lee, Sung-Eun; Cho, Byung-Sik; Eom, Ki-Seong; Kim, Yoo-Jin; Lee, Seok; Kim, Hee-Je; Min, Chang-Ki; Lee, Jong-Wook; Min, Woo-Sung; Cho, Seok-Goo

2017-03-01

In relapsed or refractory non-Hodgkin lymphoma (NHL), allogeneic hematopoietic stem cell transplantation (allo-HSCT) provides graft-versus-lymphoma activity resulting in fewer incidences of relapse. However, therapy-related mortality (TRM) remains an important challenge. We attempted to introduce our reduced-intensity conditioning (RIC) regimen. From 2007 to 2013, we treated 28 relapsed or refractory NHLs with allo-HSCT. All were pre-conditioned with fludarabine [FLU, 180 mg/body surface area (BSA)/6 days] and melphalan (MEL, 70 mg/BSA/1 day); 25 (all but 3) were additionally treated with total body irradiation (TBI, 800 cGy/4Fx/2 days). Peripheral blood stem cells were collected from matched siblings (n = 10) or suitably matched unrelated (n = 18) donors. There were eight diffuse large B-cell lymphomas, seven peripheral T-cell lymphoma not otherwise specified, give lymphoblastic lymphomas, two mantle cell lymphomas, and six various other lymphomas. Of these patients, 10 relapsed after auto-HSCT, 5 relapsed after chemotherapy, and 13 were refractory lymphomas. After allo-HSCT, complete remission was achieved in 22 (78.5%) patients. After a median follow-up of 24.8 months, 3-year overall survival and disease-free survival were 62.4 and 59.2% and the 3-year TRM and relapse incidence were 14.9 and 28.6% respectively. Acute and chronic graft-versus-host diseases (GVHDs) were identified in 17 (≥Grade II in 12 patients) and 18 patients respectively, and the group with chronic GVHD showed favourable survival outcomes. In relapsed or refractory NHL, RIC-allo-HSCT using FLU + MEL + 800 cGy TBI showed favourable survival outcomes with acceptable TRM and relapse incidence. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yagishita, Shigehiro; Horinouchi, Hidehito, E-mail: hhorinou@ncc.go.jp; Katsui Taniyama, Tomoko

Purpose: To determine the frequency and clinical significance of epidermal growth factor receptor (EGFR) mutations in patients with potentially curable stage III non–small-cell lung cancer (NSCLC) who are eligible for definitive chemoradiotherapy (CRT). Patients and Methods: Between January 2001 and December 2010, we analyzed the EGFR mutational status in consecutive NSCLC patients who were treated by CRT. The response rate, relapse-free survival, 2-year relapse-free rate, initial relapse sites, and overall survival of the patients were investigated. Results: A total of 528 patients received CRT at our hospital during the study period. Of these, 274 were diagnosed as having nonsquamous NSCLC. Sufficientmore » specimens for mutational analyses could be obtained from 198 of these patients. The proportion of patients with EGFR activating mutations was 17%. In addition to the well-known characteristics of patients carrying EGFR mutations (female, adenocarcinoma, and never/light smoker), the proportion of cases with smaller primary lesions (T1/2) was found to be higher in patients with EGFR mutations than in those with wild-type EGFR. Patients with EGFR mutations showed similar response rate, relapse-free survival, and 2-year relapse-free rates as compared to patients with wild-type EGFR. Local relapses as the site of initial relapse occurred significantly less frequently in patients with EGFR mutation (4% vs 21%; P=.045). Patients with EGFR mutations showed longer local control (adjusted hazard ratio 0.49; P=.043). After disease progression, a majority of the patients with EGFR mutations received EGFR tyrosine kinase inhibitors (62%), and these patients showed longer postprogression survival than those with wild-type EGFR. Conclusions: Our study is the first to show radiosensitive biology of EGFR-mutated tumors in definitive CRT with curative intent. This finding could serve as a credible baseline estimate of EGFR-mutated population in stage III nonsquamous NSCLC.« less

The risk of central nervous system relapses in patients with peripheral T-cell lymphoma

PubMed Central

Fanale, Michelle A.; Miranda, Roberto N.; Noorani, Mansoor; Westin, Jason R.; Nastoupil, Loretta J.; Hagemeister, Fredrick B.; Fayad, Luis E.; Romaguera, Jorge E.; Samaniego, Felipe; Turturro, Francesco; Lee, Hun J.; Neelapu, Sattva S.; Rodriguez, M. Alma; Wang, Michael; Fowler, Nathan H.; Davis, Richard E.; Medeiros, L. Jeffrey; Oki, Yasuhiro

2018-01-01

We performed a retrospective analysis to identify risk factors and survival outcome for central nervous system (CNS) relapse of peripheral T-cell lymphoma (PTCL) by histologic type. Records of 600 PTCL patients diagnosed between 1999 and 2014 were analyzed including PTCL not otherwise specified (PTCL-NOS, 174 patients), angoimmunoblastic T-cell lymphoma (AITL, 144), ALK+anaplastic large cell lymphoma (ALCL, 74), ALK-ALCL (103), extranodal NK-cell lymphoma (ENKL, 54), or others (51). With a median follow up of 57 months, 13 patients (4 PTCL-NOS, 1 AITL, 4 ALK+ALCL, 2 ALK-ALCL, 2 ENKL) experienced CNS relapse. One-year and 5-year cumulative incidence of CNS relapse were 1.5% (95%CI: 0.7–2.8%) and 2.1% (95%CI: 1.1–3.5%), respectively. The 5-year cumulative incidence of CNS relapse was 1.8% in PTCL-NOS, 0.7% in AITL, 5.4% in ALK+ALCL, 2.1% in ALK-ALCL and 3.7% in ENKL. Extranodal involvement >1 site was the only significant factor associated with higher chance of CNS relapse (HR: 4.9, 95%CI: 1.6–15.0, p = 0.005). Patients with ALK+ALCL who had extranodal involvement >1 (N = 19) had very high risk of CNS relapse with one year cumulative incidence of 17% (95%CI: 4%-37%), all occurring within six months after diagnosis. All patients with CNS relapse eventually died (median, 1.5 months; range, 0.1–10.1 months). CNS relapse in patients with PTCL is rare event but the risk varies by subtype. ALK+ALCL patients with extranodal involvement >1 site have a very high risk of early CNS relapse, and thus evaluation of CNS involvement at the time of diagnosis and possible CNS-directed prophylaxis may be considered. PMID:29538376

Categorization of multiple sclerosis relapse subtypes by B cell profiling in the blood.

PubMed

Hohmann, Christopher; Milles, Bianca; Schinke, Michael; Schroeter, Michael; Ulzheimer, Jochen; Kraft, Peter; Kleinschnitz, Christoph; Lehmann, Paul V; Kuerten, Stefanie

2014-09-16

B cells are attracting increasing attention in the pathogenesis of multiple sclerosis (MS). B cell-targeted therapies with monoclonal antibodies or plasmapheresis have been shown to be successful in a subset of patients. Here, patients with either relapsing-remitting (n = 24) or secondary progressive (n = 6) MS presenting with an acute clinical relapse were screened for their B cell reactivity to brain antigens and were re-tested three to nine months later. Enzyme-linked immunospot technique (ELISPOT) was used to identify brain-reactive B cells in peripheral blood mononuclear cells (PBMC) directly ex vivo and after 96 h of polyclonal stimulation. Clinical severity of symptoms was determined using the Expanded Disability Status Scale (EDSS). Nine patients displayed B cells in the blood producing brain-specific antibodies directly ex vivo. Six patients were classified as B cell positive donors only after polyclonal B cell stimulation. In 15 patients a B cell response to brain antigens was absent. Based on the autoreactive B cell response we categorized MS relapses into three different patterns. Patients who displayed brain-reactive B cell responses both directly ex vivo and after polyclonal stimulation (pattern I) were significantly younger than patients in whom only memory B cell responses were detectable or entirely absent (patterns II and III; p = 0.003). In one patient a conversion to a positive B cell response as measured directly ex vivo and subsequently also after polyclonal stimulation was associated with the development of a clinical relapse. The evaluation of the predictive value of a brain antigen-specific B cell response showed that seven of eight patients (87.5%) with a pattern I response encountered a clinical relapse during the observation period of 10 months, compared to two of five patients (40%) with a pattern II and three of 14 patients (21.4%) with a pattern III response (p = 0.0005; hazard ratio 6.08 (95% confidence interval 1.87-19.77). Our data indicate actively ongoing B cell-mediated immunity against brain antigens in a subset of MS patients that may be causative of clinical relapses and provide new diagnostic and therapeutic options for a subset of patients.

Genetically Modified T-cell Immunotherapy in Treating Patients With Relapsed/Refractory Acute Myeloid Leukemia and Persistent/Recurrent Blastic Plasmacytoid Dendritic Cell Neoplasm

ClinicalTrials.gov

2018-03-02

Adult Acute Myeloid Leukemia in Remission; Acute Biphenotypic Leukemia; Early Relapse of Acute Myeloid Leukemia; Late Relapse of Acute Myeloid Leukemia; Recurrent Adult Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia; Blastic Plasmacytoid Dendritic Cell Neoplasm; Acute Myeloid Leukemia; Adult Acute Lymphoblastic Leukemia; Interleukin-3 Receptor Subunit Alpha Positive; Minimal Residual Disease; Refractory Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia

Over-expression of Thioredoxin-1 mediates growth, survival, and chemoresistance and is a druggable target in diffuse large B-cell lymphoma

PubMed Central

Li, Changping; Thompson, Michael A.; Tamayo, Archito T.; Zuo, Zhuang; Lee, John; Vega, Francisco; Ford, Richard J.; Pham, Lan V.

2012-01-01

Diffuse Large B cell lymphomas (DLBCL) are the most prevalent of the non-Hodgkin lymphomas and are currently initially treated fairly successfully, but frequently relapse as refractory disease, resulting in poor salvage therapy options and short survival. The greatest challenge in improving survival of DLBCL patients is overcoming chemo-resistance, whose basis is poorly understood. Among the potential mediators of DLBCL chemo-resistance is the thioredxoin (Trx) family, primarily because Trx family members play critical roles in the regulation of cellular redox homeostasis, and recent studies have indicated that dysregulated redox homeostasis also plays a key role in chemoresistance. In this study, we showed that most of the DLBCL-derived cell lines and primary DLBCL cells express higher basal levels of Trx-1 than normal B cells and that Trx-1 expression level is associated with decreased patients survival. Our functional studies showed that inhibition of Trx-1 by small interfering RNA or a Trx-1 inhibitor (PX-12) inhibited DLBCL cell growth, clonogenicity, and also sensitized DLBCL cells to doxorubicin-induced cell growth inhibition in vitro. These results indicate that Trx-1 plays a key role in cell growth and survival, as well as chemoresistance, and is a potential target to overcome drug resistance in relapsed/refractory DLBCL. PMID:22447839

The future of small molecule inhibitors in lymphoma.

PubMed

Gerecitano, John

2009-09-01

For the many patients with lymphoma that has relapsed after and/or has become refractory to existing treatments, the development of novel therapeutics is imperative. Investigation into intracellular processes that are dysregulated during lymphomagenesis has uncovered several new potential targets for anticancer agents. Although monoclonal antibodies and other immunotherapeutics have led to dramatic advances in the treatment of patients with lymphoma, the parallel development of small molecule inhibitors has been equally exciting. These agents, whose small size allows direct entry into tumor cells, can target distinct proteins or complexes, thereby disrupting molecular processes on which neoplastic cells depend for survival and growth. This review surveys the published literature on many of these new targeted molecules, focusing on some of the most promising agents for which phase 2 data currently exist. It also explores the potential for incorporating these agents into broader multidrug regimens.

Alisertib in Combination With Vorinostat in Treating Patients With Relapsed or Recurrent Hodgkin Lymphoma, B-Cell Non-Hodgkin Lymphoma, or Peripheral T-Cell Lymphoma

ClinicalTrials.gov

2018-04-10

Adult B Acute Lymphoblastic Leukemia; Adult T Acute Lymphoblastic Leukemia; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-Cell Lymphoma; Chronic Lymphocytic Leukemia; Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue; Hepatosplenic T-Cell Lymphoma; Intraocular Lymphoma; Lymphomatous Involvement of Non-Cutaneous Extranodal Site; Mature T-Cell and NK-Cell Non-Hodgkin Lymphoma; Nodal Marginal Zone Lymphoma; Primary Cutaneous B-Cell Non-Hodgkin Lymphoma; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-Cell Leukemia/Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides and Sezary Syndrome; Recurrent Non-Hodgkin Lymphoma; Recurrent Primary Cutaneous T-Cell Non-Hodgkin Lymphoma; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Small Intestinal Lymphoma; Splenic Marginal Zone Lymphoma; T-Cell Large Granular Lymphocyte Leukemia; Testicular Lymphoma; Waldenstrom Macroglobulinemia

Towards an understanding of the biology and targeted treatment of paediatric relapsed acute lymphoblastic leukaemia.

PubMed

Irving, Julie A E

2016-03-01

Acute lymphoblastic leukaemia is the most common childhood cancer and for those children who relapse, prognosis is poor and new therapeutic strategies are needed. Recurrent pathways implicated in relapse include RAS, JAK STAT, cell cycle, epigenetic regulation, B cell development, glucocorticoid response, nucleotide metabolism and DNA repair. Targeting these pathways is a rational therapeutic strategy and may deliver novel, targeted therapies into the clinic. Relapse often stems from a minor clone present at diagnosis and thus analysis of persisting leukaemia during upfront therapy may allow targeted drug intervention to prevent relapse. © 2015 John Wiley & Sons Ltd.

Predictors of relapses in ANCA-associated small vessel vasculitis with kidney involvement

PubMed Central

Iuliana, Andreiana; Simona, Stancu; Andreea, Avram; Ludmila, Taran; Gabriel, Mircescu

2014-01-01

Rationale: Almost half of the patients with anti-neutrophil cytoplasmic antibodies (ANCA) associated small vessel vasculitis relapse and their characteristics are still to be defined Objective: We aimed to evaluate the relapse rate and its determinants in a cohort of patients with ANCA associated vasculitis with severe kidney involvement. Methods and results: This is a retrospective study which included 100 patients consecutively admitted in a Nephrology Department with crescentic pauci-immune glomerulonephritis diagnosed by kidney biopsy. ANCAs were assessed by capture ELISA or indirect immunofluorescence (IFI). Patients were followed for a median period of 3.2 [0.1; 5.5] years. The median age was 61.6 years. The clinical condition at presentation was severe (median BVAS 16 and BVAS over 21 in one quarter of patients), mostly because of general, kidney and lung scores. Median creatinine was 5.7 mg/dL and 17% of the patients needed temporary dialysis. Eight patients relapsed (13.8%): one in the lung and seven in the kidney. The median time to relapse was 11.3 [9.2; 19.9] months. None of the investigated parameters allowed for differentiating patients who relapsed from those who did not, except higher hematuria in those who relapsed. Discussion: In our patients with ANCA vasculitis and severe kidney involvement, the relapse rate is low and hematuria but not ANCA specificity or clinical presentation allows the prediction of relapse. PMID:27057255

Efficacy of a cancer vaccine against ALK-rearranged lung tumors

PubMed Central

Voena, Claudia; Di Giacomo, Filomena; Longo, Dario Livio; Castella, Barbara; Merlo, Maria Elena Boggio; Ambrogio, Chiara; Wang, Qi; Minero, Valerio Giacomo; Poggio, Teresa; Martinengo, Cinzia; D'Amico, Lucia; Panizza, Elena; Mologni, Luca; Cavallo, Federica; Altruda, Fiorella; Butaney, Mohit; Capelletti, Marzia; Inghirami, Giorgio; Jänne, Pasi A.; Chiarle, Roberto

2015-01-01

Non-small cell lung cancer (NSCLC) harboring chromosomal rearrangements of the anaplastic lymphoma kinase (ALK) gene is treated with ALK tyrosine kinase inhibitors (TKIs), but is successful for only a limited amount of time; most cases relapse due to the development of drug resistance. Here we show that a vaccine against ALK induced a strong and specific immune response that both prophylactically and therapeutically impaired the growth of ALK-positive lung tumors in mouse models. The ALK vaccine was efficacious also in combination with ALK TKI treatment and significantly delayed tumor relapses after TKI suspension. We found that lung tumors containing ALK rearrangements induced an immunosuppressive microenvironment, regulating the expression of PD-L1 on the surface of lung tumor cells. High PD-L1 expression reduced ALK vaccine efficacy, which could be restored by administration of anti-PD-1 immunotherapy. Thus, combinations of ALK vaccine with TKIs and immune checkpoint blockade therapies might represent a powerful strategy for the treatment of ALK-driven NSCLC. PMID:26419961

Chemoimmunotherapy of small cell bronchogenic carcinoma with VP-16-213, ifosfamide, vincristine, adriamycin, and Corynebacterium parvum

DOE Office of Scientific and Technical Information (OSTI.GOV)

Valdivieso, M.; Tenczynski, T.F.; Rodriguez, V.

1981-07-15

Thirty-five consecutive patients with small cell bronchogenic carcinoma (SCBC) received chemoimmunotherapy with VP-16-213, Ifosfamide, vincristine, Adriamycin, and Corynebacterium parvum. Of 33 evaluable patients, 26 (79%) responded with complete (55%) or partial (24%) remissions. Complete remissions were more common among patients with limited disease (11/14 patients, 79%) compared with those with extensive disease (7/19 patients, 37%) and among patients (11/14 patients, 79%) compared with those with extensive disease (7/19 patients, 37%) and among patients who were ambulatory prior to therapy (16/25 patients, 64%) compared with those who were nonambulatory (2/8 patients, 25%). Myelosuppression consisted primarily of neutropenia. Eight percent of themore » treatment courses in 29% of the patients were associated with hematuria and/or documented episodes of infection during neutropenia. There were three deaths possibly related to treatment, in two of which there was no evidence of disease at post-mortem examination. Six patients relapsed in the central nervous system (CNS). In four instances, CNS relapse was the only site of tumor progression. Central nervous system relapse was more common among evaluable patients who did not receive prophylactic brain irradiation (5/17 patients, 29%, vs. 1/15 patients, 7%; P . 0.23). The median survival duration for all patients was 63 weeks, being slightly longer for patients with limited disease than for those with extensive disease (70.9 weeks vs. 56 weeks; P . 0.18). This was also true for patients who achieved complete rather than partial remissions (71 weeks vs. 50 weeks; P . 0.09). Patients receiving prophylactic brain irradiation experienced longer survival (100.8 weeks vs. 48 weeks; P . 0.01).« less

Isolated Brain Metastases as the First Relapse After the Curative Surgical Resection in Non-Small-Cell Lung Cancer Patients With an EGFR Mutation.

PubMed

Sadoyama, Shinko; Sekine, Akimasa; Satoh, Hiroaki; Iwasawa, Tae; Kato, Terufumi; Ikeda, Satoshi; Sata, Masafumi; Baba, Tomohisa; Tabata, Erina; Minami, Yuko; Nemoto, Kenji; Hayashihara, Kenji; Saito, Takefumi; Okudela, Koji; Ohashi, Kenichi; Tajiri, Michihiko; Ogura, Takashi

2018-01-01

The aim of this study was to clarify the incidence and disease behavior of brain metastases (BM) without extracranial disease (ie, isolated BM) as the first relapse after curative surgery in non-small-cell lung cancer (NSCLC) patients, analyzed according to epidermal growth factor receptor (EGFR) mutation status. A review of the medical charts of consecutive NSCLC patients diagnosed between 2005 and 2016 with BM as the first relapse after curative surgery was performed. Among 1191 patients evaluated for EGFR mutation status, 28 patients who met the inclusion criteria were divided into 2 groups: EGFR mutation group (16 patients) and wild type group (12 patients). At BM diagnosis, the EGFR-mutation group tended to have more commonly isolated BM compared with that in the wild type group (11 of 16 vs. 3 of 12; P = .054). In the EGFR mutation group, the patients with isolated BM showed longer overall survival than those with non-isolated BM (39.6 vs. 18.7 months; P = .038). Notably, isolated BM in the EGFR mutation group was neurologically asymptomatic in 10 of the 11 patients. With regard to upfront treatment for isolated BM in the EGFR mutation group, 10 of 11 patients were treated with only cranial radiotherapy without EGFR tyrosine kinase inhibitors, but two-thirds of the patients (7 of 11; 64%) developed extracranial disease during the study period. In curatively resected NSCLC patients with EGFR mutation, isolated BM would be correlated with better prognosis, but regarded as a precursor to systemic disease. Because isolated BM can be neurologically asymptomatic, it would be important to periodically perform cranial evaluation to detect isolated BM. Copyright © 2017 Elsevier Inc. All rights reserved.

Cabazitaxel Versus Topotecan in Patients with Small-Cell Lung Cancer with Progressive Disease During or After First-Line Platinum-Based Chemotherapy.

PubMed

Evans, Tracey L; Cho, Byoung Chul; Udud, Katalin; Fischer, Juergen R; Shepherd, Frances A; Martinez, Pablo; Ramlau, Rodryg; Syrigos, Konstantinos N; Shen, Liji; Chadjaa, Mustapha; Wolf, Martin

2015-08-01

Patients with small-cell lung cancer (SCLC) typically respond well to initial chemotherapy. However, relapse invariably occurs, and topotecan, the only approved second-line treatment option, has limited efficacy. Taxanes have activity in SCLC, and cabazitaxel is a second-generation taxane with potential for enhanced activity in chemorefractory malignancies. Patients with SCLC who relapsed after initial platinum-based chemotherapy were randomly assigned to receive cabazitaxel 25 mg/m every 21 days or topotecan 1.5 mg/m on days 1-5 every 21 days. Two patient subgroups, defined by chemosensitive and chemo-resistant/refractory disease, were assessed in combination and separately. The safety profile of cabazitaxel and topotecan was consistent with previous studies, and despite considerable toxicity in both arms, no new safety concerns were identified. Patients receiving cabazitaxel had inferior progression-free survival compared with topotecan (1.4 versus 3.0 months, respectively; two-sided p < 0.0001; hazard ratio = 2.17, 95% confidence interval = 1.563-3.010), and results were similar in both the chemosensitive and chemorefractory subgroups. No complete responses were observed in either arm, and no partial responses were observed in the cabazitaxel group. The partial response rate in the topotecan arm was 10%. Median overall survival was 5.2 months in the cabazitaxel arm and 6.8 months in the topotecan arm (two-sided p = 0.0125; hazard ratio = 1.57, 95% confidence interval = 1.10-2.25). Cabazitaxel, a next-generation taxane, had inferior efficacy when compared with standard-dose topotecan in the treatment of relapsed SCLC. Topotecan remains a suboptimal therapy, and continued efforts to develop improved second-line treatments are warranted.

Reduced hematopoietic stem cell frequency predicts outcome in acute myeloid leukemia.

PubMed

Wang, Wenwen; Stiehl, Thomas; Raffel, Simon; Hoang, Van T; Hoffmann, Isabel; Poisa-Beiro, Laura; Saeed, Borhan R; Blume, Rachel; Manta, Linda; Eckstein, Volker; Bochtler, Tilmann; Wuchter, Patrick; Essers, Marieke; Jauch, Anna; Trumpp, Andreas; Marciniak-Czochra, Anna; Ho, Anthony D; Lutz, Christoph

2017-09-01

In patients with acute myeloid leukemia and low percentages of aldehyde-dehydrogenase-positive cells, non-leukemic hematopoietic stem cells can be separated from leukemic cells. By relating hematopoietic stem cell frequencies to outcome we detected poor overall- and disease-free survival of patients with low hematopoietic stem cell frequencies. Serial analysis of matched diagnostic and follow-up samples further demonstrated that hematopoietic stem cells increased after chemotherapy in patients who achieved durable remissions. However, in patients who eventually relapsed, hematopoietic stem cell numbers decreased dramatically at the time of molecular relapse demonstrating that hematopoietic stem cell levels represent an indirect marker of minimal residual disease, which heralds leukemic relapse. Upon transplantation in immune-deficient mice cases with low percentages of hematopoietic stem cells of our cohort gave rise to leukemic or no engraftment, whereas cases with normal hematopoietic stem cell levels mostly resulted in multi-lineage engraftment. Based on our experimental data, we propose that leukemic stem cells have increased niche affinity in cases with low percentages of hematopoietic stem cells. To validate this hypothesis, we developed new mathematical models describing the dynamics of healthy and leukemic cells under different regulatory scenarios. These models suggest that the mechanism leading to decreases in hematopoietic stem cell frequencies before leukemic relapse must be based on expansion of leukemic stem cells with high niche affinity and the ability to dislodge hematopoietic stem cells. Thus, our data suggest that decreasing numbers of hematopoietic stem cells indicate leukemic stem cell persistence and the emergence of leukemic relapse. Copyright© 2017 Ferrata Storti Foundation.

Adjuvant and induction chemotherapy in non-small cell lung cancer.

PubMed

Pirker, R; Malayeri, R; Huber, H

1999-01-01

About 25%-30% of patients with non-small cell lung cancer can be resected with curative intent. However, systemic relapses occur in up to 70% of these patients. Thus, postoperative adjuvant chemotherapy was evaluated in several randomised trials but the results of these trials were inconclusive with a survival benefit only in some trials. Shortcomings of these trials included low number of patients, poor patient compliance and inadequate chemotherapy protocols. A recent meta-analysis suggested an absolute survival benefit of 5% at five years for postoperative cisplatin-based chemotherapy as compared to surgery alone. Thus adjuvant chemotherapy with both improved chemotherapy protocols and improved anti-emetics is currently re-evaluated in several randomised trials on large patient populations.

Relapse risk after autologous stem cell transplantation in patients with lymphoma based on CD34+ cell dose.

PubMed

Sorigue, Marc; Sancho, Juan-Manuel; Morgades, Mireia; Moreno, Miriam; Grífols, Juan-Ramon; Alonso, Eva; Juncà, Jordi; Ferrà, Christelle; Batlle, Montserrat; Vives, Susana; Motlló, Cristina; García-Caro, Montserrat; Navarro, Jose-Tomás; Millà, Fuensanta; Feliu, Evarist; Ribera, Josep-María

2017-04-01

It is unclear whether higher CD34 + cell doses infused for ASCT have any influence on survival or relapse in patients with lymphoma. We analyzed the correlation of infused CD34 + cell dose with relapse, survival, and hematopoietic recovery in 146 consecutive patients undergoing ASCT for lymphoma. Higher doses (>5 × 10 6 /kg) were significantly correlated with earlier hematopoietic recovery, fewer infectious episodes, lower transfusion needs. No differences were observed in lymphoma outcomes (4-year relapse incidence of 38% [95%CI: 29%-48%] in the lower dose group versus 51% [95%CI: 30%-69%] in the higher dose group, 10-year OS probabilities of 58% [95%CI: 48%-68%] versus 75% [95%CI: 59%-91%], 10-year DFS probabilities of 47% [95%CI: 37%-57%] versus 42% [95%CI: 23%-61%], p = NS for all outcomes). In this series, a higher infused CD34 + cell dose did not correlate with survival or relapse but correlated with earlier hematopoietic recovery and lower resource consumption.

Partial T-cell depletion improves the composite endpoint graft-versus-host disease-free, relapse-free survival after allogeneic hematopoietic stem cell transplantation.

PubMed

Simonetta, Federico; Masouridi-Levrat, Stavroula; Beauverd, Yan; Tsopra, Olga; Tirefort, Yordanka; Koutsi, Aikaterini; Stephan, Caroline; Polchlopek-Blasiak, Karolina; Pradier, Amandine; Dantin, Carole; Ansari, Marc; Roosnek, Eddy; Chalandon, Yves

2018-03-01

Graft-versus-host disease (GvHD)-free, relapse-free survival (GRFS) is a recently reported composite endpoint that allows to simultaneously estimate risk of death, relapse and GvHD after allogeneic hematopoietic stem cell transplantation (HSCT). In this retrospective study comprising 333 patients transplanted for hematologic malignancies, we compared GRFS in patients receiving partial T-cell-depleted (pTCD) grafts with patients receiving T-cell-replete grafts (No-TCD). pTCD was associated with a significantly improved GRFS. The beneficial effect of pTCD on GRFS remained highly significant in multivariable analysis taking into account clinical factors differing between patient groups. We observed no effect of pTCD on overall survival, progression-free survival, and relapse cumulative incidence, while non-relapse mortality cumulative incidence was significantly lower in patients receiving pTCD. The results of our retrospective analysis suggest that pTCD could improve GRFS in allogeneic HSCT recipients without significantly affecting OS and PFS, thus improving patients' quality of life without impairing the curative potential of allogeneic HSCT.

The GHSG Approach to Treating Hodgkin's Lymphoma.

PubMed

Bröckelmann, Paul J; Engert, Andreas

2015-09-01

Hodgkin's lymphoma (HL) is a relatively rare disease accounting for 15 % of all lymphoma. This disease has developed from an incurable disease to the adult malignancy with the most favorable prognosis. With current therapeutic approaches consisting of polychemo- and small-field radiotherapy, up to 80 % of all patients can be cured long term. In refractory or relapsed HL, intensified treatment including high-dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT) is associated with progression-free survival (PFS) of 50 %. Evaluation of novel drugs in multiple relapsed or refractory cases, better treatment options for elderly patients and reducing treatment-related side effects are the main focus of current research. Recent clinical developments and future approaches in the treatment of HL will be discussed in this review.

Outcome of and prognostic factors for relapse in children and adolescents with mature B-cell lymphoma and leukemia treated in three consecutive prospective "Lymphomes Malins B" protocols. A Société Française des Cancers de l'Enfant study.

PubMed

Jourdain, Anne; Auperin, Anne; Minard-Colin, Véronique; Aladjidi, Nathalie; Zsiros, Josef; Coze, Carole; Gandemer, Virginie; Bertrand, Yves; Leverger, Guy; Bergeron, Christophe; Michon, Jean; Patte, Catherine

2015-06-01

To describe relapsed B-cell lymphoma or leukemia in children/adolescents treated with a "Lymphomes Malins B" regimen and their outcome and to identify prognostic factors for survival, we studied relapses in the LMB89, 96 and 2001 studies of the Société Française d'Oncologie Pédiatrique (Société Française des Cancers de l'Enfant). Therapeutic guidelines at relapse were to obtain a second complete remission and to consolidate the remission with high-dose chemotherapy followed by autologous stem-cell transplantation. Between July 1989 and March 2007, 67 patients of 1322 (5%) relapsed: 57 had Burkitt lymphoma and 10 had large-cell histology. Three patients were initially treated in risk group A, 41 in group B and 23 in group C. Thirty-three patients had a relapse in one site (15 in the central nervous system) and 34 at multiple sites. Sixty-five patients received salvage chemotherapy and 33 achieved complete remission. Forty-one patients also received high-dose chemotherapy followed by autologous (n=33) or allogeneic (n=8) transplantation. With a median follow-up of 6.4 years, the 5-year survival rate was 29.9%. Nineteen patients were still alive, all but one (group A) received consolidation treatment. Multivariate analysis showed the following factors to be significantly associated with better survival: relapse at one site (P=0.0006), large-cell histology (P=0.012), initial prognostic group A or B with lactate dehydrogenase level below twice the normal value (P=0.005), and time to relapse more than 6 months (P=0.04). Copyright© Ferrata Storti Foundation.

Durable responses to ibrutinib in patients with relapsed CLL after allogeneic stem cell transplantation.

PubMed

Link, C S; Teipel, R; Heidenreich, F; Rücker-Braun, E; Schmiedgen, M; Reinhardt, J; Oelschlägel, U; von Bonin, M; Middeke, J M; Muetherig, A; Trautmann-Grill, K; Platzbecker, U; Bornhäuser, M; Schetelig, J

2016-06-01

Ibrutinib, a recently approved inhibitor of Bruton's tyrosine kinase (BTK), has shown great efficacy in patients with high-risk CLL. Nevertheless, there are few data regarding its use in patients who relapsed after allogeneic stem cell transplantation (alloSCT). We report clinical data from five CLL patients treated with ibrutinib for relapse after first or even second allogeneic transplantation. Additionally, we performed analyses on cytokine levels and direct measuring of CD4 Th1 and CD4 Th2 cells to evaluate possible clinically relevant immunomodulatory effects of ibrutinib. All patients achieved partial responses including one minimal residual disease (MRD)-negative remission. Within 1 year of follow-up, no relapse was observed. One patient died of severe pneumonia while on ibrutinib treatment. Beside this, no unexpected adverse events were observed. Flow cytometry and analyses of T cell-mediated cytokine levels (IL10 and TNFα) did not reveal substantial changes in T-cell distribution in favor of a CD4 Th1 T-cell shift in our patients. No acute exacerbation of GvHD was reported. In conclusion, these results support further evaluation of ibrutinib in CLL patients relapsing after alloSCT.

Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia

PubMed Central

Porter, David L.; Hwang, Wei-Ting; Frey, Noelle V.; Lacey, Simon F.; Shaw, Pamela A.; Loren, Alison W.; Bagg, Adam; Marcucci, Katherine T.; Shen, Angela; Gonzalez, Vanessa; Ambrose, David; Grupp, Stephan A.; Chew, Anne; Zheng, Zhaohui; Milone, Michael C.; Levine, Bruce L.; Melenhorst, Jan J.; June, Carl H.

2018-01-01

Patients with multiply relapsed or refractory chronic lymphocytic leukemia (CLL) have a poor prognosis. Chimeric antigen receptor (CAR)–modified T cells targeting CD19 have the potential to improve on the low complete response rates with conventional therapies by inducing sustained remissions in patients with refractory B cell malignancies. We previously reported preliminary results on three patients with refractory CLL. We report the mature results from our initial trial using CAR-modified T cells to treat 14 patients with relapsed and refractory CLL. Autologous T cells transduced with a CD19-directed CAR (CTL019) lentiviral vector were infused into patients with relapsed/refractory CLL at doses of 0.14 × 108 to 11 × 108 CTL019 cells (median, 1.6 × 108 cells). Patients were monitored for toxicity, response, expansion, and persistence of circulating CTL019 T cells. The overall response rate in these heavily pretreated CLL patients was 8 of 14 (57%), with 4 complete remissions (CR) and 4 partial remissions (PR). The in vivo expansion of the CAR T cells correlated with clinical responses, and the CAR T cells persisted and remained functional beyond 4 years in the first two patients achieving CR. No patient in CR has relapsed. All responding patients developed B cell aplasia and experienced cytokine release syndrome, coincident with T cell proliferation. Minimal residual disease was not detectable in patients who achieved CR, suggesting that disease eradication may be possible in some patients with advanced CLL. PMID:26333935

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang Xinxing; Xie Conghua; Xu Yong

Purpose: To evaluate the clinical outcome of salvage treatment for patients with relapsed natural killer (NK)/T-cell lymphoma, nasal type. Methods and Materials: Forty-four patients who had achieved complete response during initial treatment and experienced histologically proven relapse were reviewed. Twenty-nine of them received salvage treatment with radiotherapy (RT) alone (n = 7), chemotherapy (CT) alone (n = 10), or both RT and CT (n = 12); the other 15 patients received best supportive care alone. Results: The estimated 5-year overall survival (OS) rate for patients with or without salvage treatment was 37.8% vs. 0 (p < 0.0001), respectively. Salvage CTmore » did not improve survival of relapsed Stage IE and IIE patients. Among relapsed Stage IIIE and IVE patients who received salvage treatment, RT developed significantly better survival when compared with that of non-RT (1-year OS, 62.5% vs. 0, p = 0.006). Relapsed Ann Arbor stage and receiving salvage treatment were found to be significant factors influencing OS at both univariate and multivariate levels. Conclusions: Salvage treatment improved survival in patients with relapsed NK/T-cell lymphoma, nasal type. Salvage RT may play an important role in salvage treatment of relapsed extranodal NK/T-cell lymphoma.« less

Relapsed Acute Promyelocytic Leukemia Lacks "Classic" Leukemic Promyelocyte Morphology and Can Create Diagnostic Challenges.

PubMed

Dayton, Vanessa J; McKenna, Robert W; Yohe, Sophia L; Dolan, Michelle M; Courville, Elizabeth; Alvarez, Harold; Linden, Michael A

2017-01-01

Although current therapies for acute promyelocytic leukemia (APL), such as all- trans retinoic acid and arsenic trioxide, usually result in remission, some patients relapse. Early recognition of relapse is critical for prompt intervention. In this study, we systematically reviewed morphologic, immunophenotypic, and cytogenetic findings in paired diagnostic and relapsed APL cases and describe and quantify the changes in blast morphology at relapse. By electronic database search, we identified eight paired diagnostic and relapsed APL cases for which peripheral blood or bone marrow smears were available for review. For two cases, diagnostic material was available for relapse after hematopoietic cell transplantation. Neoplastic hypergranular or microgranular promyelocytes with indented or bivalve nuclei predominated at diagnosis in all patients. Most patients had undifferentiated blasts at relapse and/or hypergranular blast equivalents with round to oval nuclei. Classic acute promyelocytic leukemia cells with bivalve nuclei and bundles of cytoplasmic Auer rods were easily identifiable in fewer than half of cases at diagnosis and rare to absent in all relapsed cases. Morphologic features of relapsed APL overlap with other types of acute myeloid leukemia, creating diagnostic challenges, especially if no history is available when relapsing patients seek treatment for care. © American Society for Clinical Pathology, 2017. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

Outcomes of diffuse large B-cell lymphoma patients relapsing after autologous stem cell transplantation: an analysis of patients included in the CORAL study.

PubMed

Van Den Neste, E; Schmitz, N; Mounier, N; Gill, D; Linch, D; Trneny, M; Bouadballah, R; Radford, J; Bargetzi, M; Ribrag, V; Dührsen, U; Ma, D; Briere, J; Thieblemont, C; Bachy, E; Moskowitz, C H; Glass, B; Gisselbrecht, C

2017-02-01

In the CORAL study, 255 chemosensitive relapses with diffuse large B-cell lymphoma (DLBCL) were consolidated with autologous stem cell transplantation (ASCT), and 75 of them relapsed thereafter. The median time between ASCT and progression was 7.1 months. The median age was 56.1 years; tertiary International Prognosis Index (tIPI) observed at relapse was 0-2 in 71.6% of the patients and >2 in 28.4%. The overall response rate to third-line chemotherapy was 44%. The median overall survival (OS) was 10.0 months (median follow-up: 32.8 months). Thirteen patients received an allogeneic SCT, and three a second ASCT. The median OS was shorter among patients who relapsed <6 months (5.7 months) compared with those relapsing ⩾12 months after ASCT (12.6 months, P=0.0221). The median OS in patients achieving CR, PR or no response after the third-line regimen was 37.7 (P<0.0001), 10.0 (P=0.03) and 6.3 months, respectively. The median OS varied according to tIPI: 0-2: 12.6 months and >2: 5.3 months (P=0.0007). In multivariate analysis, tIPI >2, achievement of response and remission lasting <6 months predicted the OS. This report identifies the prognostic factors for DLBCL relapsing after ASCT and thus helps to select patients for experimental therapy.

Treating Multiply Relapsed or Refractory Hairy Cell Leukemia

Cancer.gov

In this trial, patients with hairy cell leukemia who have not responded or relapsed after initial chemotherapy will be randomly assigned to receive rituximab combined with either pentostatin or bendamustine.

Novel therapeutic options for relapsed hairy cell leukemia.

PubMed

Jain, Preetesh; Polliack, Aaron; Ravandi, Farhad

2015-01-01

The majority of patients with hairy cell leukemia (HCL) achieve a response to therapy with cladribine or pentostatin with or without rituximab. However, late relapses can occur. Treatment of relapsed HCL can be difficult due to a poor tolerance to chemotherapy, increased risk of infections and decreased responsiveness to chemotherapy. The identification of BRAFV600E mutations and the role of aberrant MEK kinase and Bruton's tyrosine kinase (BTK) pathways in the pathogenesis of HCL have helped to develop novel targeted therapies for these patients. Currently, the most promising therapeutic strategies for relapsed or refractory HCL include recombinant immunoconjugates targeting CD22 (e.g. moxetumomab pasudotox), BRAF inhibitors such as vemurafenib and B cell receptor signaling kinase inhibitors such as ibrutinib. Furthermore, the VH4-34 molecular variant of classic HCL has been identified to be less responsive to chemotherapy. Herein, we review the results of the ongoing clinical trials and potential future therapies for relapsed/refractory HCL.

Flavopiridol in Treating Children With Relapsed or Refractory Solid Tumors or Lymphomas

ClinicalTrials.gov

2013-07-01

Recurrent Childhood Brain Stem Glioma; Recurrent Childhood Cerebellar Astrocytoma; Recurrent Childhood Cerebral Astrocytoma; Recurrent Childhood Ependymoma; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Liver Cancer; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Malignant Germ Cell Tumor; Recurrent Childhood Medulloblastoma; Recurrent Childhood Rhabdomyosarcoma; Recurrent Childhood Small Noncleaved Cell Lymphoma; Recurrent Childhood Soft Tissue Sarcoma; Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumor; Recurrent Childhood Visual Pathway and Hypothalamic Glioma; Recurrent Childhood Visual Pathway Glioma; Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Recurrent Neuroblastoma; Recurrent Osteosarcoma; Recurrent Retinoblastoma; Recurrent Wilms Tumor and Other Childhood Kidney Tumors; Recurrent/Refractory Childhood Hodgkin Lymphoma; Unspecified Childhood Solid Tumor, Protocol Specific

Study of Safety,Efficacy and Pharmacokinetics of CT-1530 in Patients With Relapsed or Refractory B Cell Non-Hodgkin Lymphoma, Chronic Lymphocytic Leukemia, and Waldenstrom's Macroglobulinemia

ClinicalTrials.gov

2017-07-18

Relapsed or Refractory B Cell Non-Hodgkin Lymphoma; Chronic Lymphocytic Leukemia; Waldenstrom's Macroglobulinemia; Mantle Zone Lymphoma Refractory/Recurrent; Follicle Centre Lymphoma Diffuse; Diffuse Large B Cell Lymphoma

T-cell-replete haploidentical stem cell transplantation is highly efficacious for relapsed and refractory childhood acute leukaemia.

PubMed

Kobayashi, S; Ito, M; Sano, H; Mochizuki, K; Akaihata, M; Waragai, T; Ohara, Y; Hosoya, M; Ohto, H; Kikuta, A

2014-10-01

Despite improvements in first-line therapies, the outcomes of relapsed or refractory childhood acute leukaemia that has not achieved complete remission after relapse, has relapsed after stem cell transplantation (SCT), has primary induction failure and has relapsed with a very unfavourable cytogenetic risk profile, are dismal. We evaluated the feasibility and efficacy of T-cell-replete haploidentical peripheral blood stem cell transplantation (haplo-SCT) with low-dose anti-human thymocyte immunoglobulin (ATG), tacrolimus, methotrexate and prednisolone (PSL) in 14 paediatric patients with high-risk childhood acute leukaemia. All patients achieved complete engraftment. The median time to reaching an absolute neutrophil count of more than 0.5 × 10(9) L(-1) was 14 days. Acute graft-vs-host disease (aGVHD) of grades II-IV and III-IV developed in 10 (71%) and 2 (14%) patients, respectively. Treatment-related mortality and relapse occurred in one (7%) patient and six (43%) patients, respectively. Eleven patients were alive and seven of them were disease-free with a median follow-up of 36 months (range: 30-159 months). The probability of event-free survival after 2 years was 50%. These findings indicate that T-cell-replete haplo-SCT, with low-dose ATG and PSL, provides sustained remission with an acceptable risk of GVHD in paediatric patients with advanced haematologic malignancies. © 2014 The Authors. Transfusion Medicine published by John Wiley & Sons Ltd on behalf of British Blood Transfusion Society.

Evolution of acute myelogenous leukemia stem cell properties after treatment and progression.

PubMed

Ho, Tzu-Chieh; LaMere, Mark; Stevens, Brett M; Ashton, John M; Myers, Jason R; O'Dwyer, Kristen M; Liesveld, Jane L; Mendler, Jason H; Guzman, Monica; Morrissette, Jennifer D; Zhao, Jianhua; Wang, Eunice S; Wetzler, Meir; Jordan, Craig T; Becker, Michael W

2016-09-29

Most cancers evolve over time as patients initially responsive to therapy acquire resistance to the same drugs at relapse. Cancer stem cells have been postulated to represent a therapy-refractory reservoir for relapse, but formal proof of this model is lacking. We prospectively characterized leukemia stem cell populations (LSCs) from a well-defined cohort of patients with acute myelogenous leukemia (AML) at diagnosis and relapse to assess the effect of the disease course on these critical populations. Leukemic samples were collected from patients with newly diagnosed AML before therapy and after relapse, and LSC frequency was assessed by limiting dilution analyses. LSC populations were identified using fluorescent-labeled cell sorting and transplantation into immunodeficient NOD/SCID/interleukin 2 receptor γ chain null mice. The surface antigen expression profiles of pretherapy and postrelapse LSCs were determined for published LSC markers. We demonstrate a 9- to 90-fold increase in LSC frequency between diagnosis and relapse. LSC activity at relapse was identified in populations of leukemic blasts that did not demonstrate this activity before treatment and relapse. In addition, we describe genetic instability and exceptional phenotypic changes that accompany the evolution of these new LSC populations. This study is the first to characterize the evolution of LSCs in vivo after chemotherapy, identifying a dramatic change in the physiology of primitive AML cells when the disease progresses. Taken together, these findings provide a new frame of reference by which to evaluate candidate AML therapies in which both disease control and the induction of more advanced forms of disease should be considered. © 2016 by The American Society of Hematology.

Evolution of acute myelogenous leukemia stem cell properties after treatment and progression

PubMed Central

Ho, Tzu-Chieh; LaMere, Mark; Stevens, Brett M.; Ashton, John M.; Myers, Jason R.; O’Dwyer, Kristen M.; Liesveld, Jane L.; Mendler, Jason H.; Guzman, Monica; Morrissette, Jennifer D.; Zhao, Jianhua; Wang, Eunice S.; Wetzler, Meir; Jordan, Craig T.

2016-01-01

Most cancers evolve over time as patients initially responsive to therapy acquire resistance to the same drugs at relapse. Cancer stem cells have been postulated to represent a therapy-refractory reservoir for relapse, but formal proof of this model is lacking. We prospectively characterized leukemia stem cell populations (LSCs) from a well-defined cohort of patients with acute myelogenous leukemia (AML) at diagnosis and relapse to assess the effect of the disease course on these critical populations. Leukemic samples were collected from patients with newly diagnosed AML before therapy and after relapse, and LSC frequency was assessed by limiting dilution analyses. LSC populations were identified using fluorescent-labeled cell sorting and transplantation into immunodeficient NOD/SCID/interleukin 2 receptor γ chain null mice. The surface antigen expression profiles of pretherapy and postrelapse LSCs were determined for published LSC markers. We demonstrate a 9- to 90-fold increase in LSC frequency between diagnosis and relapse. LSC activity at relapse was identified in populations of leukemic blasts that did not demonstrate this activity before treatment and relapse. In addition, we describe genetic instability and exceptional phenotypic changes that accompany the evolution of these new LSC populations. This study is the first to characterize the evolution of LSCs in vivo after chemotherapy, identifying a dramatic change in the physiology of primitive AML cells when the disease progresses. Taken together, these findings provide a new frame of reference by which to evaluate candidate AML therapies in which both disease control and the induction of more advanced forms of disease should be considered. PMID:27421961

High efficacy and safety of low-dose CD19-directed CAR-T cell therapy in 51 refractory or relapsed B acute lymphoblastic leukemia patients.

PubMed

Pan, J; Yang, J F; Deng, B P; Zhao, X J; Zhang, X; Lin, Y H; Wu, Y N; Deng, Z L; Zhang, Y L; Liu, S H; Wu, T; Lu, P H; Lu, D P; Chang, A H; Tong, C R

2017-12-01

Refractory or relapsed B lymphoblastic leukemia (B-ALL) patients have a dismal outcome with current therapy. We treated 42 primary refractory/hematological relapsed (R/R) and 9 refractory minimal residual disease by flow cytometry (FCM-MRD + ) B-ALL patients with optimized second generation CD19-directed CAR-T cells. The CAR-T-cell infusion dosages were initially ranged from 0.05 to 14 × 10 5 /kg and were eventually settled at 1 × 10 5 /kg for the most recent 20 cases. 36/40 (90%) evaluated R/R patients achieved complete remission (CR) or CR with incomplete count recovery (CRi), and 9/9 (100%) FCM-MRD + patients achieved MRD - . All of the most recent 20 patients achieved CR/CRi. Most cases only experienced mild to moderate CRS. 8/51 cases had seizures that were relieved by early intervention. Twenty three of twenty seven CR/CRi patients bridged to allogeneic hematopoietic stem cell transplantation (allo-HCT) remained in MRD - with a median follow-up time of 206 (45-427) days, whereas 9 of 18 CR/CRi patients without allo-HCT relapsed. Our results indicate that a low CAR-T-cell dosage of 1 × 10 5 /kg, is effective and safe for treating refractory or relapsed B-ALL, and subsequent allo-HCT could further reduce the relapse rate.

Characteristic patterns of relapse after allogeneic hematopoietic SCT for adult T-cell leukemia-lymphoma: a comparative study of recurrent lesions after transplantation and chemotherapy by the Nagasaki Transplant Group.

PubMed

Itonaga, H; Sawayama, Y; Taguchi, J; Honda, S; Taniguchi, H; Makiyama, J; Matsuo, E; Sato, S; Ando, K; Imanishi, D; Imaizumi, Y; Yoshida, S; Hata, T; Moriuchi, Y; Fukushima, T; Miyazaki, Y

2015-04-01

Allogeneic hematopoietic SCT (allo-SCT) is a promising therapy that may provide long-term durable remission for adult T-cell leukemia-lymphoma (ATL) patients; however, the incidence of relapse associated with ATL remains high. To determine the clinical features of these patients at relapse, we retrospectively analyzed tumor lesions in 30 or 49 patients who relapsed following allo-SCT or chemotherapy (CHT), respectively, at three institutions in Nagasaki prefecture between 1997 and 2011. A multivariate analysis revealed that the development of abnormal lymphocytes in the peripheral blood of patients at relapse was less frequent after allo-SCT than after CHT (P<0.001). Furthermore, relapse with a new lesion only in the absence of the primary lesion was more frequent in allo-SCT (P=0.014). Lesions were more frequently observed in the central nervous systems of patients who relapsed with new lesions only (P=0.005). Thus, the clinical manifestation of relapsed ATL was slightly complex, especially in post-transplant patients. Our results emphasized the need to develop adoptive modalities for early and accurate diagnoses of relapsed ATL.

Global map of physical interactions among differentially expressed genes in multiple sclerosis relapses and remissions.

PubMed

Tuller, Tamir; Atar, Shimshi; Ruppin, Eytan; Gurevich, Michael; Achiron, Anat

2011-09-15

Multiple sclerosis (MS) is a central nervous system autoimmune inflammatory T-cell-mediated disease with a relapsing-remitting course in the majority of patients. In this study, we performed a high-resolution systems biology analysis of gene expression and physical interactions in MS relapse and remission. To this end, we integrated 164 large-scale measurements of gene expression in peripheral blood mononuclear cells of MS patients in relapse or remission and healthy subjects, with large-scale information about the physical interactions between these genes obtained from public databases. These data were analyzed with a variety of computational methods. We find that there is a clear and significant global network-level signal that is related to the changes in gene expression of MS patients in comparison to healthy subjects. However, despite the clear differences in the clinical symptoms of MS patients in relapse versus remission, the network level signal is weaker when comparing patients in these two stages of the disease. This result suggests that most of the genes have relatively similar expression levels in the two stages of the disease. In accordance with previous studies, we found that the pathways related to regulation of cell death, chemotaxis and inflammatory response are differentially expressed in the disease in comparison to healthy subjects, while pathways related to cell adhesion, cell migration and cell-cell signaling are activated in relapse in comparison to remission. However, the current study includes a detailed report of the exact set of genes involved in these pathways and the interactions between them. For example, we found that the genes TP53 and IL1 are 'network-hub' that interacts with many of the differentially expressed genes in MS patients versus healthy subjects, and the epidermal growth factor receptor is a 'network-hub' in the case of MS patients with relapse versus remission. The statistical approaches employed in this study enabled us to report new sets of genes that according to their gene expression and physical interactions are predicted to be differentially expressed in MS versus healthy subjects, and in MS patients in relapse versus remission. Some of these genes may be useful biomarkers for diagnosing MS and predicting relapses in MS patients.

Surveillance imaging in mantle cell lymphoma in first remission lacks clinical utility.

PubMed

Guidot, Daniel M; Switchenko, Jeffrey M; Nastoupil, Loretta J; Koff, Jean L; Blum, Kristie A; Maly, Joseph; Flowers, Christopher R; Cohen, Jonathon B

2018-04-01

Mantle cell lymphoma (MCL) is a heterogeneous disease with high relapse rates. Limited data guide the use of surveillance imaging following treatment. We constructed a retrospective cohort from two academic institutions of patients with MCL who completed first-line therapy and underwent follow-up for relapse, analyzing the effect of surveillance imaging on survival. Of 217 patients, 102 had documented relapse, with 38 (37%) diagnosed by surveillance imaging and 64 (63%) by other methods. Relapse diagnosis by surveillance imaging had no significant advantage in overall survival from diagnosis date (hazard ratio [HR] = 0.80, p = .39) or relapse date (HR = 0.72, p = .22). Of 801 surveillance images, PET/CT had a positive predictive value (PPV) of 24% and number needed-to-scan/treat (NNT) of 51 to detect one relapse, and CT had a PPV of 49% and NNT of 24. For MCL after first-line therapy, relapse detection by surveillance imaging was not associated with improved survival and lacks clinical benefit.

MicroRNA-93 inhibits tumor growth and early relapse of human colorectal cancer by affecting genes involved in the cell cycle.

PubMed

Yang, I-Ping; Tsai, Hsiang-Lin; Hou, Ming-Feng; Chen, Ku-Chung; Tsai, Pei-Chien; Huang, Szu-Wei; Chou, Wen-Wen; Wang, Jaw-Yuan; Juo, Suh-Hang Hank

2012-08-01

Colorectal cancer (CRC) is associated with high recurrence and mortality. Because deregulation of microRNAs is associated with CRC development and recurrence, the expression levels of microRNAs can be a simple and reliable biomarker to detect postoperative early relapse, thereby helping physicians to treat high-risk patients more efficiently. We used microRNA arrays and observed that microRNA-93 had substantially different expression levels in early (recurrence within 12 months after surgery) and non-early relapse CRC patients. The replication study, which included 35 early relapse and 42 non-early relapse subjects, further confirmed overexpression of microRNA-93 in non-early relapse samples. The in vitro and in vivo effects of microRNA-93 were investigated by examining cell proliferation, migration and invasion, as well as cell cycles, target-gene expression and xenograft in null mice. Cellular studies showed that the overexpression of microRNA-93 inhibited colon cancer cell proliferation and migration but not invasion. The cell cycle studies also revealed that microRNA-93 caused an accumulation of the G2 population. However, microRNA-93 could not induce cell apoptosis or necrosis. Functional studies showed that microRNA-93 could suppress CCNB1 protein expression leading to cell cycle arrest in the G2 phase. Moreover, microRNA-93 repressed expression of ERBB2, p21 and VEGF, all of which are involved in cell proliferation. MicroRNA-93 also suppressed tumor growth in null mice. This study showed that microRNA-93 can inhibit tumorigenesis and reduce the recurrence of CRC; these findings may have potential clinical applications for predicting the recurrence of CRC.

Co-infusion of haplo-identical CD19-chimeric antigen receptor T cells and stem cells achieved full donor engraftment in refractory acute lymphoblastic leukemia.

PubMed

Cai, Bo; Guo, Mei; Wang, Yao; Zhang, Yajing; Yang, Jun; Guo, Yelei; Dai, Hanren; Yu, Changlin; Sun, Qiyun; Qiao, Jianhui; Hu, Kaixun; Zuo, Hongli; Dong, Zheng; Zhang, Zechuan; Feng, Mingxing; Li, Bingxia; Sun, Yujing; Liu, Tieqiang; Liu, Zhiqing; Wang, Yi; Huang, Yajing; Yao, Bo; Han, Weidong; Ai, Huisheng

2016-11-25

Elderly patients with relapsed and refractory acute lymphoblastic leukemia (ALL) have poor prognosis. Autologous CD19 chimeric antigen receptor-modified T (CAR-T) cells have potentials to cure patients with B cell ALL; however, safety and efficacy of allogeneic CD19 CAR-T cells are still undetermined. We treated a 71-year-old female with relapsed and refractory ALL who received co-infusion of haplo-identical donor-derived CD19-directed CAR-T cells and mobilized peripheral blood stem cells (PBSC) following induction chemotherapy. Undetectable minimal residual disease by flow cytometry was achieved, and full donor cell engraftment was established. The transient release of cytokines and mild fever were detected. Significantly elevated serum lactate dehydrogenase, alanine transaminase, bilirubin and glutamic-oxalacetic transaminase were observed from days 14 to 18, all of which were reversible after immunosuppressive therapy. Our preliminary results suggest that co-infusion of haplo-identical donor-derived CAR-T cells and mobilized PBSCs may induce full donor engraftment in relapsed and refractory ALL including elderly patients, but complications related to donor cell infusions should still be cautioned. Allogeneic CART-19 for Elderly Relapsed/Refractory CD19+ ALL. NCT02799550.

Incidental Prophylactic Nodal Irradiation and Patterns of Nodal Relapse in Inoperable Early Stage NSCLC Patients Treated With SBRT: A Case-Matched Analysis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lao, Louis; Department of Radiation Oncology, Auckland City Hospital, Auckland; Hope, Andrew J.

2014-09-01

Purpose: Reported rates of non-small cell lung cancer (NSCLC) nodal failure following stereotactic body radiation therapy (SBRT) are lower than those reported in the surgical series when matched for stage. We hypothesized that this effect was due to incidental prophylactic nodal irradiation. Methods and Materials: A prospectively collected group of medically inoperable early stage NSCLC patients from 2004 to 2010 was used to identify cases with nodal relapses. Controls were matched to cases, 2:1, controlling for tumor volume (ie, same or greater) and tumor location (ie, same lobe). Reference (normalized to equivalent dose for 2-Gy fractions [EQD2]) point doses atmore » the ipsilateral hilum and carina, demographic data, and clinical outcomes were extracted from the medical records. Univariate conditional logistical regression analyses were performed with variables of interest. Results: Cases and controls were well matched except for size. The controls, as expected, had larger gross tumor volumes (P=.02). The mean ipsilateral hilar doses were 9.6 Gy and 22.4 Gy for cases and controls, respectively (P=.014). The mean carinal doses were 7.0 Gy and 9.2 Gy, respectively (P=.13). Mediastinal nodal relapses, with and without ipsilateral hilar relapse, were associated with mean ipsilateral hilar doses of 3.6 Gy and 19.8 Gy, respectively (P=.01). The conditional density plot appears to demonstrate an inverse dose-effect relationship between ipsilateral hilar normalized total dose and risk of ipsilateral hilar relapse. Conclusions: Incidental hilar dose greater than 20 Gy is significantly associated with fewer ipsilateral hilar relapses in inoperable early stage NSCLC patients treated with SBRT.« less

Pattern of relapse in paediatric acute lymphoblastic leukaemia in a tertiary care unit.

PubMed

Siddiqui, Emad Uddin; Kazi, Sayyeda Ghazala; Habib, Muhammad Irfan; Ahmed Khan, Khalid Mehmood; Zia, Nukhba

2016-08-01

To determine the frequency, site and time to relapse from diagnosis, and to see the relationship of relapse with important prognostic factors. The prospective descriptive observational study was conducted at the National Institute of Child Health, Karachi, June 2005 to May 2007, and comprised newly-diagnosed cases of acute lymphoblastic leukaemia. Bone marrow aspiration was done on reappearance of blast cells in peripheral smear and cerebrospinal fluid. Detailed report was done each time when intra-thecal chemotherapy was given or there were signs and symptoms suggestive of central nervous system relapse. SPSS 12 was used for data analysis. Of the 60 patients enrolled, 4(6.6%) expired and 1(1.7%) was lost to follow-up. Of the 55(91.6%) who comprised the study sample, 35(58%) were males and 25(42%) females. Mean age of relapse was 6.8±3.27 years. Mean time to relapse from diagnosis was 1.3±0.54 years; 12(20%) patients suffered relapse, and of them 5(14%) were boys. Central nervous system relapse in 8(67%) patients was the most common site, with 3(25%) bone-marrow relapses. Out of 12 patient with relapses, 9(75%) had white blood cell count less than 50,000/cm. Relapse in acute lymphoblastic leukaemia was common, although treatment modalities are improving day by day.

CXC chemokine ligand 4 (CXCL4) is predictor of tumour angiogenic activity and prognostic biomarker in non-small cell lung cancer (NSCLC) patients undergoing surgical treatment.

PubMed

Spaks, Artjoms; Svirina, Darja; Spaka, Irina; Jaunalksne, Inta; Breiva, Donats; Tracums, Ilmars; Krievins, Dainis

2016-07-01

To evaluate the association of CXC chemokine ligand 4 (CXCL4) plasma levels with tumour angiogenesis in non-small cell lung cancer (NSCLC) and to assess association of CXCL4 with clinical outcomes. Fifty patients with early stage NSCLC who underwent pulmonary resection. CXCL4 levels were analysed by ELISA. Angiogenesis was assessed by immunohistochemistry, and microvessel density (MVD) count. There was positive correlation between MVD and CXCL4 levels. Patients with higher CXCL4 levels had worse overall and disease-free survival. Plasma levels of CXCL4 are associated with tumour vascularity. Increased CXCL4 levels in NSCLC patients undergoing treatment may indicate active cancer-induced angiogenesis associated with relapse and worse outcome.

Alectinib Dose Escalation Re-induces Central Nervous System Responses in ALK-Positive Non-Small Cell Lung Cancer (NSCLC) Patients Relapsing on Standard Dose Alectinib

PubMed Central

Gainor, Justin F.; Chi, Andrew S.; Logan, Jennifer; Hu, Ranliang; Oh, Kevin S.; Brastianos, Priscilla K.; Shih, Helen A.; Shaw, Alice T.

2015-01-01

The central nervous system (CNS) is an important and increasingly recognized site of treatment failure in ALK-positive, non-small cell lung cancer (NSCLC) patients receiving ALK inhibitors. In this report, we describe two ALK-positive patients who experienced initial improvements in CNS metastases on standard-dose alectinib (600 mg twice daily), but subsequently recurred with symptomatic leptomeningeal metastases. Both patients were dose-escalated to alectinib 900 mg twice daily, resulting in repeat clinical and radiographic responses. Our results suggest that dose intensification of alectinib may be necessary to overcome incomplete ALK inhibition in the CNS and prolong the durability of responses in patients with CNS metastases, particularly those with leptomeningeal carcinomatosis. PMID:26845119

Prognostic Prediction Model for Second Allogeneic Stem-Cell Transplantation in Patients With Relapsed Acute Myeloid Leukemia: Single-Center Report.

PubMed

Park, Sung-Soo; Kim, Hee-Je; Min, Kyoung Il; Min, Gi June; Jeon, Young-Woo; Yoon, Jae-Ho; Yahng, Seung-Ah; Shin, Seung-Hwan; Lee, Sung-Eun; Cho, Byung-Sik; Eom, Ki-Seong; Kim, Yoo-Jin; Lee, Seok; Min, Chang-Ki; Cho, Seok-Goo; Kim, Dong-Wook; Lee, Jong Wook; Min, Woo-Sung

2018-04-01

To identify factors affecting survival outcomes and to develop a prognostic model for second allogeneic stem-cell transplantation (allo-SCT2) for relapsed acute myeloid leukemia (AML) after the first autologous or allogeneic stem-cell transplantation. Seventy-eight consecutive adult AML patients who received allo-SCT2 were analyzed in this retrospective study. The 4-year overall survival (OS) rate was 28.7%. In multivariate analysis, poor cytogenetic risk at diagnosis, circulating blast ≥ 20% at relapse, duration from first transplantation to relapse < 9 months, and failure to achieve morphologic complete remission after allo-SCT2 were factors associated with poor OS. A prognostic model was developed with the following score system: intermediate and poor cytogenetic risk at diagnosis (0.5 and 1 point), peripheral blast ≥ 20% at relapse (1 point), duration from the first transplantation to relapse < 9 months (1 point), and failure to achieve morphologic complete remission after allo-SCT2 (1 point). The model identified 2 subgroups according to the 4-year OS rate: 51.3% in the low-risk group (score < 2) and 2.8% in the high-risk group (score ≥ 2) (P < .001). This prognostic model might be useful to make an appropriate decision for allo-SCT2 in relapsed AML after the first autologous or allogeneic stem-cell transplantation. Copyright © 2018 Elsevier Inc. All rights reserved.

Dual CD19 and CD123 targeting prevents antigen-loss relapses after CD19-directed immunotherapies

PubMed Central

Barrett, David M.; Shestova, Olga; Hofmann, Ted J.; Perazzelli, Jessica; Klichinsky, Michael; Aikawa, Vania; Nazimuddin, Farzana; Kozlowski, Miroslaw; Scholler, John; Lacey, Simon F.; Melenhorst, Jan J.; Morrissette, Jennifer J.D.; Christian, David A.; Hunter, Christopher A.; Kalos, Michael; Porter, David L.; June, Carl H.; Grupp, Stephan A.

2016-01-01

Potent CD19-directed immunotherapies, such as chimeric antigen receptor T cells (CART) and blinatumomab, have drastically changed the outcome of patients with relapsed/refractory B cell acute lymphoblastic leukemia (B-ALL). However, CD19-negative relapses have emerged as a major problem that is observed in approximately 30% of treated patients. Developing approaches to preventing and treating antigen-loss escapes would therefore represent a vertical advance in the field. Here, we found that in primary patient samples, the IL-3 receptor α chain CD123 was highly expressed on leukemia-initiating cells and CD19-negative blasts in bulk B-ALL at baseline and at relapse after CART19 administration. Using intravital imaging in an antigen-loss CD19-negative relapse xenograft model, we determined that CART123, but not CART19, recognized leukemic blasts, established protracted synapses, and eradicated CD19-negative leukemia, leading to prolonged survival. Furthermore, combining CART19 and CART123 prevented antigen-loss relapses in xenograft models. Finally, we devised a dual CAR-expressing construct that combined CD19- and CD123-mediated T cell activation and demonstrated that it provides superior in vivo activity against B-ALL compared with single-expressing CART or pooled combination CART. In conclusion, these findings indicate that targeting CD19 and CD123 on leukemic blasts represents an effective strategy for treating and preventing antigen-loss relapses occurring after CD19-directed therapies PMID:27571406

Central nervous system relapse in peripheral T-cell lymphomas: a Swedish Lymphoma Registry study.

PubMed

Ellin, Fredrik; Landström, Jenny; Jerkeman, Mats; Relander, Thomas

2015-07-02

Central nervous system (CNS) relapse in non-Hodgkin lymphoma (NHL) carries a very poor prognosis. Risk factors and outcome have been studied in aggressive B-cell lymphomas, but very little is known about the risk in peripheral T-cell lymphoma (PTCL). We aimed at analyzing risk factors for CNS involvement at first relapse or progression, as well as the outcome of these patients, in a large population-based cohort of patients with PTCL. Twenty-eight out of 625 patients (4.5%) developed CNS disease over time. In multivariable analysis, disease characteristics at diagnosis independently associated with an increased risk for later CNS involvement were involvement of more than 1 extranodal site (hazard ratio [HR], 2.60; 95% confidence interval [CI], 1.07-6.29; P = .035) and skin (HR, 3.51; 95% CI, 1.26-9.74; P = .016) and gastrointestinal involvement (HR, 3.06; 95% CI, 1.30-7.18; P = .010). The outcome of relapsed/refractory patients was very poor, and CNS involvement was not associated with a significantly worse outcome compared with relapsed/refractory patients without CNS involvement in multivariable analysis (HR, 1.6; 95% CI, 0.96-2.6; P = .074). The results from the present study indicate that CNS relapse in PTCL occurs at a frequency similar to what is seen in aggressive B-cell lymphomas, but the poor outcomes in relapse are largely driven by systemic rather than CNS disease. © 2015 by The American Society of Hematology.

Donor Peripheral Stem Cell Transplant in Treating Patients With Hematolymphoid Malignancies

ClinicalTrials.gov

2016-11-17

Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Nasal Type Extranodal NK/T-cell Lymphoma; Cutaneous B-cell Non-Hodgkin Lymphoma; Extranodal Marginal Zone B-cell Lymphoma; Hepatosplenic T-cell Lymphoma; Intraocular Lymphoma; Nodal Marginal Zone B-cell Lymphoma; Peripheral T-cell Lymphoma; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Relapsing Chronic Myelogenous Leukemia; Splenic Marginal Zone Lymphoma; Waldenstrom Macroglobulinemia

Pomalidomide and Dexamethasone in Treating Patients With Relapsed or Refractory Primary Central Nervous System Lymphoma or Newly Diagnosed or Relapsed or Refractory Intraocular Lymphoma

ClinicalTrials.gov

2017-08-28

B-Cell Lymphoma, Unclassifiable, With Features Intermediate Between Diffuse Large B-Cell Lymphoma and Burkitt Lymphoma; Central Nervous System Lymphoma; Intraocular Lymphoma; Primary Diffuse Large B-Cell Lymphoma of the Central Nervous System; Recurrent Adult Diffuse Large Cell Lymphoma; Retinal Lymphoma

Clonal selection in xenografted human T cell acute lymphoblastic leukemia recapitulates gain of malignancy at relapse.

PubMed

Clappier, Emmanuelle; Gerby, Bastien; Sigaux, François; Delord, Marc; Touzri, Farah; Hernandez, Lucie; Ballerini, Paola; Baruchel, André; Pflumio, Françoise; Soulier, Jean

2011-04-11

Genomic studies in human acute lymphoblastic leukemia (ALL) have revealed clonal heterogeneity at diagnosis and clonal evolution at relapse. In this study, we used genome-wide profiling to compare human T cell ALL samples at the time of diagnosis and after engraftment (xenograft) into immunodeficient recipient mice. Compared with paired diagnosis samples, the xenograft leukemia often contained additional genomic lesions in established human oncogenes and/or tumor suppressor genes. Mimicking such genomic lesions by short hairpin RNA-mediated knockdown in diagnosis samples conferred a selective advantage in competitive engraftment experiments, demonstrating that additional lesions can be drivers of increased leukemia-initiating activity. In addition, the xenograft leukemias appeared to arise from minor subclones existing in the patient at diagnosis. Comparison of paired diagnosis and relapse samples showed that, with regard to genetic lesions, xenograft leukemias more frequently more closely resembled relapse samples than bulk diagnosis samples. Moreover, a cell cycle- and mitosis-associated gene expression signature was present in xenograft and relapse samples, and xenograft leukemia exhibited diminished sensitivity to drugs. Thus, the establishment of human leukemia in immunodeficient mice selects and expands a more aggressive malignancy, recapitulating the process of relapse in patients. These findings may contribute to the design of novel strategies to prevent or treat relapse.

Distinct genetic evolution patterns of relapsing diffuse large B-cell lymphoma revealed by genome-wide copy number aberration and targeted sequencing analysis.

PubMed

Juskevicius, D; Lorber, T; Gsponer, J; Perrina, V; Ruiz, C; Stenner-Liewen, F; Dirnhofer, S; Tzankov, A

2016-12-01

Recurrences of diffuse large B-cell lymphomas (DLBCL) result in significant morbidity and mortality, but their underlying genetic and biological mechanisms are unclear. Clonal relationship in DLBCL relapses so far is mostly addressed by the investigation of immunoglobulin (IG) rearrangements, therefore, lacking deeper insights into genome-wide lymphoma evolution. We studied mutations and copy number aberrations in 20 paired relapsing and 20 non-relapsing DLBCL cases aiming to test the clonal relationship between primaries and relapses to track tumors' genetic evolution and to investigate the genetic background of DLBCL recurrence. Three clonally unrelated DLBCL relapses were identified (15%). Also, two distinct patterns of genetic evolution in clonally related relapses were detected as follows: (1) early-divergent/branching evolution from a common progenitor in 6 patients (30%), and (2) late-divergent/linear progression of relapses in 11 patients (65%). Analysis of recurrent genetic events identified potential early drivers of lymphomagenesis (KMT2D, MYD88, CD79B and PIM1). The most frequent relapse-specific events were additional mutations in KMT2D and alterations of MEF2B. SOCS1 mutations were exclusive to non-relapsing DLBCL, whereas primaries of relapsing DLBCL more commonly displayed gains of 10p15.3-p12.1 containing the potential oncogenes PRKCQ, GATA3, MLLT10 and ABI1. Altogether, our study expands the knowledge on clonal relationship, genetic evolution and mutational basis of DLBCL relapses.

Evodiamine selectively targets cancer stem-like cells through the p53-p21-Rb pathway

DOE Office of Scientific and Technical Information (OSTI.GOV)

Han, Seula; Woo, Jong Kyu; Jung, Yuchae

In spite of the recent improvements, the resistance to chemotherapy/radiotherapy followed by relapse is the main hurdle for the successful treatment of breast cancer, a leading cause of death in women. A small population of breast cancer cells that have stem-like characteristics (cancer stem-like cells; CSLC) may contribute to this resistance and relapse. Here, we report on a component of a traditional Chinese medicine, evodiamine, which selectively targets CSLC of breast cancer cell lines MCF7 and MDAMB 231 at a concentration that does show a little or no cytotoxic effect on bulk cancer cells. While evodiamine caused the accumulation of bulkmore » cancer cells at the G2/M phase, it did not hold CSLC in a specific cell cycle phase but instead, selectively killed CSLC. This was not due to the culture of CSLC in suspension or without FBS. A proteomic analysis and western blotting revealed that evodiamine changed the expression of cell cycle regulating molecules more efficiently in CSLC cells than in bulk cancer cells. Surprisingly, evodiamine selectively activated p53 and p21 and decreased inactive Rb, the master molecules in G1/S checkpoint. These data collectively suggest a novel mechanism involving CSLC-specific targeting by evodiamine and its possible use to the therapy of breast cancer. - Highlights: • Evodiamine selectively kills breast cancer stem like cells at G1 phase. • Evodiamine utilizes different mechanism of cell cycle modulation in CSLC and in bulk cancer cells. • Evodiamine activate the p53, p21 and Rb pathway.« less

CD19 chimeric antigen receptor (CD19 CAR)-redirected adoptive T-cell immunotherapy for the treatment of relapsed or refractory B-cell Non-Hodgkin's Lymphomas.

PubMed

Onea, Alexandra S; Jazirehi, Ali R

2016-01-01

Recovery rates for B-cell Non-Hodgkin's Lymphoma (NHL) are up to 70% with current standard-of-care treatments including rituximab (chimeric anti-CD20 monoclonal antibody) in combination with chemotherapy (R-CHOP). However, patients who do not respond to first-line treatment or develop resistance have a very poor prognosis. This signifies the need for the development of an optimal treatment approach for relapsed/refractory B-NHL. Novel CD19- chimeric antigen receptor (CAR) T-cell redirected immunotherapy is an attractive option for this subset of patients. Anti-CD19 CAR T-cell therapy has already had remarkable efficacy in various leukemias as well as encouraging outcomes in phase I clinical trials of relapsed/refractory NHL. In going forward with additional clinical trials, complementary treatments that may circumvent potential resistance mechanisms should be used alongside anti-CD19 T-cells in order to prevent relapse with resistant strains of disease. Some such supplementary tactics include conditioning with lymphodepletion agents, sensitizing with kinase inhibitors and Bcl-2 inhibitors, enhancing function with multispecific CAR T-cells and CD40 ligand-expressing CAR T-cells, and safeguarding with lymphoma stem cell-targeted treatments. A therapy regimen involving anti-CD19 CAR T-cells and one or more auxiliary treatments could dramatically improve prognoses for patients with relapsed/refractory B-cell NHL. This approach has the potential to revolutionize B-NHL salvage therapy in much the same way rituximab did for first-line treatments.

CD19 chimeric antigen receptor (CD19 CAR)-redirected adoptive T-cell immunotherapy for the treatment of relapsed or refractory B-cell Non-Hodgkin’s Lymphomas

PubMed Central

Onea, Alexandra S; Jazirehi, Ali R

2016-01-01

Recovery rates for B-cell Non-Hodgkin’s Lymphoma (NHL) are up to 70% with current standard-of-care treatments including rituximab (chimeric anti-CD20 monoclonal antibody) in combination with chemotherapy (R-CHOP). However, patients who do not respond to first-line treatment or develop resistance have a very poor prognosis. This signifies the need for the development of an optimal treatment approach for relapsed/refractory B-NHL. Novel CD19- chimeric antigen receptor (CAR) T-cell redirected immunotherapy is an attractive option for this subset of patients. Anti-CD19 CAR T-cell therapy has already had remarkable efficacy in various leukemias as well as encouraging outcomes in phase I clinical trials of relapsed/refractory NHL. In going forward with additional clinical trials, complementary treatments that may circumvent potential resistance mechanisms should be used alongside anti-CD19 T-cells in order to prevent relapse with resistant strains of disease. Some such supplementary tactics include conditioning with lymphodepletion agents, sensitizing with kinase inhibitors and Bcl-2 inhibitors, enhancing function with multispecific CAR T-cells and CD40 ligand-expressing CAR T-cells, and safeguarding with lymphoma stem cell-targeted treatments. A therapy regimen involving anti-CD19 CAR T-cells and one or more auxiliary treatments could dramatically improve prognoses for patients with relapsed/refractory B-cell NHL. This approach has the potential to revolutionize B-NHL salvage therapy in much the same way rituximab did for first-line treatments. PMID:27186412

MK2206 in Treating Younger Patients With Recurrent or Refractory Solid Tumors or Leukemia

ClinicalTrials.gov

2014-04-28

Accelerated Phase Chronic Myelogenous Leukemia; Acute Leukemias of Ambiguous Lineage; Acute Myeloid Leukemia/Transient Myeloproliferative Disorder; Acute Undifferentiated Leukemia; Aggressive NK-cell Leukemia; Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative; Blastic Phase Chronic Myelogenous Leukemia; Blastic Plasmacytoid Dendritic Cell Neoplasm; Childhood Burkitt Lymphoma; Childhood Chronic Myelogenous Leukemia; Childhood Diffuse Large Cell Lymphoma; Childhood Grade III Lymphomatoid Granulomatosis; Childhood Immunoblastic Large Cell Lymphoma; Childhood Nasal Type Extranodal NK/T-cell Lymphoma; Chronic Eosinophilic Leukemia; Chronic Myelomonocytic Leukemia; Chronic Neutrophilic Leukemia; Chronic Phase Chronic Myelogenous Leukemia; Intraocular Lymphoma; Juvenile Myelomonocytic Leukemia; Mast Cell Leukemia; Myeloid/NK-cell Acute Leukemia; Noncutaneous Extranodal Lymphoma; Post-transplant Lymphoproliferative Disorder; Primary Central Nervous System Hodgkin Lymphoma; Primary Central Nervous System Non-Hodgkin Lymphoma; Progressive Hairy Cell Leukemia, Initial Treatment; Prolymphocytic Leukemia; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Childhood Anaplastic Large Cell Lymphoma; Recurrent Childhood Grade III Lymphomatoid Granulomatosis; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Small Noncleaved Cell Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Recurrent/Refractory Childhood Hodgkin Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; Unspecified Childhood Solid Tumor, Protocol Specific; Waldenström Macroglobulinemia

Reduction of Breast Cancer Relapses with Perioperative Non-Steroidal Anti-Inflammatory Drugs: New Findings and a Review

PubMed Central

Retsky, Michael; Demicheli, Romano; Hrushesky, William J.M; Forget, Patrice; Kock, Marc De; Gukas, Isaac; Rogers, Rick A; Baum, Michael; Sukhatme, Vikas; Vaidya, Jayant S

2013-01-01

To explain a bimodal pattern of hazard of relapse among early stage breast cancer patients identified in multiple databases, we proposed that late relapses result from steady stochastic progressions from single dormant malignant cells to avascular micrometastases and then on to growing deposits. However in order to explain early relapses, we had to postulate that something happens at about the time of surgery to provoke sudden exits from dormant phases to active growth and then to detection. Most relapses in breast cancer are in the early category. Recent data from Forget et al. suggest an unexpected mechanism. They retrospectively studied results from 327 consecutive breast cancer patients comparing various perioperative analgesics and anesthetics in one Belgian hospital and one surgeon. Patients were treated with mastectomy and conventional adjuvant therapy. Relapse hazard updated Sept 2011 are presented. A common Non-Steroidal Anti-Inflammatory Drug (NSAID) analgesic used in surgery produced far superior disease-free survival in the first 5 years after surgery. The expected prominent early relapse events in months 9-18 are reduced 5-fold. If this observation holds up to further scrutiny, it could mean that the simple use of this safe, inexpensive and effective anti-inflammatory agent at surgery might eliminate early relapses. Transient systemic inflammation accompanying surgery could facilitate angiogenesis of dormant micrometastases, proliferation of dormant single cells, and seeding of circulating cancer stem cells (perhaps in part released from bone marrow) resulting in early relapse and could have been effectively blocked by the perioperative anti-inflammatory agent. PMID:23992307

Gene Expression Profiling of Acute Lymphoblastic Leukemia in Children with Very Early Relapse.

PubMed

Núñez-Enríquez, Juan Carlos; Bárcenas-López, Diego Alberto; Hidalgo-Miranda, Alfredo; Jiménez-Hernández, Elva; Bekker-Méndez, Vilma Carolina; Flores-Lujano, Janet; Solis-Labastida, Karina Anastacia; Martínez-Morales, Gabriela Bibiana; Sánchez-Muñoz, Fausto; Espinoza-Hernández, Laura Eugenia; Velázquez-Aviña, Martha Margarita; Merino-Pasaye, Laura Elizabeth; García Velázquez, Alejandra Jimena; Pérez-Saldívar, María Luisa; Mojica-Espinoza, Raúl; Ramírez-Bello, Julián; Jiménez-Morales, Silvia; Mejía-Aranguré, Juan Manuel

2016-11-01

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer worldwide. Mexican patients have high mortality rates, low frequency of good prognosis biomarkers (i.e., ETV6-RUNX1) and a high proportion is classified at the time of diagnosis with a high risk to relapse according to clinical features. In addition, very early relapses are more frequently observed than in other populations. The aim of the study was to identify new potential biomarkers associated with very early relapse in Mexican ALL children through transcriptome analysis. Microarray gene expression profiling on bone marrow samples of 54 pediatric ALL patients, collected at time of diagnosis and/or at relapse, was performed. Eleven patients presented relapse within the first 18 months after diagnosis. Affymetrix Human Transcriptome Array 2.0 (HTA 2.0) was used to perform gene expression analysis. Annotation and functional enrichment analyses were carried out using Gene Ontology, KEGG pathway analysis and Ingenuity Pathway Analysis tools. BLVRB, ZCCHC7, PAX5, EBF1, TMOD1 and BLNK were differentially expressed (fold-change >2.0 and p value <0.01) between relapsed and non-relapsed patients. Functional analysis of abnormally expressed genes revealed their important role in cellular processes related to the development of hematological diseases, cancer, cell death and survival and in cell-to-cell signaling interaction. Our data support previous findings showing the relevance of PAX5, EBF1 and ZCCHC7 as potential biomarkers to identify a subgroup of ALL children in high risk to relapse. Copyright © 2016 IMSS. Published by Elsevier Inc. All rights reserved.

Initial experience with CMC-544 (inotuzumab ozogamicin) in pediatric patients with relapsed B-cell acute lymphoblastic leukemia.

PubMed

Rytting, Michael; Triche, Lisa; Thomas, Deborah; O'Brien, Susan; Kantarjian, Hagop

2014-02-01

Survival is poor in pediatric patients with relapsed or refractory acute B-cell lymphoblastic leukemia (ALL) and therapeutic options are limited. CMC-544 (inotuzumab ozogamicin) has shown significant activity in adult patients with relapsed and refractory ALL. We evaluated CMC-544 in pediatric patients with multiply relapsed ALL. Five children 4-15 years old with relapsed, CD 22 positive B-cell ALL were enrolled on a phase II non-randomized trial of CMC-544. CMC-544 was initially administered at 1.3 mg/m(2) every 3 weeks. The dose then increased to 1.8 mg/m(2) every 3 weeks. Subsequently, a weekly schedule of CMC-544 given as 0.8 mg/m(2) on day 1 followed by 0.5 mg/m(2) on days 8 and 15 was administered. All five patients had refractory relapsed B-cell ALL. Lymphoblasts for all patients highly expressed CD22. Four patients had two or more relapses before starting the study drug. One patient achieved a complete remission in the bone marrow and normal peripheral counts, and two patients achieved bone marrow morphologic remission with absolute neutrophils >1,000/µl but platelets <100,000/µl. Two patients had no response to the drug. Toxicities consisted of fever, sepsis, and liver enzyme elevation. Single agent CMC-544 given at the single dose of 1.8 mg/m(2) every 3 weeks or given as a split, weekly dose was generally well tolerated considering the inherent risks in this population of patients and showed promising activity in pediatric patients with relapsed and refractory ALL. © 2013 Wiley Periodicals, Inc.

Genomic and transcriptional landscape of P2RY8-CRLF2-positive childhood acute lymphoblastic leukemia

PubMed Central

Vesely, C; Frech, C; Eckert, C; Cario, G; Mecklenbräuker, A; zur Stadt, U; Nebral, K; Kraler, F; Fischer, S; Attarbaschi, A; Schuster, M; Bock, C; Cavé, H; von Stackelberg, A; Schrappe, M; Horstmann, M A; Mann, G; Haas, O A; Panzer-Grümayer, R

2017-01-01

Children with P2RY8-CRLF2-positive acute lymphoblastic leukemia have an increased relapse risk. Their mutational and transcriptional landscape, as well as the respective patterns at relapse remain largely elusive. We, therefore, performed an integrated analysis of whole-exome and RNA sequencing in 41 major clone fusion-positive cases including 19 matched diagnosis/relapse pairs. We detected a variety of frequently subclonal and highly instable JAK/STAT but also RTK/Ras pathway-activating mutations in 76% of cases at diagnosis and virtually all relapses. Unlike P2RY8-CRLF2 that was lost in 32% of relapses, all other genomic alterations affecting lymphoid development (58%) and cell cycle (39%) remained stable. Only IKZF1 alterations predominated in relapsing cases (P=0.001) and increased from initially 36 to 58% in matched cases. IKZF1’s critical role is further corroborated by its specific transcriptional signature comprising stem cell features with signs of impaired lymphoid differentiation, enhanced focal adhesion, activated hypoxia pathway, deregulated cell cycle and increased drug resistance. Our findings support the notion that P2RY8-CRLF2 is dispensable for relapse development and instead highlight the prominent rank of IKZF1 for relapse development by mediating self-renewal and homing to the bone marrow niche. Consequently, reverting aberrant IKAROS signaling or its disparate programs emerges as an attractive potential treatment option in these leukemias. PMID:27899802

Terminal deoxynucleotidyl transferase (TdT)-negative T-cell lymphoblastic lymphoma with loss of the T-cell lineage-specific marker CD3 at relapse: a rare entity with an aggressive outcome.

PubMed

Hassan, Masroor; Abdullah, Hafez Mohammad Ammar; Wahid, Abdul; Qamar, Muhammad Ashraf

2018-06-08

Terminal deoxynucleotidyl transferase (TdT)-negative T-cell lymphoblastic lymphoma is a variant of T-cell lymphoblastic lymphoma/T-cell lymphoblastic leukaemia. TdT is a marker of immaturity expressed in 90%-95% cases of lymphoblastic lymphoma and useful in differentiating it from other mature lymphomas/leukaemias. It has been associated with poorer response to chemotherapy and a more aggressive outcome. Here we present a case of TdT-negative T-cell lymphoblastic lymphoma in a 28-year-old man who presented with superior vena cava syndrome. The patient was treated with hyper-cyclophosphamide,vincristine, Adriamycin, dexamethasone (CVAD), however unfortunately suffered a relapse 1 year later. A unique feature of our case was that on relapse, the patient lost expression of the T-cell lineage-specific marker CD3, which has previously not been reported in association with TdT-negative T-cell lymphoblastic lymphoma. The patient failed to respond to chemotherapy on his relapse and died. © BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Mesenchymal-Epithelial Transition and Circulating Tumor Cells in Small Cell Lung Cancer.

PubMed

Hamilton, Gerhard; Rath, Barbara

2017-01-01

Cancer patients die of metastatic disease but knowledge regarding individual steps of this complex process of intravasation, spread and extravasation leading to secondary lesions is incomplete. Subpopulations of tumor cells are supposed to undergo an epithelial-mesenchymal transition (EMT), to enter the bloodstream and eventually establish metastases in a reverse process termed mesenchymal-epithelial transition (MET). Small cell lung cancer (SCLC) represents a unique model to study metastatic spread due to early dissemination and relapse, as well as availability of a panel of circulating cancer cell (CTC) lines recently. Additionally, chemosensitive SCLC tumor cells switch to a completely resistant phenotype during cancer recurrence. In advanced disease, SCLC patients display extremely high blood counts of CTCs in contrast to other tumors, like breast, prostate and colon cancer. Local inflammatory conditions at the primary tumor site and recruitment of macrophages seem to increase the shedding of tumor cells into the circulation in processes which may proceed independently of EMT. Since millions of cells are released by tumors into the circulation per day, analysis of a limited number of CTCs at specific time points are difficult to be related to the development of metastatic lesions which may occur approximately one year later. We have obtained a panel of SCLC CTC cell line from patients with relapsing disease, which share characteristic markers of this malignancy and a primarily epithelial phenotype with unique formation of large tumorospheres, containing quiescent and hypoxic cells. Although smoking and inflammation promote EMT, partial expression of vimentin indicates a transitional state with partial EMT in these cell lines at most. The CTC lines exhibit high expression of EpCAM , absent phosphorylation of β-catenin and background levels of Snail. Provided that these tumor cells had ever undergone EMT, here in advanced disease MET seem to have occurred already in the peripheral circulation. Alternative explanations for the expression of mesenchymal markers of the CTC lines are the heterogeneity of SCLC cells, cooperative migration or altered gene expression in response to the inflammatory tumor microenvironment allowing for tumor spread without EMT/MET.

Natural killer cell therapy in children with relapsed leukemia.

PubMed

Rubnitz, Jeffrey E; Inaba, Hiroto; Kang, Guolian; Gan, Kwan; Hartford, Christine; Triplett, Brandon M; Dallas, Mari; Shook, David; Gruber, Tanja; Pui, Ching-Hon; Leung, Wing

2015-08-01

Novel therapies are needed for children with relapsed or refractory leukemia. We therefore tested the safety and feasibility of haploidentical natural killer cell therapy in this patient population. Twenty-nine children who had relapsed or refractory leukemia were treated with chemotherapy followed by the infusion of haploidentical NK cells. Cohort 1 included 14 children who had not undergone prior allogeneic hematopoietic cell transplantation (HCT), whereas Cohort 2 included 15 children with leukemia that had relapsed after HCT. Twenty-six (90%) NK donors were KIR mismatched (14 with one KIR and 12 with 2 KIRs). The peak NK chimerism levels were >10% donor in 87% of the evaluable recipients. In Cohort 1, 10 had responsive disease and 12 proceeded to HCT thereafter. Currently, 5 (36%) are alive without leukemia. In Cohort 2, 10 had responsive disease after NK therapy and successfully proceeded to second HCT. At present, 4 (27%) are alive and leukemia-free. The NK cell infusions and the IL-2 injections were well-tolerated. NK cell therapy is safe, feasible, and should be further investigated in patients with chemotherapy-resistant leukemia. © 2015 Wiley Periodicals, Inc.

Ki-67 is a strong predictor of central nervous system relapse in patients with mantle cell lymphoma (MCL).

PubMed

Chihara, D; Asano, N; Ohmachi, K; Nishikori, M; Okamoto, M; Sawa, M; Sakai, R; Okoshi, Y; Tsukamoto, N; Yakushijin, Y; Nakamura, S; Kinoshita, T; Ogura, M; Suzuki, R

2015-05-01

Central nervous system (CNS) relapse is an uncommon but challenging complication in patients with mantle cell lymphoma (MCL). Survival after CNS relapse is extremely poor. Identification of high-risk populations is therefore critical in determining patients who might be candidates for a prophylactic approach. A total of 608 patients (median age, 67 years; range 22-92) with MCL newly diagnosed between 1994 and 2012 were evaluated. Pretreatment characteristics and treatment regimens were evaluated for their association with CNS relapse by competing risk regression analysis. None of the patients received intrathecal prophylaxis. Overall, 33 patients (5.4%) experienced CNS relapse during a median follow-up of 42.7 months. Median time from diagnosis to CNS relapse was 20.3 months (range: 2.2-141.3 months). Three-year cumulative incidence of CNS relapse was 5.6% [95% confidence interval (95% CI) 3.7% to 8.0%]. Univariate analysis revealed several risk factors including blastoid variant, leukemic presentation, high-risk MCL International Prognostic Index and high Ki-67 (proliferation marker). Multivariate analyses revealed that Ki-67 ≥ 30 was the only significant risk factor for CNS relapse (hazard ratio: 6.0, 95% CI 1.9-19.4, P = 0.003). Two-year cumulative incidence of CNS relapse in patients with Ki-67 ≥ 30 was 25.4% (95% CI 13.5-39.1), while that in the patients with Ki-67 < 30 was 1.6% (95% CI 0.4-4.2). None of the treatment modalities, including rituximab, high-dose cytarabine, high-dose methotrexate or consolidative autologous stem-cell transplant, were associated with a lower incidence of CNS relapse. Survival after CNS relapse was poor, with median survival time of 8.3 months. There was no significant difference in the survival by the site of CNS involvement. © The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

A phase I trial of NK-92 cells for refractory hematological malignancies relapsing after autologous hematopoietic cell transplantation shows safety and evidence of efficacy

PubMed Central

Williams, Brent A.; Law, Arjun Datt; Routy, Bertrand; denHollander, Neal; Gupta, Vikas; Wang, Xing-Hua; Chaboureau, Amélie; Viswanathan, Sowmya; Keating, Armand

2017-01-01

Background Autologous NK cell therapy can treat a variety of malignancies, but is limited by patient-specific variations in potency and cell number expansion. In contrast, allogeneic NK cell lines can overcome many of these limitations. Cells from the permanent NK-92 line are constitutively activated, lack inhibitory receptors and appear to be safe based on two prior phase I trials. Materials and Methods We conducted a single-center, non-randomized, non-blinded, open-label, Phase I dose-escalation trial of irradiated NK-92 cells in adults with refractory hematological malignancies who relapsed after autologous hematopoietic cell transplantation (AHCT). The objectives were to determine safety, feasibility and evidence of activity. Patients were treated at one of three dose levels (1 × 109 cells/m2, 3 × 109 cells/m2 and 5 × 109 cells/m2), given on day 1, 3 and 5 for a planned total of six monthly cycles. Results Twelve patients with lymphoma or multiple myeloma who relapsed after AHCT for relapsed/refractory disease were enrolled in this trial. The treatment was well tolerated, with minor toxicities restricted to acute infusional events, including fever, chills, nausea and fatigue. Two patients achieved a complete response (Hodgkin lymphoma and multiple myeloma), two patients had minor responses and one had clinical improvement on the trial. Conclusions Irradiated NK-92 cells can be administered at very high doses with minimal toxicity in patients with refractory blood cancers, who had relapsed after AHCT. We conclude that high dose NK-92 therapy is safe, shows some evidence of efficacy in patients with refractory blood cancers and warrants further clinical investigation. PMID:29179517

Supersaturated Calcium Phosphate Rinse in Preventing Oral Mucositis in Young Patients Undergoing Autologous or Donor Stem Cell Transplant

ClinicalTrials.gov

2017-03-28

Childhood Acute Lymphoblastic Leukemia in Remission; Childhood Acute Myeloid Leukemia in Remission; Childhood Chronic Myelogenous Leukemia; Childhood Myelodysplastic Syndromes; Chronic Eosinophilic Leukemia; Chronic Myelomonocytic Leukemia; Chronic Neutrophilic Leukemia; de Novo Myelodysplastic Syndromes; Disseminated Neuroblastoma; Juvenile Myelomonocytic Leukemia; Mucositis; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Previously Treated Childhood Rhabdomyosarcoma; Previously Treated Myelodysplastic Syndromes; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Rhabdomyosarcoma; Recurrent Childhood Small Noncleaved Cell Lymphoma; Recurrent Malignant Testicular Germ Cell Tumor; Recurrent Wilms Tumor and Other Childhood Kidney Tumors; Recurrent/Refractory Childhood Hodgkin Lymphoma; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes; Unspecified Childhood Solid Tumor, Protocol Specific

A model of the effects of cancer cell motility and cellular adhesion properties on tumour-immune dynamics.

PubMed

Frascoli, Federico; Flood, Emelie; Kim, Peter S

2017-06-01

We present a three-dimensional model simulating the dynamics of an anti-cancer T-cell response against a small, avascular, early-stage tumour. Interactions at the tumour site are accounted for using an agent-based model (ABM), while immune cell dynamics in the lymph node are modelled as a system of delay differential equations (DDEs). We combine these separate approaches into a two-compartment hybrid ABM-DDE system to capture the T-cell response against the tumour. In the ABM at the tumour site, movement of tumour cells is modelled using effective physical forces with a specific focus on cell-to-cell adhesion properties and varying levels of tumour cell motility, thus taking into account the ability of cancer cells to spread and form clusters. We consider the effectiveness of the immune response over a range of parameters pertaining to tumour cell motility, cell-to-cell adhesion strength and growth rate. We also investigate the dependence of outcomes on the distribution of tumour cells. Low tumour cell motility is generally a good indicator for successful tumour eradication before relapse, while high motility leads, almost invariably, to relapse and tumour escape. In general, the effect of cell-to-cell adhesion on prognosis is dependent on the level of tumour cell motility, with an often unpredictable cross influence between adhesion and motility, which can lead to counterintuitive effects. In terms of overall tumour shape and structure, the spatial distribution of cancer cells in clusters of various sizes has shown to be strongly related to the likelihood of extinction. © The authors 2016. Published by Oxford University Press on behalf of the Institute of Mathematics and its Applications. All rights reserved.

Ispinesib in Treating Young Patients With Relapsed or Refractory Solid Tumors or Lymphoma

ClinicalTrials.gov

2013-01-15

Childhood Burkitt Lymphoma; Childhood Central Nervous System Germ Cell Tumor; Childhood Choroid Plexus Tumor; Childhood Craniopharyngioma; Childhood Grade I Meningioma; Childhood Grade II Meningioma; Childhood Grade III Meningioma; Childhood High-grade Cerebral Astrocytoma; Childhood Infratentorial Ependymoma; Childhood Low-grade Cerebral Astrocytoma; Childhood Spinal Cord Neoplasm; Childhood Supratentorial Ependymoma; Recurrent Childhood Brain Stem Glioma; Recurrent Childhood Brain Tumor; Recurrent Childhood Cerebellar Astrocytoma; Recurrent Childhood Cerebral Astrocytoma; Recurrent Childhood Ependymoma; Recurrent Childhood Grade III Lymphomatoid Granulomatosis; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Medulloblastoma; Recurrent Childhood Small Noncleaved Cell Lymphoma; Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumor; Recurrent Childhood Visual Pathway and Hypothalamic Glioma; Unspecified Childhood Solid Tumor, Protocol Specific

Etanercept in Treating Young Patients With Idiopathic Pneumonia Syndrome After Undergoing a Donor Stem Cell Transplant

ClinicalTrials.gov

2017-09-01

Accelerated Phase Chronic Myelogenous Leukemia; Blastic Phase Chronic Myelogenous Leukemia; Childhood Acute Lymphoblastic Leukemia in Remission; Childhood Acute Myeloid Leukemia in Remission; Childhood Chronic Myelogenous Leukemia; Childhood Myelodysplastic Syndromes; Chronic Phase Chronic Myelogenous Leukemia; de Novo Myelodysplastic Syndromes; Disseminated Neuroblastoma; Juvenile Myelomonocytic Leukemia; Previously Treated Childhood Rhabdomyosarcoma; Previously Treated Myelodysplastic Syndromes; Pulmonary Complications; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Rhabdomyosarcoma; Recurrent Childhood Small Noncleaved Cell Lymphoma; Recurrent Neuroblastoma; Recurrent Wilms Tumor and Other Childhood Kidney Tumors; Recurrent/Refractory Childhood Hodgkin Lymphoma; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes

Pembrolizumab Alone or With Idelalisib or Ibrutinib in Treating Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia or Other Low-Grade B-Cell Non-Hodgkin Lymphomas

ClinicalTrials.gov

2017-06-30

Recurrent Chronic Lymphocytic Leukemia; Recurrent Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Lymphoplasmacytic Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Nodal Marginal Zone Lymphoma; Recurrent Small Lymphocytic Lymphoma; Recurrent Splenic Marginal Zone Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue; Refractory Follicular Lymphoma; Refractory Lymphoplasmacytic Lymphoma; Refractory Nodal Marginal Zone Lymphoma; Refractory Small Lymphocytic Lymphoma; Refractory Splenic Marginal Zone Lymphoma; Richter Syndrome; Waldenstrom Macroglobulinemia

Efficacy of a Cancer Vaccine against ALK-Rearranged Lung Tumors.

PubMed

Voena, Claudia; Menotti, Matteo; Mastini, Cristina; Di Giacomo, Filomena; Longo, Dario Livio; Castella, Barbara; Merlo, Maria Elena Boggio; Ambrogio, Chiara; Wang, Qi; Minero, Valerio Giacomo; Poggio, Teresa; Martinengo, Cinzia; D'Amico, Lucia; Panizza, Elena; Mologni, Luca; Cavallo, Federica; Altruda, Fiorella; Butaney, Mohit; Capelletti, Marzia; Inghirami, Giorgio; Jänne, Pasi A; Chiarle, Roberto

2015-12-01

Non-small cell lung cancer (NSCLC) harboring chromosomal rearrangements of the anaplastic lymphoma kinase (ALK) gene is treated with ALK tyrosine kinase inhibitors (TKI), but the treatment is successful for only a limited amount of time; most patients experience a relapse due to the development of drug resistance. Here, we show that a vaccine against ALK induced a strong and specific immune response that both prophylactically and therapeutically impaired the growth of ALK-positive lung tumors in mouse models. The ALK vaccine was efficacious also in combination with ALK TKI treatment and significantly delayed tumor relapses after TKI suspension. We found that lung tumors containing ALK rearrangements induced an immunosuppressive microenvironment, regulating the expression of PD-L1 on the surface of lung tumor cells. High PD-L1 expression reduced ALK vaccine efficacy, which could be restored by administration of anti-PD-1 immunotherapy. Thus, combinations of ALK vaccine with TKIs and immune checkpoint blockade therapies might represent a powerful strategy for the treatment of ALK-driven NSCLC. ©2015 American Association for Cancer Research.

Autoantibody-producing plasmablasts after B cell depletion identified in muscle-specific kinase myasthenia gravis

PubMed Central

Stathopoulos, Panos; Kumar, Aditya; Nowak, Richard J.; O’Connor, Kevin C.

2017-01-01

Myasthenia gravis (MG) is a B cell–mediated autoimmune disorder of neuromuscular transmission. Pathogenic autoantibodies to muscle-specific tyrosine kinase (MuSK) can be found in patients with MG who do not have detectable antibodies to the acetylcholine receptor (AChR). MuSK MG includes immunological and clinical features that are generally distinct from AChR MG, particularly regarding responsiveness to therapy. B cell depletion has been shown to affect a decline in serum autoantibodies and to induce sustained clinical improvement in the majority of MuSK MG patients. However, the duration of this benefit may be limited, as we observed disease relapse in MuSK MG patients who had achieved rituximab-induced remission. We investigated the mechanisms of such relapses by exploring autoantibody production in the reemerging B cell compartment. Autoantibody-expressing CD27+ B cells were observed within the reconstituted repertoire during relapse but not during remission or in controls. Using two complementary approaches, which included production of 108 unique human monoclonal recombinant immunoglobulins, we demonstrated that antibody-secreting CD27hiCD38hi B cells (plasmablasts) contribute to the production of MuSK autoantibodies during relapse. The autoantibodies displayed hallmarks of antigen-driven affinity maturation. These collective findings introduce potential mechanisms for understanding both MuSK autoantibody production and disease relapse following B cell depletion. PMID:28878127

Effect of immune modulation in relapsed peripheral T-cell lymphomas after post-allogeneic stem cell transplantation: a study by the Société Française de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC).

PubMed

Mamez, A C; Lévy, V; Chevallier, P; Blaise, D; Vigouroux, S; Xhaard, A; Fegueux, N; Contentin, N; Beguin, Y; Ifrah, N; Bulabois, C E; Suarez, F; Yakoub-Agha, I; Turlure, P; Deconink, E; Lamy, T; Cahn, J Y; Huynh, A; Maury, S; Fornecker, L M; Ouzegdouh, M; Bay, J O; Guillerm, G; Maillard, N; Michallet, M; Malfuson, J V; Bourhis, J H; Rialland, F; Oumedaly, R; Jubert, C; Leblond, V; Boubaya, M; Mohty, M; Nguyen, S

2016-03-01

Peripheral T-cell lymphoma carries a poor prognosis. To document a possible graft-versus-lymphoma effect in this setting, we evaluated the impact of immunomodulation in 63 patients with peripheral T-cell lymphoma who relapsed after allogeneic transplant in 27 SFGM-TC centers. Relapse occurred after a median of 2.8 months. Patients were then treated with non-immunologic strategies (chemotherapy, radiotherapy) and/or immune modulation (donor lymphocyte infusions (DLI) and/or discontinuation of immunosuppressive therapy). Median overall survival (OS) after relapse was 6.1 months (DLI group: 23.6 months, non-DLI group: 3.6 months). Among the 14 patients who received DLI, 9 responded and 2 had stable disease. Among the remaining 49 patients, a complete response accompanied by extensive chronic GvHD was achieved in two patients after tapering of immunosuppressive drugs. Thirty patients received radio-chemotherapy, with an overall response rate of 50%. In multivariate analysis, chronic GvHD (odds ratio: 11.25 (2.68-48.21), P=0.0009) and skin relapse (odds ratio: 4.15 (1.04-16.50), P=0.043) were associated with a better response to treatment at relapse. In a time-dependent analysis, the only factor predictive of OS was the time from transplantation to relapse (hazards ratio: 0.33 (0.17-0.640), P=0.0009). This large series provides encouraging evidence of a true GvL effect in this disease.

Autologous bone marrow transplantation in relapsed adult acute leukemia.

PubMed

Dicke, K A; Zander, A R; Spitzer, G; Verma, D S; Peters, L J; Vellekoop, L; Thomson, S; Stewart, D; Hester, J P; McCredie, K B

1979-01-01

From March, 1976 to February, 1979, 28 cases of adult acute leukemia of which 24 were evaluable were treated in irreversible relapse with high dose chemotherapy (piperazinedione) and supra-lethal total body irradiation (TBI) in conjunction with autologous bone marrow transplantation (ABMT). The marrow cells grafted were collected and stored in liquid nitrogen at the time of remission. In 12 patients the marrow cells were fractionated using discontinuous albumin gradients in an attempt to separate normal cells from residual leukemic cells. Twelve patients achieved complete remission (CR); in 9 additional patients signs of engraftment were evident but death occurred before achievement of CR. Seven of 12 AML patients, which were treated with bone marrow transplantation as first treatment of their relapse, achieved CR. Four of 5 patients with ALL, whose bone marrows were collected during first remission, reached CR. The median CR duration was 4+ months and the median survival of the patients reaching CR was 6+ months. Autologous bone marrow transplantation offers a good chance of CR (66%), when marrow is collected during first remission and used as first treatment for AML in third relapse and ALL in second relapse.

Autologous bone marrow transplantation in relapsed adult acute leukemia.

PubMed

Dicke, K A; Zander, A R; Spitzer, G; Verma, D S; Peters, L; Vellekoop, L; Thomson, S; Stewart, D; McCredie, K B

1980-01-01

From March, 1976 to February, 1979, 28 cases of adult acute leukemia of which 24 were evaluable were treated in irreversible relapse with high dose chemotherapy (piperazinedione) and supra-lethal total body irradiation (TBI) in conjunction with autologous bone marrow transplantation (ABMT). The marrow cells grafted were collected and stored in liquid nitrogen at the time of remission. In 12 patients the marrow cells were fractionated using discontinuous albumin gradients in an attempt to separate normal cells from residual leukemic cells. Twelve patients achieved complete remission (CR); in 9 additional patients signs of engraftment were evident but death occurred before achievement of CR. Seven of 12 AML patients, which were treated with bone marrow transplantation as first treatment of their relapse, achieved CR. Four of 5 patients with ALL, whose bone marrows were collected during first remission, reached CR. The median CR duration was 4+ months and the median survival of the patients reaching CR was 6+ months. Autologous bone marrow transplantation offers a good chance of CR (66%) when marrow is collected during first remission and used as first treatment for AML in third relapse and ALL in second relapse.

Protective effect of CMV reactivation on relapse after allogeneic hematopoietic cell transplantation in AML patients is influenced by their conditioning regimen

PubMed Central

Manjappa, Shivaprasad; Bhamidipati, Pavan Kumar; Stokerl-Goldstein, Keith E.; DiPersio, John F.; Uy, Geoffrey L.; Westervelt, Peter; Liu, Jingxia; Schroeder, Mark A.; Vij, Ravi; Abboud, Camille N.; Fehniger, Todd A; Cashen, Amanda F.; Pusic, Iskra; Jacoby, Meagan; Meera, Srinidhi J.; Romee, Rizwan

2014-01-01

Cytomegalovirus (CMV) reactivation after allogeneic hematopoietic cell transplant (allo-HCT) has been associated with reduced risk of relapse in patients with acute myeloid leukemia (AML). However the influence of the conditioning regimen on this protective effect of CMV reactivation after allo-HCT is relatively unexplored. To address this, we evaluated the risk of relapse in 264 AML patients who received T cell replete, 6/6 HLA matched sibling or 10/10 HLA matched unrelated donor transplantation at a single institution between 2006 and 2011. Out of these 264 patients, 206 received myeloablative (MA) and 58 received reduced intensity conditioning (RIC) regimens. CMV reactivation was observed in 88 patients with MA conditioning and 37 patients with RIC. At a median follow up of 299 days, CMV reactivation was associated with significantly lower risk of relapse in patients who received MA conditioning both in univariate (P= .01) and multivariate analyses (hazard ratio of 0.5246, P= .006), however CMV reactivation did not significantly affect the risk of relapse in our RIC cohort. These results confirm the protective effect of CMV reactivation on relapse in AML patients after allo-HCT reported by previous studies, however they suggest that this protective effect of CMV reactivation on relapse is influenced by the conditioning regimen used with the transplant. PMID:24120526

NCI 1st International Workshop on the Biology, Prevention, and Treatment of Relapse After Allogeneic Hematopoietic Stem Cell Transplantation: Summary and Recommendations from the Organizing Committee

PubMed Central

Bishop, Michael R.; Alyea, Edwin P.; Cairo, Mitchell S.; Falkenburg, J.H. Frederik; June, Carl H.; Kröger, Nicolaus; Little, Richard F.; Miller, Jeffrey S.; Pavletic, Steven Z.; Porter, David L.; Riddell, Stanley R.; van Besien, Koen; Wayne, Alan S.; Weisdorf, Daniel J.; Wu, Roy S.; Giralt, Sergio

2011-01-01

The First International Workshop on The Biology, Prevention, and Treatment of Relapse After Allogeneic Hematopoietic Stem Cell Transplantation was organized and convened to identify, prioritize, and coordinate future research activities related to relapse after allogeneic hematopoietic stem cell transplantation (alloHSCT). Each of the Workshop’s six working committees have published individual reports of ongoing basic, translational and clinical research and recommended areas for future research related to the areas of relapse biology, epidemiology, prevention and treatment. This document summarizes each of the committees’ recommendations and suggests three major initiatives for a coordinated research effort to address the problem of relapse after alloHSCT. The first is the need to establish multi-center correlative and clinical trials networks for basic/translational, epidemiological, and clinical research. Second, there is a need for a network of biorepositories for the collection of samples pre- and post-alloHSCT to aid in laboratory and clinical studies. Third, there should be further refinement, implementation, and study of the proposed Workshop disease-specific response and relapse definitions and the recommendations for monitoring of minimal residual disease. These recommendations, in coordination with ongoing research initiatives and transplant organizations, provide a research framework to rapidly and efficiently address the significant problem of relapse following alloHSCT. PMID:21224011

Pegfilgrastim and Rituximab in Treating Patients With Untreated, Relapsed, or Refractory Follicular Lymphoma, Small Lymphocytic Lymphoma, or Marginal Zone Lymphoma

ClinicalTrials.gov

2017-09-08

Contiguous Stage II Grade 1 Follicular Lymphoma; Contiguous Stage II Grade 2 Follicular Lymphoma; Contiguous Stage II Grade 3 Follicular Lymphoma; Contiguous Stage II Marginal Zone Lymphoma; Contiguous Stage II Small Lymphocytic Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Nodal Marginal Zone B-cell Lymphoma; Noncontiguous Stage II Grade 1 Follicular Lymphoma; Noncontiguous Stage II Grade 2 Follicular Lymphoma; Noncontiguous Stage II Grade 3 Follicular Lymphoma; Noncontiguous Stage II Marginal Zone Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Small Lymphocytic Lymphoma; Splenic Marginal Zone Lymphoma; Stage I Grade 1 Follicular Lymphoma; Stage I Grade 2 Follicular Lymphoma; Stage I Grade 3 Follicular Lymphoma; Stage I Marginal Zone Lymphoma; Stage I Small Lymphocytic Lymphoma; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Marginal Zone Lymphoma; Stage III Small Lymphocytic Lymphoma; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Marginal Zone Lymphoma; Stage IV Small Lymphocytic Lymphoma

Donor Lymphocyte Infusions for Chronic Myeloid Leukemia Relapsing after Allogeneic Stem Cell Transplantation: May We Predict Graft-versus-Leukemia Without Graft-versus-Host Disease?

PubMed

Radujkovic, Aleksandar; Guglielmi, Cesare; Bergantini, Stefania; Iacobelli, Simona; van Biezen, Anja; Milojkovic, Dragana; Gratwohl, Alois; Schattenberg, Antonius V M B; Verdonck, Leo F; Niederwieser, Dietger W; de Witte, Theo; Kröger, Nicolaus; Olavarria, Eduardo

2015-07-01

Donor lymphocyte infusions (DLI) are an effective treatment for relapsed chronic myeloid leukemia (CML) after allogeneic stem cell transplantation (alloSCT). Leukemia resistance and secondary graft-versus-host disease (GVHD) are major obstacles to success with DLI. The aim of this study was to identify pre-DLI factors associated with prolonged survival in remission without secondary GVHD. We retrospectively analyzed 500 patients treated with DLI for CML relapse (16% molecular, 30% cytogenetic, and 54% hematological) after alloSCT. The overall probabilities of failure- and secondary GVHD-free survival (FGFS) were 29% and 27% at 5 and 10 years after DLI, respectively. The type of relapse was the major factor influencing FGFS (40% for molecular and/or cytogenetic relapse and 20% for hematological relapse at 5 years, P < .001). Chronic GVHD before DLI and an interval <1 year between alloSCT and first DLI were independently associated with inferior FGFS in patients with molecular and/or cytogenetic relapse. Consequently, FGFS was 13%, 35%, to 56% at 5 years in patients with 2, 1, and 0 adverse features, respectively. In patients with hematological relapse, independent adverse prognostic factors for FGFS were initial dose of CD3(+) cells ≥ 50 × 10(6)/kg, donor-recipient sex mismatch, and chronic GVHD before DLI. FGFS was 0%, 17%, 33%, to 37% in patients with 3, 2, 1, and 0 adverse features, respectively. The probability of survival in remission without secondary GVHD was highest (>50% at 5 years) when DLI were given beyond 1 year from alloSCT for molecular and/or cytogenetic CML relapse that was not preceded by chronic GVHD. Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Apolizumab in Treating Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

ClinicalTrials.gov

2013-07-15

Noncontiguous Stage II Small Lymphocytic Lymphoma; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Stage III Small Lymphocytic Lymphoma; Stage IV Small Lymphocytic Lymphoma

Prevention and treatment of relapse after stem cell transplantation in lymphoid malignancies.

PubMed

Sureda, Anna; Dreger, Peter; Bishop, Michael R; Kroger, Nicolaus; Porter, David L

2018-05-24

Relapse is now the major cause of treatment failure after allogeneic HSCT (alloHSCT). Many novel strategies to address this critical issue are now being developed and tested. At the 3rd International Workshop on Biology, Prevention, and Treatment of Relapse held in Hamburg, Germany in November 2016, international experts presented and discussed recent developments in the field. Some approaches may be applicable to a wide range of patients after transplant, whereas some may be very disease-specific. We present a report from the session dedicated to issues related to prevention and treatment of relapse of lymphoid malignancies after alloHSCT. This session included detailed reviews as well as forward-looking commentaries that focused on Hodgkin lymphoma, chronic lymphocytic leukemia and mantle cell lymphoma, diffuse large cell and follicular lymphoma, and multiple myeloma.

Increased Coexpression of PD-1, TIGIT, and KLRG-1 on Tumor-Reactive CD8+ T Cells During Relapse after Allogeneic Stem Cell Transplantation.

PubMed

Hutten, Tim J A; Norde, Wieger J; Woestenenk, Rob; Wang, Ruo Chen; Maas, Frans; Kester, Michel; Falkenburg, J H Frederik; Berglund, Sofia; Luznik, Leo; Jansen, Joop H; Schaap, Nicolaas; Dolstra, Harry; Hobo, Willemijn

2018-04-01

Allogeneic stem cell transplantation (allo-SCT) can be a curative treatment for patients with a hematologic malignancy due to alloreactive T cell responses recognizing minor histocompatibility antigens (MiHA). Yet tumor immune escape mechanisms can cause failure of T cell immunity, leading to relapse. Tumor cells display low expression of costimulatory molecules and can up-regulate coinhibitory molecules that inhibit T cell functionality on ligation with their counter-receptors on the tumor-reactive T cells. The aim of this explorative study was to evaluate immune checkpoint expression profiles on T cell subsets and on cytomegalovirus (CMV)- and/or MiHA-reactive CD8 + T cells of allo-SCT recipients using a 13-color flow cytometry panel, and to correlate these expression patterns to clinical outcomes. MiHA-reactive CD8 + T cells exhibited an early differentiated CD27 ++ /CD28 ++ phenotype with low KLRG-1 and CD57 expression. These T cells also displayed increased expression of PD-1, TIM-3, and TIGIT compared with total effector memory T cells and CMV-specific CD8 + T cells in healthy donors and allo-SCT recipients. Remarkably, high coexpression of PD-1, TIGIT, and KLRG-1 on MiHA-reactive CD8 + T cells was associated with relapse after allo-SCT. Taken together, these findings indicate that MiHA-specific CD8 + T cells of relapsed patients have a distinctive coinhibitory expression signature compared with patients who stay in remission. This phenotype may serve as a potential monitoring tool in patients. Moreover, these findings suggest that PD-1 and TIGIT play important roles in regulating T cell-mediated tumor control, providing a rationale for immunotherapy with blocking antibodies to treat relapse after allo-SCT. Copyright © 2017 The American Society for Blood and Marrow Transplantation. All rights reserved.

Haploidentical Stem Cell Transplantation for Refractory/Relapsed Neuroblastoma.

PubMed

Illhardt, Toni; Toporski, Jacek; Feuchtinger, Tobias; Turkiewicz, Dominik; Teltschik, Heiko-Manuel; Ebinger, Martin; Schwarze, Carl-Philipp; Holzer, Ursula; Lode, Holger N; Albert, Michael H; Gruhn, Bernd; Urban, Christian; Dykes, Josefina H; Teuffel, Oliver; Schumm, Michael; Handgretinger, Rupert; Lang, Peter

2018-05-01

Pediatric patients with refractory or relapsed metastatic neuroblastoma (NBL) have a poor prognosis despite autologous stem cell transplantation (SCT). Allogeneic SCT from a haploidentical donor has a remarkable alloreactive effect in patients with leukemia; thus, we evaluated this approach in children with very high-risk NBL. We analyzed data from 2 prospective phase I/II trials. A total of 26 patients with refractory (n = 5), metastatic relapsed (n = 20), or locally relapsed MYCN-positive (n = 1) NBL received a median of 17 × 10 6 /kg T/B cell-depleted CD34 + stem cells with 68 × 10 3 /kg residual T cells and 107 × 10 6 /kg natural killer cells. The conditioning regimen comprised melphalan, fludarabine, thiotepa, OKT3, and a short course of mycophenolate mofetil post-transplantation. Engraftment occurred in 96% of the patients. Event-free survival and overall survival at 5 years were 19% and 23%, respectively. No transplantation-related mortality was observed, and the single death was due to progression/subsequent relapse. The median duration of follow-up was 8.1 years. Patients in complete remission before SCT had a significantly better prognosis than those with residual tumor load (P < .01). All patients with progressive disease before SCT relapsed within 1 year. Grade II and grade III acute graft-versus-host disease (GVHD) occurred in 31% and 12% of the patients, respectively. Chronic limited and extensive GVHD occurred in 28% and 10%, respectively. Our data indicate that haploidentical SCT is a feasible treatment option that can induce long-term remission in some patients with NBL with tolerable side effects, and may enable the development of further post-transplantation therapeutic strategies based on the donor-derived immune system. Copyright © 2018. Published by Elsevier Inc.

Carfilzomib demonstrates broad anti-tumor activity in pre-clinical non-small cell and small cell lung cancer models.

PubMed

Baker, Amanda F; Hanke, Neale T; Sands, Barbara J; Carbajal, Liliana; Anderl, Janet L; Garland, Linda L

2014-12-31

Carfilzomib (CFZ) is a proteasome inhibitor that selectively and irreversibly binds to its target and has been approved in the US for treatment of relapsed and refractory multiple myeloma. Phase 1B studies of CFZ reported signals of clinical activity in solid tumors, including small cell lung cancer (SCLC). The aim of this study was to investigate the activity of CFZ in lung cancer models. A diverse panel of human lung cancer cell lines and a SHP77 small cell lung cancer xenograft model were used to investigate the anti-tumor activity of CFZ. CFZ treatment inhibited both the constitutive proteasome and the immunoproteasome in lung cancer cell lines. CFZ had marked anti-proliferative activity in A549, H1993, H520, H460, and H1299 non-small cell lung cancer (NSCLC) cell lines, with IC50 values after 96 hour exposure from <1.0 nM to 36 nM. CFZ had more variable effects in the SHP77 and DMS114 SCLC cell lines, with IC50 values at 96 hours from <1 nM to 203 nM. Western blot analysis of CFZ-treated H1993 and SHP77 cells showed cleavage of poly ADP ribose polymerase (PARP) and caspase-3, indicative of apoptosis, and induction of microtubule-associated protein-1 light chain-3B (LC3B), indicative of autophagy. In SHP77 flank xenograft tumors, CFZ monotherapy inhibited tumor growth and prolonged survival, while no additive or synergistic anti-tumor efficacy was observed for CFZ + cisplatin (CDDP). CFZ demonstrated anti-proliferative activity in lung cancer cell lines in vitro and resulted in a significant survival advantage in mice with SHP77 SCLC xenografts, supporting further pre-clinical and clinical investigations of CFZ in NSCLC and SCLC.

Extramedullary Relapse Following Total Marrow and Lymphoid Irradiation in Patients Undergoing Allogeneic Hematopoietic Cell Transplantation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kim, Ji Hyun; Stein, Anthony; Tsai, Nicole

Purpose: Approximately 5% to 20% of patients who undergo total body irradiation (TBI) in preparation for hematopoietic cell transplantation (HCT) can develop extramedullary (EM) relapse. Whereas total marrow and lymphoid irradiation (TMLI) provides a more conformally targeted radiation therapy for patients, organ sparing has the potential to place the patient at a higher risk for EM relapse than TBI. This study evaluated EM relapse in patients treated with TMLI at our institution. Methods and Materials: Patients eligible for analysis had been enrolled in 1 of 3 prospective TMLI trials between 2006 and 2012. The TMLI targeted bones, major lymph nodemore » chains, liver, spleen, testes, and brain, using image-guided tomotherapy with total dose ranging from 12 to 15 Gy. Results: A total of 101 patients with a median age of 47 years were studied. The median follow-up was 12.8 months. Incidence of EM relapse and bone marrow (BM) relapse were 12.9% and 25.7%, respectively. Of the 13 patients who had EM relapse, 4 also had BM relapse, and 7 had EM disease prior to HCT. There were a total of 19 EM relapse sites as the site of initial recurrence: 11 soft tissue, 6 lymph node, 2 skin. Nine of these sites were within the target region and received ≥12 Gy. Ten initial EM relapse sites were outside of the target region: 5 sites received 10.1 to 11.4 Gy while 5 sites received <10 Gy. Pretransplantation EM was the only significant predictor of subsequent EM relapse. The cumulative incidence of EM relapse was 4% at 1 year and 11.4% at 2 years. Conclusions: EM relapse incidence was as frequent in regions receiving ≥10 Gy as those receiving <10 Gy. EM relapse rates following TMLI that included HCT regimens were comparable to published results with regimens including TBI and suggest that TMLI is not associated with an increased EM relapse risk.« less

Tracking Genomic Cancer Evolution for Precision Medicine: The Lung TRACERx Study

PubMed Central

Jamal-Hanjani, Mariam; Hackshaw, Alan; Ngai, Yenting; Shaw, Jacqueline; Dive, Caroline; Quezada, Sergio; Middleton, Gary; de Bruin, Elza; Le Quesne, John; Shafi, Seema; Falzon, Mary; Horswell, Stuart; Blackhall, Fiona; Khan, Iftekhar; Janes, Sam; Nicolson, Marianne; Lawrence, David; Forster, Martin; Fennell, Dean; Lee, Siow-Ming; Lester, Jason; Kerr, Keith; Muller, Salli; Iles, Natasha; Smith, Sean; Murugaesu, Nirupa; Mitter, Richard; Salm, Max; Stuart, Aengus; Matthews, Nik; Adams, Haydn; Ahmad, Tanya; Attanoos, Richard; Bennett, Jonathan; Birkbak, Nicolai Juul; Booton, Richard; Brady, Ged; Buchan, Keith; Capitano, Arrigo; Chetty, Mahendran; Cobbold, Mark; Crosbie, Philip; Davies, Helen; Denison, Alan; Djearman, Madhav; Goldman, Jacki; Haswell, Tom; Joseph, Leena; Kornaszewska, Malgorzata; Krebs, Matthew; Langman, Gerald; MacKenzie, Mairead; Millar, Joy; Morgan, Bruno; Naidu, Babu; Nonaka, Daisuke; Peggs, Karl; Pritchard, Catrin; Remmen, Hardy; Rowan, Andrew; Shah, Rajesh; Smith, Elaine; Summers, Yvonne; Taylor, Magali; Veeriah, Selvaraju; Waller, David; Wilcox, Ben; Wilcox, Maggie; Woolhouse, Ian; McGranahan, Nicholas; Swanton, Charles

2014-01-01

The importance of intratumour genetic and functional heterogeneity is increasingly recognised as a driver of cancer progression and survival outcome. Understanding how tumour clonal heterogeneity impacts upon therapeutic outcome, however, is still an area of unmet clinical and scientific need. TRACERx (TRAcking non-small cell lung Cancer Evolution through therapy [Rx]), a prospective study of patients with primary non-small cell lung cancer (NSCLC), aims to define the evolutionary trajectories of lung cancer in both space and time through multiregion and longitudinal tumour sampling and genetic analysis. By following cancers from diagnosis to relapse, tracking the evolutionary trajectories of tumours in relation to therapeutic interventions, and determining the impact of clonal heterogeneity on clinical outcomes, TRACERx may help to identify novel therapeutic targets for NSCLC and may also serve as a model applicable to other cancer types. PMID:25003521

Donor-derived CD19-targeted T cell infusion induces minimal residual disease-negative remission in relapsed B-cell acute lymphoblastic leukaemia with no response to donor lymphocyte infusions after haploidentical haematopoietic stem cell transplantation.

PubMed

Chen, Yuhong; Cheng, Yifei; Suo, Pan; Yan, Chenhua; Wang, Yu; Chen, Yao; Han, Wei; Xu, Lanping; Zhang, Xiaohui; Liu, Kaiyan; Chang, Lungji; Xiao, Lei; Huang, Xiaojun

2017-11-01

Relapse is a common cause of failure in patients with B-cell acute lymphoblastic leukaemia (B-ALL) after haploidentical haematopoietic stem cell transplantation (haplo-HSCT), and non-responders to donor lymphoblastic infusion after HSCT have a very poor prognosis. Although donor-derived CD19-directed chimeric antigen receptor-modified (CAR) T cells can potentially cure leukaemia, their effectiveness and safety have not been confirmed in relapsed B-ALL cases after haplo-HSCT. Between January 2015 and January 2017, two and four patients each received one and two infusions of CAR T cells from haplo-HSCT donors. Five (83·33%) achieved minimal residual disease (MRD)-negative remission; one patient was discharged automatically without evaluation after developing severe thrombotic microangiopathies. Four of five responsive patients relapsed after 2-7 months, and one died of sepsis following MRD-negative remission after a second infusion. None of the other second infusion recipients achieved a second complete remission. Five patients (83·33%) experienced eight courses of grade 1-3 cytokine release syndrome; two were treated with tocilizumab. Two (33·3%) and one patient developed grade 2 and 3 acute graft-versus-host disease (aGVHD), respectively; the former was controlled with glucocorticoids. Donor-derived CAR T-cell infusion seems be effective and safe for relapsed B-ALL after haplo-HSCT, although larger clinical studies are needed. © 2017 John Wiley & Sons Ltd.

Soluble thrombomodulin levels in plasma of multiple sclerosis patients and their implication.

PubMed

Festoff, Barry W; Li, Chaoyang; Woodhams, Barry; Lynch, Sharon

2012-12-15

Thrombomodulin (TM) on the cell-surface of cerebrovascular endothelial cells (CECs) is released into blood upon CEC damage. TM promotes activation of protein C (APC), an anticoagulant, anti-inflammatory, neuroprotective molecule that protects CECs and impedes inflammatory cell migration across the blood-brain barrier (BBB). Multiple sclerosis (MS) is associated with CEC damage and BBB dysfunction. We evaluated soluble TM (sTM) levels as a biomarker of BBB integrity and whether glatiramer acetate (GA) influenced sTM levels in MS patients. sTM levels quantified by 2-site ELISA from sera of healthy controls and systemic lupus erythematosus (SLE) patients (CEC-damage positive control) were compared with levels from patients with relapsing-remitting (RRMS) or secondary-progressive MS (SPMS), stratified as: RRMS/GA/no relapse, RRMS/GA/in relapse, RRMS no GA/no relapse, RRMS/no GA/in relapse; and SPMS/no GA. Additionally, soluble endothelial protein C receptor (sEPCR) levels were assessed in the non-stratified MS group, SLE patients, and controls. sTM levels were highest in RRMS patients taking GA with or without relapse, followed in decreasing order by SLE, RRMS/no GA/in relapse, SPMS, RRMS/no GA/no relapse, healthy controls. sEPCR levels were highest in MS patients, then SLE, then controls. sTM may be a useful biomarker of BBB integrity in RRMS patients. Further evaluation of sEPCR is needed. The finding that the highest sTM levels were in RRMS patients taking GA is interesting and warrants further investigation. Published by Elsevier B.V.

Successful treatment with biweekly CHOP for bone marrow relapse of blastic plasmacytoid dendritic cell neoplasm.

PubMed

Ono, Keiko; Ise, Mikiko; Ikebe, Dai; Sato, Akiyasu; Wang, Xiaofei; Sugawara, Takeaki; Tsujimura, Hideki; Itami, Makiko; Kumagai, Kyoya

2017-01-01

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive hematological malignancy derived from precursors of plasmacytoid dendritic cells. The majority of patients initially respond to multi-agent chemotherapy, though most relapse within a year and the prognosis is very poor. We report a 67-year-old man with erythema on the right chest and a nasopharyngeal mass. Histological examination revealed a mass of tumor cells expressing CD4, CD56, and CD123, but neither CD3 nor CD20. He was diagnosed with BPDCN. Bone marrow involvement was not seen at diagnosis. He achieved complete remission (CR) with CHOP-like chemotherapy. After 1 year, he relapsed with a cutaneous tumor on the head, a nasopharyngeal tumor, and massive bone marrow involvement. Relapsed BPDCN is generally resistant to chemotherapy and the prognosis is dismal. However, he was successfully treated with biweekly CHOP therapy and achieved a second CR lasting 16 months.

Docetaxel-induced polyploidization may underlie chemoresistance and disease relapse.

PubMed

Ogden, Angela; Rida, Padmashree C G; Knudsen, Beatrice S; Kucuk, Omer; Aneja, Ritu

2015-10-28

Although docetaxel significantly improves survival in a variety of malignancies, its clinical utility is severely restricted by acquired chemoresistance and disease relapse. To uncover the mechanisms underlying these all too common occurrences, an abundance of research has focused on mutations and gene expression patterns; however, these findings are yet to translate into improved outcomes for patients being administered this drug. These analyses have overlooked a promising lead in the quest to discern key mediators of resistance and relapse following docetaxel therapy: polyploidization. This process is manifested following docetaxel-mediated mitotic arrest by the appearance of giant, multinucleated cells, which slipped from mitosis without undergoing cytokinesis. Polyploid cells generally possess supernumerary centrosomes, are chromosomally instable, and resist chemotherapy. We thus suspect that chemoresistance and relapse following treatment with docetaxel might be combatted by co-administration of centrosome declustering drugs, which could selectively destroy polyploid cells given that normal cells do not possess amplified centrosomes, an intriguing paradigm that warrants further investigation. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Early relapse of Burkitt lymphoma heralded by a bone marrow necrosis and numb chin syndrome successfully treated with allogeneic stem cell transplantation

PubMed Central

Cerny, Jan; Devitt, Katherine; Yu, Hongbo; Ramanathan, Muthalagu; Woda, Bruce; Nath, Rajneesh

2014-01-01

The optimal salvage therapy for patients with relapsed Burkitt lymphoma is unknown. Bone marrow necrosis is an underreported (<1% of bone marrow failures). Numb chin syndrome is another rare syndrome associated with aggressive malignancies. Survival of these syndromes is dictated by the underlying disease and is usually dismal. Our 35-year-old patient experienced an early relapse of Burkitt lymphoma accompanied by syndromes, achieved second complete remission and underwent allogeneic stem cell transplantation. He remains alive and well >2 years after the transplant. To our knowledge, this is the longest reported survival of the two syndromes in the setting of BL relapse. PMID:25068102

Early relapse of Burkitt lymphoma heralded by a bone marrow necrosis and numb chin syndrome successfully treated with allogeneic stem cell transplantation.

PubMed

Cerny, Jan; Devitt, Katherine; Yu, Hongbo; Ramanathan, Muthalagu; Woda, Bruce; Nath, Rajneesh

2014-01-01

The optimal salvage therapy for patients with relapsed Burkitt lymphoma is unknown. Bone marrow necrosis is an underreported (<1% of bone marrow failures). Numb chin syndrome is another rare syndrome associated with aggressive malignancies. Survival of these syndromes is dictated by the underlying disease and is usually dismal. Our 35-year-old patient experienced an early relapse of Burkitt lymphoma accompanied by syndromes, achieved second complete remission and underwent allogeneic stem cell transplantation. He remains alive and well >2 years after the transplant. To our knowledge, this is the longest reported survival of the two syndromes in the setting of BL relapse.

Early relapse after autologous hematopoietic cell transplantation remains a poor prognostic factor in multiple myeloma but outcomes have improved over time.

PubMed

Kumar, S K; Dispenzieri, A; Fraser, R; Mingwei, F; Akpek, G; Cornell, R; Kharfan-Dabaja, M; Freytes, C; Hashmi, S; Hildebrandt, G; Holmberg, L; Kyle, R; Lazarus, H; Lee, C; Mikhael, J; Nishihori, T; Tay, J; Usmani, S; Vesole, D; Vij, R; Wirk, B; Krishnan, A; Gasparetto, C; Mark, T; Nieto, Y; Hari, P; D'Souza, A

2018-04-01

Duration of initial disease response remains a strong prognostic factor in multiple myeloma (MM) particularly for upfront autologous hematopoietic cell transplant (AHCT) recipients. We hypothesized that new drug classes and combinations employed prior to AHCT as well as after post-AHCT relapse may have changed the natural history of MM in this population. We analyzed the Center for International Blood and Marrow Transplant Research database to track overall survival (OS) of MM patients receiving single AHCT within 12 months after diagnosis (N=3256) and relapsing early post-AHCT (<24 months), and to identify factors predicting for early vs late relapses (24-48 months post-AHCT). Over three periods (2001-2004, 2005-2008, 2009-2013), patient characteristics were balanced except for lower proportion of Stage III, higher likelihood of one induction therapy with novel triplets and higher rates of planned post-AHCT maintenance over time. The proportion of patients relapsing early was stable over time at 35-38%. Factors reducing risk of early relapse included lower stage, chemosensitivity, transplant after 2008 and post-AHCT maintenance. Shorter post-relapse OS was associated with early relapse, IgA MM, Karnofsky <90, stage III, >1 line of induction and lack of maintenance. Post-AHCT early relapse remains a poor prognostic factor, even though outcomes have improved over time.

Secondary central nervous system relapse in diffuse large B cell lymphoma in a resource limited country: result from the Thailand nationwide multi-institutional registry.

PubMed

Wudhikarn, Kitsada; Bunworasate, Udomsak; Julamanee, Jakrawadee; Lekhakula, Arnuparp; Chuncharunee, Suporn; Niparuck, Pimjai; Ekwattanakit, Supachai; Khuhapinant, Archrob; Norasetthada, Lalita; Nawarawong, Weerasak; Makruasi, Nisa; Kanitsap, Nonglak; Sirijerachai, Chittima; Chansung, Kanchana; Wong, Peerapon; Numbenjapon, Tontanai; Prayongratana, Kannadit; Suwanban, Tawatchai; Wongkhantee, Somchai; Praditsuktavorn, Pannee; Intragumtornchai, Tanin

2017-01-01

Secondary central nervous system (CNS) relapse is a serious and fatal complication of diffuse large B cell lymphoma (DLBCL). Data on secondary CNS (SCNS) relapse were mostly obtained from western countries with limited data from developing countries. We analyzed the data of 2034 newly diagnosed DLBCL patients enrolled into the multi-center registry under Thai Lymphoma Study Group from setting. The incidence, September 2006 to December 2013 to represent outcome from a resource limited pattern, management, and outcome of SCNS relapse were described. The 2-year cumulative incidence (CI) of SCNS relapse was 2.7 %. A total of 729, 1024, and 281 patients were classified as low-, intermediate-, and high-risk CNS international prognostic index (CNS-IPI) with corresponding 2-year CI of SCNS relapse of 1.5, 3.1, and 4.6 %, respectively (p < 0.001). Univariate analysis demonstrated advance stage disease, poor performance status, elevated lactate dehydrogenase, presence of B symptoms, more than one extranodal organ involvement, high IPI, and high CNS-IPI group as predictive factors for SCNS relapse. Rituximab exposure and intrathecal chemoprophylaxis offered no protective effect against SCNS relapse. At the time of analysis, six patients were alive. Median OS in SCNS relapsed patients was significantly shorter than relapsed patients without CNS involvement (13.2 vs 22.6 months) (p < 0.001). Primary causes of death were progressive disease (n = 35, 63.6 %) and infection (n = 9, 16.7 %). In conclusion, although the incidence of SCNS relapse in our cohort was low, the prognosis was dismal. Prophylaxis for SCNS involvement was underused even in high-risk patients. Novel approaches for SCNS relapse prophylaxis and managements are warranted.

Nephrogenic diabetes insipidus in initial stage of acute lymphoblastic leukemia and relapse after haploidentical hematopoietic stem-cell transplantation: A case report.

PubMed

Li, Dezhi; Liu, Qian; Feng, Zhifang; Zhang, Qi; Feng, Saran

2018-06-01

Nephrogenic diabetes insipidus (NDI) rarely presents in the initial stage of acute lymphoblastic leukemia (ALL) and relapse due to renal infiltration is also rare. A 19-year-old man presented with weakness, polydipsia, and polyuria for 1 month. NDI was diagnosed with insignificant response to a water deprivation test after stimulation with vasopressin injection. Bone marrow examination combined with immunophenotypic analysis, cerebrospinal cytology, and abdominal ultrasonography confirmed the diagnoses of precursor B cell ALL with renal infiltration. The patient accepted standardized combination chemotherapy and ultimately had sustained remission, and his polydipsia and polyuria disappeared after 3 days of treatment. The ALL relapsed 1 year later and he received haploidentical stem cell transplantation (haplo-SCT) from his father. One year later, he again developed NDI, with bilateral renal enlargement because of extramedullary relapse, leading to subsequent death. This case demonstrates unusual early renal involvement in ALL presenting with initial NDI. Interestingly, the NDI returned with the relapse of renal infiltration 1 year after haplo-SCT. This case suggests that NDI was probably secondary to renal leukemic infiltration.

Late recurrences of germ cell malignancies: a population-based experience over three decades

PubMed Central

Oldenburg, J; Alfsen, G C; Wæhre, H; Fosså, S D

2006-01-01

The purpose of this study was to explore the incidence of late relapse in patients with malignant germ cell tumour (MGCT) in a population-based series, with emphasis on the mode of detection, survival, and the relevance of histological findings. The clinical records from a population-based cohort of patients with seminoma (n=1123) or non-seminoma (n=826) were evaluated for late relapses. Twenty-five patients developed a late relapse. The cumulative 10-year incidence rate was 1.3%. All 10 seminoma patients, but only eight of 15 non-seminoma patients relapsed with vital malignant tumour (P=0.02). Teratoma or necrosis was found in seven of nine primarily chemotherapy-treated non-seminoma patients with normal tumour markers at late relapse. Six of nine patients operated with limited retroperitoneal lymph node dissection as part of the primary treatment had relapsed retroperitoneally outside the original operation field. The 10-year cause-specific survival was 68% in all patients, 50% in patients relapsing with vital malignant tumour and 100% in those with teratoma/ necrosis before or after salvage chemotherapy. The 10-year incidence rate of late relapses of 1.3% might reflect the true incidence rate in a population-based cohort of MGCT patients, with cure in at least half of them. PMID:16508636

Comparable post-relapse outcomes between haploidentical and matched related donor allogeneic stem cell transplantation.

PubMed

Ma, Y-R; Xu, L-P; Zhang, X-H; Yan, C-H; Wang, Y; Wang, F-R; Wang, J-Z; Chen, Y; Han, W; Chen, Y-H; Chen, H; Liu, K-Y; Huang, X-J

2017-03-01

We investigated the impact of donor type on post-relapse survival (PRS) in 85 patients with hematological relapse after their first allogeneic hematological stem cell transplantation (allo-HSCT) for hematological malignancy. The median follow-up was 64 months among survivors. Both 3-year overall survival and 3-year PRS were similar in haploidentical donor (HID) and matched sibling donor (MRD) transplantation (13.0%±4.7% vs 19.4%±7.1%, P=0.913 and 7.7±3.9% vs 9.7±5.3%, P= 0.667). Higher rates of post-relapse grade II-IV and III-IV acute GvHD (aGvHD) were observed in HID transplantation patients. A higher cumulative incidence of post-relapse extensive chronic GvHD was also observed for HID transplantation patients. Multivariate analyses confirmed that treatment including donor lymphocyte infusion (DLI), late relapse >1 year, and in first CR at transplantation were associated with superior PRS (P=0.012, hazard ratio (HR)=0.527 (0.320-0.866)); P=0.033, HR=0.534 (0.300-0.952) and P=0.046, HR=0.630 (0.400-0.992). The data suggest that post-relapse outcomes are comparable in HID and MRD transplantation, and that DLI is safe for relapsed patients after haploidentical transplantation.

Diagnostic value of highly-sensitive chimerism analysis after allogeneic stem cell transplantation.

PubMed

Sellmann, Lea; Rabe, Kim; Bünting, Ivonne; Dammann, Elke; Göhring, Gudrun; Ganser, Arnold; Stadler, Michael; Weissinger, Eva M; Hambach, Lothar

2018-05-02

Conventional analysis of host chimerism (HC) frequently fails to detect relapse before its clinical manifestation in patients with hematological malignancies after allogeneic stem cell transplantation (allo-SCT). Quantitative PCR (qPCR)-based highly-sensitive chimerism analysis extends the detection limit of conventional (short tandem repeats-based) chimerism analysis from 1 to 0.01% host cells in whole blood. To date, the diagnostic value of highly-sensitive chimerism analysis is hardly defined. Here, we applied qPCR-based chimerism analysis to 901 blood samples of 71 out-patients with hematological malignancies after allo-SCT. Receiver operating characteristics (ROC) curves were calculated for absolute HC values and for the increments of HC before relapse. Using the best cut-offs, relapse was detected with sensitivities of 74 or 85% and specificities of 69 or 75%, respectively. Positive predictive values (PPVs) were only 12 or 18%, but the respective negative predictive values were 98 or 99%. Relapse was detected median 38 or 45 days prior to clinical diagnosis, respectively. Considering also durations of steadily increasing HC of more than 28 days improved PPVs to more than 28 or 59%, respectively. Overall, highly-sensitive chimerism analysis excludes relapses with high certainty and predicts relapses with high sensitivity and specificity more than a month prior to clinical diagnosis.

Late ovarian relapse of TEL/AML1 positive ALL confirming that TEL deletion is a secondary event in leukemogenesis.

PubMed

Ly-Sunnaram, Beatrice; Henry, Catherine; Gandemer, Virginie; Mee, Franseza Le; Burtin, Florence; Blayau, Martine; Cayuela, Jean-Michel; Oster, Magalie; Clech, Philippe; Rambeau, Marc; Marie, Celine; Pampin, Cecilia; Edan, Christine; Gall, Edouard Le; Goasguen, Jean E

2005-09-01

We describe here a late extramedullary ovarian relapse in an 18-year-old female who was diagnosed with hypotetraploid cell acute lymphoblastic leukaemia (cALL) at the age of 6. At both occurrences of the disease cells were analyzed by morphology, immunophenotyping, cytogenetics and molecular methods. TEL/AML1 was detected by RT-PCR and FISH analysis in both events. We demonstrated, using detection of IGH/TCR rearrangements and TEL/AML1 breakpoints sequencing that the cells were clonally related. Moreover, interphasic FISH using TEL and AML1 probes showed the loss of a second TEL at the time of relapse. This observation confirms that TEL/AML1 alone is not sufficient to trigger ALL and that TEL deletion is a secondary event in leukemogenesis. To our knowledge, it is the first complete description of extramedullary ALL relapse combining all methodologies.

Epigenetic heterogeneity affects the risk of relapse in children with t(8;21)RUNX1-RUNX1T1-rearranged AML.

PubMed

Zampini, Matteo; Tregnago, Claudia; Bisio, Valeria; Simula, Luca; Borella, Giulia; Manara, Elena; Zanon, Carlo; Zonta, Francesca; Serafin, Valentina; Accordi, Benedetta; Campello, Silvia; Buldini, Barbara; Pession, Andrea; Locatelli, Franco; Basso, Giuseppe; Pigazzi, Martina

2018-05-01

The somatic translocation t(8;21)(q22;q22)/RUNX1-RUNX1T1 is one of the most frequent rearrangements found in children with standard-risk acute myeloid leukemia (AML). Despite the favorable prognostic role of this aberration, we recently observed a higher than expected frequency of relapse. Here, we employed an integrated high-throughput approach aimed at identifying new biological features predicting relapse among 34 t(8;21)-rearranged patients. We found that the DNA methylation status of patients who suffered from relapse was peculiarly different from that of children maintaining complete remission. The epigenetic signature, made up of 337 differentially methylated regions, was then integrated with gene and protein expression profiles, leading to a network, where cell-to-cell adhesion and cell-motility pathways were found to be aberrantly activated in relapsed patients. We identified most of these factors as RUNX1-RUNX1T1 targets, with Ras Homolog Family Member (RHOB) overexpression being the core of this network. We documented how RHOB re-organized the actin cytoskeleton through its downstream ROCK-LIMK-COFILIN axis: this increases blast adhesion by stress fiber formation, and reduces mitochondrial apoptotic cell death after chemotherapy treatment. Altogether, our data show an epigenetic heterogeneity within t(8;21)-rearranged AML patients at diagnosis able to influence the program of the chimeric transcript, promoting blast re-emergence and progression to relapse.

Promising efficacy and acceptable safety of venetoclax plus bortezomib and dexamethasone in relapsed/refractory MM.

PubMed

Moreau, Philippe; Chanan-Khan, Asher; Roberts, Andrew W; Agarwal, Amit B; Facon, Thierry; Kumar, Shaji; Touzeau, Cyrille; Punnoose, Elizabeth A; Cordero, Jaclyn; Munasinghe, Wijith; Jia, Jia; Salem, Ahmed Hamed; Freise, Kevin J; Leverson, Joel D; Enschede, Sari Heitner; Ross, Jeremy A; Maciag, Paulo C; Verdugo, Maria; Harrison, Simon J

2017-11-30

The antiapoptotic proteins BCL-2 and myeloid cell leukemia sequence 1 (MCL-1) promote multiple myeloma (MM) cell survival. Venetoclax is a selective, orally bioavailable small-molecule BCL-2 inhibitor; bortezomib can indirectly inhibit MCL-1. In preclinical studies, venetoclax enhanced bortezomib activity, suggesting that cotargeting of BCL-2 and MCL-1 could be an effective treatment strategy in myeloma. This phase 1b trial studied patients with relapsed/refractory MM receiving daily venetoclax (50-1200 mg per designated dose cohort; 800 mg in safety expansion) in combination with bortezomib and dexamethasone. A total of 66 patients were enrolled (54 in the dose-escalation cohorts and 12 in the safety expansion). Patients had received a median of 3 prior therapies (range, 1-13); 26 (39%) were refractory to prior bortezomib and 35 (53%) to lenalidomide; 39 (59%) had prior stem cell transplant. The combination was generally well tolerated, and common adverse events included mild gastrointestinal toxicities (diarrhea [46%], constipation [41%], and nausea [38%]) and grade 3/4 cytopenias (thrombocytopenia [29%] and anemia [15%]). The overall response rate (ORR) was 67% (44/66); 42% achieved very good partial response or better (≥VGPR). Median time to progression and duration of response were 9.5 and 9.7 months, respectively. ORR of 97% and ≥VGPR 73% were seen in patients not refractory to bortezomib who had 1 to 3 prior therapies. Patients with high BCL2 expression had a higher ORR (94% [17/18]) than patients with low BCL2 expression (59% [16/27]). This novel combination of venetoclax with bortezomib and dexamethasone has an acceptable safety profile and promising efficacy in patients with relapsed/refractory MM. This trial was registered at www.clinicaltrials.gov as #NCT01794507. © 2017 by The American Society of Hematology.

Positron emission tomography response at the time of autologous stem cell transplantation predicts outcome of patients with relapsed and/or refractory Hodgkin’s lymphoma responding to prior salvage therapy

PubMed Central

Devillier, Raynier; Coso, Diane; Castagna, Luca; Brenot Rossi, Isabelle; Anastasia, Antonella; Chiti, Arturo; Ivanov, Vadim; Schiano, Jean Marc; Santoro, Armando; Chabannon, Christian; Balzarotti, Monica; Blaise, Didier; Bouabdallah, Reda

2012-01-01

Background High-dose chemotherapy followed by autologous stem cell transplantation is the standard treatment for relapsed and/or refractory Hodgkin’s lymphoma although half of patients relapse after transplantation. Predictive factors, such as relapse within 12 months, Ann-Arbor stage at relapse, and relapse in previously irradiated fields are classically used to identify patients with poor outcome. Recently, 18-fluorodeoxyglucose positron emission tomography has emerged as a new method for providing information to predict outcome. The aim of this study was to confirm the predictive value of positron emission tomography status after salvage therapy and to compare single versus tandem autologous stem cell transplantation in patients with relapsed and/or refractory Hodgkin’s lymphoma. Design and Methods We report a series of 111 consecutive patients with treatment-sensitive relapsed and/or treatment-refractory Hodgkin’s lymphoma who achieved complete (positron emission tomography-negative group) or partial remission (positron emission tomography-positive group) at positron emission tomography evaluation after salvage chemotherapy and who underwent single or tandem autologous stem cell transplantation. Results Five-year overall and progression-free survival rates were 81% and 64%, respectively. There were significant differences in 5-year progression-free survival (79% versus 23%; P<0.001) and 5-year overall survival (90% versus 55%, P=0.001) between the positron emission tomography-negative and -positive groups, respectively. A complete response, as determined by positron emission tomography evaluation, after salvage therapy predicted significantly better 5-year overall survival rates in both intermediate (91% versus 50%; P=0.029) and unfavorable (89% versus 58%; P=0.026) risk subgroup analyses. In the positron emission tomography-positive subgroup, tandem transplantation improved 5-year progression-free survival from 0% (in the single transplantation group) to 43% (P=0.034). Multivariate analysis showed that positron emission tomography status (hazard ratio: 5.26 [2.57–10.73]) and tandem transplantation (hazard ratio: 0.39 [0.19–0.78]) but not risk factors at relapse (hazard ratio: 1.77 [0.80–3.92]) significantly influenced progression-free survival, while only tomography status significantly influenced overall survival (hazard ratio: 4.03 [1.38–11.75]). Conclusions In patients with relapsed/refractory Hodgkin’s lymphoma responding to prior salvage therapy, positron emission tomography response at time of autologous stem cell transplantation favorably influences outcome and enables identification of patients requiring single or tandem transplantation. PMID:22271893

Urgent Chemotherapy for Life-Threatening Complications Related to Solid Neoplasms.

PubMed

Zerbib, Yoann; Rabbat, Antoine; Fartoukh, Muriel; Bigé, Naïke; Andréjak, Claire; Mayaux, Julien; De Prost, Nicolas; Misset, Benoît; Lemiale, Virginie; Bruneel, Fabrice; Maizel, Julien; Ricome, Sylvie; Jacobs, Frédéric; Bornstain, Caroline; Dupont, Hervé; Baudin, François; Azoulay, Elie; Pène, Frédéric

2017-07-01

Solid neoplasms can be directly responsible for organ failures at the time of diagnosis or relapse. The management of such specific complications relies on urgent chemotherapy and eventual instrumental or surgical procedures, combined with advanced life support. We conducted a multicenter study to address the prognosis of this condition. A multicenter retrospective (2001-2015) chart review. Medical and respiratory ICUs. Adult patients who received urgent chemotherapy in the ICU for organ failure related to solid neoplasms were included. The modalities of chemotherapy, requirements of adjuvant instrumental or surgical procedures, and organ supports were collected. Endpoints were short- and long-term survival rates. None. One hundred thirty-six patients were included. Lung cancer was the most common malignancy distributed into small cell lung cancer (n = 57) and non-small cell lung cancer (n = 33). The main reason for ICU admission was acute respiratory failure in 111 patients (81.6%), of whom 89 required invasive mechanical ventilation. Compression and tissue infiltration by tumor cells were the leading mechanisms resulting in organ involvement in 78 (57.4%) and 47 (34.6%) patients. The overall in-ICU, in-hospital, 6-month, and 1-year mortality rates were 37%, 58%, 74%, and 88%, respectively. Small cell lung cancer was identified as an independent predictor of hospital survival. However, this gain in survival was not sustained since the 1-year survival rates of small cell lung cancer, non-small cell lung cancer, and non-lung cancer patients all dropped below 20%. Urgent chemotherapy along with aggressive management of organ failures in the ICU can be lifesaving in very selected cancer patients, most especially with small cell lung cancer, although the long-term survival is hardly sustainable.

Successful treatment of post-transplant relapsed acute myeloid leukemia with FLT3 internal tandem duplication using the combination of induction chemotherapy, donor lymphocyte infusion, sorafenib and azacitidine. Report of three cases

PubMed Central

Campregher, Paulo Vidal; de Mattos, Vinicius Renan Pinto; Salvino, Marco Aurélio; Santos, Fabio Pires de Souza; Hamerschlak, Nelson

2017-01-01

ABSTRACT Acute myeloid leukemia is a hematopoietic stem cell neoplastic disease associated with high morbidity and mortality. The presence of FLT3 internal tandem duplication mutations leads to high rates of relapse and decreased overall survival. Patients with FLT3 internal tandem duplication are normally treated with hematopoietic stem cell transplantation in first complete remission. Nevertheless, the incidence of post-transplant relapse is considerable in this group of patients, and the management of this clinical condition is challenging. The report describes the outcomes of patients with FLT3 internal tandem duplication positive acute myeloid leukemia who relapsed after allogeneic hematopoietic stem cell transplantation and were treated with the combination of re-induction chemotherapy, donor lymphocyte infusion, sorafenib and azacitidine. Three cases are described and all patients achieved prolonged complete remission with the combined therapy. The combination of induction chemotherapy followed by donor lymphocyte infusion, and the maintenance with azacitidine and sorafenib can be effective approaches in the treatment of post-hematopoietic stem cell transplant and relapsed FLT3 internal tandem duplication positive acute myeloid leukemia patients. This strategy should be further explored in the context of clinical trials. PMID:28746590

Genetic heterogeneity in primary and relapsed mantle cell lymphomas: Impact of recurrent CARD11 mutations.

PubMed

Wu, Chenglin; de Miranda, Noel Fcc; Chen, Longyun; Wasik, Agata M; Mansouri, Larry; Jurczak, Wojciech; Galazka, Krystyna; Dlugosz-Danecka, Monika; Machaczka, Maciej; Zhang, Huilai; Peng, Roujun; Morin, Ryan D; Rosenquist, Richard; Sander, Birgitta; Pan-Hammarström, Qiang

2016-06-21

The genetic mechanisms underlying disease progression, relapse and therapy resistance in mantle cell lymphoma (MCL) remain largely unknown. Whole-exome sequencing was performed in 27 MCL samples from 13 patients, representing the largest analyzed series of consecutive biopsies obtained at diagnosis and/or relapse for this type of lymphoma. Eighteen genes were found to be recurrently mutated in these samples, including known (ATM, MEF2B and MLL2) and novel mutation targets (S1PR1 and CARD11). CARD11, a scaffold protein required for B-cell receptor (BCR)-induced NF-κB activation, was subsequently screened in an additional 173 MCL samples and mutations were observed in 5.5% of cases. Based on in vitro cell line-based experiments, overexpression of CARD11 mutants were demonstrated to confer resistance to the BCR-inhibitor ibrutinib and NF-κB-inhibitor lenalidomide. Genetic alterations acquired in the relapse samples were found to be largely non-recurrent, in line with the branched evolutionary pattern of clonal evolution observed in most cases. In summary, this study highlights the genetic heterogeneity in MCL, in particular at relapse, and provides for the first time genetic evidence of BCR/NF-κB activation in a subset of MCL.

Cell motility and ECM proteolysis regulate tumor growth and tumor relapse by altering the fraction of cancer stem cells and their spatial scattering

NASA Astrophysics Data System (ADS)

Kumar, Sandeep; Kulkarni, Rahul; Sen, Shamik

2016-06-01

Tumors consist of multiple cell sub-populations including cancer stem cells (CSCs), transiently amplifying cells and terminally differentiated cells (TDCs), with the CSC fraction dictating the aggressiveness of the tumor and drug sensitivity. In epithelial cancers, tumor growth is influenced greatly by properties of the extracellular matrix (ECM), with cancer progression associated with an increase in ECM density. However, the extent to which increased ECM confinement induced by an increase in ECM density influences tumor growth and post treatment relapse dynamics remains incompletely understood. In this study, we use a cellular automata-based discrete modeling approach to study the collective influence of ECM density, cell motility and ECM proteolysis on tumor growth, tumor heterogeneity, and tumor relapse after drug treatment. We show that while increased confinement suppresses tumor growth and the spatial scattering of CSCs, this effect can be reversed when cells become more motile and proteolytically active. Our results further suggest that, in addition to the absolute number of CSCs, their spatial positioning also plays an important role in driving tumor growth. In a nutshell, our study suggests that, in confined environments, cell motility and ECM proteolysis are two key factors that regulate tumor growth and tumor relapse dynamics by altering the number and spatial distribution of CSCs.

Sequential chemotherapy followed by reduced-intensity conditioning and allogeneic haematopoietic stem cell transplantation in adult patients with relapse or refractory acute myeloid leukaemia: a survey from the Acute Leukaemia Working Party of EBMT.

PubMed

Ringdén, Olle; Labopin, Myriam; Schmid, Christoph; Sadeghi, Behnam; Polge, Emmanuelle; Tischer, Johanna; Ganser, Arnold; Michallet, Mauricette; Kanz, Lothar; Schwerdtfeger, Rainer; Nagler, Arnon; Mohty, Mohamad

2017-02-01

This study analysed the outcome of 267 patients with relapse/refractory acute myeloid leukaemia (AML) who received sequential chemotherapy including fludarabine, cytarabine and amsacrine followed by reduced-intensity conditioning (RIC) and allogeneic haematopoietic stem cell transplantation (HSCT). The transplants in 77 patients were from matched sibling donors (MSDs) and those in 190 patients were from matched unrelated donors. Most patients (94·3%) were given anti-T-cell antibodies. The incidence of acute graft-versus-host disease (GVHD) of grades II-IV was 32·1% and that of chronic GVHD was 30·2%. The 3-year probability of non-relapse mortality (NRM) was 25·9%, that of relapse was 48·5%, that of GVHD-free and relapse-free survival (GRFS) was 17·8% and that of leukaemia-free survival (LFS) was 25·6%. In multivariate analysis, unrelated donor recipients more frequently had acute GVHD of grades II-IV [hazard ratio (HR) = 1·98, P = 0·017] and suffered less relapses (HR = 0·62, P = 0·01) than MSD recipients. Treatment with anti-T-cell antibodies reduced NRM (HR = 0·35, P = 0·01) and improved survival (HR = 0·49, P = 0·01), GRFS (HR = 0·37, P = 0·0004) and LFS (HR = 0·46, P = 0·005). Thus, sequential chemotherapy followed by RIC HSCT and use of anti-T-cell antibodies seems promising in patients with refractory AML. © 2016 John Wiley & Sons Ltd.

Selective T cell-depleted haploidentical hematopoietic stem cell transplantation for relapsed/refractory neuroblastoma.

PubMed

Liu, Anthony P Y; Lee, Pamela P W; Kwok, Janette S Y; Leung, Rock Y Y; Chiang, Alan K S; Ha, Shau-Yin; Cheuk, Daniel K L; Chan, Godfrey C F

2018-06-19

Relapsed/refractory NB carries a bleak outcome, warranting novel treatment options. HaploHSCT induces a graft-versus-NB effect via natural killer cell alloreactivity. Review of patients with relapsed/refractory NB who underwent haploHSCT with ex vivo T-cell depletion in our unit from 2013 through 2018. Ten patients were identified (male=5; median age at haploHSCT=6.45 y, range: 3.49-11.02 y). Indications were relapsed in 7 and refractoriness in 3; disease status at haploHSCT was CR in 2, PR in 6, and PD in 2. All patients received peripheral blood stem cell grafts after ex vivo T-cell depletion (CD3/CD19-depletion=1; TCR-αβ/CD19-depletion=4; CD3/CD45RA-depletion=4; and TCR-αβ/CD45RA-depletion=1). Conditioning regimens were fludarabine-based. Neutrophils engrafted on median D + 10 (range: D + 9 to +13), and platelets engrafted (≥20 × 10 9 /L) on median D + 8 (range: D + 5 to D + 14). Early T- and NK-cell recovery were evident. Of the 10 patients, acute rejection developed in 1 (who died of PD despite rescue HSCT), and 1 died of sepsis before engraftment; 8 experienced full donor-chimerism post-HSCT. Among the 8, 6 experienced CR, 1 died of PD, and 1 died of pulmonary hypertensive crisis before evaluation. At publication, 4 were in remission (2.8, 7.4, 28.5, and 58.9 months). No significant GvHD occurred. HaploHSCT with selective ex vivo T-cell depletion may be a safe and useful salvage strategy for relapsed/refractory NB. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Evaluation of somatostatin and nucleolin receptors for therapeutic delivery in non-small cell lung cancer stem cells applying the somatostatin-analog DOTATATE and the nucleolin-targeting aptamer AS1411.

PubMed

Holmboe, Sif; Hansen, Pernille Lund; Thisgaard, Helge; Block, Ines; Müller, Carolin; Langkjær, Niels; Høilund-Carlsen, Poul Flemming; Olsen, Birgitte Brinkmann; Mollenhauer, Jan

2017-01-01

Cancer stem cells represent the putative tumor-driving subpopulation thought to account for drug resistance, relapse, and metastatic spread of epithelial and other cancer types. Accordingly, cell surface markers for therapeutic delivery to cancer stem cells are subject of intense research. Somatostatin receptor 2 and nucleolin are known to be overexpressed by various cancer types, which have elicited comprehensive efforts to explore their therapeutic utilization. Here, we evaluated somatostatin receptor 2 targeting and nucleolin targeting for therapeutic delivery to cancer stem cells from lung cancer. Nucleolin is expressed highly but not selectively, while somatostatin receptor 2 is expressed selectively but not highly by cancer cells. The non-small cell lung cancer cell lines A549 and H1299, displayed average levels of both surface molecules as judged based on analysis of a larger cell line panel. H1299 compared to A549 cells showed significantly elevated sphere-forming capacity, indicating higher cancer stem cell content, thus qualifying as suitable test system. Nucleolin-targeting 57Co-DOTA-AS1411 aptamer showed efficient internalization by cancer cells and, remarkably, at even higher efficiency by cancer stem cells. In contrast, somatostatin receptor 2 expression levels were not sufficiently high in H1299 cells to confer efficient uptake by either non-cancer stem cells or cancer stem cells. The data provides indication that the nucleolin-targeting AS1411 aptamer might be used for therapeutic delivery to non-small cell lung cancer stem cells.

Effect of Routine Surveillance Imaging on the Outcomes of Patients With Classical Hodgkin Lymphoma After Autologous Hematopoietic Cell Transplantation.

PubMed

Kapke, Jonathan T; Epperla, Narendranath; Shah, Namrata; Richardson, Kristin; Carrum, George; Hari, Parameswaran N; Pingali, Sai R; Hamadani, Mehdi; Karmali, Reem; Fenske, Timothy S

2017-07-01

Patients with relapsed and refractory classical Hodgkin lymphoma (cHL) are often treated with autologous hematopoietic cell transplantation (auto-HCT). After auto-HCT, most transplant centers implement routine surveillance imaging to monitor for disease relapse; however, there is limited evidence to support this practice. In this multicenter, retrospective study, we identified cHL patients (n = 128) who received auto-HCT, achieved complete remission (CR) after transplantation, and then were followed with routine surveillance imaging. Of these, 29 (23%) relapsed after day 100 after auto-HCT. Relapse was detected clinically in 14 patients and with routine surveillance imaging in 15 patients. When clinically detected relapse was compared with to radiographically detected relapse respectively, the median overall survival (2084 days [range, 225-4161] vs. 2737 days [range, 172-2750]; P = .51), the median time to relapse (247 days [range, 141-3974] vs. 814 days [range, 96-1682]; P = .30) and the median postrelapse survival (674 days [range, 13-1883] vs. 1146 days [range, 4-2548]; P = .52) were not statistically different. In patients who never relapsed after auto-HCT, a median of 4 (range, 1-25) surveillance imaging studies were performed over a median follow-up period of 3.5 years. A minority of patients with cHL who achieve CR after auto-HCT will ultimately relapse. Surveillance imaging detected approximately half of relapses; however, outcomes were similar for those whose relapse was detected using routine surveillance imaging versus detected clinically in between surveillance imaging studies. There appears to be limited utility for routine surveillance imaging in cHL patients who achieve CR after auto-HCT. Copyright © 2017 Elsevier Inc. All rights reserved.

Relapsing tumefactive lesion in an adult with medulloblastoma previously treated with chemoradiotherapy and stem cell transplant.

PubMed

Mahta, Ali; Qu, Yan; Nastic, Denis; Sundstrom, Maria; Kim, Ryan Y; Saria, Marlon; Santagata, Sandro; Kesari, Santosh

2012-04-01

Herein, we present an adult case of medulloblastoma who received chemotherapy, radiation therapy and stem cell transplantation, and underwent multiple surgical resections for what were thought to be recurrences; however pathology confirmed a diagnosis of relapsing tumefactive lesions. This phenomenon seems to be a consequence of stem cell transplantation rather than a simple radiation treatment effect.

Cancer stem cells and differentiation therapy.

PubMed

Jin, Xiong; Jin, Xun; Kim, Hyunggee

2017-10-01

Cancer stem cells can generate tumors from only a small number of cells, whereas differentiated cancer cells cannot. The prominent feature of cancer stem cells is its ability to self-renew and differentiate into multiple types of cancer cells. Cancer stem cells have several distinct tumorigenic abilities, including stem cell signal transduction, tumorigenicity, metastasis, and resistance to anticancer drugs, which are regulated by genetic or epigenetic changes. Like normal adult stem cells involved in various developmental processes and tissue homeostasis, cancer stem cells maintain their self-renewal capacity by activating multiple stem cell signaling pathways and inhibiting differentiation signaling pathways during cancer initiation and progression. Recently, many studies have focused on targeting cancer stem cells to eradicate malignancies by regulating stem cell signaling pathways, and products of some of these strategies are in preclinical and clinical trials. In this review, we describe the crucial features of cancer stem cells related to tumor relapse and drug resistance, as well as the new therapeutic strategy to target cancer stem cells named "differentiation therapy."

[Myeloid sarcoma of the small bowel with inversion of chromosome 16: a description of 3 clinical cases].

PubMed

Gavrilina, O A; Bariakh, E A; Parovichnikova, E N; Troitskaia, V V; Zvonkov, E E; Kravchenko, S K; Sinitsyna, M N; Obukhova, T N; Gitis, M K; Savchenko, V G

2014-01-01

Myeloid sarcoma (MS) is a rare malignant solid tumor presented with myeloid blast cells showing varying degrees of maturation. MS may have an extramedullary site, precede, or develop simultaneously with the clinical manifestations of acute myeloid leukemia (AML); it may also occur as an AML relapse. Besides AML, MS may be a manifestation of chronic myeloid leukemia or other chronic myeloproliferative diseases. Due to the fact that this disease is rare, the bulk of the literature on MS is presented with single descriptions of retrospective studies and clinical cases. The paper describes 3 cases of MS with inversion of chromosome 16 and small bowel lesion.

Prognostic impact of paraneoplastic cushing's syndrome in small-cell lung cancer.

PubMed

Nagy-Mignotte, Hélène; Shestaeva, Oxana; Vignoud, Lucile; Guillem, Pascale; Ruckly, Stéphane; Chabre, Olivier; Sakhri, Linda; Duruisseaux, Michael; Mousseau, Mireille; Timsit, Jean-François; Moro-Sibilot, Denis

2014-04-01

Paraneoplastic Cushing's syndrome (CushingPS) in small-cell lung cancer is rare but severe. We studied 383 patients with small-cell lung cancer diagnosed between 1998 and 2012. Among them, 23 patients had CushingPS, 56 had other paraneoplastic syndrome (OtherPS), and 304 had no paraneoplastic syndrome (NoPS). After comparison of the three groups, we observed that CushingPS patients had more extensive disease: 82.6% versus 67.8% versus 53.3% (p = 0.005), respectively, with more than two metastatic sites: 63.2% versus 15.8% and 24.1% (p ≤ 0.001), a higher World Health Organization performance status (2-4): 73.9% versus 57.1% versus 43.7% (p = 0.006), greater weight loss (≥10%): 47.8% versus 33.9% versus 16.4% (p ≤ 0.001), reduced objective response to first-line treatment: 47.6% versus 74.1% versus 71.1% (p = 0.04), and poorer sensitivity to first-line treatment: 19% versus 38.9% versus 48.6% (p = 0.01). NoPS patients, with World Health Organization performance status of 3-4, had extensive disease at diagnosis, with response, sensitivity to first-line treatment, and survival similar to the CushingPS group. At relapse, the CushingPS group had no objective response to second-line treatment versus 25% versus 42.8% in OtherPS and NoPS groups, respectively (p = 0.005). The median survival of CushingPS patients was 6.6 months versus 9.2 months for OtherPS and 13.1 months for NoPS patients (p ≤ 0.001). CushingPS is a prognostic factor of death (hazard ratio, 2.31; p ≤ 0.001). CushingPS is the worst form of the paraneoplastic syndromes with particularly extensive tumors. Reduced objective response and sensitivity to first-line treatment and no response to second-line treatment suggest starting palliative care early at first line and exclusively at relapse.

IIVP salvage regimen induces high response rates in patients with relapsed lymphoma before autologous stem cell transplantation.

PubMed

Abali, Huseyin; Oyan, Basak; Koc, Yener; Kars, Ayse; Barista, Ibrahim; Uner, Aysegul; Turker, Alev; Demirkazik, Figen; Tekin, Fatma; Tekuzman, Gulten; Kansu, Emin

2005-06-01

Patients with relapsed lymphoma can be cured with high-dose chemotherapy and autologous hematopoietic stem cell transplantation (HSCT). New therapeutic approaches with better cytoreductive capacity are needed for relapsed patients to keep their chance for cure with transplantation. We report 30 patients with relapsed lymphoma, median age 43 years, treated with IIVP salvage regimen consisting of ifosfamide, mesna, idarubicin, and etoposide for 2 or 3 cycles. Seventeen patients had non-Hodgkin lymphoma (NHL) and 13 patients had Hodgkin disease (HD). Fourteen (47%) patients were at their first relapse. Overall response rate was 86.6% (n = 26) with 19 patients (63.3%) achieving complete response. Overall response rate was 92% in patients with HD and 82% in NHL. The most frequent side effects observed were grade III-IV neutropenia (87%) and thrombocytopenia (73%). IIVP regimen is a highly effective salvage therapy for patients with relapsed HD or NHL who are candidates for autologous HSCT. Close follow up is necessary because of the high incidence of grade III-IV hematologic toxicity.

Isolated CNS relapse following stem cell transplantation for juvenile myelomonocytic leukemia.

PubMed

Wilson, David B; Michalski, Jeff M; Grossman, William J; Hayashi, Robert J

2003-11-01

A 1-year-old girl with juvenile myelomonocytic leukemia (JMML) underwent allogeneic bone marrow transplantation (BMT) from her HLA-matched brother. A few months after BMT she experienced a bone marrow relapse that did not respond to withdrawal of immunosuppression. To enhance the graft-versus-leukemia (GVL) effect, she underwent peripheral stem cell transplantation (PSCT) from the same donor, using a nonmyeloablative conditioning regimen. She achieved clinical remission and developed chronic graft-versus-host disease (GVHD), which was treated with prednisone and cyclosporine A. One year after PSCT she experienced an isolated central nervous system (CNS) relapse. She was treated with intrathecal Ara-C followed by craniospinal irradiation and achieved a third clinical remission. While extramedullary relapses have been described in JMML, this is the first report of a CNS relapse. Based on this case and others in the literature, the authors suggest that newer therapies are changing the natural history of JMML. By manipulating the GVL effect it is possible to achieve a prolonged bone marrow remission, but only at the expense of unmasking the risk of late extramedullary relapse.

Dual origin of relapses in retinoic-acid resistant acute promyelocytic leukemia.

PubMed

Lehmann-Che, Jacqueline; Bally, Cécile; Letouzé, Eric; Berthier, Caroline; Yuan, Hao; Jollivet, Florence; Ades, Lionel; Cassinat, Bruno; Hirsch, Pierre; Pigneux, Arnaud; Mozziconacci, Marie-Joelle; Kogan, Scott; Fenaux, Pierre; de Thé, Hugues

2018-05-24

Retinoic acid (RA) and arsenic target the t(15;17)(q24;q21) PML/RARA driver of acute promyelocytic leukemia (APL), their combination now curing over 95% patients. We report exome sequencing of 64 matched samples collected from patients at initial diagnosis, during remission, and following relapse after historical combined RA-chemotherapy treatments. A first subgroup presents a high incidence of additional oncogenic mutations disrupting key epigenetic or transcriptional regulators (primarily WT1) or activating MAPK signaling at diagnosis. Relapses retain these cooperating oncogenes and exhibit additional oncogenic alterations and/or mutations impeding therapy response (RARA, NT5C2). The second group primarily exhibits FLT3 activation at diagnosis, which is lost upon relapse together with most other passenger mutations, implying that these relapses derive from ancestral pre-leukemic PML/RARA-expressing cells that survived RA/chemotherapy. Accordingly, clonogenic activity of PML/RARA-immortalized progenitors ex vivo is only transiently affected by RA, but selectively abrogated by arsenic. Our studies stress the role of cooperating oncogenes in direct relapses and suggest that targeting pre-leukemic cells by arsenic contributes to its clinical efficacy.

Pertuzumab and Erlotinib in Patients With Relapsed Non-Small Cell Lung Cancer: A Phase II Study Using 18F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography Imaging

PubMed Central

Mileshkin, Linda; Townley, Peter; Gitlitz, Barbara; Eaton, Keith; Mitchell, Paul; Hicks, Rodney; Wood, Katie; Amler, Lucas; Fine, Bernard M.; Loecke, David; Pirzkall, Andrea

2014-01-01

Background. Combination blockade of human epidermal growth factor receptor (HER) family signaling may confer enhanced antitumor activity than single-agent blockade. We performed a single-arm study of pertuzumab, a monoclonal antibody that inhibits HER2 dimerization, and erlotinib in relapsed non-small cell lung cancer (NSCLC). Methods. Patients received pertuzumab (840-mg loading dose and 420-mg maintenance intravenously every 3 weeks) and erlotinib (150-mg or 100-mg dose orally, daily). The primary endpoint was response rate (RR) by 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) at day 56 in all patients and those with EGFR wild-type tumors. Results. Of 41 patients, 28 (68.3%) experienced treatment-related grade ≥3 adverse events, including pneumatosis intestinalis (3 patients), resulting in early cessation of enrollment. Tissue samples from 32 patients showed mutated EGFR status in 9 of 41 (22%) and wild-type EGFR in 23 of 41 (56%). The FDG-PET RR for patients with assessments at day 56 was 19.5% in all patients (n = 41) and 8.7% in patients with wild-type EGFR NSCLC (n = 23). Investigator-assessed computed tomography RR at day 56 was 12.2%. Conclusion. FDG-PET suggests that pertuzumab plus erlotinib is an active combination, but combination therapy was poorly tolerated, which limits its clinical applicability. More research is warranted to identify drug combinations that disrupt HER receptor signaling but that exhibit improved tolerability profiles. PMID:24457379

Prognostic significance of CCND1 (cyclin D1) overexpression in primary resected non-small-cell lung cancer.

PubMed Central

Betticher, D. C.; Heighway, J.; Hasleton, P. S.; Altermatt, H. J.; Ryder, W. D.; Cerny, T.; Thatcher, N.

1996-01-01

Amplification of the CCDN1 gene encoding cyclin D1 was examined by Southern blotting and multiplex polymerase chain reaction (PCR) and occurred in 8 of 53 patients (15%) with primary resected non-small-cell lung cancer (NSCLC). These tumours and 17 additional tumours with a normal gene copy number showed overexpression of cyclin D1 (25/53, 47%), as assessed by immunostaining using a monoclonal antibody. In 22/25 cases, cyclin D1 was localised in the cytoplasm, but some (7/25) had simultaneous nuclear staining. This result is in marked contrast to that reported in breast, hepatocellular and colorectal carcinoma studies where immunostaining was invariably nuclear. Examination of a restriction fragment length polymorphic (RFLP) site within the 3'untranslated region of the cDNA following reverse transcriptase (RT)-PCR (29/53 informative cases) showed a strong association between cytoplasmic staining and imbalance in allele-specific message levels. Cyclin D1 overexpression was associated with a poorly differentiated histology (P = 0.04), less lymphocytic infiltration of the tumour (P = 0.02) and a reduction in local relapse rate (P = 0.01). The relative risk of local relapse was 9.1 in tumours without cyclin D1 overexpression (P = 0.01, Cox regression analysis). We conclude that genetic alteration of cyclin D1 is a key abnormality in lung carcinogenesis and may have diagnostic and prognostic importance in the treatment of resectable NSCLC. Images Figure 1 Figure 2 Figure 3 PMID:8562333

Amrubicin for relapsed small-cell lung cancer: a systematic review and meta-analysis of 803 patients

PubMed Central

Horita, Nobuyuki; Yamamoto, Masaki; Sato, Takashi; Tsukahara, Toshinori; Nagakura, Hideyuki; Tashiro, Ken; Shibata, Yuji; Watanabe, Hiroki; Nagai, Kenjiro; Nakashima, Kentaro; Ushio, Ryota; Ikeda, Misako; Kobayashi, Nobuaki; Shinkai, Masaharu; Kudo, Makoto; Kaneko, Takeshi

2016-01-01

Currently, amrubicin is permitted for relapsed small-cell lung carcinoma (SCLC) only in Japan. The efficacy and adverse effects of amrubicin as reported by previous studies varied greatly. The inclusion criterion was a prospective study that was able to provide data for efficacy and safety by the AMR single agent regimen as second-line chemotherapy for a patient with SCLC. Binary data were meta-analyzed with the random-model generic inverse variance method. We included nine articles consisted of 803 patients. The pooled three-, six-, and nine-month progression-free survival were 63% (95% CI 57–69%, I2 = 53%), 28% (95% CI 21–35%, I2 = 71%), and 10% (95% CI 6–14%, I2 = 41%), respectively. The pooled six-, 12-, and 18-month overall survival were 69% (95% CI 61–78%, I2 = 83%), 36% (95% CI 28–44%, I2 = 80%), and 15% (95% CI 8–21%, I2 = 81%), respectively. Amrubicin seemed much more beneficial for Japanese patients. However, compared to the efficacy of topotecan presented in a previous meta-analysis, amrubicin may be a better treatment option than topotecan for both Japanese and Euro-American. Adverse effects by amrubicin were almost exclusively observed to be hematological. Notably, grade III/IV neutropenia incidence was 70% and febrile neutropenia incidence was 12%. PMID:26750506

Intestinal Microbiota and Relapse After Hematopoietic-Cell Transplantation.

PubMed

Peled, Jonathan U; Devlin, Sean M; Staffas, Anna; Lumish, Melissa; Khanin, Raya; Littmann, Eric R; Ling, Lilan; Kosuri, Satyajit; Maloy, Molly; Slingerland, John B; Ahr, Katya F; Porosnicu Rodriguez, Kori A; Shono, Yusuke; Slingerland, Ann E; Docampo, Melissa D; Sung, Anthony D; Weber, Daniela; Alousi, Amin M; Gyurkocza, Boglarka; Ponce, Doris M; Barker, Juliet N; Perales, Miguel-Angel; Giralt, Sergio A; Taur, Ying; Pamer, Eric G; Jenq, Robert R; van den Brink, Marcel R M

2017-05-20

Purpose The major causes of mortality after allogeneic hematopoietic-cell transplantation (allo-HCT) are relapse, graft-versus-host disease (GVHD), and infection. We have reported previously that alterations in the intestinal flora are associated with GVHD, bacteremia, and reduced overall survival after allo-HCT. Because intestinal bacteria are potent modulators of systemic immune responses, including antitumor effects, we hypothesized that components of the intestinal flora could be associated with relapse after allo-HCT. Methods The intestinal microbiota of 541 patients admitted for allo-HCT was profiled by means of 16S ribosomal sequencing of prospectively collected stool samples. We examined the relationship between abundance of microbiota species or groups of related species and relapse/progression of disease during 2 years of follow-up time after allo-HCT by using cause-specific proportional hazards in a retrospective discovery-validation cohort study. Results Higher abundance of a bacterial group composed mostly of Eubacterium limosum in the validation set was associated with a decreased risk of relapse/progression of disease (hazard ratio [HR], 0.82 per 10-fold increase in abundance; 95% CI, 0.71 to 0.95; P = .009). When the patients were categorized according to presence or absence of this bacterial group, presence also was associated with less relapse/progression of disease (HR, 0.52; 95% CI, 0.31 to 0.87; P = .01). The 2-year cumulative incidences of relapse/progression among patients with and without this group of bacteria were 19.8% and 33.8%, respectively. These associations remained significant in multivariable models and were strongest among recipients of T-cell-replete allografts. Conclusion We found associations between the abundance of a group of bacteria in the intestinal flora and relapse/progression of disease after allo-HCT. These might serve as potential biomarkers or therapeutic targets to prevent relapse and improve survival after allo-HCT.

Metformin decreases the dose of chemotherapy for prolonging tumor remission in mouse xenografts involving multiple cancer cell types.

PubMed

Iliopoulos, Dimitrios; Hirsch, Heather A; Struhl, Kevin

2011-05-01

Metformin, the first-line drug for treating diabetes, selectively kills the chemotherapy resistant subpopulation of cancer stem cells (CSC) in genetically distinct types of breast cancer cell lines. In mouse xenografts, injection of metformin and the chemotherapeutic drug doxorubicin near the tumor is more effective than either drug alone in blocking tumor growth and preventing relapse. Here, we show that metformin is equally effective when given orally together with paclitaxel, carboplatin, and doxorubicin, indicating that metformin works together with a variety of standard chemotherapeutic agents. In addition, metformin has comparable effects on tumor regression and preventing relapse when combined with a four-fold reduced dose of doxorubicin that is not effective as a monotherapy. Finally, the combination of metformin and doxorubicin prevents relapse in xenografts generated with prostate and lung cancer cell lines. These observations provide further evidence for the CSC hypothesis for cancer relapse, an experimental rationale for using metformin as part of combinatorial therapy in a variety of clinical settings, and for reducing the chemotherapy dose in cancer patients.

Alectinib Dose Escalation Reinduces Central Nervous System Responses in Patients with Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer Relapsing on Standard Dose Alectinib.

PubMed

Gainor, Justin F; Chi, Andrew S; Logan, Jennifer; Hu, Ranliang; Oh, Kevin S; Brastianos, Priscilla K; Shih, Helen A; Shaw, Alice T

2016-02-01

The central nervous system (CNS) is an important and increasingly recognized site of treatment failure in anaplastic lymphoma kinase (ALK)-positive, non-small cell lung cancer (NSCLC) patients receiving ALK inhibitors. In this report, we describe two ALK-positive patients who experienced initial improvements in CNS metastases on standard dose alectinib (600 mg twice daily), but who subsequently experienced recurrences with symptomatic leptomeningeal metastases. Both patients were dose-escalated to alectinib 900 mg twice daily, resulting in repeat clinical and radiographic responses. Our results suggest that dose intensification of alectinib may be necessary to overcome incomplete ALK inhibition in the CNS and prolong the durability of responses in patients with CNS metastases, particularly those with leptomeningeal carcinomatosis. Copyright © 2015 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

Allogeneic stem cell transplantation in children with acute lymphoblastic leukemia after isolated central nervous system relapse: our experiences and review of the literature.

PubMed

Yoshihara, T; Morimoto, A; Kuroda, H; Imamura, T; Ishida, H; Tsunamoto, K; Naya, M; Hibi, S; Todo, S; Imashuku, S

2006-01-01

The prognosis of patients with acute lymphoblastic leukemia (ALL) and central nervous system (CNS) relapse has historically been very poor. Although chemo-radiotherapy has improved outcomes, some patients still have a poor prognosis after CNS relapse. Therefore, allogeneic hematopoietic stem cell transplantation (allo-SCT) has recently become an option for treatment of CNS leukemia; however, information, particularly on the long-term outcome of transplant recipients, is limited. We performed allo-SCT in eight pediatric patients with ALL (n=7) or T-cell type non-Hodgkin's lymphoma (n=1), who had isolated CNS relapse. All patients survived for a median of 70.5 (range, 13-153) months after SCT. Sequelae developed late in some patients: mental retardation (IQ=47) in one patient, severe alopecia in two patients, limited chronic graft-versus-host-disease in three patients, and amenorrhea and/or hypothyroidism in three patients. Except for a pre-school child with post transplant CNS relapse, six out of seven patients show normal school/social performance. Our results clearly indicate a high cure rate of isolated CNS relapse by allo-SCT in pediatric lymphoid malignancies; however, there needs to be further studies to determine which are the appropriate candidates for transplantation and what is the best transplant regimen to achieve high cure rate and maintain good quality of life.

Survival after stem-cell transplant in pediatric and young-adult patients with relapsed and refractory B-cell acute lymphoblastic leukemia.

PubMed

Crotta, Alessandro; Zhang, Jie; Keir, Christopher

2018-03-01

Allogeneic stem-cell transplant (allo-SCT) is the standard of care for pediatric patients with acute lymphoblastic leukemia (ALL) who relapse after frontline chemotherapy; however, for patients who relapse after allo-SCT, outcomes are very poor. Few studies have examined overall survival in this patient population, particularly in patients who received a second allo-SCT. This was a retrospective analysis using data from the Center for International Blood and Marrow Transplant Research (CIBMTR) registry. The study population included patients aged 3 to 21 years who were diagnosed with B-ALL and underwent their first allo-SCT between 2009 and 2013. The primary endpoint was the time from the date of posttransplant relapse to the date of death due to any reason. Outcomes in 1349 pediatric and young-adult patients were included in this analysis. The Kaplan-Meier estimated probability of survival at 3 years after first allo-SCT was 63.1% (95% CI, 60.2%-65.8%). Overall, 29.2% of patients relapsed after first allo-SCT and had a median survival of 7.4 months (95% CI, 6.0-9.6 months). Twenty-five patients in the analysis developed secondary malignancies, most of which were lymphoproliferative disorders. Survival rates are low in pediatric and young-adult patients who relapse after first and second allo-SCT, and new therapies are needed to improve outcomes in this population. This data can be used as a historical comparison for single-arm trials of novel therapies for this patient population, including chimeric antigen receptor T-cell therapy.

Rituximab used in three cases with relapsed non-Hodgkin’s lymphoma

PubMed Central

ELLI, MURAT; YILMAZ, SEMA; AYDIN, RAMAZAN; MURAT, SADRIYE; BILGICI, MELTEM CEYHAN; DAGDEMIR, AYHAN

2013-01-01

Relapsed or refractory B-cell non-Hodgkin’s lymphoma (B-NHL) patients have a poor prognosis. New treatment modalities have been used to improve survival rates in children with relapsed or refractory B-NHL. CD20 is expressed in >98% of childhood B-NHL and a chimeric anti-CD20 monoclonal antibody, rituximab, is increasingly being used at relapse. The aim of the present study was to determine the efficacy of rituximab on relapsed B-NHL. Three B-NHL cases were treated successfully with a combination of intensive chemotherapy protocol plus rituximab. PMID:24649209

RET fusions define a unique molecular and clinicopathologic subtype of non-small-cell lung cancer.

PubMed

Wang, Rui; Hu, Haichuan; Pan, Yunjian; Li, Yuan; Ye, Ting; Li, Chenguang; Luo, Xiaoyang; Wang, Lei; Li, Hang; Zhang, Yang; Li, Fei; Lu, Yongming; Lu, Qiong; Xu, Jie; Garfield, David; Shen, Lei; Ji, Hongbin; Pao, William; Sun, Yihua; Chen, Haiquan

2012-12-10

The RET fusion gene has been recently described in a subset of non-small-cell lung cancers (NSCLCs). Because we have limited knowledge about these tumors, this study was aimed at determining the clinicopathologic characteristics of patients with NSCLC harboring the RET fusion gene. We examined the RET fusion gene in 936 patients with surgically resected NSCLC using a reverse transcriptase polymerase chain reaction (PCR) plus quantitative real-time PCR strategy, with validation using immunohistochemical and fluorescent in situ hybridization assays. A subset of 633 lung adenocarcinomas was also studied for EGFR, KRAS, HER2, and BRAF mutations, as well as ALK rearrangements. Patient characteristics, including age, sex, smoking history, stage, grade, International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification of subtypes of lung adenocarcinoma, and relapse-free survival, were collected. Of 936 patients with NSCLC, the RET fusion gene was exclusively detected in 13 patients (11 of 633 patients with adenocarcinomas and two of 24 patients with adenosquamous cell carcinomas). Of the 13 patients, nine patients had KIF5B-RET, three patients had CCDC6-RET, and one patient had a novel NCOA4-RET fusion. Patients with lung adenocarcinomas with RET fusion gene had more poorly differentiated tumors (63.6%; P = .029 for RET v ALK, P = .007 for RET v EGFR), with a tendency to be younger (≤ 60 years; 72.7%) and never-smokers (81.8%) and to have solid subtype (63.6%) and a smaller tumor (≤ 3 cm) with N2 disease (54.4%). The median relapse-free survival was 20.9 months. RET fusion occurs in 1.4% of NSCLCs and 1.7% of lung adenocarcinomas and has identifiable clinicopathologic characteristics, warranting further clinical consideration and targeted therapy investigation.

Tamoxifen induces a pluripotency signature in breast cancer cells and human tumors.

PubMed

Notas, George; Pelekanou, Vassiliki; Kampa, Marilena; Alexakis, Konstantinos; Sfakianakis, Stelios; Laliotis, Aggelos; Askoxilakis, John; Tsentelierou, Eleftheria; Tzardi, Maria; Tsapis, Andreas; Castanas, Elias

2015-11-01

Tamoxifen is the treatment of choice in estrogen receptor alpha breast cancer patients that are eligible for adjuvant endocrine therapy. However, ∼50% of ERα-positive tumors exhibit intrinsic or rapidly acquire resistance to endocrine treatment. Unfortunately, prediction of de novo resistance to endocrine therapy and/or assessment of relapse likelihood remain difficult. While several mechanisms regulating the acquisition and the maintenance of endocrine resistance have been reported, there are several aspects of this phenomenon that need to be further elucidated. Altered metabolic fate of tamoxifen within patients and emergence of tamoxifen-resistant clones, driven by evolution of the disease phenotype during treatment, appear as the most compelling hypotheses so far. In addition, tamoxifen was reported to induce pluripotency in breast cancer cell lines, in vitro. In this context, we have performed a whole transcriptome analysis of an ERα-positive (T47D) and a triple-negative breast cancer cell line (MDA-MB-231), exposed to tamoxifen for a short time frame (hours), in order to identify how early pluripotency-related effects of tamoxifen may occur. Our ultimate goal was to identify whether the transcriptional actions of tamoxifen related to induction of pluripotency are mediated through specific ER-dependent or independent mechanisms. We report that even as early as 3 hours after the exposure of breast cancer cells to tamoxifen, a subset of ERα-dependent genes associated with developmental processes and pluripotency are induced and this is accompanied by specific phenotypic changes (expression of pluripotency-related proteins). Furthermore we report an association between the increased expression of pluripotency-related genes in ERα-positive breast cancer tissues samples and disease relapse after tamoxifen therapy. Finally we describe that in a small group of ERα-positive breast cancer patients, with disease relapse after surgery and tamoxifen treatment, ALDH1A1 (a marker of pluripotency in epithelial cancers which is absent in normal breast tissue) is increased in relapsing tumors, with a concurrent modification of its intra-cellular localization. Our data could be of value in the discrimination of patients susceptible to develop tamoxifen resistance and in the selection of optimized patient-tailored therapies. Copyright © 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Efficacy of L-asparaginase with methotrexate and dexamethasone (AspaMetDex regimen) in patients with refractory or relapsing extranodal NK/T-cell lymphoma, a phase 2 study.

PubMed

Jaccard, Arnaud; Gachard, Nathalie; Marin, Benoit; Rogez, Sylvie; Audrain, Marie; Suarez, Felipe; Tilly, Hervé; Morschhauser, Franck; Thieblemont, Catherine; Ysebaert, Loic; Devidas, Alain; Petit, Barbara; de Leval, Laurence; Gaulard, Philippe; Feuillard, Jean; Bordessoule, Dominique; Hermine, Olivier

2011-02-10

Extranodal NK/T-cell lymphoma, nasal type, is a rare and highly aggressive disease with a grim prognosis. No therapeutic strategy is currently identified in relapsing patients. We report the results of a French prospective phase II trial of an L-asparaginase-containing regimen in 19 patients with relapsed or refractory disease treated in 13 centers. Eleven patients were in relapse and 8 patients were refractory to their first line of treatment. L-Asparaginase-based treatment yielded objective responses in 14 of the 18 evaluable patients after 3 cycles. Eleven patients entered complete remission (61%), and only 4 of them relapsed. The median overall survival time was 1 year, with a median response duration of 12 months. The main adverse events were hepatitis, cytopenia, and allergy. The absence of antiasparaginase antibodies and the disappearance of Epstein-Barr virus serum DNA were significantly associated with a better outcome. These data confirm the excellent activity of L-asparaginase-containing regimens in extranodal NK/T-cell lymphoma. L-Asparaginase-based treatment should thus be considered for salvage therapy, especially in patients with disseminated disease. First-line L-asparaginase combination therapy for extranodal NK/T-cell lymphoma warrants evaluation in prospective trials. This trial is registered at www.clinicaltrials.gov as #NCT00283985.

Adoptive transfer of T cells transduced with a chimeric antigen receptor to treat relapsed or refractory acute leukemia: efficacy and feasibility of immunotherapy approaches.

PubMed

Ding, Guoliang; Chen, Hu

2016-07-01

Treatment outcomes of acute leukemia (AL) have not improved over the past several decades and relapse rates remain high despite the availability of aggressive therapies. Conventional relapsed leukemia treatment includes second allogeneic hematopoietic stem cell transplantation (allo-HSCT) and donor lymphocyte infusion (DLI), which in most cases mediate, at best, a modest graft-versus-leukemia effect, although their clinical efficacy is still limited. Although allo-HSCT following myeloablative conditioning is a curative treatment option for younger patients with acute myeloid leukemia (AML) in a first complete remission (CR), allo-HSCT as a clinical treatment is usually limited because of treatment-related toxicity. The overall DLI remission rate is only 15%-42% and 2-year overall survival (OS) is approximately 15%-20%, with a high (40%-60%) incidence of DLI-related graft-versus-host disease (GVHD). Therefore, development of new, targeted treatment strategies for relapsed and refractory AL patients is ongoing. Adoptive transfer of T cells with genetically engineered chimeric antigen receptors (CARs) is an encouraging approach for treating hematological malignancies. These T cells are capable of selectively recognizing tumor-associated antigens and may overcome many limitations of conventional therapies, inducing remission in patients with chemotherapy-refractory or relapsed AL. In this review, we aimed to highlight the current understanding of this promising treatment modality, discussing its adverse effects and efficacy.

Sunitinib in relapsed or refractory diffuse large B-cell lymphoma: a clinical and pharmacodynamic phase II multicenter study of the NCIC Clinical Trials Group.

PubMed

Buckstein, Rena; Kuruvilla, John; Chua, Neil; Lee, Christina; Macdonald, David A; Al-Tourah, Abdulwahab J; Foo, Alison H; Walsh, Wendy; Ivy, S Percy; Crump, Michael; Eisenhauer, Elizabeth A

2011-05-01

There are limited effective therapies for most patients with relapsed diffuse large B-cell lymphoma (DLBCL). We conducted a phase II trial of the multi-targeted vascular endothelial growth factor receptor (VEGFR) kinase inhibitor, sunitinib, 37.5 mg given orally once daily in adult patients with relapsed or refractory DLBCL. Of 19 enrolled patients, 17 eligible patients were evaluable for toxicity and 15 for response. No objective responses were seen and nine patients achieved stable disease (median duration 3.4 months). As a result, the study was closed at the end of the first stage. Grades 3-4 neutropenia and thrombocytopenia were observed in 29% and 35%, respectively. There was no relationship between change in circulating endothelial cell numbers (CECs) and bidimensional tumor burden over time. Despite some activity in solid tumors, sunitinib showed no evidence of response in relapsed/refractory DLBCL and had greater than expected hematologic toxicity.

Sunitinib in relapsed or refractory diffuse large B-cell lymphoma: a clinical and pharmacodynamic phase II multicenter study of the NCIC Clinical Trials Group

PubMed Central

Buckstein, Rena; Kuruvilla, John; Chua, Neil; Lee, Christina; Macdonald, David A; Al-Tourah, Abdulwahab J; Foo, Alison H; Walsh, Wendy; Ivy, S Percy; Crump, Michael; Eisenhauer, Elizabeth A

2011-01-01

There are limited effective therapies for most patients with relapsed diffuse large B-cell lymphoma (DLBCL). We conducted a phase II trial of the multi-targeted vascular endothelial growth factor receptor (VEGFR) kinase inhibitor, sunitinib, 37.5 mg given orally once daily in adult patients with relapsed or refractory DLBCL. Of 19 enrolled patients, 17 eligible patients were evaluable for toxicity and 15 for response. No objective responses were seen and nine patients achieved stable disease (median duration 3.4 months). As a result, the study was closed at the end of the first stage. Grades 3—4 neutropenia and thrombocytopenia were observed in 29% and 35%, respectively. There was no relationship between change in circulating endothelial cell numbers (CECs) and bidimensional tumor burden over time. Despite some activity in solid tumors, sunitinib showed no evidence of response in relapsed/refractory DLBCL and had greater than expected hematologic toxicity. PMID:21463120

Maintenance azacitidine after myeloablative allogeneic hematopoietic cell transplantation for myeloid malignancies.

PubMed

Maples, Kathryn T; Sabo, Roy T; McCarty, John M; Toor, Amir A; Hawks, Kelly G

2018-04-04

Allogeneic hematopoietic cell transplantation (HCT) is a curative option for patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), but carries a high risk of relapse. This retrospective review evaluates the effectiveness of maintenance azacitidine in high-risk AML and MDS patients to reduce the probability of relapse. Twenty-five patients who received maintenance azacitidine were matched to historical controls in a two-to-one ratio based on diagnosis, donor type, conditioning regimen intensity, and age. Over 90% of patients received myeloablative conditioning. There was no difference in time to hematologic relapse, overall survival, or non-relapse mortality. Maintenance therapy was stopped early in 72% of patients due to graft-versus-host-disease, relapse, infection, and intolerance (13 of 25 patients received less than 4 cycles). There was a trend towards higher toxicity in the azacitidine group. The use of prophylactic azacitidine following myeloablative allogeneic HCT outside a clinical trial cannot be recommended at this time.

Radiotherapy timing in the treatment of limited-stage small cell lung cancer: the impact of thoracic and brain irradiation on survival.

PubMed

Scotti, Vieri; Meattini, Icro; Franzese, Ciro; Saieva, Calogero; Bertocci, Silvia; Meacci, Fiammetta; Furfaro, Ilaria; Scartoni, Daniele; Cecchini, Sara; Desideri, Isacco; Ferrari, Katia; Bruni, Alessio; De Luca Cardillo, Carla; Bastiani, Paolo; Agresti, Benedetta; Mangoni, Monica; Livi, Lorenzo; Biti, Giampaolo

2014-01-01

Small cell lung cancer is an aggressive histologic subtype of lung cancer in which the role of chemotherapy and radiotherapy has been well established in limited-stage disease. We retrospectively reviewed a series of limited-stage small cell lung cancers treated with chemotherapy and thoracic and brain radiotherapy. A total of 124 patients affected by limited-stage small cell lung cancer has been treated over 10 years in our Institute. Fifty-three patients (42.8%) had concomitant radio-chemotherapy treatment and 71 patients (57.2%) a sequential treatment. Eighty-eight patients (70.9%) underwent an association of a platinum-derived drug (cisplatinum or carboplatinum) and etoposide. Prophylactic cranial irradiation was planned in all patients with histologically proven complete response to primary radio-chemotherapy. With a mean follow-up of 2.2 years, complete response was obtained in 50.8% of cases. We found a significant difference between different radio-chemotherapy association approaches (P = 0.007): percentages of overall survival were respectively 10.0%, 12.9% and 5.6% in early, late concomitant and sequential radio-chemotherapy timing. Cranial prophylaxis did not seem to influence overall survival (P = 0.21) or disease-free survival for local relapse (P = 0.34). Concomitant radio-chemotherapy is the best approach according to our experience. Our results show a benefit of prophylactic cranial irradiation in distant metastasis-free survival.

Alemtuzumab, Fludarabine Phosphate, and Total-Body Irradiation Followed by Cyclosporine and Mycophenolate Mofetil in Treating Patients Who Are Undergoing Donor Stem Cell Transplant for Hematologic Cancer

ClinicalTrials.gov

2017-04-25

Acute Undifferentiated Leukemia; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia in Remission; Adult Nasal Type Extranodal NK/T-cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative; Childhood Acute Lymphoblastic Leukemia in Remission; Childhood Acute Myeloid Leukemia in Remission; Childhood Burkitt Lymphoma; Childhood Chronic Myelogenous Leukemia; Childhood Diffuse Large Cell Lymphoma; Childhood Immunoblastic Large Cell Lymphoma; Childhood Myelodysplastic Syndromes; Childhood Nasal Type Extranodal NK/T-cell Lymphoma; Chronic Myelomonocytic Leukemia; Chronic Phase Chronic Myelogenous Leukemia; Cutaneous B-cell Non-Hodgkin Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Hepatosplenic T-cell Lymphoma; Intraocular Lymphoma; Juvenile Myelomonocytic Leukemia; Mast Cell Leukemia; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Nodal Marginal Zone B-cell Lymphoma; Noncutaneous Extranodal Lymphoma; Peripheral T-cell Lymphoma; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Childhood Anaplastic Large Cell Lymphoma; Recurrent Childhood Grade III Lymphomatoid Granulomatosis; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Small Noncleaved Cell Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Recurrent/Refractory Childhood Hodgkin Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Refractory Multiple Myeloma; Relapsing Chronic Myelogenous Leukemia; Secondary Myelodysplastic Syndromes; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; Testicular Lymphoma; Waldenström Macroglobulinemia

Mature and immature teratoma: A report from the second Italian pediatric study.

PubMed

Terenziani, Monica; D'Angelo, Paolo; Inserra, Alessandro; Boldrini, Renata; Bisogno, Gianni; Babbo, Gian Luca; Conte, Massimo; Dall' Igna, Patrizia; De Pasquale, Maria Debora; Indolfi, Paolo; Piva, Luigi; Riccipetitoni, Giovanna; Siracusa, Fortunato; Spreafico, Filippo; Tamaro, Paolo; Cecchetto, Giovanni

2015-07-01

Teratomas demonstrate a benign clinical behavior, however they may recur with malignant components or as teratoma, and in a small group of patients prognosis could be fatal. After the first Italian study, we collected cases of teratoma, alongside the protocol for malignant germ cell tumors. Patients with teratoma were collected from 2004 to 2014. Teratomas were classified according to the WHO classifications, as mature and immature. Patients with pathological aFP and/or bHCG, and those with a malignant germ cell component were not included. The study enrolled 219 patients (150 mature, 69 immature teratomas) with a median age at diagnosis of 42 months. The primary sites involved were: 118 gonadal and 101 extragonadal teratomas. Two females with ovarian teratoma had a positive family history. Complete and incomplete surgeries were performed in 85% and 9% of cases. Seventeen events occurred: six females had a second metachronous tumor (5 contralateral ovarian teratoma, 1 adrenal neuroblastoma) and 11 teratomas relapsed/progressed (3 mature, 8 immature teratomas). Two patients died, one of progressive immature teratoma and one of surgical complications. At a median follow up of 68 months, the event-free, relapse-free, and overall survival rates were 90.6%, 94.3%, 98.6%, respectively. Teratomas show a good prognosis, especially the mature ones: surgery and follow-up remain the standard approach. Incomplete surgery in immature teratoma is the group at greatest risk of relapse. Bilateral ovarian tumors are a possibility, and the rare family predisposition to ovarian mature teratoma warrants further analyses. © 2015 Wiley Periodicals, Inc.

Characteristics predicting outcomes of allogeneic stem-cell transplantation in relapsed acute myelogenous leukemia.

PubMed

Frazer, J; Couban, S; Doucette, S; Shivakumar, S

2017-04-01

Allogeneic hematopoietic stem-cell transplantation (ahsct) is associated with significant morbidity and mortality, but it can cure carefully selected patients with acute myeloid leukemia (aml) in second remission (cr2). In a cohort of patients with aml who underwent ahsct in cr2, we determined the pre-transplant factors that predicted for overall survival (os), relapse, and non-relapse mortality. We also sought to validate the prognostic risk groups derived by Michelis and colleagues in this independent population. In a retrospective chart review, we obtained data for 55 consecutive patients who underwent ahsct for aml in cr2. Hazard ratios were used to describe the independent effects of pre-transplant variables on outcome, and Kaplan-Meier curves were used to assess outcomes in the three prognostic groups identified by Michelis and colleagues. At 1, 3, and 5 years post-transplant, os was 60%, 45.5%, and 37.5% respectively. Statistically significant differences in os, relapse mortality, and non-relapse mortality were not identified between the prognostic risk groups identified by Michelis and colleagues. Women were less likely than men to relapse, and a modified European Society for Blood and Marrow Transplantation (mebmt) score of 3 or less was associated with a lower non-relapse mortality. The 37.5% 5-year os in this cohort suggests that, compared with other options, ahsct offers patients with aml in cr2 a better chance of cure. Our study supports the use of the mebmt score to predict non-relapse mortality in this population.

Outcome after intensive reinduction therapy and allogeneic stem cell transplant in paediatric relapsed acute myeloid leukaemia.

PubMed

Karlsson, Lene; Forestier, Erik; Hasle, Henrik; Jahnukainen, Kirsi; Jónsson, Ólafur G; Lausen, Birgitte; Norén Nyström, Ulrika; Palle, Josefine; Tierens, Anne; Zeller, Bernward; Abrahamsson, Jonas

2017-08-01

Given that 30-40% of children with acute myeloid leukaemia (AML) relapse after primary therapy it is important to define prognostic factors and identify optimal therapy. From 1993 to 2012, 543 children from the Nordic countries were treated according to two consecutive protocols: 208 children relapsed. The influence of disease characteristics, first line treatment, relapse therapy and duration of first remission on outcome was analysed. Second complete remission (CR2) was achieved in 146 (70%) patients. Estimated 5-year overall survival (OS 5y ) was 39 ± 4% for the whole group and 43 ± 4% for the 190 patients given re-induction therapy, of whom 76% received regimens that included fludarabine, cytarabine (FLA) ± anthracyclines, 18% received Nordic Society for Paediatric Haematology and Oncology (NOPHO) upfront blocks and 5% received other regimens. Late relapse ≥1 year from diagnosis, no allogeneic stem cell transplantation (SCT) in first remission and core binding factor AML were independent favourable prognostic factors for survival. For the 128 children (124 in CR2) that received SCT as consolidation therapy after relapse, OS 5y was 61 ± 5%. Four of 19 children (21%) survived without receiving SCT as part of relapse therapy. Our data show that intensive re-induction followed by SCT can give cure rates of 40% in children with relapsed AML. © 2017 John Wiley & Sons Ltd.

VDJ-Seq: Deep Sequencing Analysis of Rearranged Immunoglobulin Heavy Chain Gene to Reveal Clonal Evolution Patterns of B Cell Lymphoma.

PubMed

Jiang, Yanwen; Nie, Kui; Redmond, David; Melnick, Ari M; Tam, Wayne; Elemento, Olivier

2015-12-28

Understanding tumor clonality is critical to understanding the mechanisms involved in tumorigenesis and disease progression. In addition, understanding the clonal composition changes that occur within a tumor in response to certain micro-environment or treatments may lead to the design of more sophisticated and effective approaches to eradicate tumor cells. However, tracking tumor clonal sub-populations has been challenging due to the lack of distinguishable markers. To address this problem, a VDJ-seq protocol was created to trace the clonal evolution patterns of diffuse large B cell lymphoma (DLBCL) relapse by exploiting VDJ recombination and somatic hypermutation (SHM), two unique features of B cell lymphomas. In this protocol, Next-Generation sequencing (NGS) libraries with indexing potential were constructed from amplified rearranged immunoglobulin heavy chain (IgH) VDJ region from pairs of primary diagnosis and relapse DLBCL samples. On average more than half million VDJ sequences per sample were obtained after sequencing, which contain both VDJ rearrangement and SHM information. In addition, customized bioinformatics pipelines were developed to fully utilize sequence information for the characterization of IgH-VDJ repertoire within these samples. Furthermore, the pipeline allows the reconstruction and comparison of the clonal architecture of individual tumors, which enables the examination of the clonal heterogeneity within the diagnosis tumors and deduction of clonal evolution patterns between diagnosis and relapse tumor pairs. When applying this analysis to several diagnosis-relapse pairs, we uncovered key evidence that multiple distinctive tumor evolutionary patterns could lead to DLBCL relapse. Additionally, this approach can be expanded into other clinical aspects, such as identification of minimal residual disease, monitoring relapse progress and treatment response, and investigation of immune repertoires in non-lymphoma contexts.

PDL Progenitor-Mediated PDL Recovery Contributes to Orthodontic Relapse.

PubMed

Feng, L; Yang, R; Liu, D; Wang, X; Song, Y; Cao, H; He, D; Gan, Y; Kou, X; Zhou, Y

2016-08-01

Periodontal ligament (PDL) is subjected to mechanical force during physiologic activities. PDL stem /: progenitor cells are the main mesenchymal stem cells in PDL. However, how PDL progenitors participate in PDL homeostasis upon and after mechanical force is largely unknown. In this study, force-triggered orthodontic tooth movement and the following relapse were used as models to demonstrate the response of PDL progenitors and their role in PDL remodeling upon and after mechanical force. Upon orthodontic force, PDL collagen on the compression side significantly degraded, showing a broken and disorganized pattern. After force withdrawal, the degraded PDL collagen recovered during the early stage of relapse. Correspondingly, increased CD90(+) PDL progenitors with suppressed expression of type I collagen (Col-I) were observed upon orthodontic force, whereas these cells accumulated at the degradation regions and regained Col-I expression after force withdrawal during early relapse. Our results further showed that compressive force altered cell morphology and repressed collagen expression in cultured PDL progenitors, which both recovered after force withdrawal. Force withdrawal-induced recovery of collagen expression in cultured PDL progenitors could be regulated by transforming growth factor-β (TGF-β), a key molecule for tissue homeostasis and extracellular matrix remodeling. More interesting, inhibiting the regained Col-I expression in CD90(+) PDL progenitors by blocking TGF-β interrupted PDL collagen recovery and partially inhibited the early relapse. These data suggest that PDL progenitors can respond to mechanical force and may process intrinsic stability to recover to original status after force withdrawal. PDL progenitors with intrinsic stability are required for PDL recovery and consequently contribute to early orthodontic relapse, which can be regulated by TGF-β signaling. © International & American Associations for Dental Research 2016.

Primary cutaneous marginal zone B-cell lymphoma: response to treatment and disease-free survival in a series of 137 patients.

PubMed

Servitje, Octavio; Muniesa, Cristina; Benavente, Yolanda; Monsálvez, Verónica; Garcia-Muret, M Pilar; Gallardo, Fernando; Domingo-Domenech, Eva; Lucas, Anna; Climent, Fina; Rodriguez-Peralto, Jose L; Ortiz-Romero, Pablo L; Sandoval, Juan; Pujol, Ramon M; Estrach, M Teresa

2013-09-01

Primary cutaneous marginal zone B-cell lymphomas are low-grade lymphomas running an indolent course. Skin relapses have been frequently reported but little information about disease-free survival (DFS) is available. We sought to evaluate relapse rate and DFS in patients with primary cutaneous marginal zone B-cell lymphomas. Clinical features, European Organization for Research and Treatment of Cancer/International Society for Cutaneous Lymphomas stage, light chain restriction, clonality, treatments, skin relapses, DFS, stage progression, extracutaneous disease, and outcome are analyzed in a series of 137 patients. Patients were classified as solitary lesion (T1) (n = 70; 51%), regional skin involvement (T2) (n = 40; 29%), and generalized skin lesions (T3) (n = 27; 20%). Surgical excision, local radiotherapy, or a combination were the initial treatment in 118 patients (86%). In 121 of 137 patients (88%) a complete remission was observed after initial treatment, including 99 of 106 patients (93%) with solitary or localized disease and 22 of 31 patients (71%) with multifocal lesions. Cutaneous relapses were observed in 53 patients (44%). Median DFS was 47 months. Patients with multifocal lesions or T3 disease showed higher relapse rate and shorter DFS. No significant differences were observed between surgery and radiotherapy, but surgery alone was associated with more recurrences at initial site. Overall survival at 5 and 10 years was 93%. Six patients (4%) developed extracutaneous disease during follow-up. This was a case series retrospective study. Our results support long-term follow-up in patients with primary cutaneous marginal zone B-cell lymphomas. Disseminated skin lesions have higher relapse rate and shorter DFS suggesting further investigation on systemic therapies in such a group of patients. Copyright © 2013 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.

Early recovery of T-cell function predicts improved survival after T-cell depleted allogeneic transplant.

PubMed

Goldberg, Jenna D; Zheng, Junting; Ratan, Ravin; Small, Trudy N; Lai, Kuan-Chi; Boulad, Farid; Castro-Malaspina, Hugo; Giralt, Sergio A; Jakubowski, Ann A; Kernan, Nancy A; O'Reilly, Richard J; Papadopoulos, Esperanza B; Young, James W; van den Brink, Marcel R M; Heller, Glenn; Perales, Miguel-Angel

2017-08-01

Infection, relapse, and GVHD can complicate allogeneic hematopoietic stem cell transplantation (allo-HSCT). Although the effect of poor immune recovery on infection risk is well-established, there are limited data on the effect of immune reconstitution on relapse and survival, especially following T-cell depletion (TCD). To characterize the pattern of immune reconstitution in the first year after transplant and its effects on survival and relapse, we performed a retrospective study in 375 recipients of a myeloablative TCD allo-HSCT for hematologic malignancies. We noted that different subsets recover sequentially, CD8 + T cells first, followed by total CD4 + and naïve CD4 + T cells, indicating thymic recovery during the first year after HSCT. In the multivariate model, a fully HLA-matched donor and recovery of T-cell function, assessed by PHA response at 6 months, were the only factors independently associated with OS and EFS. In conclusion, T-cell recovery is an important predictor of outcome after TCD allo-HSCT.

Temporal changes in incidence and pattern of central nervous system relapses in children with acute lymphoblastic leukaemia treated on four consecutive Medical Research Council Trials, 1985–2001

PubMed Central

Krishnan, Shekhar; Wade, Rachel; Moorman, Anthony V; Mitchell, Chris; Kinsey, Sally E; Eden, TOB; Parker, Catriona; Vora, Ajay; Richards, Sue; Saha, Vaskar

2009-01-01

Despite the success of contemporary treatment protocols in childhood acute lymphoblastic leukaemia (ALL), relapse within the central nervous system (CNS) remains a challenge. To better understand this phenomenon, we have analysed the changes in incidence and pattern of CNS relapses in 5564 children enrolled on four successive MRC-ALL trials between 1985 and 2001. Changes in the incidence and pattern of CNS relapses were examined and the relationship with patient characteristics assessed. Factors affecting post-relapse outcome were determined. Overall, relapses declined by 49%. Decreases occurred primarily in non-CNS and combined relapses with a progressive shift towards later (≥30 months from diagnosis) relapses (p<0·0001). Although isolated CNS relapses declined, the proportional incidence and timing of relapse remained unchanged. Age and presenting white cell count were risk factors for CNS relapse. On multivariate analysis, the time to relapse and the trial period influenced post-relapse outcomes. Relapse trends differed within biological subtypes. In ETV6-RUNX1 ALL, relapse patterns mirrored overall trends while in High Hyperdiploidy ALL, these appear to have plateaued over the latter two trial periods. Intensive systemic and intrathecal chemotherapy have decreased the overall CNS relapse rates and changed the patterns of recurrence. The heterogeneity of therapeutic response in the biological subtypes suggests room for further optimisation using currently available chemotherapy. PMID:20016529

Jab1/Csn5-thioredoxin signaling in relapsed acute monocytic leukemia under oxidative stress

PubMed Central

Zhou, Fuling; Pan, Yunbao; Wei, Yongchang; Zhang, Ronghua; Bai, Gaigai; Shen, Qiuju; Meng, Shan; Le, Xiao-Feng; Andreeff, Michael; Claret, Francois X.

2018-01-01

Purpose High levels of ROS and ineffective antioxidant systems contribute to oxidative stress, which affects the function of hematopoietic cells in acute myeloid leukemia (AML); however, the mechanisms by which ROS lead to malignant transformation in relapsed AML-M5 are not completely understood. We hypothesized that alterations in intracellular ROS would trigger AML-M5 relapse by activating the intrinsic pathway. Experimental Design We studied ROS levels and conducted JAB1/COPS5 and TRX gene expression analyses with blood samples obtained from 60 matched AML-M5 patients at diagnosis and relapse and conducted mechanism studies of Jab1’s regulation of Trx in leukemia cell lines. Results Our data showed that increased production of ROS and a low capacity of antioxidant enzymes were characteristics of AML-M5, both at diagnosis and at relapse. Consistently, increased gene expression levels of thioredoxin (TRX) and c-Jun activation domain-binding protein-1 (JAB1/COPS5) were associated with low overall survival rates in patients with AML-M5. In addition, stimulating AML-M5 cells with low concentrations of hydrogen peroxide led to increased Jab1 and Trx expression. Consistently, transfection of ectopic Jab1 into leukemia cells increased Trx expression, whereas silencing of Jab1 in leukemia cells reduced Trx expression. Mechanistically, Jab1 interacted with Trx and stabilized Trx protein. Moreover, Jab1 transcriptionally regulated Trx. Furthermore, depletion of Jab1 inhibited leukemia cell growth both in vitro and in vivo. Conclusions We identified a novel Jab1-Trx axis that is a key cellular process in the pathobiologic characteristics of AML-M5. Targeting the ROS/Jab1/Trx pathway could be beneficial in the treatment of AML-M5. PMID:28270496

Myelodysplastic syndrome evolving from aplastic anemia treated with immunosuppressive therapy: efficacy of hematopoietic stem cell transplantation.

PubMed

Kim, Sung-Yong; Le Rademacher, Jennifer; Antin, Joseph H; Anderlini, Paolo; Ayas, Mouhab; Battiwalla, Minoo; Carreras, Jeanette; Kurtzberg, Joanne; Nakamura, Ryotaro; Eapen, Mary; Deeg, H Joachim

2014-12-01

A proportion of patients with aplastic anemia who are treated with immunosuppressive therapy develop clonal hematologic disorders, including post-aplastic anemia myelodysplastic syndrome. Many will proceed to allogeneic hematopoietic stem cell transplantation. We identified 123 patients with post-aplastic anemia myelodysplastic syndrome who from 1991 through 2011 underwent allogeneic hematopoietic stem cell transplantation, and in a matched-pair analysis compared outcome to that in 393 patients with de novo myelodysplastic syndrome. There was no difference in overall survival. There were no significant differences with regard to 5-year probabilities of relapse, non-relapse mortality, relapse-free survival and overall survival; these were 14%, 40%, 46% and 49% for post-aplastic anemia myelodysplastic syndrome, and 20%, 33%, 47% and 49% for de novo myelodysplastic syndrome, respectively. In multivariate analysis, relapse (hazard ratio 0.71; P=0.18), non-relapse mortality (hazard ratio 1.28; P=0.18), relapse-free survival (hazard ratio 0.97; P=0.80) and overall survival (hazard ratio 1.02; P=0.88) of post-aplastic anemia myelodysplastic syndrome were similar to those of patients with de novo myelodysplastic syndrome. Cytogenetic risk was independently associated with overall survival in both groups. Thus, transplant success in patients with post-aplastic anemia myelodysplastic syndrome was similar to that in patients with de novo myelodysplastic syndrome, and cytogenetics was the only significant prognostic factor for post-aplastic anemia myelodysplastic syndrome patients. Copyright© Ferrata Storti Foundation.

Suppressors and activators of JAK-STAT signaling at diagnosis and relapse of acute lymphoblastic leukemia in Down syndrome

PubMed Central

Schwartzman, Omer; Savino, Angela Maria; Gombert, Michael; Palmi, Chiara; Cario, Gunnar; Schrappe, Martin; Eckert, Cornelia; von Stackelberg, Arend; Huang, Jin-Yan; Hameiri-Grossman, Michal; Avigad, Smadar; te Kronnie, Geertruy; Geron, Ifat; Birger, Yehudit; Rein, Avigail; Zarfati, Giulia; Fischer, Ute; Mukamel, Zohar; Stanulla, Martin; Biondi, Andrea; Cazzaniga, Giovanni; Vetere, Amedeo; Wagner, Bridget K.; Chen, Zhu; Chen, Sai-Juan; Tanay, Amos; Borkhardt, Arndt; Izraeli, Shai

2017-01-01

Children with Down syndrome (DS) are prone to development of high-risk B-cell precursor ALL (DS-ALL), which differs genetically from most sporadic pediatric ALLs. Increased expression of cytokine receptor-like factor 2 (CRLF2), the receptor to thymic stromal lymphopoietin (TSLP), characterizes about half of DS-ALLs and also a subgroup of sporadic “Philadelphia-like” ALLs. To understand the pathogenesis of relapsed DS-ALL, we performed integrative genomic analysis of 25 matched diagnosis-remission and -relapse DS-ALLs. We found that the CRLF2 rearrangements are early events during DS-ALL evolution and generally stable between diagnoses and relapse. Secondary activating signaling events in the JAK-STAT/RAS pathway were ubiquitous but highly redundant between diagnosis and relapse, suggesting that signaling is essential but that no specific mutations are “relapse driving.” We further found that activated JAK2 may be naturally suppressed in 25% of CRLF2pos DS-ALLs by loss-of-function aberrations in USP9X, a deubiquitinase previously shown to stabilize the activated phosphorylated JAK2. Interrogation of large ALL genomic databases extended our findings up to 25% of CRLF2pos, Philadelphia-like ALLs. Pharmacological or genetic inhibition of USP9X, as well as treatment with low-dose ruxolitinib, enhanced the survival of pre-B ALL cells overexpressing mutated JAK2. Thus, somehow counterintuitive, we found that suppression of JAK-STAT “hypersignaling” may be beneficial to leukemic B-cell precursors. This finding and the reduction of JAK mutated clones at relapse suggest that the therapeutic effect of JAK specific inhibitors may be limited. Rather, combined signaling inhibitors or direct targeting of the TSLP receptor may be a useful therapeutic strategy for DS-ALL. PMID:28461505

Suppressors and activators of JAK-STAT signaling at diagnosis and relapse of acute lymphoblastic leukemia in Down syndrome.

PubMed

Schwartzman, Omer; Savino, Angela Maria; Gombert, Michael; Palmi, Chiara; Cario, Gunnar; Schrappe, Martin; Eckert, Cornelia; von Stackelberg, Arend; Huang, Jin-Yan; Hameiri-Grossman, Michal; Avigad, Smadar; Te Kronnie, Geertruy; Geron, Ifat; Birger, Yehudit; Rein, Avigail; Zarfati, Giulia; Fischer, Ute; Mukamel, Zohar; Stanulla, Martin; Biondi, Andrea; Cazzaniga, Giovanni; Vetere, Amedeo; Wagner, Bridget K; Chen, Zhu; Chen, Sai-Juan; Tanay, Amos; Borkhardt, Arndt; Izraeli, Shai

2017-05-16

Children with Down syndrome (DS) are prone to development of high-risk B-cell precursor ALL (DS-ALL), which differs genetically from most sporadic pediatric ALLs. Increased expression of cytokine receptor-like factor 2 (CRLF2), the receptor to thymic stromal lymphopoietin (TSLP), characterizes about half of DS-ALLs and also a subgroup of sporadic "Philadelphia-like" ALLs. To understand the pathogenesis of relapsed DS-ALL, we performed integrative genomic analysis of 25 matched diagnosis-remission and -relapse DS-ALLs. We found that the CRLF2 rearrangements are early events during DS-ALL evolution and generally stable between diagnoses and relapse. Secondary activating signaling events in the JAK-STAT/RAS pathway were ubiquitous but highly redundant between diagnosis and relapse, suggesting that signaling is essential but that no specific mutations are "relapse driving." We further found that activated JAK2 may be naturally suppressed in 25% of CRLF2 pos DS-ALLs by loss-of-function aberrations in USP9X, a deubiquitinase previously shown to stabilize the activated phosphorylated JAK2. Interrogation of large ALL genomic databases extended our findings up to 25% of CRLF2 pos , Philadelphia-like ALLs. Pharmacological or genetic inhibition of USP9X, as well as treatment with low-dose ruxolitinib, enhanced the survival of pre-B ALL cells overexpressing mutated JAK2. Thus, somehow counterintuitive, we found that suppression of JAK-STAT "hypersignaling" may be beneficial to leukemic B-cell precursors. This finding and the reduction of JAK mutated clones at relapse suggest that the therapeutic effect of JAK specific inhibitors may be limited. Rather, combined signaling inhibitors or direct targeting of the TSLP receptor may be a useful therapeutic strategy for DS-ALL.

Rationale and design of the German-Speaking Myeloma Multicenter Group (GMMG) trial ReLApsE: a randomized, open, multicenter phase III trial of lenalidomide/dexamethasone versus lenalidomide/dexamethasone plus subsequent autologous stem cell transplantation and lenalidomide maintenance in patients with relapsed multiple myeloma.

PubMed

Baertsch, Marc-Andrea; Schlenzka, Jana; Mai, Elias K; Merz, Maximilian; Hillengaß, Jens; Raab, Marc S; Hose, Dirk; Wuchter, Patrick; Ho, Anthony D; Jauch, Anna; Hielscher, Thomas; Kunz, Christina; Luntz, Steffen; Klein, Stefan; Schmidt-Wolf, Ingo G H; Goerner, Martin; Schmidt-Hieber, Martin; Reimer, Peter; Graeven, Ullrich; Fenk, Roland; Salwender, Hans; Scheid, Christof; Nogai, Axel; Haenel, Mathias; Lindemann, Hans W; Martin, Hans; Noppeney, Richard; Weisel, Katja; Goldschmidt, Hartmut

2016-04-25

Despite novel therapeutic agents, most multiple myeloma (MM) patients eventually relapse. Two large phase III trials have shown significantly improved response rates (RR) of lenalidomide/dexamethasone compared with placebo/dexamethasone in relapsed MM (RMM) patients. These results have led to the approval of lenalidomide for RMM patients and lenalidomide/dexamethasone has since become a widely accepted second-line treatment. Furthermore, in RMM patients consolidation with high-dose chemotherapy plus autologous stem cell transplantation has been shown to significantly increase progression free survival (PFS) as compared to cyclophosphamide in a phase III trial. The randomized prospective ReLApsE trial is designed to evaluate PFS after lenalidomide/dexamethasone induction, high-dose chemotherapy consolidation plus autologous stem cell transplantation and lenalidomide maintenance compared with the well-established lenalidomide/dexamethasone regimen in RMM patients. ReLApsE is a randomized, open, multicenter phase III trial in a planned study population of 282 RMM patients. All patients receive three lenalidomide/dexamethasone cycles and--in absence of available stem cells from earlier harvesting--undergo peripheral blood stem cell mobilization and harvesting. Subsequently, patients in arm A continue on consecutive lenalidomide/dexamethasone cycles, patients in arm B undergo high dose chemotherapy plus autologous stem cell transplantation followed by lenalidomide maintenance until discontinuation criteria are met. Therapeutic response is evaluated after the 3(rd) (arm A + B) and the 5(th) lenalidomide/dexamethasone cycle (arm A) or 2 months after autologous stem cell transplantation (arm B) and every 3 months thereafter (arm A + B). After finishing the study treatment, patients are followed up for survival and subsequent myeloma therapies. The expected trial duration is 6.25 years from first patient in to last patient out. The primary endpoint is PFS, secondary endpoints include overall survival (OS), RR, time to best response and the influence of early versus late salvage high dose chemotherapy plus autologous stem cell transplantation on OS. This phase III trial is designed to evaluate whether high dose chemotherapy plus autologous stem cell transplantation and lenalidomide maintenance after lenalidomide/dexamethasone induction improves PFS compared with the well-established continued lenalidomide/dexamethasone regimen in RMM patients. ISRCTN16345835 (date of registration 2010-08-24).

A partial differential equation model and its reduction to an ordinary differential equation model for prostate tumor growth under intermittent hormone therapy.

PubMed

Tao, Youshan; Guo, Qian; Aihara, Kazuyuki

2014-10-01

Hormonal therapy with androgen suppression is a common treatment for advanced prostate tumors. The emergence of androgen-independent cells, however, leads to a tumor relapse under a condition of long-term androgen deprivation. Clinical trials suggest that intermittent androgen suppression (IAS) with alternating on- and off-treatment periods can delay the relapse when compared with continuous androgen suppression (CAS). In this paper, we propose a mathematical model for prostate tumor growth under IAS therapy. The model elucidates initial hormone sensitivity, an eventual relapse of a tumor under CAS therapy, and a delay of a relapse under IAS therapy, which are due to the coexistence of androgen-dependent cells, androgen-independent cells resulting from reversible changes by adaptation, and androgen-independent cells resulting from irreversible changes by genetic mutations. The model is formulated as a free boundary problem of partial differential equations that describe the evolution of populations of the abovementioned three types of cells during on-treatment periods and off-treatment periods. Moreover, the model can be transformed into a piecewise linear ordinary differential equation model by introducing three new volume variables, and the study of the resulting model may help to devise optimal IAS schedules.

Preventing Relapse to Cigarette Smoking by Behavioral Skill Training.

ERIC Educational Resources Information Center

Hall, Sharon M.; And Others

Although smoking cessation techniques have been effective, few programs have long term results. To investigate the effectiveness of a tobacco dependence relapse prevention program, 123 adult smokers (51 male, 72 female) voluntarily participated in one of four small group treatment conditions (6 or 30 second aversive smoking plus skill training, or…

Cancer evolution, mutations, and clonal selection in relapse neuroblastoma.

PubMed

Schulte, Marc; Köster, Johannes; Rahmann, Sven; Schramm, Alexander

2018-05-01

The notion of cancer as a complex evolutionary system has been validated by in-depth molecular analyses of tumor progression over the last years. While a complex interplay of cell-autonomous programs and cell-cell interactions determines proliferation and differentiation during normal development, intrinsic and acquired plasticity of cancer cells allow for evasion of growth factor limitations, apoptotic signals, or attacks from the immune system. Treatment-induced molecular selection processes have been described by a number of studies already, but understanding of those events facilitating metastatic spread, organ-specific homing, and resistance to anoikis is still in its early days. In principle, somatic events giving rise to cancer progression should be easier to follow in childhood tumors bearing fewer mutations and genomic aberrations than their counterparts in adulthood. We have previously reported on the genetic events accompanying relapsing neuroblastoma, a solid tumor of early childhood. Our results indicated significantly higher single nucleotide variants in relapse tumors, gave hints for branched tumor evolution upon treatment and clonal selection as deduced from shifts in allelic frequencies between primary and relapsing neuroblastoma. Here, we will review these findings and give an outlook on dealing with intratumoral heterogeneity and sub-clonal diversity in neuroblastoma for future targeted treatments.

A Mathematical Model of Intermittent Androgen Suppression for Prostate Cancer

NASA Astrophysics Data System (ADS)

Ideta, Aiko Miyamura; Tanaka, Gouhei; Takeuchi, Takumi; Aihara, Kazuyuki

2008-12-01

For several decades, androgen suppression has been the principal modality for treatment of advanced prostate cancer. Although the androgen deprivation is initially effective, most patients experience a relapse within several years due to the proliferation of so-called androgen-independent tumor cells. Bruchovsky et al. suggested in animal models that intermittent androgen suppression (IAS) can prolong the time to relapse when compared with continuous androgen suppression (CAS). Therefore, IAS has been expected to enhance clinical efficacy in conjunction with reduction in adverse effects and improvement in quality of life of patients during off-treatment periods. This paper presents a mathematical model that describes the growth of a prostate tumor under IAS therapy based on monitoring of the serum prostate-specific antigen (PSA). By treating the cancer tumor as a mixed assembly of androgen-dependent and androgen-independent cells, we investigate the difference between CAS and IAS with respect to factors affecting an androgen-independent relapse. Numerical and bifurcation analyses show how the tumor growth and the relapse time are influenced by the net growth rate of the androgen-independent cells, a protocol of the IAS therapy, and the mutation rate from androgen-dependent cells to androgen-independent ones.

Waldenstrom macroglobulinemia: prognosis and management

PubMed Central

Oza, A; Rajkumar, S V

2015-01-01

Waldenstrom macroglobulinemia (WM) is a B-cell lymphoplasmacytic lymphoma characterized by monoclonal immunoglobulin M protein in the serum and infiltration of bone marrow with lymphoplasmacytic cells. Asymptomatic patients can be observed without therapy. First-line therapy should consist of the monoclonal anti-CD20 antibody, rituximab, given typically in combination with other agents. We prefer dexamethasone, rituximab, cyclophosphamide (DRC) as initial therapy for most patients with symptomatic WM. Other reasonable options are bortezomib, rituximab, dexamethasone (BoRD) or bendamustine plus rituximab (BR). All of these regimens are associated with excellent response and tolerability. Initial therapy is usually administered for 6 months, followed by observation. Response to therapy is assessed using the standard response criteria developed by the International Working Group on Waldenstrom macroglobulinemia. Relapse is almost inevitable in WM but may occur years after initial therapy. In symptomatic patients relapsing more than 1–2 years after initial therapy, the original treatment can be repeated. For relapse occurring sooner, an alternative regimen is used. In select patients, high-dose chemotherapy followed by autologous hematopoietic cell transplantation may be an option at relapse. Options for therapy of relapsed WM besides regimens used in the front-line setting include ibrutinib, purine nucleoside analogs (cladribine, fludarabine), carfilzomib and immunomodulatory agents (thalidomide, lenalidomide). PMID:25815903

Monitoring of minimal residual disease after allogeneic stem-cell transplantation in relapsed childhood acute lymphoblastic leukemia allows for the identification of impending relapse: results of the ALL-BFM-SCT 2003 trial.

PubMed

Bader, Peter; Kreyenberg, Hermann; von Stackelberg, Arend; Eckert, Cornelia; Salzmann-Manrique, Emilia; Meisel, Roland; Poetschger, Ulrike; Stachel, Daniel; Schrappe, Martin; Alten, Julia; Schrauder, Andre; Schulz, Ansgar; Lang, Peter; Müller, Ingo; Albert, Michael H; Willasch, Andre M; Klingebiel, Thomas E; Peters, Christina

2015-04-10

To elucidate the impact of minimal residual disease (MRD) after allogeneic transplantation, the Acute Lymphoblastic Leukemia Berlin-Frankfurt-Münster Stem Cell Transplantation Group (ALL-BFM-SCT) conducted a prospective clinical trial. In the ALL-BFM-SCT 2003 trial, MRD was assessed in the bone marrow at days +30, +60, +90, +180, and +365 after transplantation in 113 patients with relapsed disease. Standardized quantification of MRD was performed according to the guidelines of the Euro-MRD Group. All patients showed a 3-year probability of event-free survival (pEFS) of 55%. The cumulative incidence rates of relapse and treatment-related mortality were 32% and 12%, respectively. The pEFS was 60% for patients who received their transplantations in second complete remission, 50% for patients in ≥ third complete remission, and 0% for patients not in remission (P = .015). At all time points, the level of MRD was inversely correlated with event-free survival (EFS; P < .004) and positively correlated with the cumulative incidence of relapse (P < .01). A multivariable Cox model was fitted for each time point, which showed that MRD ≥ 10(-4) leukemic cells was consistently correlated with inferior EFS (P < .003). The accuracy of MRD measurements in predicting relapse was investigated with time-dependent receiver operating curves at days +30, +60, +90, and +180. From day +60 onward, the discriminatory power of MRD detection to predict the probability of relapse after 1, 3, 6, and 9 months was more than 96%, more than 87%, more than 71%, and more than 61%, respectively. MRD after transplantation was a reliable marker for predicting impending relapses and could thus serve as the basis for pre-emptive therapy. © 2015 by American Society of Clinical Oncology.

Single or Double Donor Umbilical Cord Blood Transplant in Treating Patients With High-Risk Hematologic Malignancies

ClinicalTrials.gov

2016-07-13

Accelerated Phase Chronic Myelogenous Leukemia; Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Nasal Type Extranodal NK/T-cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Blastic Phase Chronic Myelogenous Leukemia; Cutaneous B-cell Non-Hodgkin Lymphoma; de Novo Myelodysplastic Syndromes; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Hepatosplenic T-cell Lymphoma; Intraocular Lymphoma; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Nodal Marginal Zone B-cell Lymphoma; Noncutaneous Extranodal Lymphoma; Peripheral T-cell Lymphoma; Post-transplant Lymphoproliferative Disorder; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Refractory Multiple Myeloma; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; T-cell Large Granular Lymphocyte Leukemia; Testicular Lymphoma; Waldenström Macroglobulinemia

Allogeneic hematopoietic cell transplantation after failed autologous transplant for lymphoma using TLI and anti-thymocyte globulin conditioning.

PubMed

Rezvani, A R; Kanate, A S; Efron, B; Chhabra, S; Kohrt, H E; Shizuru, J A; Laport, G G; Miklos, D B; Benjamin, J E; Johnston, L J; Arai, S; Weng, W-K; Negrin, R S; Strober, S; Lowsky, R

2015-10-01

We describe 47 patients with lymphoma and failed prior autologous hematopoietic cell transplantation (HCT) who received TLI-ATG (anti-thymocyte globulin) conditioning followed by allogeneic HCT. Thirty-two patients had non-Hodgkin lymphoma (NHL; diffuse large B-cell lymphoma (n=19), T-cell NHL (n=6), mantle cell lymphoma (n=4) or other B-cell subtypes (n=3)), and 15 had Hodgkin lymphoma. The median follow-up was 4.9 (range, 2.1-11.9) years. The cumulative incidence of grade II-IV acute GvHD at day +100 was 12%, and the cumulative incidence of extensive chronic GvHD at 1 year was 36%. The 3-year cumulative incidences of overall survival (OS), PFS and non-relapse mortality (NRM) were 81%, 44% and 7%, respectively. Fifteen patients died (relapse, n=10; NRM, n=5). Among the 25 patients with relapse after allogeneic HCT, 11 (44%) achieved durable (>1 year) CRs following donor lymphocyte infusion or chemoradiotherapy. The majority of surviving patients (75%; n=24) were able to discontinue all immunosuppression. For patients with relapsed lymphoma after autologous HCT, allogeneic HCT using TLI-ATG conditioning is a well-tolerated, predominantly outpatient therapy with low NRM (7% at 3 years), a low incidence of GvHD, durable disease control and excellent OS (81% at 3 years).

The Management of Classical Hodgkin's Lymphoma: Past, Present, and Future.

PubMed

Richardson, S E; McNamara, C

2011-01-01

The management of classical Hodgkin's lymphoma (CHL) is a success story of modern multi-agent haemato-oncology. Prior to the middle of the twentieth century CHL was fatal in the majority of cases. Introduction of single agent radiotherapy (RT) demonstrated for the first time that these patients could be cured. Developments in chemotherapy including the mechlorethamine, vincristine, procarbazine and prednisolone (MOPP) and Adriamycin, bleomycin, vinblastine and dacarbazine (ABVD) regimens have resulted in cure rates of over 80%. Even in relapse, CHL patients can be salvaged with high dose chemotherapy and autologous haematopoietic stem cell transplantation (ASCT). Challenges remain, however, in finding new strategies to manage the small number of patients who continue to relapse or progress. In addition, the young age of many Hodgkin's patients forces difficult decisions in balancing the benefit of early disease control against the survival disadvantage of late toxicity. In this article we aim to summarise past trials, define the current standard of care and appraise future developments in the management of CHL.

Venetoclax: Management and Care for Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia
.

PubMed

Brumbaugh Paradis, Heather; Alter, Debbie; Llerandi, Diane

2017-10-01

Venetoclax (Venclexta™) is a potent, selective, orally available, small-molecule B-cell lymphoma 2 inhibitor that achieves response rates of about 80% and has an acceptable safety profile for patients with relapsed or refractory chronic lymphocytic leukemia (CLL).
. The aim was to describe treatment management considerations when caring for patients using venetoclax.
. A review was done of safety and management considerations based on current clinical practice and 240 patients with CLL who received venetoclax monotherapy on clinical trials from 2011-2016.
. Common adverse events were neutropenia, diarrhea, nausea, anemia, upper respiratory tract infection, thrombocytopenia, and fatigue. Because of rapid tumor reduction with venetoclax, nurses should be aware of the potential for tumor lysis syndrome (TLS) and the need to educate patients on steps to minimize risks, including gradual dose ramp-up, adequate hydration, and use of prophylactic antihyperuricemia agents. Following implementation of these risk-reducing measures, no clinical TLS events were reported in ongoing trials.

Management of relapsed/refractory classical Hodgkin lymphoma in transplant-ineligible patients.

PubMed

Mehta-Shah, Neha; Bartlett, Nancy L

2018-04-12

Addition of brentuximab vedotin, a CD30-targeted antibody-drug conjugate, and the programmed death 1 (PD-1) inhibitors nivolumab and pembrolizumab to the armamentarium for transplant-ineligible relapsed/refractory classical Hodgkin lymphoma has resulted in improved outcomes, including the potential for cure in a small minority of patients. For patients who have failed prior transplant or are unsuitable for dose-intense approaches based on age or comorbidities, an individualized approach with sequential use of single agents such as brentuximab vedotin, PD-1 inhibitors, everolimus, lenalidomide, or conventional agents such as gemcitabine or vinorelbine may result in prolonged survival with a minimal or modest effect on quality of life. Participation in clinical trials evaluating new approaches such as combination immune checkpoint inhibition, novel antibody-drug conjugates, or cellular therapies such as Epstein-Barr virus-directed cytotoxic T lymphocytes and chimeric antigen receptor T cells offer additional options for eligible patients. © 2018 by The American Society of Hematology.

The Epidemiology and Geographic Distribution of Relapsing Fever Borreliosis in West and North Africa, with a Review of the Ornithodoros erraticus Complex (Acari: Ixodida)

PubMed Central

Trape, Jean-François; Diatta, Georges; Arnathau, Céline; Bitam, Idir; Sarih, M’hammed; Belghyti, Driss; Bouattour, Ali; Elguero, Eric; Vial, Laurence; Mané, Youssouph; Baldé, Cellou; Pugnolle, Franck; Chauvancy, Gilles; Mahé, Gil; Granjon, Laurent; Duplantier, Jean-Marc

2013-01-01

Background Relapsing fever is the most frequent bacterial disease in Africa. Four main vector / pathogen complexes are classically recognized, with the louse Pediculus humanus acting as vector for B. recurrentis and the soft ticks Ornithodoros sonrai, O. erraticus and O. moubata acting as vectors for Borrelia crocidurae, B. hispanica and B. duttonii, respectively. Our aim was to investigate the epidemiology of the disease in West, North and Central Africa. Methods And Findings From 2002 to 2012, we conducted field surveys in 17 African countries and in Spain. We investigated the occurrence of Ornithodoros ticks in rodent burrows in 282 study sites. We collected 1,629 small mammals that may act as reservoir for Borrelia infections. Using molecular methods we studied genetic diversity among Ornithodoros ticks and Borrelia infections in ticks and small mammals. Of 9,870 burrows investigated, 1,196 (12.1%) were inhabited by Ornithodoros ticks. In West Africa, the southern and eastern limits of the vectors and Borrelia infections in ticks and small mammals were 13°N and 01°E, respectively. Molecular studies revealed the occurrence of nine different Ornithodoros species, including five species new for science, with six of them harboring Borrelia infections. Only B. crocidurae was found in West Africa and three Borrelia species were identified in North Africa: B. crocidurae, B. hispanica, and B. merionesi. Conclusions Borrelia Spirochetes responsible for relapsing fever in humans are highly prevalent both in Ornithodoros ticks and small mammals in North and West Africa but Ornithodoros ticks seem absent south of 13°N and small mammals are not infected in these regions. The number of Ornithodoros species acting as vector of relapsing fever is much higher than previously known. PMID:24223812

[Central nervous system relapse in diffuse large B cell lymphoma: Risk factors].

PubMed

Sancho, Juan-Manuel; Ribera, Josep-Maria

2016-01-15

Central nervous system (CNS) involvement by lymphoma is a complication associated, almost invariably, with a poor prognosis. The knowledge of the risk factors for CNS relapse is important to determine which patients could benefit from prophylaxis. Thus, patients with very aggressive lymphomas (such as lymphoblastic lymphoma or Burkitt's lymphoma) must systematically receive CNS prophylaxis due to a high CNS relapse rate (25-30%), while in patients with indolent lymphoma (such as follicular lymphoma or marginal lymphoma) prophylaxis is unnecessary. However, the question about CNS prophylaxis in patients with diffuse large B-cell lymphoma (DLBCL), the most common type of lymphoma, remains controversial. The information available is extensive, mainly based on retrospective and heterogeneous studies. There seems that immunochemotherapy based on rituximab reduces the CNS relapse rate. On the other hand, patients with increased serum lactate dehydrogenase plus more than one extranodal involvement seem to have a higher risk of CNS relapse, but a prophylaxis strategy based only on the presence of these 2 factors does not prevent all CNS relapses. Patients with involvement of testes or breast have high risk of CNS relapse and prophylaxis is mandatory. Finally, CNS prophylaxis could be considered in patients with DLBCL and renal or epidural space involvement, as well as in those cases with MYC rearrangements, although additional studies are necessary. Copyright © 2015 Elsevier España, S.L.U. All rights reserved.

AR-42 in Treating Patients With Advanced or Relapsed Multiple Myeloma, Chronic Lymphocytic Leukemia, or Lymphoma

ClinicalTrials.gov

2017-02-21

Adult Nasal Type Extranodal NK/T-cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Cutaneous B-cell Non-Hodgkin Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Hepatosplenic T-cell Lymphoma; Intraocular Lymphoma; Nodal Marginal Zone B-cell Lymphoma; Peripheral T-cell Lymphoma; Post-transplant Lymphoproliferative Disorder; Prolymphocytic Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Multiple Myeloma; Stage III Adult Burkitt Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Mixed Cell Lymphoma; Stage III Adult Diffuse Small Cleaved Cell Lymphoma; Stage III Adult Hodgkin Lymphoma; Stage III Adult Immunoblastic Large Cell Lymphoma; Stage III Adult Lymphoblastic Lymphoma; Stage III Adult T-cell Leukemia/Lymphoma; Stage III Chronic Lymphocytic Leukemia; Stage III Cutaneous T-cell Non-Hodgkin Lymphoma; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage III Marginal Zone Lymphoma; Stage III Multiple Myeloma; Stage III Mycosis Fungoides/Sezary Syndrome; Stage III Small Lymphocytic Lymphoma; Stage IV Adult Burkitt Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Mixed Cell Lymphoma; Stage IV Adult Diffuse Small Cleaved Cell Lymphoma; Stage IV Adult Hodgkin Lymphoma; Stage IV Adult Immunoblastic Large Cell Lymphoma; Stage IV Adult Lymphoblastic Lymphoma; Stage IV Adult T-cell Leukemia/Lymphoma; Stage IV Chronic Lymphocytic Leukemia; Stage IV Cutaneous T-cell Non-Hodgkin Lymphoma; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma; Stage IV Marginal Zone Lymphoma; Stage IV Mycosis Fungoides/Sezary Syndrome; Stage IV Small Lymphocytic Lymphoma; Testicular Lymphoma; Waldenstrom Macroglobulinemia

[Outcome of patients with relapsed/refractory adult T-cell leukemia-lymphoma after salvage therapy].

PubMed

Taniguchi, Hiroaki; Imaizumi, Yoshitaka; Makiyama, Junya; Itonaga, Hidehiro; Ando, Koji; Sawayama, Yasushi; Imanishi, Daisuke; Taguchi, Jun; Tsushima, Hideki; Hata, Tomoko; Hasegawa, Hiroo; Hayashi, Tomayoshi; Niino, Daisuke; Ohshima, Koichi; Tsukasaki, Kunihiro; Miyazaki, Yasushi

2013-12-01

We retrospectively analyzed 81 relapsed or refractory adult T-cell leukemia-lymphoma (ATL) patients who received salvage therapy in our institution between 2000 and 2010. These patients had received chemotherapy, radiation, or hematopoietic stem cell transplantation (HSCT) as an initial treatment, and were then given chemotherapy, radiation, HSCT, or donor lymphocyte infusion (DLI) as salvage therapy. Median survival time was 3.9 months. Of 5 long-term survivors, who survived more than 2 years after the first salvage therapy, 4 patients received HSCT or DLI, and the other was given mogamulizumab as the salvage therapy. For patients with relapsed or refractory ATL, HSCT/DLI is a promising treatment for achieving long-term survival. Mogamulizumab may be the good choice for those who are ineligible for HSCT.

Relapsed or refractory pediatric acute lymphoblastic leukemia: current and emerging treatments.

PubMed

Martin, Alissa; Morgan, Elaine; Hijiya, Nobuko

2012-12-01

Relapsed acute lymphoblastic leukemia (ALL) represents a major cause of morbidity and mortality in pediatrics. With contemporary chemotherapy, >85% of patients with newly diagnosed ALL survive. Unfortunately, 20% of these patients will relapse and for these children, outcomes remain poor despite our best known chemotherapy protocols. Most of these children will achieve a second complete remission, but maintaining this remission remains difficult. Because relapsed ALL is such a significant cause of morbidity and mortality, it is the focus of much research interest. Efforts have been made and continue to focus on understanding the underlying biology that drives relapse. The role of hematopoietic stem cell transplantation in relapsed ALL remains unclear, but many clinicians still favor this for high-risk patients given the poor prognosis with current chemotherapy alone. It is important to use new drugs with little cross-resistance in the treatment of relapsed ALL. New classes of agents are currently being studied. We also discuss prognostic factors and the biology of relapsed ALL.

Bruton Tyrosine Kinase Inhibitor Ibrutinib (PCI-32765) Has Significant Activity in Patients With Relapsed/Refractory B-Cell Malignancies

PubMed Central

Buggy, Joseph J.; Sharman, Jeff P.; Smith, Sonali M.; Boyd, Thomas E.; Grant, Barbara; Kolibaba, Kathryn S.; Furman, Richard R.; Rodriguez, Sara; Chang, Betty Y.; Sukbuntherng, Juthamas; Izumi, Raquel; Hamdy, Ahmed; Hedrick, Eric; Fowler, Nathan H.

2013-01-01

Purpose Survival and progression of mature B-cell malignancies depend on signals from the B-cell antigen receptor, and Bruton tyrosine kinase (BTK) is a critical signaling kinase in this pathway. We evaluated ibrutinib (PCI-32765), a small-molecule irreversible inhibitor of BTK, in patients with B-cell malignancies. Patients and Methods Patients with relapsed or refractory B-cell lymphoma and chronic lymphocytic leukemia received escalating oral doses of ibrutinib. Two schedules were evaluated: one, 28 days on, 7 days off; and two, once-daily continuous dosing. Occupancy of BTK by ibrutinib in peripheral blood was monitored using a fluorescent affinity probe. Dose escalation proceeded until either the maximum-tolerated dose (MTD) was achieved or, in the absence of MTD, until three dose levels above full BTK occupancy by ibrutinib. Response was evaluated every two cycles. Results Fifty-six patients with a variety of B-cell malignancies were treated over seven cohorts. Most adverse events were grade 1 and 2 in severity and self-limited. Dose-limiting events were not observed, even with prolonged dosing. Full occupancy of the BTK active site occurred at 2.5 mg/kg per day, and dose escalation continued to 12.5 mg/kg per day without reaching MTD. Pharmacokinetic data indicated rapid absorption and elimination, yet BTK occupancy was maintained for at least 24 hours, consistent with the irreversible mechanism. Objective response rate in 50 evaluable patients was 60%, including complete response of 16%. Median progression-free survival in all patients was 13.6 months. Conclusion Ibrutinib, a novel BTK-targeting inhibitor, is well tolerated, with substantial activity across B-cell histologies. PMID:23045577

Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant activity in patients with relapsed/refractory B-cell malignancies.

PubMed

Advani, Ranjana H; Buggy, Joseph J; Sharman, Jeff P; Smith, Sonali M; Boyd, Thomas E; Grant, Barbara; Kolibaba, Kathryn S; Furman, Richard R; Rodriguez, Sara; Chang, Betty Y; Sukbuntherng, Juthamas; Izumi, Raquel; Hamdy, Ahmed; Hedrick, Eric; Fowler, Nathan H

2013-01-01

Survival and progression of mature B-cell malignancies depend on signals from the B-cell antigen receptor, and Bruton tyrosine kinase (BTK) is a critical signaling kinase in this pathway. We evaluated ibrutinib (PCI-32765), a small-molecule irreversible inhibitor of BTK, in patients with B-cell malignancies. Patients with relapsed or refractory B-cell lymphoma and chronic lymphocytic leukemia received escalating oral doses of ibrutinib. Two schedules were evaluated: one, 28 days on, 7 days off; and two, once-daily continuous dosing. Occupancy of BTK by ibrutinib in peripheral blood was monitored using a fluorescent affinity probe. Dose escalation proceeded until either the maximum-tolerated dose (MTD) was achieved or, in the absence of MTD, until three dose levels above full BTK occupancy by ibrutinib. Response was evaluated every two cycles. Fifty-six patients with a variety of B-cell malignancies were treated over seven cohorts. Most adverse events were grade 1 and 2 in severity and self-limited. Dose-limiting events were not observed, even with prolonged dosing. Full occupancy of the BTK active site occurred at 2.5 mg/kg per day, and dose escalation continued to 12.5 mg/kg per day without reaching MTD. Pharmacokinetic data indicated rapid absorption and elimination, yet BTK occupancy was maintained for at least 24 hours, consistent with the irreversible mechanism. Objective response rate in 50 evaluable patients was 60%, including complete response of 16%. Median progression-free survival in all patients was 13.6 months. Ibrutinib, a novel BTK-targeting inhibitor, is well tolerated, with substantial activity across B-cell histologies.

Histone deacetylase inhibitors reduce differentiating osteoblast-mediated protection of acute myeloid leukemia cells from cytarabine

PubMed Central

Sterner, Rosalie M.; Kremer, Kimberly N.; Al-Kali, Aref; Patnaik, Mrinal M.; Gangat, Naseema; Litzow, Mark R.; Kaufmann, Scott H.; Westendorf, Jennifer J.; van Wijnen, Andre J.; Hedin, Karen E.

2017-01-01

The bone marrow microenvironment protects acute myeloid leukemia (AML) cells during chemotherapy and is a major factor in relapse. Here, we examined which type(s) of bone marrow cells are responsible for the relapse of AML following treatment with cytarabine (Ara-C), and we identified a means to inhibit this protection. To determine the protective cell type(s), AML cells were treated with Ara-C, and AML cell survival in the presence or absence of osteoblast lineage cells was assessed. Cultured AML cells and patient bone marrow isolates were each significantly protected from Ara-C-induced apoptosis by co-culture with differentiating osteoblasts. Moreover, pretreating differentiating osteoblasts with the histone deacetylase inhibitors (HDACi) vorinostat and panobinostat abrogated the ability of the differentiating osteoblasts to protect AML cells. Together, our results indicate that differentiating osteoblasts have the potential to promote residual AML in the bone marrow following standard chemotherapy and act via a mechanism requiring HDACi-sensitive gene expression. Using HDACi to target the leukemic microenvironment in combination with Ara-C could potentially improve treatment of AML. Moreover, other strategies for manipulating bone marrow osteoblasts may also help eradicate AML cells and reduce relapse. PMID:29212250

Venetoclax in Patients with Previously Treated Chronic Lymphocytic Leukemia.

PubMed

Roberts, Andrew W; Stilgenbauer, Stephan; Seymour, John F; Huang, David C S

2017-08-15

Venetoclax is the first BCL2 inhibitor to enter routine clinical practice. It is an orally bioavailable small molecule that binds BCL2 very specifically. Acting as a pharmacologic mimic of the proteins that initiate apoptosis (a so-called BH3 mimetic), venetoclax rapidly induces apoptosis in chronic lymphocytic leukemia (CLL) cells, which express high levels of BCL2 and rely on it to maintain their survival. As a single agent, daily venetoclax treatment induced durable responses in 79% of patients with relapsed or refractory CLL or small lymphocytic lymphoma in a phase I study, including complete remissions in 20% of patients. Its use was approved by the FDA in April 2016 for patients with previously treated del(17p) CLL on the basis of a single-arm phase II trial demonstrating a 79% response rate and an estimated 1-year progression-free survival of 72% with 400 mg/day continuous therapy. This review focuses on venetoclax, its mechanism of action, pharmacology, and clinical trial data and seeks to place it in the context of rapid advances in therapy for patients with relapsed CLL, especially those with del(17p) CLL. Clin Cancer Res; 23(16); 4527-33. ©2017 AACR . ©2017 American Association for Cancer Research.

Pathogenesis and treatment of adult-type granulosa cell tumor of the ovary.

PubMed

Färkkilä, Anniina; Haltia, Ulla-Maija; Tapper, Johanna; McConechy, Melissa K; Huntsman, David G; Heikinheimo, Markku

2017-08-01

Adult-type granulosa cell tumor is a clinically and molecularly unique subtype of ovarian cancer. These tumors originate from the sex cord stromal cells of the ovary and represent 3-5% of all ovarian cancers. The majority of adult-type granulosa cell tumors are diagnosed at an early stage with an indolent prognosis. Surgery is the cornerstone for the treatment of both primary and relapsed tumor, while chemotherapy is applied only for advanced or non-resectable cases. Tumor stage is the only factor consistently associated with prognosis. However, every third of the patients relapse, typically in 4-7 years from diagnosis, leading to death in 50% of these patients. Anti-Müllerian Hormone and inhibin B are currently the most accurate circulating biomarkers. Adult-type granulosa cell tumors are molecularly characterized by a pathognomonic somatic missense point mutation 402C->G (C134W) in the transcription factor FOXL2. The FOXL2 402C->G mutation leads to increased proliferation and survival of granulosa cells, and promotes hormonal changes. Histological diagnosis of adult-type granulosa cell tumor is challenging, therefore testing for the FOXL2 mutation is crucial for differential diagnosis. Large international collaborations utilizing molecularly defined cohorts are essential to improve and validate new treatment strategies for patients with high-risk or relapsed adult-type granulosa cell tumor. Key Messages: Adult-type granulosa cell tumor is a unique ovarian cancer with an indolent, albeit unpredictable disease course. Adult-type granulosa cell tumors harbor a pathognomonic somatic missense mutation in transcription factor FOXL2. The key challenges in the treatment of patients with adult-type granulosa cell tumor lie in the identification and management of patients with high-risk or relapsed disease.

Cytokine-primed bone marrow stem cells vs. peripheral blood stem cells for autologous transplantation: a randomized comparison of GM-CSF vs. G-CSF.

PubMed

Weisdorf, D; Miller, J; Verfaillie, C; Burns, L; Wagner, J; Blazar, B; Davies, S; Miller, W; Hannan, P; Steinbuch, M; Ramsay, N; McGlave, P

1997-10-01

Autologous transplantation for non-Hodgkins lymphoma and Hodgkin's disease is widely used as standard therapy for those with high-risk or relapsed tumor. Peripheral blood stem cell (PBSC) collections have nearly completely replaced bone marrow stem cell (BMSC) harvests because of the perceived advantages of more rapid engraftment, less tumor contamination in the inoculum, and better survival after therapy. The advantage of PBSC, however, may derive from the hematopoietic stimulating cytokines used for PBSC mobilization. Therefore, we tested a randomized comparison of GM-CSF vs. G-CSF used to prime either BMSC or PBSC before collection for use in autologous transplantation. Sixty-two patients receiving transplants (31 PBSC; 31 BMSC) for non-Hodgkin's lymphoma (n = 51) or Hodgkin's disease (n = 11) were treated. All patients received 6 days of randomly assigned cytokine. Those with cellular marrow in morphologic remission underwent BMSC harvest, while those with hypocellular marrow or microscopic marrow tumor involvement had PBSC collected. Neutrophil recovery was similarly rapid in all groups (median 14 days; range 10-23 days), though two patients had delayed neutrophil recovery using GM-CSF primed PBSC (p = 0.01). Red cell and platelet recovery were significantly quicker after BMSC mobilized with GM-CSF or PBSC mobilized with G-CSF. This speedier hematologic recovery resulted in earlier hospital discharge as well. However, in multivariate analysis, neither the stem cell source nor randomly assigned G-CSF vs. GM-CSF was independently associated with earlier multilineage hematologic recovery or shorter hospital stay. Relapse-free survival was not independently affected by either the assigned stem cell source or the randomly assigned priming cytokine, though malignant relapse was more frequent in those assigned to PBSC (RR of relapse 3.15, p = 0.03). These data document that BMSC, when collected following cytokine priming, can yield a similarly rapid hematologic recovery and short hospital stay compared with cytokine-primed PBSC. Using primed BMSC, no difference in malignant relapse or relapse-free survival was observed. These findings suggest that despite widespread use of PBSC for transplantation, BMSC, when collected following hematopoietically stimulating cytokines, may remain a satisfactory source of stem cells for autologous transplantation. G-CSF and GM-CSF are both effective in priming autologous PBSC or BMSC for collection.

Gemcitabine, dexamethasone, and cisplatin (GDP) is an effective and well-tolerated salvage therapy for relapsed/refractory diffuse large B-cell lymphoma and Hodgkin lymphoma.

PubMed

Moccia, Alden A; Hitz, Felicitas; Hoskins, Paul; Klasa, Richard; Power, Maryse M; Savage, Kerry J; Shenkier, Tamara; Shepherd, John D; Slack, Graham W; Song, Kevin W; Gascoyne, Randy D; Connors, Joseph M; Sehn, Laurie H

2017-02-01

The optimal choice of salvage therapy for patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) or Hodgkin lymphoma (HL) remains unknown. Based on promising results of phase II trials, the preferred salvage regimen in British Columbia since 2002 has been the out-patient regimen, gemcitabine, dexamethasone, and cisplatin (GDP). We conducted a retrospective analysis including all patients with relapsed/refractory DLBCL or HL who received GDP as salvage therapy between September 2002 and June 2010. We identified 235 patients: 152 DLBCL, 83 HL. Overall response rates were 49% and 71% for patients with DLBCL and HL, respectively. Within the transplant-eligible population, 52% of patients with DLBCL and 96% of patients with HL proceeded to stem cell transplantation. The 2-year progression-free survival and overall survival were 21% and 28% in the DLBCL cohort, and 58% and 85% in the HL group. GDP is an effective and well-tolerated out-patient salvage regimen for relapsed/refractory DLBCL and HL.

Ibrutinib for the treatment of mantle cell lymphoma.

PubMed

Herrera, Alex F; Jacobsen, Eric D

2014-11-01

Ibrutinib (PCI-32765)--a potent, covalent inhibitor of Bruton tyrosine kinase (BTK), an important kinase in the B-cell receptor signaling pathway--was recently approved by the FDA for the treatment of relapsed or refractory mantle cell lymphoma (MCL). The drug was granted accelerated approval based on the findings of an international, multicenter, single-arm phase II study that enrolled patients with relapsed or refractory MCL. In the study, ibrutinib (560 mg daily) was well tolerated as a single agent and resulted in an overall response rate of 68% and an estimated median response duration of 17.5 months. Ibrutinib's response rate and duration of response compare favorably with those for other novel agents approved for the treatment of relapsed or refractory MCL, while being less toxic than most chemotherapy or chemoimmunotherapy regimens. Ibrutinib is currently being studied in combination with chemoimmunotherapy, monoclonal antibody therapy, and novel agents in both the initial and the relapsed/refractory treatment settings. We review the mechanism of action, preclinical and clinical development, and the role of ibrutinib in the context of other available treatments. ©2014 American Association for Cancer Research.

Treatment outcome and patterns of relapse following adjuvant carboplatin for stage I testicular seminomatous germ-cell tumour: results from a 17-year UK experience.

PubMed

Chau, C; Cathomas, R; Wheater, M; Klingbiel, D; Fehr, M; Bennett, J; Markham, H; Lee, C; Crabb, S J; Geldart, T

2015-09-01

Following inguinal orchidectomy, management options for patients with stage I seminoma include initial surveillance or treatment with adjuvant radiotherapy or chemotherapy. The anticipated relapse rate for patients followed by surveillance alone is ∼15%, with adjuvant treatment this risk is reduced to ∼4%-5% at 5 years. After carboplatin treatment, follow-up strategies vary and there are no validated, predictive markers of relapse. We conducted a retrospective analysis of all patients presenting with stage I seminoma who received a single cycle of adjuvant carboplatin in South Central England between 1996 and 2013. We report on outcome and the results of univariate and multivariate analysis evaluating possible risk factors for post carboplatin relapse. A total of 517 eligible patients were identified. All underwent nuclear medicine estimation of glomerular filtration rate before treatment with carboplatin (dosed at area under the curve × 7). With a median follow-up of 47.2 months (range 0.4-214 months), 21/517 patients have relapsed resulting in a 5-year estimated relapse-free survival of 95.0% (95% confidence interval 92.8% to 97.3%). Median time to relapse was 22.7 months (range 12.5-109.5 months). Relapse beyond 3 years was rare (4/517; 0.8%). Twenty of 21 (95%) relapsed patients had retroperitoneal lymph node metastases. The majority (16/21; 76%) of patients had elevated tumour markers at relapse. Twenty of 517 (3.9%) patients developed a new contralateral testicular germ-cell cancer. There were no seminoma-related deaths. Tumour size was the only variable significantly associated with an increased risk of relapse. Overall results for this large cohort of patients confirm an excellent prognosis for these patients with outcomes equivalent to those seen in prospective clinical trials. Increasing tumour size alone appears to be associated with an increased risk of post chemotherapy relapse. © The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Clonal evolution in relapsed and refractory diffuse large B-cell lymphoma is characterized by high dynamics of subclones.

PubMed

Melchardt, Thomas; Hufnagl, Clemens; Weinstock, David M; Kopp, Nadja; Neureiter, Daniel; Tränkenschuh, Wolfgang; Hackl, Hubert; Weiss, Lukas; Rinnerthaler, Gabriel; Hartmann, Tanja N; Greil, Richard; Weigert, Oliver; Egle, Alexander

2016-08-09

Little information is available about the role of certain mutations for clonal evolution and the clinical outcome during relapse in diffuse large B-cell lymphoma (DLBCL). Therefore, we analyzed formalin-fixed-paraffin-embedded tumor samples from first diagnosis, relapsed or refractory disease from 28 patients using next-generation sequencing of the exons of 104 coding genes. Non-synonymous mutations were present in 74 of the 104 genes tested. Primary tumor samples showed a median of 8 non-synonymous mutations (range: 0-24) with the used gene set. Lower numbers of non-synonymous mutations in the primary tumor were associated with a better median OS compared with higher numbers (28 versus 15 months, p=0.031). We observed three patterns of clonal evolution during relapse of disease: large global change, subclonal selection and no or minimal change possibly suggesting preprogrammed resistance. We conclude that targeted re-sequencing is a feasible and informative approach to characterize the molecular pattern of relapse and it creates novel insights into the role of dynamics of individual genes.

Central diabetes insipidus as a very late relapse limited to the pituitary stalk in Langerhans cell histiocytosis.

PubMed

Nakagawa, Shunsuke; Shinkoda, Yuichi; Hazeki, Daisuke; Imamura, Mari; Okamoto, Yasuhiro; Kawakami, Kiyoshi; Kawano, Yoshifumi

2016-07-01

Central diabetes insipidus (CDI) and relapse are frequently seen in multifocal Langerhans cell histiocytosis (LCH). We present two females with multifocal LCH who developed CDI 9 and 5 years after the initial diagnosis, respectively, as a relapse limited to the pituitary stalk. Combination chemotherapy with cytarabine reduced the mass in the pituitary stalk. Although CDI did not improve, there has been no anterior pituitary hormone deficiency (APHD), neurodegenerative disease in the central nervous system (ND-CNS) or additional relapse for 2 years after therapy. It was difficult to predict the development of CDI in these cases. CDI might develop very late in patients with multifocal LCH, and therefore strict follow-up is necessary, especially with regard to symptoms of CDI such as polydipsia and polyuria. For new-onset CDI with LCH, chemotherapy with cytarabine might be useful for preventing APHD and ND-CNS.

Implications and Management of Central Nervous System Involvement before Allogeneic Hematopoietic Cell Transplantation in Acute Lymphoblastic Leukemia.

PubMed

Aldoss, Ibrahim; Al Malki, Monzr M; Stiller, Tracey; Cao, Thai; Sanchez, James F; Palmer, Joycelynne; Forman, Stephen J; Pullarkat, Vinod

2016-03-01

Acute lymphoblastic leukemia (ALL) with a history of central nervous system (CNS) involvement, either at diagnosis or relapse, poses challenges when the decision is made to proceed with allogeneic hematopoietic cell transplantation (alloHCT), as there is no evidence-based consensus on the best peri-transplantation approach to reduce subsequent CNS relapse risk. Here, we retrospectively analyzed outcomes of 87 patients with ALL and a history of CNS involvement who later underwent alloHCT. Patients with pretransplantation CNS involvement had higher risk of CNS relapse after transplantation (2-year CNS relapse: 9.6% versus 1.4%, P < .0001), inferior event-free survival (EFS) (hazard ratio [HR], 1.52; P = .003), and worse overall survival (OS) (HR, 1.55; P = .003) compared with patients without pretransplantation CNS involvement (n = 543). There was no difference in post-transplantation CNS relapse, EFS, or OS among patients presenting with CNS involvement at diagnosis, those with isolated CNS relapse, and those with combined bone marrow and CNS relapse before HCT. Interestingly, neither pretransplantation cranial irradiation, use of total body irradiation-based conditioning, nor post-transplantation prophylactic intrathecal chemotherapy were associated with a reduction of CNS relapse risk after transplantation. Thus, among the patients in the cohort studied, there was no clear benefit of CNS-directed therapy in the peri-transplantation period among patients who had prior CNS involvement and underwent subsequent alloHCT. Copyright © 2016 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Plasma exchange therapy in steroid-unresponsive relapses in patients with multiple sclerosis.

PubMed

Trebst, Corinna; Reising, Ansgar; Kielstein, Jan T; Hafer, Carsten; Stangel, Martin

2009-01-01

Plasma exchange (PE) is well established for conditions such as rapid progressive vasculitis associated with autoantibodies against neutrophil cytoplasmic antigens (ANCA), anti-glomerular basement membrane (GBM) antibody disease, or thrombotic thrombocytopenic purpura (TTP). Also, several neurological disorders, such as acute worsening in myasthenia gravis, Guillan-Barré syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP), can successfully be treated with PE. Only small case series have previously shown that PE is also effective in relapses in patients with multiple sclerosis (MS). We report our experiences of PE therapy in a series of 20 patients with 21 steroid unresponsive MS relapses. A marked-to-moderate clinical response with clear gain of function in 76% of patients with uni- or bilateral optic neuritis and in 87.5% of patients with relapses other than optic neuritis was observed. PE is an effective and well tolerated therapeutic option for steroid-unresponsive MS relapses.

CD56bright natural killer cells and response to daclizumab HYP in relapsing-remitting MS

PubMed Central

Sheridan, J.; Amaravadi, L.; Riester, K.; Selmaj, K.; Bielekova, B.; Parr, E.; Giovannoni, G.

2015-01-01

Objective: To assess the relationship between CD56bright natural killer (NK) cells and multiple sclerosis (MS) disease activity in patients with relapsing-remitting MS treated with daclizumab high-yield process (DAC HYP). Methods: Data were from patients enrolled in a 52-week randomized, double-blind, placebo-controlled study of DAC HYP and its extension study. Assessments included relationships of CD56bright NK cell numbers (identified using fluorescence-activated cell sorting) at weeks 4 and 8 with the numbers of new or newly enlarging T2-hyperintense lesions between weeks 24 and 52 and the annualized relapse rate. Results: In DAC HYP–treated patients but not placebo-treated patients, the numbers of CD56bright NK cells increased over 52 weeks of treatment, and their numbers at weeks 4 and 8 predicted the number of new or newly enlarging T2-hyperintense lesions between weeks 24 and 52 of treatment (p ≤ 0.005 for each comparison). Similar but nonsignificant trends were observed between CD56bright NK cell counts and the annualized relapse rate in DAC HYP–treated patients. DAC HYP–treated patients who showed lower levels of expansion of CD56bright NK cells still developed fewer new or newly enlarging T2-hyperintense lesions than placebo-treated patients during the first year of treatment. Conclusions: CD56bright NK cells appear to mediate some of the treatment-related effects of DAC HYP, but their numbers do not account for the full effect of DAC HYP on MS-related outcomes. PMID:25635261

Outcome of children with acute leukemia given HLA-haploidentical HSCT after αβ T-cell and B-cell depletion.

PubMed

Locatelli, Franco; Merli, Pietro; Pagliara, Daria; Li Pira, Giuseppina; Falco, Michela; Pende, Daniela; Rondelli, Roberto; Lucarelli, Barbarella; Brescia, Letizia Pomponia; Masetti, Riccardo; Milano, Giuseppe Maria; Bertaina, Valentina; Algeri, Mattia; Pinto, Rita Maria; Strocchio, Luisa; Meazza, Raffaella; Grapulin, Lavinia; Handgretinger, Rupert; Moretta, Alessandro; Bertaina, Alice; Moretta, Lorenzo

2017-08-03

Allogeneic hematopoietic stem cell transplantation (HSCT) from an HLA-haploidentical relative (haplo-HSCT) is a suitable option for children with acute leukemia (AL) either relapsed or at high-risk of treatment failure. We developed a novel method of graft manipulation based on negative depletion of αβ T and B cells and conducted a prospective trial evaluating the outcome of children with AL transplanted with this approach. Eighty AL children, transplanted between September 2011 and September 2014, were enrolled in the trial. All children were given a fully myeloablative preparative regimen. Anti-T-lymphocyte globulin from day -5 to -3 was used for preventing graft rejection and graft-versus-host disease (GVHD); no patient received any posttransplantation GVHD prophylaxis. Two children experienced primary graft failure. The cumulative incidence of skin-only, grade 1-2 acute GVHD was 30%; no patient developed extensive chronic GVHD. Four patients died, the cumulative incidence of nonrelapse mortality being 5%, whereas 19 relapsed, resulting in a 24% cumulative incidence of relapse. With a median follow-up of 46 months for surviving patients, the 5-year probability of chronic GVHD-free, relapse-free survival (GRFS) is 71%. Total body irradiation-containing preparative regimen was the only variable favorably influencing relapse incidence and GRFS. The outcomes of these 80 patients are comparable to those of 41 and 51 children given transplantation from an HLA-identical sibling or a 10/10 allelic-matched unrelated donor in the same period. These data indicate that haplo-HSCT after αβ T- and B-cell depletion represents a competitive alternative for children with AL in need of urgent allograft. This trial was registered at www.clinicaltrials.gov as #NCT01810120. © 2017 by The American Society of Hematology.

[Allogeneic hematopoietic cell transplantation for Hodgkin's disease, mantle cell lymphoma and other rare entities: Guidelines from the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC)].

PubMed

Gauthier, Jordan; Chantepie, Sylvain; Bouabdallah, Krimo; Jost, Edgar; Nguyen, Stéphanie; Gac, Anne-Claire; Damaj, Gandhi; Duléry, Rémy; Michallet, Mauricette; Delage, Jérémy; Lewalle, Philippe; Morschhauser, Franck; Salles, Gilles; Yakoub-Agha, Ibrahim; Cornillon, Jérôme

2017-12-01

Despite great improvements in the outcome of patients with lymphoma, some may still relapse or present with primary refractory disease. In these situations, allogeneic haematopoietic cell transplantation is a potentially curative option, in particular in the case of relapse after autologous stem cell transplantation. Recently, novel agents such as anti-PD1 and BTK inhibitors have started to challenge the use of allogeneic haematopoietic cell transplantation for relapsed or refractory lymphoma. During the 2016 annual workshop of the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC), we performed a comprehensive review of the literature published in the last 10 years and established guidelines to clarify the indications and transplant modalities in this setting. This manuscript specifically reports on our conclusions regarding Hodgkin's lymphoma as well as rarer entities, such as T cell lymphomas. Copyright © 2017 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.

Medulloblastoma stem cells: Promising targets in medulloblastoma therapy.

PubMed

Huang, Guo-Hao; Xu, Qing-Fu; Cui, You-Hong; Li, Ningning; Bian, Xiu-Wu; Lv, Sheng-Qing

2016-05-01

Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Despite great improvements in the therapeutic regimen, relapse and leptomeningeal dissemination still pose great challenges to the long-term survival of MB patients. Developing more effective strategies has become extremely urgent. In recent years, a number of malignancies, including MB, have been found to contain a subpopulation of cancer cells known as cancer stem cells (CSCs), or tumor initiating/propagating cells. The CSCs are thought to be largely responsible for tumor initiation, maintenance, dissemination, and relapse; therefore, their pivotal roles have revealed them to be promising targets in MB therapy. Our growing understanding of the major medulloblastoma molecular subgroups and the derivation of some of these groups from specific stem or progenitor cells adds additional layers to the CSC knowledge base. Herein we review the current knowledge of MB stem cells, highlight the molecular mechanisms relating to MB relapse and leptomeningeal dissemination, and incorporate these with the need to develop more effective and accurate therapies for MB patients. © 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Is there a stronger graft-versus-leukemia effect using HLA-haploidentical donors compared with HLA-identical siblings?

PubMed

Ringdén, O; Labopin, M; Ciceri, F; Velardi, A; Bacigalupo, A; Arcese, W; Ghavamzadeh, A; Hamladji, R M; Schmid, C; Nagler, A; Mohty, M

2016-02-01

Haploidentical hematopoietic stem cell transplants (HSCTs) are increasingly used, but it is unknown whether they have a stronger graft-versus-leukemia (GVL) effect. We analyzed 10 679 acute leukemia patients who underwent HSCT from an HLA-matched sibling donor (MSD, n=9815) or a haploidentical donor (⩾2 HLA-antigen disparity, n=864) between 2007 and 2012, reported to the European Group for Blood and Marrow Transplantation. In a Cox regression model, acute and chronic graft-versus-host disease (GVHD) was added as time-dependent variables. There was no difference in probability of relapse between recipients of haploidentical and MSD grafts. Factors of importance for relapse after T-cell-replete grafts included remission status at HSCT, Karnofsky score ⩽80, acute GVHD of grade II or higher and chronic GVHD (P<10(-5)). Patients with post-transplant cyclophosphamide (n=194) had similar outcome as other T-cell-replete haploidentical transplants (n=369). Non-relapse mortality was significantly higher in the haploidentical group compared with that in MSD patients (P<10(-5)). Leukemia-free survival was superior in the MSD patients receiving T-cell-replete (P<10(-5)) or T-cell-depleted grafts (P=0.0006). The risk of relapse was the same in acute leukemia patients who received haploidentical donor grafts as in those given MSD transplants, suggesting a similar GVL effect.

Individualized relapse prediction: Personality measures and striatal and insular activity during reward-processing robustly predict relapse.

PubMed

Gowin, Joshua L; Ball, Tali M; Wittmann, Marc; Tapert, Susan F; Paulus, Martin P

2015-07-01

Nearly half of individuals with substance use disorders relapse in the year after treatment. A diagnostic tool to help clinicians make decisions regarding treatment does not exist for psychiatric conditions. Identifying individuals with high risk for relapse to substance use following abstinence has profound clinical consequences. This study aimed to develop neuroimaging as a robust tool to predict relapse. 68 methamphetamine-dependent adults (15 female) were recruited from 28-day inpatient treatment. During treatment, participants completed a functional MRI scan that examined brain activation during reward processing. Patients were followed 1 year later to assess abstinence. We examined brain activation during reward processing between relapsing and abstaining individuals and employed three random forest prediction models (clinical and personality measures, neuroimaging measures, a combined model) to generate predictions for each participant regarding their relapse likelihood. 18 individuals relapsed. There were significant group by reward-size interactions for neural activation in the left insula and right striatum for rewards. Abstaining individuals showed increased activation for large, risky relative to small, safe rewards, whereas relapsing individuals failed to show differential activation between reward types. All three random forest models yielded good test characteristics such that a positive test for relapse yielded a likelihood ratio 2.63, whereas a negative test had a likelihood ratio of 0.48. These findings suggest that neuroimaging can be developed in combination with other measures as an instrument to predict relapse, advancing tools providers can use to make decisions about individualized treatment of substance use disorders. Published by Elsevier Ireland Ltd.

Current status and future clinical directions in the prevention and treatment of relapse following hematopoietic transplantation for acute myeloid and lymphoblastic leukemia.

PubMed

Craddock, Charles; Hoelzer, Dieter; Komanduri, Krishna V

2018-05-31

In recent years we have seen a dramatic evolution of therapeutic approaches in the management of acute leukemia with hematopoietic stem cell transplantation (HCT). For both acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), alloHCT provides the best chance of long-term disease-free survival for significant subsets of patients. During this interval, we have witnessed an evolution of HCT from a therapy based on high-dose conditioning to our current understanding that its success depends both on cytoreduction and graft-versus-leukemia (GVL) effects mediated by adoptively transferred donor immune cells. Improvements in conditioning, infectious disease monitoring and management, histocompatibility testing and graft selection have successively improved outcomes, primarily due to a reduction in non-relapse mortality. Unfortunately, disease relapse remains a significant cause of treatment failure in both AML and ALL. Here, two distinguished experts, Prof. Charles Craddock and Prof. Dieter Hoelzer, reflect on the significant challenge of disease relapse following allogeneic HCT for AML and ALL, respectively. This is a review of the biology, current approaches, and future directions in the field and reflects concepts that were presented at the Third International Workshop on Biology, Prevention, and Treatment of Relapse after Stem Cell Transplantation held in Hamburg, Germany in November 2016 under the auspices of the EBMT and the ASBMT.

Deep NPM1 Sequencing Following Allogeneic Hematopoietic Cell Transplantation Improves Risk Assessment in Adults with NPM1-Mutated AML.

PubMed

Zhou, Yi; Othus, Megan; Walter, Roland B; Estey, Elihu H; Wu, David; Wood, Brent L

2018-04-21

Relapse is the major cause of death in patients with acute myeloid leukemia (AML) after allogeneic hematopoietic cell transplantation (HCT). Measurable residual disease (MRD) detected by multiparameter flow cytometry (MFC) before and after HCT is a strong, independent risk factor for relapse. As next-generation sequencing (NGS) is increasingly applied in AML MRD detection, it remains to be determined if NGS can improve prediction of post-HCT relapse. Herein, we investigated pre-HCT MRD detected by MFC and NGS in 59 adult patients with NPM1-mutated AML in morphologic remission; 45 of the 59 had post-HCT MRD determined by MFC and NGS around day 28. Before HCT, MRD detected by MFC was the most significant risk factor for relapse (hazard ratio [HR], 4.63; P < .001), whereas MRD detected only by NGS was not. After HCT, MRD detected by either MFC or NGS was significant risk factor for relapse (HR, 4.96, P = .004 and HR, 4.36, P = .002, respectively). Combining pre- and post-HCT MRD provided the best prediction for relapse (HR, 5.25; P < .001), with a sensitivity at 83%. We conclude that NGS testing of mutated NPM1 post-HCT improves the risk assessment for relapse, whereas pre-HCT MFC testing identifies a subset of high-risk patients in whom additional therapy should be tested. Copyright © 2018 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

New positron emission tomography derived parameters as predictive factors for recurrence in resected stage I non-small cell lung cancer.

PubMed

Melloni, G; Gajate, A M S; Sestini, S; Gallivanone, F; Bandiera, A; Landoni, C; Muriana, P; Gianolli, L; Zannini, P

2013-11-01

The recurrence rate for stage I non-small cell lung cancer is high, with 20-40% of patients that relapse after surgery. The aim of this study was to evaluate new F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) derived parameters, such as standardized uptake value index (SUVindex), metabolic tumor volume (MTV) and total lesion glycolysis (TLG), as predictive factors for recurrence in resected stage I non-small cell lung cancer. We retrospectively reviewed 99 resected stage I non-small cell lung cancer patients that were grouped by SUVindex, TLG and MTV above or below their median value. Disease free survival was evaluated as primary end point. The 5-year overall survival and the 5-year disease free survival rates were 62% and 73%, respectively. The median SUVindex, MTL and TLG were 2.73, 2.95 and 9.61, respectively. Patients with low SUVindex, MTV and TLG were more likely to have smaller tumors (p ≤ 0.001). Univariate analysis demonstrated that SUVindex (p = 0.027), MTV (p = 0.014) and TLG (p = 0.006) were significantly related to recurrence showing a better predictive performance than SUVmax (p = 0.031). The 5-year disease free survival rates in patients with low and high SUVindex, MTV and TLG were 84% and 59%, 86% and 62% and 88% and 60%, respectively. The multivariate analysis showed that only TLG was an independent prognostic factor (p = 0.014) with a hazard ratio of 4.782. Of the three PET-derived parameters evaluated, TLG seems to be the most accurate in stratifying surgically treated stage I non-small cell lung cancer patients according to their risk of recurrence. Copyright © 2013 Elsevier Ltd. All rights reserved.

Development of symptomatic brain metastases after chemoradiotherapy for stage III non-small cell lung cancer: Does the type of chemotherapy regimen matter?

PubMed

Hendriks, Lizza E L; Brouns, Anita J W M; Amini, Mohammad; Uyterlinde, Wilma; Wijsman, Robin; Bussink, Jan; Biesma, Bonne; Oei, S Bing; Stigt, Jos A; Bootsma, Gerben P; Belderbos, José S A; De Ruysscher, Dirk K M; Van den Heuvel, Michel M; Dingemans, Anne-Marie C

2016-11-01

Symptomatic brain metastases (BM) occur frequently after chemoradiotherapy (CRT) for stage III NSCLC. Aim of the current study was to determine whether the specific chemotherapy used in a CRT regimen influences BM development. Retrospective multicenter study including all consecutive stage III NSCLC who completed CRT. Primary endpoints: symptomatic BM development, whether this was the only site of first relapse. Differences between regimens were assessed with a logistic regression model including known BM risk factors and the specific chemotherapy: concurrent versus sequential (cCRT/sCRT), within cCRT: daily low dose cisplatin (LDC)-cyclic dose polychemotherapy; LDC-(non-)taxane cyclic dose; LDC-polychemotherapy subgroups of ≥50 patients. Between January 2006 and June 2014, 838 patients were eligible (737 cCRT, 101 sCRT). 18.2% developed symptomatic BM, 8.0% had BM as only site of first relapse. BM patients were significantly younger, female, had more advanced N-stage and had adenocarcinoma histology. In both cCRT and sCRT BM were found in 18% (p=0.904). In cyclic dose cCRT (N=346) and LDC (N=391) BM were found in 18.8% and 17.9%, respectively (p=0.757). In 7.2% and 8.7%, respectively, BM were the only site of first relapse (p=0.463). The chemotherapy used (cCRT versus sCRT) had no influence on BM development, not for all brain relapses nor as only site of first relapse (OR 0.88 (p=0.669), OR 0.93 (p=0.855), respectively). LDC versus cyclic dose cCRT was not significantly different: neither for all brain relapses nor as only site of first relapse (OR 0.96 (p=0.819), OR 1.21 (p=0.498), respectively). Comparable results were found for LDC versus cyclic dose non-taxane (N=277) and cyclic dose taxane regimens (N=69) and for cCRT regimens with ≥50 patients (LDC versus cisplatin/etoposide (N=188), cisplatin/vinorelbin (N=65), weekly cisplatin/docetaxel (N=60)). approximately 18% developed symptomatic BM after stage III diagnosis, not dependent on type of chemotherapy regimen used within a CRT treatment. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Pro-gastrin-releasing peptide (ProGRP) as a biomarker in small-cell lung cancer diagnosis, monitoring and evaluation of treatment response.

PubMed

Wojcik, Ewa; Kulpa, Jan Kanty

2017-01-01

Lung cancer belongs to malignant tumors that possess the highest rates of morbidity and mortality in the world. A number of morphological, biological and clinical features justify the distinction of small-cell carcinoma with respect to the other histological types of lung cancer. The predominant neuroendocrine phenotype is critical for the selection of biomarkers used in diagnostics, monitoring and evaluation of treatment response; early onset relapses in patients with small-cell lung cancer (SCLC) and the evaluation of their prognosis. Although for a long time the neuron-specific enolase (NSE) was considered to be the marker of choice for this tumor, it is now increasingly important to pay attention to concentrations of pro-gastrin-releasing peptide (ProGRP). The results of this marker have been implicated in the differential diagnosis of non-small lung cancer and SCLC, chemotherapy and radiotherapy monitoring as well as evaluation of treatment response. The subject of this series of studies is to determine the usefulness of ProGRP in the evaluation of patients' prognosis and its predictive value. The current aim for the optimization of the effectiveness of biochemical diagnostics of SCLC is recommended by complementary ProGRP and NSE studies. The present work is a summary of the latest reports regarding diagnostic utility of these markers in SCLC.

Patterns of nodal relapse after surgery and postoperative radiation therapy for carcinomas of the major and minor salivary glands: What is the role of elective neck irradiation?

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chen, Allen M.; Garcia, Joaquin; Lee, Nancy Y.

2007-03-15

Purpose: To evaluate the incidence of nodal relapses from carcinomas of the salivary glands among patients with clinically negative necks in an attempt to determine the potential utility of elective neck irradiation (ENI). Methods and Materials: Between 1960 and 2004, 251 patients with clinically N0 carcinomas of the salivary glands were treated with surgery and postoperative radiation therapy. None of the patients had undergone previous neck dissection. Histology was: adenoid cystic (84 patients), mucoepidermoid (60 patients), adenocarcinoma (58 patients), acinic cell (21 patients), undifferentiated (11 patients), carcinoma ex pleomorphic adenoma (7 patients), squamous cell (7 patients), and salivary duct carcinomamore » (3 patients); 131 patients (52%) had ENI. Median follow-up was 62 months (range, 3-267 months). Results: The 5- and 10-year actuarial estimates of nodal relapse were 11% and 13%, respectively. The 10-year actuarial rates of nodal failure were 7%, 5%, 12%, and 16%, for patients with T1, T2, T3, and T4 disease, respectively (p = 0.11). The use of ENI reduced the 10-year nodal failure rate from 26% to 0% (p = 0.0001). The highest crude rates of nodal relapse among those treated without ENI were found in patients with squamous cell carcinoma (67%), undifferentiated carcinoma (50%), adenocarcinoma (34%), and mucoepidermoid carcinoma (29%). There were no nodal failures observed among patients with adenoid cystic or acinic cell histology. Conclusion: ENI effectively prevents nodal relapses and should be used for select patients at high risk for regional failure.« less

ALK in Non-Small Cell Lung Cancer (NSCLC) Pathobiology, Epidemiology, Detection from Tumor Tissue and Algorithm Diagnosis in a Daily Practice

PubMed Central

Hofman, Paul

2017-01-01

Patients with advanced-stage non-small cell lung carcinoma (NSCLC) harboring an ALK rearrangement, detected from a tissue sample, can benefit from targeted ALK inhibitor treatment. Several increasingly effective ALK inhibitors are now available for treatment of patients. However, despite an initial favorable response to treatment, in most cases relapse or progression occurs due to resistance mechanisms mainly caused by mutations in the tyrosine kinase domain of ALK. The detection of an ALK rearrangement is pivotal and can be done using different methods, which have variable sensitivity and specificity depending, in particular, on the quality and quantity of the patient’s sample. This review will first highlight briefly some information regarding the pathobiology of an ALK rearrangement and the epidemiology of patients harboring this genomic alteration. The different methods used to detect an ALK rearrangement as well as their advantages and disadvantages will then be examined and algorithms proposed for detection in daily routine practice. PMID:28805682

Alectinib: a selective, next-generation ALK inhibitor for treatment of ALK-rearranged non-small-cell lung cancer.

PubMed

Santarpia, Mariacarmela; Altavilla, Giuseppe; Rosell, Rafael

2015-06-01

Crizotinib was the first clinically available anaplastic lymphoma kinase (ALK) inhibitor, showing remarkable activity against ALK-rearranged non-small-cell lung cancer (NSCLC). Despite initial responses, acquired resistance to crizotinib inevitably develops, with the brain being a common site of relapse. Alectinib is a highly selective, next-generation ALK inhibitor with potent inhibitory activity also against ALK mutations conferring resistance to crizotinib, including the gatekeeper L1196M substitution. In a Phase I/II study from Japan, alectinib was found to be highly active and safe in crizotinib-naïve, ALK-rearranged NSCLC patients. Alectinib also demonstrated promising antitumor activity in crizotinib-resistant patients, including those with CNS metastases. Based on these data, the drug received Breakthrough Therapy Designation by the US FDA and has been recently approved in Japan for the treatment of ALK-positive, advanced NSCLC patients. However, patients may eventually develop resistance to alectinib, highlighting the need for novel therapeutic strategies to further improve the management of ALK-rearranged NSCLC.

ALK in Non-Small Cell Lung Cancer (NSCLC) Pathobiology, Epidemiology, Detection from Tumor Tissue and Algorithm Diagnosis in a Daily Practice.

PubMed

Hofman, Paul

2017-08-12

Patients with advanced-stage non-small cell lung carcinoma (NSCLC) harboring an ALK rearrangement, detected from a tissue sample, can benefit from targeted ALK inhibitor treatment. Several increasingly effective ALK inhibitors are now available for treatment of patients. However, despite an initial favorable response to treatment, in most cases relapse or progression occurs due to resistance mechanisms mainly caused by mutations in the tyrosine kinase domain of ALK. The detection of an ALK rearrangement is pivotal and can be done using different methods, which have variable sensitivity and specificity depending, in particular, on the quality and quantity of the patient's sample. This review will first highlight briefly some information regarding the pathobiology of an ALK rearrangement and the epidemiology of patients harboring this genomic alteration. The different methods used to detect an ALK rearrangement as well as their advantages and disadvantages will then be examined and algorithms proposed for detection in daily routine practice.

Ibrutinib versus temsirolimus in patients with relapsed or refractory mantle-cell lymphoma: an international, randomised, open-label, phase 3 study.

PubMed

Dreyling, Martin; Jurczak, Wojciech; Jerkeman, Mats; Silva, Rodrigo Santucci; Rusconi, Chiara; Trneny, Marek; Offner, Fritz; Caballero, Dolores; Joao, Cristina; Witzens-Harig, Mathias; Hess, Georg; Bence-Bruckler, Isabelle; Cho, Seok-Goo; Bothos, John; Goldberg, Jenna D; Enny, Christopher; Traina, Shana; Balasubramanian, Sriram; Bandyopadhyay, Nibedita; Sun, Steven; Vermeulen, Jessica; Rizo, Aleksandra; Rule, Simon

2016-02-20

Mantle-cell lymphoma is an aggressive B-cell lymphoma with a poor prognosis. Both ibrutinib and temsirolimus have shown single-agent activity in patients with relapsed or refractory mantle-cell lymphoma. We undertook a phase 3 study to assess the efficacy and safety of ibrutinib versus temsirolimus in relapsed or refractory mantle-cell lymphoma. This randomised, open-label, multicentre, phase 3 clinical trial enrolled patients with relapsed or refractory mantle-cell lymphoma confirmed by central pathology in 21 countries who had received one or more rituximab-containing treatments. Patients were stratified by previous therapy and simplified mantle-cell lymphoma international prognostic index score, and were randomly assigned with a computer-generated randomisation schedule to receive daily oral ibrutinib 560 mg or intravenous temsirolimus (175 mg on days 1, 8, and 15 of cycle 1; 75 mg on days 1, 8, and 15 of subsequent 21-day cycles). Randomisation was balanced by using randomly permuted blocks. The primary efficacy endpoint was progression-free survival assessed by a masked independent review committee with the primary hypothesis that ibrutinib compared with temsirolimus significantly improves progression-free survival. The analysis followed the intention-to-treat principle. The trial is ongoing and is registered with ClinicalTrials.gov (number NCT01646021) and with the EU Clinical Trials Register, EudraCT (number 2012-000601-74). Between Dec 10, 2012, and Nov 26, 2013, 280 patients were randomised to ibrutinib (n=139) or temsirolimus (n=141). Primary efficacy analysis showed significant improvement in progression-free survival (p<0·0001) for patients treated with ibrutinib versus temsirolimus (hazard ratio 0·43 [95% CI 0·32-0·58]; median progression-free survival 14·6 months [95% CI 10·4-not estimable] vs 6·2 months [4·2-7·9], respectively). Ibrutinib was better tolerated than temsirolimus, with grade 3 or higher treatment-emergent adverse events reported for 94 (68%) versus 121 (87%) patients, and fewer discontinuations of study medication due to adverse events for ibrutinib versus temsirolimus (9 [6%] vs 36 [26%]). Ibrutinib treatment resulted in significant improvement in progression-free survival and better tolerability versus temsirolimus in patients with relapsed or refractory mantle-cell lymphoma. These data lend further support to the positive benefit-risk ratio for ibrutinib in relapsed or refractory mantle-cell lymphoma. Janssen Research & Development, LLC. Copyright © 2016 Elsevier Ltd. All rights reserved.

Cytomegalovirus Reactivation after Allogeneic Hematopoietic Stem Cell Transplantation is Associated with a Reduced Risk of Relapse in Patients with Acute Myeloid Leukemia Who Survived to Day 100 after Transplantation: The Japan Society for Hematopoietic Cell Transplantation Transplantation-related Complication Working Group.

PubMed

Takenaka, Katsuto; Nishida, Tetsuya; Asano-Mori, Yuki; Oshima, Kumi; Ohashi, Kazuteru; Mori, Takehiko; Kanamori, Heiwa; Miyamura, Koichi; Kato, Chiaki; Kobayashi, Naoki; Uchida, Naoyuki; Nakamae, Hirohisa; Ichinohe, Tatsuo; Morishima, Yasuo; Suzuki, Ritsuro; Yamaguchi, Takuhiro; Fukuda, Takahiro

2015-11-01

Cytomegalovirus (CMV) infection is a major infectious complication after allogeneic hematopoietic cell transplantation (allo-HSCT). Recently, it was reported that CMV reactivation is associated with a decreased risk of relapse in patients with acute myeloid leukemia (AML). The aim of this study was to evaluate the impact of early CMV reactivation on the incidence of disease relapse after allo-HSCT in a large cohort of patients. The Japan Society for Hematopoietic Cell Transplantation's Transplantation-Related Complication Working Group retrospectively surveyed the database of the Transplant Registry Unified Management Program at the Japan Society for Hematopoietic Cell Transplantation. Patients with AML (n = 1836), acute lymphoblastic leukemia (ALL, n = 911), chronic myeloid leukemia (CML, n = 223), and myelodysplastic syndrome (MDS, n = 569) who underwent their first allo-HSCT from HLA-matched related or unrelated donors between 2000 and 2009 and who survived without disease relapse until day 100 after transplantation were analyzed. Patients who received umbilical cord blood transplantation were not included. Patients underwent surveillance by pp65 antigenemia from the time of engraftment, and the beginning of preemptive therapy was defined as CMV reactivation. Cox proportional hazards models were used to evaluate the risk factors of relapse, nonrelapse, and overall mortality. CMV reactivation and acute/chronic graft-versus-host disease (GVHD) were evaluated as time-dependent covariates. CMV reactivation was associated with a decreased incidence of relapse in patients with AML (20.3% versus 26.4%, P = .027), but not in patients with ALL, CML, or MDS. Among 1836 patients with AML, CMV reactivation occurred in 795 patients (43.3%) at a median of 42 days, and 436 patients (23.7%) relapsed at a median of 221 days after allo-HSCT. Acute GVHD grades II to IV developed in 630 patients (34.3%). By multivariate analysis considering competing risk factors, 3 factors were significantly associated with a decreased risk of AML relapse and 1 factor with an increased risk of AML relapse: CMV reactivation (hazard ratio [HR], .77; 95% confidence interval [CI], .59 to .99), unrelated donor compared with related donor (HR, .59; 95% CI, .42 to .84), development of chronic GVHD (HR, .77; 95% CI, .60 to .99), and pretransplantation advanced disease status compared with standard disease status (HR, 1.99; 95% CI, 1.56 to 2.52). However, CMV reactivation was associated with increased nonrelapse mortality (HR, 1.60; 95% CI, 1.18 to 2.17) and overall mortality (HR, 1.37; 95% CI, 1.11 to 1.69). A beneficial effect of CMV reactivation on subsequent risk of relapse was observed in patients with AML but not in those with other hematological malignancies. However, this benefit was nullified by the increased nonrelapse mortality. The underlying mechanism is unclear; however, immunological activation against CMV reactivation plays an essential role in this association. Thus, immune augmentation treatment options, including vaccination and adoptive T cell transfer, may be useful to take advantage of the efficacy of CMV reactivation with minimal increase in nonrelapse mortality. Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

A form of relapse prevention for men in a high security hospital.

PubMed

Newton, Liam; Coles, Dawn; Quayle, Marie

2005-01-01

Marlatt and Gordon's relapse prevention model has evolved, and been applied to many repetitive problem behaviours, including drug use, gambling and sexual offending. High security hospital patients often present with a number of such behaviours. To evaluate a relapse prevention group in one high security hospital. Nine patients were selected on clinical need for the group. In a naturalistic study design, each completed several self-report questionnaires pre- and post-group. Analysis of group results demonstrated a significant increase in guilt and acceptance of responsibility for offences (GBAI ratings), and reduced endorsement of pro-offending thinking styles (PICTS). Movement towards increased empathy, and decreased impulsivity and venturesomeness, did not reach significance. All participants showed some changes in desired directions but effects were small. Both relapse prevention and its evaluation are limited in high security hospitals by the restricted opportunities for testing out new skills. The feasibility of delivering an RP programme and evaluating it in high security has nevertheless been established. The small effects found may be promising, and suggest both justification and need for a randomized controlled trial of this approach in that setting. Copyright (c) 2005 John Wiley & Sons, Ltd.

17-N-Allylamino-17-Demethoxygeldanamycin and Bortezomib in Treating Patients With Relapsed or Refractory Hematologic Cancer

ClinicalTrials.gov

2013-06-03

Adult Acute Basophilic Leukemia; Adult Acute Eosinophilic Leukemia; Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); Adult Acute Monoblastic Leukemia (M5a); Adult Acute Monocytic Leukemia (M5b); Adult Acute Myeloblastic Leukemia With Maturation (M2); Adult Acute Myeloblastic Leukemia Without Maturation (M1); Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Myelomonocytic Leukemia (M4); Adult Erythroleukemia (M6a); Adult Pure Erythroid Leukemia (M6b); Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Nodal Marginal Zone B-cell Lymphoma; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; Waldenström Macroglobulinemia

Preoperative [18F]-fluorodeoxyglucose positron emission tomography standardized uptake value of neck lymph nodes may aid in selecting patients with oral cavity squamous cell carcinoma for salvage therapy after relapse.

PubMed

Liao, Chun-Ta; Chang, Joseph Tung-Chieh; Wang, Hung-Ming; Ng, Shu-Hang; Huang, Shiang-Fu; Chen, I-How; Hsueh, Chuen; Lee, Li-Yu; Lin, Chih-Hung; Cheng, Ann-Joy; Yen, Tzu-Chen

2009-11-01

Relapse of tumours in patients with oral cavity squamous cell carcinoma (OSCC) is associated with a dismal outcome. In this prospective study, we sought to investigate the clinical significance of the preoperative maximal standardized uptake value (SUVmax) at the neck lymph nodes in selecting patients with OSCC for salvage therapy after relapse. Between 2002 and 2007, 108 patients with early relapse of OSCC (n=75) or late relapse of OSCC (n=33) were identified. Salvage therapy was performed in 47 patients. All patients underwent 2-deoxy-2[(18)F]-fluoro-D: -glucose positron emission tomography during the 2 weeks before surgery and neck dissection. All patients were followed for 12 months or more after surgery or until death. The optimal cut-off value for the neck lymph node SUVmax (SUVnodal-max) was selected according to the 5-year disease-specific survival (DSS) rate. Independent risk factors were identified by Cox regression analysis. The mean follow-up for all patients was 20.3 months (41.1 months for surviving patients). In the early relapse group, several prognostic factors were identified in univariate and multivariate analyses, including a SUVnodal-max value of >or=4.2. A scoring system based on univariate analysis was formulated. Patients with a score of 0 had a better 5-year DSS than those with scores of 1 or higher (58% vs. 5%, p=0.0003). In patients with late relapse, a SUVnodal-max value of >or=4.2 had the highest prognostic value for predicting the 5-year DSS (45% vs. 0%, p=0.0005). Among patients with relapsed OSCC, the SUVnodal-max value may aid in selecting patients for salvage therapy.

The significance of PIWI family expression in human lung embryogenesis and non-small cell lung cancer.

PubMed

Navarro, Alfons; Tejero, Rut; Viñolas, Nuria; Cordeiro, Anna; Marrades, Ramon M; Fuster, Dolors; Caritg, Oriol; Moises, Jorge; Muñoz, Carmen; Molins, Laureano; Ramirez, Josep; Monzo, Mariano

2015-10-13

The expression of Piwi-interacting RNAs, small RNAs that bind to PIWI proteins, was until recently believed to be limited to germinal stem cells. We have studied the expression of PIWI genes during human lung embryogenesis and in paired tumor and normal tissue prospectively collected from 71 resected non-small-cell lung cancer patients. The mRNA expression analysis showed that PIWIL1 was highly expressed in 7-week embryos and downregulated during the subsequent weeks of development. PIWIL1 was expressed in 11 of the tumor samples but in none of the normal tissue samples. These results were validated by immunohistochemistry, showing faint cytoplasmic reactivity in the PIWIL1-positive samples. Interestingly, the patients expressing PIWIL1 had a shorter time to relapse (TTR) (p = 0.006) and overall survival (OS) (p = 0.0076) than those without PIWIL1 expression. PIWIL2 and 4 were downregulated in tumor tissue in comparison to the normal tissue (p < 0.001) and the patients with lower levels of PIWIL4 had shorter TTR (p = 0.048) and OS (p = 0.033). In the multivariate analysis, PIWIL1 expression emerged as an independent prognostic marker. Using 5-Aza-dC treatment and bisulfite sequencing, we observed that PIWIL1 expression could be regulated in part by methylation. Finally, an in silico study identified a stem-cell expression signature associated with PIWIL1 expression.

A Multicenter Pilot Study Examining the Role of Circulating Tumor Cells as a Blood-Based Tumor Marker in Patients with Extensive Small-Cell Lung Cancer

PubMed Central

Huang, Chao H.; Wick, Jo A.; Sittampalam, Gurusingham Sitta; Nirmalanandhan, Victor Sanjit; Ganti, Apar Kishor; Neupane, Prakash C.; Williamson, Stephen K.; Godwin, Andrew K.; Schmitt, Sarah; Smart, Nora J.; Spencer, Sarah; Van Veldhuizen, Peter J.

2014-01-01

Background: Small-cell lung cancer (SCLC), a variant of lung cancer marked by early metastases, accounts for 13% of all lung cancers diagnosed in US. Despite high response rates to treatment, it is an aggressive disease with a median survival of 9–11 months for patients with extensive stage (EX-SCLC). Detection of circulating tumor cells (CTCs) is a novel laboratory technique currently in use to determine response to therapy and to predict prognosis in breast, colorectal, and prostate cancer. We initiated a pilot study to analyze the role of CTCs as a biomarker of response and relapse in patients with EX-SCLC. Methods: We collected blood samples from chemotherapy naïve patients with EX-SCLC prior to initiation of therapy, after completion of systemic therapy, and follow-up every 6–8 weeks and at relapse. The number of CTCs was determined using the cell search system in a central laboratory. The study was conducted in four different sites, and it was reviewed and approved by respective research review committees and IRBs. Results: We enrolled 26 patients with EX-SCLC, 1 was excluded due to ineligibility, all were treated with platinum and etoposide. We observed partial response in 16 patients, stable disease in 3 patients, 1 patient with disease progression, and 6 patients were not assessed (5 deceased, 1 not available). The overall median number of CTCs in 24 patients measured at baseline and post-tx was 75 (range 0–3430) and 2 (range 0–526), respectively. A significant reduction in CTCs from baseline to post-treatment was identified for 15 subjects; the median reduction was 97.4% (range −100 to +100%, p < 0.001). Higher baseline CTCs and percentage change in post-treatment CTCs were associated with decreased survival. Conclusion: We demonstrated that it is feasible to detect CTCs in EX-SCLC. If validated in other prospective studies, CTCs could be a useful biomarker in the management of EX-SCLC by predicting patients’ clinical responses to therapy. PMID:25353007

A semi-nested real-time PCR method to detect low chimerism percentage in small quantity of hematopoietic stem cell transplant DNA samples.

PubMed

Aloisio, Michelangelo; Bortot, Barbara; Gandin, Ilaria; Severini, Giovanni Maria; Athanasakis, Emmanouil

2017-02-01

Chimerism status evaluation of post-allogeneic hematopoietic stem cell transplantation samples is essential to predict post-transplant relapse. The most commonly used technique capable of detecting small increments of chimerism is quantitative real-time PCR. Although this method is already used in several laboratories, previously described protocols often lack sensitivity and the amount of the DNA required for each chimerism analysis is too high. In the present study, we compared a novel semi-nested allele-specific real-time PCR (sNAS-qPCR) protocol with our in-house standard allele-specific real-time PCR (gAS-qPCR) protocol. We selected two genetic markers and analyzed technical parameters (slope, y-intercept, R2, and standard deviation) useful to determine the performances of the two protocols. The sNAS-qPCR protocol showed better sensitivity and precision. Moreover, the sNAS-qPCR protocol requires, as input, only 10 ng of DNA, which is at least 10-fold less than the gAS-qPCR protocols described in the literature. Finally, the proposed sNAS-qPCR protocol could prove very useful for performing chimerism analysis with a small amount of DNA, as in the case of blood cell subsets.

Neuroblastoma cells undergo transcriptomic alterations upon dissemination into the bone marrow and subsequent tumor progression.

PubMed

Rifatbegovic, Fikret; Frech, Christian; Abbasi, M Reza; Taschner-Mandl, Sabine; Weiss, Tamara; Schmidt, Wolfgang M; Schmidt, Iris; Ladenstein, Ruth; Ambros, Inge M; Ambros, Peter F

2018-01-15

Neuroblastoma is the most common extracranial solid tumor in childhood. The vast majority of metastatic (M) stage patients present with disseminated tumor cells (DTCs) in the bone marrow (BM) at diagnosis and relapse. Although these cells represent a major obstacle in the treatment of neuroblastoma patients, insights into their expression profile remained elusive. The present RNA-Seq study of stage 4/M primary tumors, enriched BM-derived diagnostic and relapse DTCs, as well as the corresponding BM-derived mononuclear cells (MNCs) from 53 patients revealed 322 differentially expressed genes in DTCs as compared to the tumors (q < 0.001, |log 2 FC|>2). Particularly, the levels of transcripts encoded by mitochondrial DNA were elevated in DTCs, whereas, for example, genes involved in angiogenesis were downregulated. Furthermore, 224 genes were highly expressed in DTCs and only slightly, if at all, in MNCs (q < 8 × 10 -75 log 2 FC > 6). Interestingly, we found the transcriptome of relapse DTCs largely resembling those of diagnostic DTCs with only 113 differentially expressed genes under relaxed cut-offs (q < 0.01, |log 2 FC|>0.5). Notably, relapse DTCs showed a positional enrichment of 31 downregulated genes on chromosome 19, including five tumor suppressor genes: SIRT6, BBC3/PUMA, STK11, CADM4 and GLTSCR2. This first RNA-Seq analysis of neuroblastoma DTCs revealed their unique expression profile in comparison to the tumors and MNCs, and less pronounced differences between diagnostic and relapse DTCs. The latter preferentially affected downregulation of genes encoded by chromosome 19. As these alterations might be associated with treatment failure and disease relapse, further functional studies on DTCs should be considered. © 2017 The Authors International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.

Haploidentical transplant for myelodysplastic syndrome: registry-based comparison with identical sibling transplant.

PubMed

Wang, Y; Wang, H-X; Lai, Y-R; Sun, Z-M; Wu, D-P; Jiang, M; Liu, D-H; Xu, K-L; Liu, Q-F; Liu, L; Wang, J-B; Gao, F; Ou-Yang, J; Gao, S-J; Xu, L-P; Huang, X-J

2016-10-01

Encouraging results from a small sample of patients with myelodysplastic syndrome (MDS) undergoing haploidentical donor (HID) hematopoietic stem cell transplantation (HSCT) must be extended. Furthermore, an algorithm derived from a comparison of the outcomes of HID and identical-sibling donor (ISD) HSCT must be established. Therefore, the outcomes of 454 MDS patients who underwent HSCT from HIDs (n=226) or ISDs (n=228) between 2003 and 2013 that were reported to the Chinese Bone Marrow Transplantation Registry were analyzed. Among the 3/6 HID (n=136), 4-5/6 HID (n=90) and ISD patient groups, the 4-year adjusted cumulative incidences of non-relapse mortality were 34, 29 and 16%, respectively (overall P=0.004), and of relapse were 6, 7 and 10%, respectively (overall P=0.36). The 4-year adjusted probabilities of overall survival were 58, 63 and 73%, respectively (overall P=0.07), and of relapse-free-survival were 58, 63 and 71%, respectively (overall P=0.14); pairwise comparison showed that the difference was only statistically significant in the 3/6 HID vs ISD pair. The data suggest that ISDs remain the best donor source for MDS patients while HIDs (perhaps 4-5/6 HID in particular) could be a valid alternative when an ISD is not available; human leukocyte antigen disparity had no effect on survival among the HID patients.

Three-year follow-up of treatment-naïve and previously treated patients with CLL and SLL receiving single-agent ibrutinib

PubMed Central

Furman, Richard R.; Coutre, Steven E.; Burger, Jan A.; Blum, Kristie A.; Coleman, Morton; Wierda, William G.; Jones, Jeffrey A.; Zhao, Weiqiang; Heerema, Nyla A.; Johnson, Amy J.; Shaw, Yun; Bilotti, Elizabeth; Zhou, Cathy; James, Danelle F.; O'Brien, Susan

2015-01-01

Ibrutinib is an orally administered inhibitor of Bruton tyrosine kinase that antagonizes B-cell receptor, chemokine, and integrin-mediated signaling. In early-phase studies, ibrutinib demonstrated high response rates and prolonged progression-free survival (PFS) in chronic lymphocytic leukemia (CLL). The durable responses observed with ibrutinib relate in part to a modest toxicity profile that allows the majority of patients to receive continuous therapy for an extended period. We report on median 3-year follow-up of 132 patients with symptomatic treatment-naïve and relapsed/refractory CLL or small lymphocytic lymphoma. Longer treatment with ibrutinib was associated with improvement in response quality over time and durable remissions. Toxicity with longer follow-up diminished with respect to occurrence of grade 3 or greater cytopenias, fatigue, and infections. Progression remains uncommon, occurring primarily in some patients with relapsed del(17)(p13.1) and/or del(11)(q22.3) disease. Treatment-related lymphocytosis remains largely asymptomatic even when persisting >1 year and does not appear to alter longer-term PFS and overall survival compared with patients with partial response or better. Collectively, these data provide evidence that ibrutinib controls CLL disease manifestations and is well tolerated for an extended period; this information can help direct potential treatment options for different subgroups to diminish the long-term risk of relapse. PMID:25700432

[Allogeneic haematopoietic cell transplantation for indolent lymphomas: Guidelines from the Francophone Society Bone Marrow Transplantation and Cellular Therapy (SFGM-TC)].

PubMed

Gauthier, Jordan; Chantepie, Sylvain; Bouabdallah, Krimo; Jost, Edgar; Nguyen, Stéphanie; Gac, Anne-Claire; Damaj, Gandhi; Duléry, Rémy; Michallet, Mauricette; Delage, Jérémy; Lewalle, Philippe; Morschhauser, Franck; Salles, Gilles; Yakoub-Agha, Ibrahim; Cornillon, Jérôme

2017-12-01

Despite great improvements in the outcome of patients with lymphoma, some may still relapse or present with primary refractory disease. In these situations, allogeneic hematopoietic cell transplantation is a potentially curative option, this is true particularly the case of relapse after autologous stem cell transplantation. Recently, novel agents such as anti-PD1 and BTK inhibitors have started to challenge the use of allogeneic hematopoietic cell transplantation for relapsed or refractory lymphoma. During the 2016 annual workshop of the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC), we performed a comprehensive review of the literature published in the last 10 years and established guidelines to clarify the indications and transplant modalities in this setting. This paper specifically reports on our conclusions regarding indolent lymphomas, mainly follicular lymphoma and chronic lymphocytic leukemia. Copyright © 2017 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.

Long-term follow-up of patients receiving allogeneic stem cell transplant for chronic lymphocytic leukaemia: mixed T-cell chimerism is associated with high relapse risk and inferior survival.

PubMed

Thompson, Philip A; Stingo, Francesco; Keating, Michael J; Wierda, William G; O'Brien, Susan M; Estrov, Zeev; Ledesma, Celina; Rezvani, Katayoun; Qazilbash, Muzaffar; Shah, Nina; Parmar, Simrit; Popat, Uday; Anderlini, Paolo; Yago, Nieto; Ciurea, Stefan O; Kebriaei, Partow; Champlin, Richard; Shpall, Elizabeth J; Hosing, Chitra M

2017-05-01

There is limited information regarding the immunological predictors of post-allogeneic stem cell transplant (alloSCT) outcome in chronic lymphocytic leukaemia (CLL), such as mixed T-cell chimerism. We analysed 143 consecutive patients with relapsed/refractory CLL, transplanted between 2000 and 2012, to determine the prognostic relevance of mixed chimerism post-alloSCT and the ability of post-transplant immunomodulation to treat relapse. Mixed T-cell chimerism occurred in 50% of patients at 3 months and 43% at 6 months post-alloSCT; upon 3- and 6-month landmark analysis, this was associated with inferior progression-free survival (PFS) [Hazard ratio (HR) 1·93, P = 0·003 and HR 2·58, P < 0·001] and survival (HR 1·66, P = 0·05 and HR 2·17, P < 0·001), independent of baseline patient characteristics, and a lower rate of grade II-IV acute graft-versus-host disease (GHVD) (16% vs. 52%, P < 0·001). Thirty-three patients were treated with immunomodulation for relapse post-alloSCT (immunosuppression withdrawal, n = 6, donor lymphocyte infusion, n = 27); 17 achieved complete response (CR), which predicted superior PFS (53 months vs. 10 months, P < 0·001) and survival (117 months vs. 30 months, P = 0·006). Relapsed patients with mixed chimerism had inferior response to immunomodulation; conversion to full donor chimerism was highly correlated both with CR and with the development of severe acute GVHD, which was fatal in 3/8 patients. Novel therapeutic strategies are required for patients with mixed T-cell chimerism post-alloSCT for CLL. © 2017 John Wiley & Sons Ltd.

Jab1/Csn5-Thioredoxin Signaling in Relapsed Acute Monocytic Leukemia under Oxidative Stress.

PubMed

Zhou, Fuling; Pan, Yunbao; Wei, Yongchang; Zhang, Ronghua; Bai, Gaigai; Shen, Qiuju; Meng, Shan; Le, Xiao-Feng; Andreeff, Michael; Claret, Francois X

2017-08-01

Purpose: High levels of ROS and ineffective antioxidant systems contribute to oxidative stress, which affects the function of hematopoietic cells in acute myeloid leukemia (AML); however, the mechanisms by which ROS lead to malignant transformation in relapsed AML-M5 are not completely understood. We hypothesized that alterations in intracellular ROS would trigger AML-M5 relapse by activating the intrinsic pathway. Experimental Design: We studied ROS levels and conducted c-Jun activation domain-binding protein-1 ( JAB1/COPS5 ) and thioredoxin ( TRX ) gene expression analyses with blood samples obtained from 60 matched AML-M5 patients at diagnosis and relapse and conducted mechanism studies of Jab1's regulation of Trx in leukemia cell lines. Results: Our data showed that increased production of ROS and a low capacity of antioxidant enzymes were characteristics of AML-M5, both at diagnosis and at relapse. Consistently, increased gene expression levels of TRX and JAB1/COPS5 were associated with low overall survival rates in patients with AML-M5. In addition, stimulating AML-M5 cells with low concentrations of hydrogen peroxide led to increased Jab1 and Trx expression. Consistently, transfection of ectopic Jab1 into leukemia cells increased Trx expression, whereas silencing of Jab1 in leukemia cells reduced Trx expression. Mechanistically, Jab1 interacted with Trx and stabilized Trx protein. Moreover, Jab1 transcriptionally regulated Trx. Furthermore, depletion of Jab1 inhibited leukemia cell growth both in vitro and in vivo Conclusions: We identified a novel Jab1-Trx axis that is a key cellular process in the pathobiologic characteristics of AML-M5. Targeting the ROS/Jab1/Trx pathway could be beneficial in the treatment of AML-M5. Clin Cancer Res; 23(15); 4450-61. ©2017 AACR . ©2017 American Association for Cancer Research.

[Outcome of haploidentical hematopoietic stem cell transplantation for non-Hodgkin lymphoma].

PubMed

Xu, T; Chen, J; Jin, Z M; Miao, M; Fu, C C; Qiu, H Y; Tang, X W; Han, Y; Sun, A N; Wu, D P

2016-08-14

To explore the efficacy and safety of haploidentical hematopoietic stem cell transplantation (Haplo- HSCT) for refractory, relapsed or highly aggressive non- Hodgkin lymphoma (NHL) patients. A total of 26 patients with refractory, relapsed or highly aggressive NHL who received Haplo- HSCT from Jan. 2004 to Mar. 2015 were analyzed retrospectively. Of them, 4 patients had diffuse large B-cell lymphoma (DLBCL), 1 had follicular lymphoma, 5 had B-lymphoblastic lymphoma/leukemia, 9 had T- lymphoblastic lymphoma/leukemia, 1 patient anaplastic large cell lymphoma (ALK-negative), 5 had peripheral T-cell lymphoma (NOS), and 1 had NK/T-cell lymphoma. At the time of initial diagnosis, 6 patients had Ann Arbor stage Ⅲ disease, 20 patients showed stage Ⅳ. At the time of Haplo- HSCT, 7 patients were in the first complete remission (CR1), 4 in the second complete remission (CR2), 7 in partial remission, 1 in stable disease, 7 in progressive disease, and 19 of 26 patients were refractory or relapsed. The neutrophil and platelet counts recovered at 12 (11-17) d and 14 (11-31) d after Haplo- HSCT, respectively. All patients achieved full donor chimerism at 30d after Haplo- HSCT. With a median follow- up of 14 (4- 136) months, 20 cases (76.92%) survived, 15 (57.69%) survived without lymphoma, and 7 (26.92%) relapsed. Conditioning regimen related adverse reactions were all disappeared after treatment. The estimated 2-year recurrence rate after Haplo-HSCT was 42.20%. The estimated 2-year overall survival (OS) and disease-free survival (DFS) rate was 71.60% and 48.90%, respectively. Patients in CR before Haplo- HSCT experienced better 2- year OS (100.0% vs 52.4%, P=0.023) and 2- year DFS (88.9% vs 27.0%, P=0.013). Haplo- HSCT may effective and safe for those relapsed, refractory or highly aggressive NHL patients who did not have matched donor nor suitable for autologous HSCT.

Salvage Regimens With Autologous Transplantation for Relapsed Large B-Cell Lymphoma in the Rituximab Era

PubMed Central

Gisselbrecht, Christian; Glass, Bertram; Mounier, Nicolas; Singh Gill, Devinder; Linch, David C.; Trneny, Marek; Bosly, Andre; Ketterer, Nicolas; Shpilberg, Ofer; Hagberg, Hans; Ma, David; Brière, Josette; Moskowitz, Craig H.; Schmitz, Norbert

2010-01-01

Purpose Salvage chemotherapy followed by high-dose therapy and autologous stem-cell transplantation (ASCT) is the standard treatment for relapsed diffuse large B-cell lymphoma (DLBCL). Salvage regimens have never been compared; their efficacy in the rituximab era is unknown. Patients and Methods Patients with CD20+ DLBCL in first relapse or who were refractory after first-line therapy were randomly assigned to either rituximab, ifosfamide, etoposide, and carboplatin (R-ICE) or rituximab, dexamethasone, high-dose cytarabine, and cisplatin (R-DHAP). Responding patients received high-dose chemotherapy and ASCT. Results The median age of the 396 patients enrolled (R-ICE, n = 202; R-DHAP, n = 194) was 55 years. Similar response rates were observed after three cycles of R-ICE (63.5%; 95% CI, 56% to 70%) and R-DHAP (62.8%; 95 CI, 55% to 69%). Factors affecting response rates (P < .001) were refractory disease/relapse less than versus more than 12 months after diagnosis (46% v 88%, respectively), International Prognostic Index (IPI) of more than 1 versus 0 to 1 (52% v 71%, respectively), and prior rituximab treatment versus no prior rituximab (51% v 83%, respectively). There was no significant difference between R-ICE and R-DHAP for 3-year event-free survival (EFS) or overall survival. Three-year EFS was affected by prior rituximab treatment versus no rituximab (21% v 47%, respectively), relapse less than versus more than 12 months after diagnosis (20% v 45%, respectively), and IPI of 2 to 3 versus 0 to 1 (18% v 40%, respectively). In the Cox model, these parameters were significant (P < .001). Conclusion In patients who experience relapse more than 12 months after diagnosis, prior rituximab treatment does not affect EFS. Patients with early relapses after rituximab-containing first-line therapy have a poor prognosis, with no difference between the effects of R-ICE and R-DHAP. PMID:20660832

Reduced-Intensity Conditioning Before Donor Stem Cell Transplant in Treating Patients With High-Risk Hematologic Malignancies

ClinicalTrials.gov

2018-03-02

Accelerated Phase Chronic Myelogenous Leukemia; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Nasal Type Extranodal NK/T-cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Blastic Phase Chronic Myelogenous Leukemia; Childhood Acute Lymphoblastic Leukemia in Remission; Childhood Burkitt Lymphoma; Childhood Chronic Myelogenous Leukemia; Childhood Diffuse Large Cell Lymphoma; Childhood Immunoblastic Large Cell Lymphoma; Childhood Myelodysplastic Syndromes; Childhood Nasal Type Extranodal NK/T-cell Lymphoma; Chronic Myelomonocytic Leukemia; Chronic Phase Chronic Myelogenous Leukemia; Cutaneous B-cell Non-Hodgkin Lymphoma; de Novo Myelodysplastic Syndromes; Essential Thrombocythemia; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Hepatosplenic T-cell Lymphoma; Intraocular Lymphoma; Juvenile Myelomonocytic Leukemia; Nodal Marginal Zone B-cell Lymphoma; Noncutaneous Extranodal Lymphoma; Peripheral T-cell Lymphoma; Polycythemia Vera; Post-transplant Lymphoproliferative Disorder; Previously Treated Myelodysplastic Syndromes; Primary Myelofibrosis; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Childhood Anaplastic Large Cell Lymphoma; Recurrent Childhood Grade III Lymphomatoid Granulomatosis; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Small Noncleaved Cell Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Recurrent/Refractory Childhood Hodgkin Lymphoma; Refractory Anemia With Excess Blasts; Refractory Anemia With Excess Blasts in Transformation; Refractory Cytopenia With Multilineage Dysplasia; Refractory Hairy Cell Leukemia; Refractory Multiple Myeloma; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; T-cell Large Granular Lymphocyte Leukemia; Testicular Lymphoma; Waldenström Macroglobulinemia

Lenalidomide, Ibrutinib, and Rituximab in Treating Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma That Is Metastatic or Cannot Be Removed by Surgery

ClinicalTrials.gov

2018-04-13

Ann Arbor Stage III Small Lymphocytic Lymphoma; Ann Arbor Stage IV Small Lymphocytic Lymphoma; Recurrent Chronic Lymphocytic Leukemia; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Small Lymphocytic Lymphoma; Stage III Chronic Lymphocytic Leukemia; Stage IV Chronic Lymphocytic Leukemia

Anti-leukaemic activity of a novel haploidentical-transplantation approach employing unmanipulated bone marrow followed by CD6-depleted peripheral blood stem cells in children with refractory/relapsed acute leukaemia.

PubMed

Schuster, Friedhelm R; Meisel, Roland; Führer, Monika; Reuther, Susanne; Hauer, Julia; Tischer, Johanna; Feuchtinger, Tobias; Laws, Hans-Jürgen; Kolb, Hans-Jochem; Borkhardt, Arndt

2013-09-01

The treatment outcome of children with refractory acute leukaemia or relapse post-stem cell transplantation is dismal. We report 10 children (non-remission n = 7) who underwent a new haploidentical transplant approach utilizing unmanipulated bone marrow followed by CD6-depleted peripheral blood stem cells. Nine patients had successful engraftment and no evidence of leukaemia. Acute and chronic graft-versus-host-disease was observed in five and three patients, respectively; two patients died of treatment-related toxicity. Seven patients relapsed after 7 (range 3-34) months, however two patients are alive at 6·5 and 7·0 years. This approach provides anti-leukaemic activity even in heavily pre-treated children but long-term disease control requires further intervention. © 2013 John Wiley & Sons Ltd.

NCCN Guidelines Insights: Non-Hodgkin's Lymphomas, Version 3.2016.

PubMed

Horwitz, Steven M; Zelenetz, Andrew D; Gordon, Leo I; Wierda, William G; Abramson, Jeremy S; Advani, Ranjana H; Andreadis, C Babis; Bartlett, Nancy; Byrd, John C; Fayad, Luis E; Fisher, Richard I; Glenn, Martha J; Habermann, Thomas M; Lee Harris, Nancy; Hernandez-Ilizaliturri, Francisco; Hoppe, Richard T; Kaminski, Mark S; Kelsey, Christopher R; Kim, Youn H; Krivacic, Susan; LaCasce, Ann S; Lunning, Matthew; Nademanee, Auayporn; Press, Oliver; Rabinovitch, Rachel; Reddy, Nishitha; Reid, Erin; Roberts, Kenneth; Saad, Ayman A; Sokol, Lubomir; Swinnen, Lode J; Vose, Julie M; Yahalom, Joachim; Zafar, Nadeem; Dwyer, Mary; Sundar, Hema; Porcu, Pierluigi

2016-09-01

Peripheral T-cell lymphomas (PTCLs) represent a relatively uncommon heterogeneous group of non-Hodgkin's lymphomas (NHLs) with an aggressive clinical course and poor prognosis. Anthracycline-based multiagent chemotherapy with or without radiation therapy followed by first-line consolidation with high-dose therapy followed by autologous stem cell rescue (HDT/ASCR) is the standard approach to most of the patients with newly diagnosed PTCL. Relapsed or refractory disease is managed with second-line systemic therapy followed by HDT/ASCR or allogeneic stem cell transplant, based on the patient's eligibility for transplant. In recent years, several newer agents have shown significant activity in patients with relapsed or refractory disease across all 4 subtypes of PTCL. These NCCN Guideline Insights highlight the important updates to the NCCN Guidelines for NHL, specific to the management of patients with relapsed or refractory PTCL. Copyright © 2016 by the National Comprehensive Cancer Network.

The degree of myelosuppression during maintenance therapy of adolescents with B-lineage intermediate risk acute lymphoblastic leukemia predicts risk of relapse.

PubMed

Schmiegelow, K; Heyman, M; Gustafsson, G; Lausen, B; Wesenberg, F; Kristinsson, J; Vettenranta, K; Schroeder, H; Forestier, E; Rosthoej, S

2010-04-01

Drug doses, blood levels of drug metabolites and myelotoxicity during 6-mercaptopurine/methotrexate (MTX) maintenance therapy were registered for 59 adolescents (>or=10 years) and 176 non-adolescents (<10 years) with B-cell precursor acute lymphoblastic leukemia (ALL) and a white blood cell count (WBC) <50 x 10(9)/l at diagnosis. Event-free survival was lower for adolescents than non-adolescents (pEFS(12y):0.71 vs 0.83, P=0.04). For adolescents staying in remission, the mean WBC during maintenance therapy (mWBC) was related to age (r(S)=0.36, P=0.02), which became nonsignificant for those who relapsed (r(S)=0.05, P=0.9). The best-fit multivariate Cox regression model to predict risk of relapse included mWBC and thiopurine methyltransferase activity, which methylates mercaptopurine and reduces the intracellular availability of cytotoxic 6-thioguanine nucleotides (coefficient: 0.11, P=0.02). The correlation of mWBC to the risk of relapse was more pronounced for adolescents (coefficient=0.65, P=0.003) than for non-adolescents (coefficient=0.42, P=0.04). Adolescents had higher mean neutrophil counts (P=0.002) than non-adolescents, but received nonsignificantly lower mercaptopurine and MTX doses during maintenance therapy. Red blood cell MTX levels were significantly related to the dose of MTX among adolescents who stayed in remission (r(S)=0.38, P=0.02), which was not the case for those who developed a relapse (r(S)=0.15, P=0.60). Thus, compliance to maintenance therapy may influence the risk of relapse for adolescents with ALL.

Measurable residual disease testing in acute myeloid leukaemia.

PubMed

Hourigan, C S; Gale, R P; Gormley, N J; Ossenkoppele, G J; Walter, R B

2017-07-01

There is considerable interest in developing techniques to detect and/or quantify remaining leukaemia cells termed measurable or, less precisely, minimal residual disease (MRD) in persons with acute myeloid leukaemia (AML) in complete remission defined by cytomorphological criteria. An important reason for AML MRD-testing is the possibility of estimating the likelihood (and timing) of leukaemia relapse. A perfect MRD-test would precisely quantify leukaemia cells biologically able and likely to cause leukaemia relapse within a defined interval. AML is genetically diverse and there is currently no uniform approach to detecting such cells. Several technologies focused on immune phenotype or cytogenetic and/or molecular abnormalities have been developed, each with advantages and disadvantages. Many studies report a positive MRD-test at diverse time points during AML therapy identifies persons with a higher risk of leukaemia relapse compared with those with a negative MRD-test even after adjusting for other prognostic and predictive variables. No MRD-test in AML has perfect sensitivity and specificity for relapse prediction at the cohort- or subject levels and there are substantial rates of false-positive and -negative tests. Despite these limitations, correlations between MRD-test results and relapse risk have generated interest in MRD-test result-directed therapy interventions. However, convincing proof that a specific intervention will reduce relapse risk in persons with a positive MRD-test is lacking and needs testing in randomized trials. Routine clinical use of MRD-testing requires further refinements and standardization/harmonization of assay platforms and results reporting. Such data are needed to determine whether results of MRD-testing can be used as a surrogate end point in AML therapy trials. This could make drug-testing more efficient and accelerate regulatory approvals. Although MRD-testing in AML has advanced substantially, much remains to be done.

Mogamulizumab for relapsed adult T-cell leukemia-lymphoma: Updated follow-up analysis of phase I and II studies.

PubMed

Ishida, Takashi; Utsunomiya, Atae; Jo, Tatsuro; Yamamoto, Kazuhito; Kato, Koji; Yoshida, Shinichiro; Takemoto, Shigeki; Suzushima, Hitoshi; Kobayashi, Yukio; Imaizumi, Yoshitaka; Yoshimura, Kenichi; Kawamura, Kouichi; Takahashi, Takeshi; Tobinai, Kensei; Ueda, Ryuzo

2017-10-01

The present study sought to elucidate the prognosis of adult T-cell leukemia-lymphoma (ATL) patients receiving mogamulizumab, a defucosylated anti-CCR4 monoclonal antibody. Progression-free survival (PFS) and overall survival (OS) of ATL patients enrolled in two studies are herein updated, namely NCT00355472 (phase I study of mogamulizumab in relapsed patients with ATL and peripheral T-cell lymphoma) and NCT00920790 (phase II study for relapsed ATL). Of 13 patients with relapsed aggressive ATL in the phase I study, four (31%) survived >3 years. For 26 relapsed patients with aggressive ATL in the phase II study, median PFS was 5.2 months and 1-year PFS was 26%, whereas median OS was 14.4 months, and 3-year OS was 23%. For patients without a rash or who developed a grade 1 rash only, median PFS was 0.8 months, and 1-year PFS was zero, with a median OS of 6.0 months, and 3-year OS of 8%. In contrast, for patients who developed a rash ≥grade 2, median PFS was 11.7 months, and 1-year PFS was 50%, with a median OS of 25.6 months, and 3-year OS of 36%. Thus, we conclude that mogamulizumab monotherapy may improve PFS and OS in some patients with relapsed aggressive ATL, especially those who develop a skin rash as a moderate immune-related adverse event. Therefore, further investigation is warranted to validate the present observations and to clarify the mechanisms involved in the activity of mogamulizumab. © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Patterns and Timing of Failure for Diffuse Large B-Cell Lymphoma After Initial Therapy in a Cohort Who Underwent Autologous Bone Marrow Transplantation for Relapse

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dhakal, Sughosh; Bates, James E.; Casulo, Carla

Purpose: To evaluate the location and timing of initial recurrence in patients with diffuse large B-cell lymphoma (DLBCL) who subsequently underwent high-dose chemotherapy with autologous stem cell transplant (HDC/ASCT), to direct approaches for disease surveillance, elucidate the patterns of failure of contemporary treatment strategies, and guide adjuvant treatment decisions. Methods and Materials: We analyzed consecutive patients with DLBCL who underwent HDC/ASCT between May 1992 and March 2014 at our institution. Of the 187 evaluable patients, 8 had incomplete data, and 79 underwent HDC/ASCT as a component of initial treatment for de novo or refractory DLBCL and were excluded from furthermore » analysis. Results: The median age was 50.8 years; the median time to relapse was 1.3 years. Patients were segregated according to the initial stage at diagnosis, with early stage (ES) defined as stage I/II and advanced stage (AS) defined as stage III/IV. In total, 40.4% of the ES and 75.5% of the AS patients relapsed in sites of initial disease; 68.4% of those with ES disease and 75.0% of those with AS disease relapsed in sites of initial disease only. Extranodal relapses were common (44.7% in ES and 35.9% in AS) and occurred in a variety of organs, although gastrointestinal tract/liver (n=12) was most frequent. Conclusions: Most patients with DLBCL who relapse and subsequently undergo HDC/ASCT initially recur in the previously involved disease site(s). Time to recurrence is brief, suggesting that frequency of screening is most justifiably greatest in the early posttherapy years. © 2016 Elsevier Inc.« less

Serodiagnosis of Louse-Borne Relapsing Fever with Glycerophosphodiester Phosphodiesterase (GlpQ) from Borrelia recurrentis

PubMed Central

Porcella, Stephen F.; Raffel, Sandra J.; Schrumpf, Merry E.; Schriefer, Martin E.; Dennis, David T.; Schwan, Tom G.

2000-01-01

Human louse-borne relapsing fever occurs in sporadic outbreaks in central and eastern Africa that are characterized by significant morbidity and mortality. Isolates of the causative agent, Borrelia recurrentis, were obtained from the blood of four patients during a recent epidemic of the disease in southern Sudan. The glpQ gene, encoding glycerophosphodiester phosphodiesterase, from these isolates was sequenced and compared with the glpQ sequences obtained from other relapsing-fever spirochetes. Previously we showed that GlpQ of Borrelia hermsii is an immunogenic protein with utility as a serological test antigen for discriminating tick-borne relapsing fever from Lyme disease. In the present work, we cloned and expressed the glpQ gene from B. recurrentis and used recombinant GlpQ in serological tests. Acute- and convalescent-phase serum samples obtained from 42 patients with louse-borne relapsing fever were tested with an indirect immunofluorescence assay (IFA) and an enzyme-linked immunosorbent assay (ELISA) that used whole cells of B. recurrentis and with immunoblotting to whole-cell lysates of the spirochete and Escherichia coli producing recombinant GlpQ. The geometric mean titers of the acute- and convalescent-phase serum samples measured by IFA were 1:83 and 1:575, respectively. The immunoblot analysis identified a high level of reactivity and seroconversion to GlpQ, and the assay was more sensitive than the whole-cell IFA and ELISA using purified, recombinant histidine-tagged GlpQ. Serum antibodies to GlpQ and other antigens persisted for 27 years in one patient. We conclude that assessment of anti-GlpQ antibodies will allow serological confirmation of louse-borne relapsing fever and determination of disease prevalence. PMID:11015364

Gene identification for risk of relapse in stage I lung adenocarcinoma patients: a combined methodology of gene expression profiling and computational gene network analysis.

PubMed

Ludovini, Vienna; Bianconi, Fortunato; Siggillino, Annamaria; Piobbico, Danilo; Vannucci, Jacopo; Metro, Giulio; Chiari, Rita; Bellezza, Guido; Puma, Francesco; Della Fazia, Maria Agnese; Servillo, Giuseppe; Crinò, Lucio

2016-05-24

Risk assessment and treatment choice remains a challenge in early non-small-cell lung cancer (NSCLC). The aim of this study was to identify novel genes involved in the risk of early relapse (ER) compared to no relapse (NR) in resected lung adenocarcinoma (AD) patients using a combination of high throughput technology and computational analysis. We identified 18 patients (n.13 NR and n.5 ER) with stage I AD. Frozen samples of patients in ER, NR and corresponding normal lung (NL) were subjected to Microarray technology and quantitative-PCR (Q-PCR). A gene network computational analysis was performed to select predictive genes. An independent set of 79 ADs stage I samples was used to validate selected genes by Q-PCR.From microarray analysis we selected 50 genes, using the fold change ratio of ER versus NR. They were validated both in pool and individually in patient samples (ER and NR) by Q-PCR. Fourteen increased and 25 decreased genes showed a concordance between two methods. They were used to perform a computational gene network analysis that identified 4 increased (HOXA10, CLCA2, AKR1B10, FABP3) and 6 decreased (SCGB1A1, PGC, TFF1, PSCA, SPRR1B and PRSS1) genes. Moreover, in an independent dataset of ADs samples, we showed that both high FABP3 expression and low SCGB1A1 expression was associated with a worse disease-free survival (DFS).Our results indicate that it is possible to define, through gene expression and computational analysis, a characteristic gene profiling of patients with an increased risk of relapse that may become a tool for patient selection for adjuvant therapy.

Risk-adapted, treosulfan-based therapy with auto- and allo-SCT for relapsed/refractory aggressive NHL: a prospective phase-II trial.

PubMed

Koenigsmann, M; Casper, J; Kahl, C; Basara, N; Sayer, H G; Behre, G; Theurich, S; Christopeit, M; Mohren, M; Reichle, A; Metzner, B; Ganser, A; Stadler, M; Uharek, L; Balleisen, L; Hinke, A; Hinke, R; Niederwieser, D

2014-03-01

Since the outcome of relapsed/refractory aggressive non-Hodgkin's lymphoma (NHL) is highly variable, a risk-adapted treatment approach was evaluated. After two cycles of DHAP, patients received high-dose treosulfan/etoposide/carboplatinum (TEC) and autologous stem cell rescue. After TEC, low-risk patients with late relapse (>1 year after first CR who achieved CR after DHAP received no further treatment. Patients with late relapse who achieved CR or PR only after TEC underwent a second cycle of TEC. High-risk patients with early relapse/refractory disease received treosulfan/fludarabine followed by allogeneic transplantation. Rituximab was added in patients with B-cell lymphoma (86%). At entry, 36% of all 57 patients had refractory disease, 32% early and 32% late relapse. During DHAP treatment, progression occurred in 32% of patients. Of 33 patients who received TEC, 5 received second TEC and 15 allogeneic transplantation. Main toxicity after TEC was oral mucositis (CTC grades 3 and 4 in 50% and 13%, respectively). In total, 42% patients achieved CR. Median OS was 21.4 months for all patients and 32.6 for those who underwent allogeneic transplantation. International prognostic index (IPI) at study entry was highly discriminative at predicting OS (P<0.0001). Risk-adapted, treosulfan-based therapy with auto- and allo-SCT is feasible. Long-term survival is possible with allogeneic transplantation.

Deep targeted sequencing in pediatric acute lymphoblastic leukemia unveils distinct mutational patterns between genetic subtypes and novel relapse-associated genes.

PubMed

Lindqvist, C Mårten; Lundmark, Anders; Nordlund, Jessica; Freyhult, Eva; Ekman, Diana; Carlsson Almlöf, Jonas; Raine, Amanda; Övernäs, Elin; Abrahamsson, Jonas; Frost, Britt-Marie; Grandér, Dan; Heyman, Mats; Palle, Josefine; Forestier, Erik; Lönnerholm, Gudmar; Berglund, Eva C; Syvänen, Ann-Christine

2016-09-27

To characterize the mutational patterns of acute lymphoblastic leukemia (ALL) we performed deep next generation sequencing of 872 cancer genes in 172 diagnostic and 24 relapse samples from 172 pediatric ALL patients. We found an overall greater mutational burden and more driver mutations in T-cell ALL (T-ALL) patients compared to B-cell precursor ALL (BCP-ALL) patients. In addition, the majority of the mutations in T-ALL had occurred in the original leukemic clone, while most of the mutations in BCP-ALL were subclonal. BCP-ALL patients carrying any of the recurrent translocations ETV6-RUNX1, BCR-ABL or TCF3-PBX1 harbored few mutations in driver genes compared to other BCP-ALL patients. Specifically in BCP-ALL, we identified ATRX as a novel putative driver gene and uncovered an association between somatic mutations in the Notch signaling pathway at ALL diagnosis and increased risk of relapse. Furthermore, we identified EP300, ARID1A and SH2B3 as relapse-associated genes. The genes highlighted in our study were frequently involved in epigenetic regulation, associated with germline susceptibility to ALL, and present in minor subclones at diagnosis that became dominant at relapse. We observed a high degree of clonal heterogeneity and evolution between diagnosis and relapse in both BCP-ALL and T-ALL, which could have implications for the treatment efficiency.

Cyclophosphamide for Prevention of Graft-Versus-Host Disease After Allogeneic Peripheral Blood Stem Cell Transplantation in Patients With Hematological Malignancies

ClinicalTrials.gov

2017-05-17

Accelerated Phase Chronic Myelogenous Leukemia; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Myeloid Leukemia in Remission; Adult Erythroleukemia (M6a); Adult Nasal Type Extranodal NK/T-cell Lymphoma; Adult Pure Erythroid Leukemia (M6b); Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Blastic Phase Chronic Myelogenous Leukemia; Childhood Acute Erythroleukemia (M6); Childhood Acute Lymphoblastic Leukemia in Remission; Childhood Acute Megakaryocytic Leukemia (M7); Childhood Acute Myeloid Leukemia in Remission; Childhood Burkitt Lymphoma; Childhood Chronic Myelogenous Leukemia; Childhood Diffuse Large Cell Lymphoma; Childhood Immunoblastic Large Cell Lymphoma; Childhood Myelodysplastic Syndromes; Childhood Nasal Type Extranodal NK/T-cell Lymphoma; Chronic Myelomonocytic Leukemia; Chronic Phase Chronic Myelogenous Leukemia; Cutaneous B-cell Non-Hodgkin Lymphoma; de Novo Myelodysplastic Syndromes; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Hepatosplenic T-cell Lymphoma; Intraocular Lymphoma; Nodal Marginal Zone B-cell Lymphoma; Noncutaneous Extranodal Lymphoma; Peripheral T-cell Lymphoma; Philadelphia Chromosome Negative Chronic Myelogenous Leukemia; Post-transplant Lymphoproliferative Disorder; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Childhood Anaplastic Large Cell Lymphoma; Recurrent Childhood Grade III Lymphomatoid Granulomatosis; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Small Noncleaved Cell Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Recurrent/Refractory Childhood Hodgkin Lymphoma; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; Stage III Multiple Myeloma; Testicular Lymphoma; Waldenström Macroglobulinemia

Relapse prevention interventions for smoking cessation.

PubMed

Hajek, Peter; Stead, Lindsay F; West, Robert; Jarvis, Martin; Hartmann-Boyce, Jamie; Lancaster, Tim

2013-08-20

A number of treatments can help smokers make a successful quit attempt, but many initially successful quitters relapse over time. Several interventions have been proposed to help prevent relapse. To assess whether specific interventions for relapse prevention reduce the proportion of recent quitters who return to smoking. We searched the Cochrane Tobacco Addiction Group trials register in May 2013 for studies mentioning relapse prevention or maintenance in title, abstracts or keywords. Randomized or quasi-randomized controlled trials of relapse prevention interventions with a minimum follow-up of six months. We included smokers who quit on their own, were undergoing enforced abstinence, or were participating in treatment programmes. We included trials that compared relapse prevention interventions with a no intervention control, or that compared a cessation programme with additional relapse prevention components with a cessation programme alone. Studies were screened and data extracted by one review author, and checked by a second. Disagreements were resolved by discussion or by referral to a third review author. Sixty-three studies met inclusion criteria but were heterogeneous in terms of populations and interventions. We considered 41 studies that randomly assigned abstainers separately from studies that randomly assigned participants before their quit date.Upon looking at studies of behavioural interventions that randomly assigned abstainers, we detected no benefit of brief and 'skills-based' relapse prevention methods for women who had quit smoking because of pregnancy, or for smokers undergoing a period of enforced abstinence during hospitalisation or military training. We also failed to detect significant effects of behavioural interventions in trials in unselected groups of smokers who had quit on their own or through a formal programme. Amongst trials randomly assigning smokers before their quit date and evaluating the effects of additional relapse prevention components, we found no evidence of benefit of behavioural interventions or combined behavioural and pharmacotherapeutic interventions in any subgroup. Overall, providing training in skills thought to be needed for relapse avoidance did not reduce relapse, but most studies did not use experimental designs best suited to the task and had limited power to detect expected small differences between interventions. For pharmacological interventions, extended treatment with varenicline significantly reduced relapse in one trial (risk ratio (RR) 1.18, 95% confidence interval (CI) 1.03 to 1.36). Pooling of six studies of extended treatment with bupropion failed to detect a significant effect (RR 1.15, 95% CI 0.98 to 1.35). Two small trials of oral nicotine replacement treatment (NRT) failed to detect an effect, but treatment compliance was low, and in two other trials of oral NRT in which short-term abstainers were randomly assigned, a significant effect of intervention was noted. At the moment, there is insufficient evidence to support the use of any specific behavioural intervention to help smokers who have successfully quit for a short time to avoid relapse. The verdict is strongest for interventions focused on identifying and resolving tempting situations, as most studies were concerned with these. Little research is available regarding other behavioural approaches.Extended treatment with varenicline may prevent relapse. Extended treatment with bupropion is unlikely to have a clinically important effect. Studies of extended treatment with nicotine replacement are needed.

Relapse prevention interventions for smoking cessation.

PubMed

Hajek, Peter; Stead, Lindsay F; West, Robert; Jarvis, Martin; Lancaster, Tim

2009-01-21

A number of treatments can help smokers make a successful quit attempt, but many initially successful quitters relapse over time. Several interventions were proposed to help prevent relapse. To assess whether specific interventions for relapse prevention reduce the proportion of recent quitters who return to smoking. We searched the Cochrane Tobacco Addiction Group trials register in August 2008 for studies mentioning relapse prevention or maintenance in title, abstracts or keywords. Randomized or quasi-randomized controlled trials of relapse prevention interventions with a minimum follow up of six months. We included smokers who quit on their own, or were undergoing enforced abstinence, or who were participating in treatment programmes. We included trials that compared relapse prevention interventions to a no intervention control, or that compared a cessation programme with additional relapse prevention components to a cessation programme alone. Studies were screened and data extracted by one author and checked by a second. Disagreements were resolved by discussion or referral to a third author. Fifty-four studies met inclusion criteria, but were heterogeneous in terms of populations and interventions. We considered 36 studies that randomized abstainers separately from studies that randomized participants prior to their quit date.Looking at studies of behavioural interventions which randomised abstainers, we detected no benefit of brief and 'skills-based' relapse prevention methods for women who had quit smoking due to pregnancy, or for smokers undergoing a period of enforced abstinence during hospitalisation or military training. We also failed to detect significant effects of behavioural interventions in trials in unselected groups of smokers who had quit on their own or with a formal programme. Amongst trials randomising smokers prior to their quit date and evaluating the effect of additional relapse prevention components we also found no evidence of benefit of behavioural interventions in any subgroup. Overall, providing training in skills thought to be needed for relapse avoidance did not reduce relapse, but most studies did not use experimental designs best suited to the task, and had limited power to detect expected small differences between interventions. For pharmacological interventions, extended treatment with varenicline significantly reduced relapse in one trial (risk ratio 1.18, 95% confidence interval 1.03 to 1.36). Pooling of five studies of extended treatment with bupropion failed to detect a significant effect (risk ratio 1.17; 95% confidence interval 0.99 to 1.39). Two small trials of oral nicotine replacement treatment (NRT) failed to detect an effect but treatment compliance was low and in two other trials of oral NRT randomizing short-term abstainers there was a significant effect of intervention. At the moment there is insufficient evidence to support the use of any specific behavioural intervention for helping smokers who have successfully quit for a short time to avoid relapse. The verdict is strongest for interventions focusing on identifying and resolving tempting situations, as most studies were concerned with these. There is little research available regarding other behavioural approaches. Extended treatment with varenicline may prevent relapse. Extended treatment with bupropion is unlikely to have a clinically important effect. Studies of extended treatment with nicotine replacement are needed.

Stem Cell-Like Gene Expression in Ovarian Cancer Predicts Type II Subtype and Prognosis

PubMed Central

Schwede, Matthew; Spentzos, Dimitrios; Bentink, Stefan; Hofmann, Oliver; Haibe-Kains, Benjamin; Harrington, David; Quackenbush, John; Culhane, Aedín C.

2013-01-01

Although ovarian cancer is often initially chemotherapy-sensitive, the vast majority of tumors eventually relapse and patients die of increasingly aggressive disease. Cancer stem cells are believed to have properties that allow them to survive therapy and may drive recurrent tumor growth. Cancer stem cells or cancer-initiating cells are a rare cell population and difficult to isolate experimentally. Genes that are expressed by stem cells may characterize a subset of less differentiated tumors and aid in prognostic classification of ovarian cancer. The purpose of this study was the genomic identification and characterization of a subtype of ovarian cancer that has stem cell-like gene expression. Using human and mouse gene signatures of embryonic, adult, or cancer stem cells, we performed an unsupervised bipartition class discovery on expression profiles from 145 serous ovarian tumors to identify a stem-like and more differentiated subgroup. Subtypes were reproducible and were further characterized in four independent, heterogeneous ovarian cancer datasets. We identified a stem-like subtype characterized by a 51-gene signature, which is significantly enriched in tumors with properties of Type II ovarian cancer; high grade, serous tumors, and poor survival. Conversely, the differentiated tumors share properties with Type I, including lower grade and mixed histological subtypes. The stem cell-like signature was prognostic within high-stage serous ovarian cancer, classifying a small subset of high-stage tumors with better prognosis, in the differentiated subtype. In multivariate models that adjusted for common clinical factors (including grade, stage, age), the subtype classification was still a significant predictor of relapse. The prognostic stem-like gene signature yields new insights into prognostic differences in ovarian cancer, provides a genomic context for defining Type I/II subtypes, and potential gene targets which following further validation may be valuable in the clinical management or treatment of ovarian cancer. PMID:23536770

Myoepithelial cell-specific expression of stefin A as a suppressor of early breast cancer invasion.

PubMed

Duivenvoorden, Hendrika M; Rautela, Jai; Edgington-Mitchell, Laura E; Spurling, Alex; Greening, David W; Nowell, Cameron J; Molloy, Timothy J; Robbins, Elizabeth; Brockwell, Natasha K; Lee, Cheok Soon; Chen, Maoshan; Holliday, Anne; Selinger, Cristina I; Hu, Min; Britt, Kara L; Stroud, David A; Bogyo, Matthew; Möller, Andreas; Polyak, Kornelia; Sloane, Bonnie F; O'Toole, Sandra A; Parker, Belinda S

2017-12-01

Mammography screening has increased the detection of early pre-invasive breast cancers, termed ductal carcinoma in situ (DCIS), increasing the urgency of identifying molecular regulators of invasion as prognostic markers to predict local relapse. Using the MMTV-PyMT breast cancer model and pharmacological protease inhibitors, we reveal that cysteine cathepsins have important roles in early-stage tumorigenesis. To characterize the cell-specific roles of cathepsins in early invasion, we developed a DCIS-like model, incorporating an immortalized myoepithelial cell line (N1ME) that restrained tumor cell invasion in 3D culture. Using this model, we identified an important myoepithelial-specific function of the cysteine cathepsin inhibitor stefin A in suppressing invasion, whereby targeted stefin A loss in N1ME cells blocked myoepithelial-induced suppression of breast cancer cell invasion. Enhanced invasion observed in 3D cultures with N1ME stefin A-low cells was reliant on cathepsin B activation, as addition of the small molecule inhibitor CA-074 rescued the DCIS-like non-invasive phenotype. Importantly, we confirmed that stefin A was indeed abundant in myoepithelial cells in breast tissue. Use of a 138-patient cohort confirmed that myoepithelial stefin A (cystatin A) is abundant in normal breast ducts and low-grade DCIS but reduced in high-grade DCIS, supporting myoepithelial stefin A as a candidate marker of lower risk of invasive relapse. We have therefore identified myoepithelial cell stefin A as a suppressor of early tumor invasion and a candidate marker to distinguish patients who are at low risk of developing invasive breast cancer, and can therefore be spared further treatment. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Evolution of platinum resistance in high-grade serous ovarian cancer.

PubMed

Cooke, Susanna L; Brenton, James D

2011-11-01

High-grade serous ovarian cancers account for most ovarian-cancer mortality. Although this disease initially responds well to platinum-based chemotherapy, relapse and progression to chemotherapy resistance are frequently seen. Time to relapse after first-line therapy is a predictor of response to secondary platinum treatment: more than 12 months is associated with high chance of a secondary response, whereas relapses within 6 months generally indicate platinum resistance. In this Personal View we discuss whether patterns of response, relapse, and the development of drug resistance in high-grade serous ovarian cancers are related to distinct underlying molecular and cellular biological characteristics. In particular, we propose that rapid relapse with platinum-resistant disease is due to minor subpopulations of intrinsically resistant cancer cells at presentation. Copyright © 2011 Elsevier Ltd. All rights reserved.

PET scan-positive cat scratch disease in a patient with T cell lymphoblastic lymphoma.

PubMed

Jeong, Woondong; Seiter, Karen; Strauchen, James; Rafael, Theodore; Lau, Har Chi; Breakstone, Beth; Ahmed, Tauseef; Liu, Delong

2005-05-01

In patients who have history of lymphoma, a positive positron emission tomography (PET) scan is frequently considered as good evidence for relapse and/or persistent disease. Thus, lymph node biopsy is not always done to confirm the diagnosis of relapse or refractory lymphoma before a patient is subjected to further chemotherapy. We report a case of patient with history of T cell lymphoblastic lymphoma who presented again with inguinal lymphadenopathy and positive study on positron emission tomography suggestive of lymphoma relapse. This was pathologically proven to be cat scratch disease. This case suggests that in the immunocompromised patients who had history of lymphoma, infectious etiology should be ruled out for PET scan-positive lymphadenopathy.

Lung excision of non-small-cell lung cancer leaves cancer cells in residual lobe: cytological detection using pulmonary vein blood.

PubMed

Sawabata, Noriyoshi; Funaki, Soichiro; Shintani, Yasushi; Okumura, Meinosin

2016-02-01

Lung excision to treat non-small-cell lung cancer (NSCLC) is associated with a worse prognosis when compared with a lobectomy. Cancer relapse may be caused by tumour cells remaining in the residual lobe, the possibility of dislodged cancer cells in the residual lobe is assessed using pulmonary vein blood (PVB) from the resected lung. Twenty-eight patients with pathological stage I NSCLC who underwent lung excision followed by a lobectomy were evaluated according to the status of isolated tumour cells (ITCs) (origin of circulating tumour cells) in PVB from the resected lobe. Survival was also assessed according to the status of ITCs. The rate of ITC presence was 60.7% and depended on margin distance/tumour size (M/T) with a threshold of 1.0-30.8% (4/13) in M/T greater than or equal to 1.0 and 86.7% (13/15) in M/T smaller than 1.0 (P = 0.001). PVB-ITC status was no ITCs (N) in 11 (39.3%), only singular cells (S) in 13 (50.0%) and clustered cells (C) in 4 (14.3%). In addition, the survival status of patients with clustered cells was exclusively wrong. After pulmonary excision for lung cancer, tumour cells remain in the residual lobe and the morphology of which may indicate recurrence. © The Author 2015. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

Secondary pure erythroid leukaemia in relapsed acute lymphoblastic leukaemia: lineage switch or chemotherapy effect?

PubMed

Gupta, Sanjeev Kumar; Kumar, Rajive; Chharchhodawala, Taher; Kumar, Lalit

2014-05-19

Pure erythroid leukaemia is a rare subtype of acute myeloid leukaemia (AML) and its occurrence at acute lymphoblastic leukaemia (ALL) relapse has not been reported earlier. A 39-year-old man received chemotherapy for Philadelphia-negative B cell ALL. Subsequently, he developed pure erythroid leukaemia with >80% immature erythroid precursors in bone marrow showing block positivity on periodic acid-Schiff stain, expressing CD71, CD34 but lacking CD235a. The interval between exposure to multidrug chemotherapy including cyclophosphamide and AML diagnosis was 2 years and 9 months. No cytogenetic abnormality was detected at the time of relapse. The patient died 2 weeks after starting AML chemotherapy. The relatively narrow time interval (usually 5-10 years) between chemotherapy and AML development and normal karyotype at relapse raises a possibility of lineage switch besides therapy-related AML as the likely pathogenesis. Further exploration of such cases may unravel the pathways responsible for lineage assignment in pluripotent stem cells. 2014 BMJ Publishing Group Ltd.

Donor single nucleotide polymorphism in the CCR9 gene affects the incidence of skin GVHD.

PubMed

Inamoto, Y; Murata, M; Katsumi, A; Kuwatsuka, Y; Tsujimura, A; Ishikawa, Y; Sugimoto, K; Onizuka, M; Terakura, S; Nishida, T; Kanie, T; Taji, H; Iida, H; Suzuki, R; Abe, A; Kiyoi, H; Matsushita, T; Miyamura, K; Kodera, Y; Naoe, T

2010-02-01

The interactions between chemokines and their receptors may have an important role in initiating GVHD after allogeneic hematopoietic SCT (allo-HSCT). CCL25 and CCR9 are unique because they are exclusively expressed in epithelial cells and in Peyer's patches of the small intestine. We focused on rs12721497 (G926A), one of the non-synonymous single nucleotide polymorphisms (SNPs) in the CCR9 gene, and analyzed the SNP of donors in 167 consecutive patients who received allo-HSCT from an HLA-identical sibling donor. Genotypes were tested for associations with acute and chronic GVHD in each organ and transplant outcome. Multivariate analyses showed that the genotype 926AG was significantly associated with the incidence of acute stage > or =2 skin GVHD (hazard ratio: 3.2; 95% confidence interval (95% CI): 1.1-9.1; P=0.032) and chronic skin GVHD (hazard ratio: 4.1; 95% CI: 1.1-15; P=0.036), but not with GVHD in other organs or with relapse, non-relapse mortality or OS. To clarify the functional differences between genotypes, each SNP in retroviral vectors was transfected into Jurkat cells. In chemotaxis assays, the 926G transfectant showed greater response to CCL25 than the 926A transfectant. In conclusion, more active homing of CCR9-926AG T cells to Peyer's patches may produce changes in Ag presentation and result in increased incidence of skin GVHD.

Metachronous solitary metastasis to the thyroid gland from squamous cell carcinoma of the lung: a case report and literature review.

PubMed

Gelsomino, Francesco; Lamberti, Giuseppe; Ambrosini, Valentina; Sperandi, Francesca; Agosti, Roberto; Morganti, Alessio G; Ardizzoni, Andrea

2017-11-15

Non-small cell lung cancer presents at an advanced stage at diagnosis in two-thirds of cases. The most frequent metastatic sites are the central nervous system, adrenal glands and bones. By contrast, the thyroid gland is an extremely rare site of dissemination. A 64-year-old Caucasian man previously treated with radiosurgery and brain metastasectomy followed by right middle lobectomy for a squamous cell lung carcinoma had a metachronous solitary metastasis to the thyroid gland, as confirmed by fine-needle aspiration cytology and open biopsy. He underwent curative radiotherapy, with an initial response. At 9 months' follow-up the tumor relapsed both in the thyroid and the lung. Review of the literature confirmed that thyroid metastasis from lung cancer is very uncommon in clinical practice. No data on the role of surgery or curative radiotherapy in thyroid metastasis are available because of the lack of prospective studies addressing the impact on survival of these treatment strategies either alone or in combination. In the case described here, radical treatment with radiotherapy allowed to obtain a modest benefit in terms of relapse-free survival. A diagnosis of metastasis to the thyroid gland should be suspected in patients who present a thyroid nodule or suggestive imaging findings when there is a history of malignancy, including lung cancer. Indeed, an early diagnosis allows to pursue radical treatment that, in selected patients, could lead to long-term survival.

The small molecule inhibitor YK-4-279 disrupts mitotic progression of neuroblastoma cells, overcomes drug resistance and synergizes with inhibitors of mitosis.

PubMed

Kollareddy, Madhu; Sherrard, Alice; Park, Ji Hyun; Szemes, Marianna; Gallacher, Kelli; Melegh, Zsombor; Oltean, Sebastian; Michaelis, Martin; Cinatl, Jindrich; Kaidi, Abderrahmane; Malik, Karim

2017-09-10

Neuroblastoma is a biologically and clinically heterogeneous pediatric malignancy that includes a high-risk subset for which new therapeutic agents are urgently required. As well as MYCN amplification, activating point mutations of ALK and NRAS are associated with high-risk and relapsing neuroblastoma. As both ALK and RAS signal through the MEK/ERK pathway, we sought to evaluate two previously reported inhibitors of ETS-related transcription factors, which are transcriptional mediators of the Ras-MEK/ERK pathway in other cancers. Here we show that YK-4-279 suppressed growth and triggered apoptosis in nine neuroblastoma cell lines, while BRD32048, another ETV1 inhibitor, was ineffective. These results suggest that YK-4-279 acts independently of ETS-related transcription factors. Further analysis reveals that YK-4-279 induces mitotic arrest in prometaphase, resulting in subsequent cell death. Mechanistically, we show that YK-4-279 inhibits the formation of kinetochore microtubules, with treated cells showing a broad range of abnormalities including multipolar, fragmented and unseparated spindles, together leading to disrupted progression through mitosis. Notably, YK-4-279 does not affect microtubule acetylation, unlike the conventional mitotic poisons paclitaxel and vincristine. Consistent with this, we demonstrate that YK-4-279 overcomes vincristine-induced resistance in two neuroblastoma cell-line models. Furthermore, combinations of YK-4-279 with vincristine, paclitaxel or the Aurora kinase A inhibitor MLN8237/Alisertib show strong synergy, particularly at low doses. Thus, YK-4-279 could potentially be used as a single-agent or in combination therapies for the treatment of high-risk and relapsing neuroblastoma, as well as other cancers. Copyright © 2017 The Author(s). Published by Elsevier B.V. All rights reserved.

RAD51 Is a Selective DNA Repair Target to Radiosensitize Glioma Stem Cells.

PubMed

King, Harry O; Brend, Tim; Payne, Helen L; Wright, Alexander; Ward, Thomas A; Patel, Karan; Egnuni, Teklu; Stead, Lucy F; Patel, Anjana; Wurdak, Heiko; Short, Susan C

2017-01-10

Patients with glioblastoma die from local relapse despite surgery and high-dose radiotherapy. Resistance to radiotherapy is thought to be due to efficient DNA double-strand break (DSB) repair in stem-like cells able to survive DNA damage and repopulate the tumor. We used clinical samples and patient-derived glioblastoma stem cells (GSCs) to confirm that the DSB repair protein RAD51 is highly expressed in GSCs, which are reliant on RAD51-dependent DSB repair after radiation. RAD51 expression and RAD51 foci numbers fall when these cells move toward astrocytic differentiation. In GSCs, the small-molecule RAD51 inhibitors RI-1 and B02 prevent RAD51 focus formation, reduce DNA DSB repair, and cause significant radiosensitization. We further demonstrate that treatment with these agents combined with radiation promotes loss of stem cells defined by SOX2 expression. This indicates that RAD51-dependent repair represents an effective and specific target in GSCs. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

The neuropharmacology of relapse to food seeking: methodology, main findings, and comparison with relapse to drug seeking.

PubMed

Nair, Sunila G; Adams-Deutsch, Tristan; Epstein, David H; Shaham, Yavin

2009-09-01

Relapse to old, unhealthy eating habits is a major problem in human dietary treatments. The mechanisms underlying this relapse are unknown. Surprisingly, until recently this clinical problem has not been systematically studied in animal models. Here, we review results from recent studies in which a reinstatement model (commonly used to study relapse to abused drugs) was employed to characterize the effect of pharmacological agents on relapse to food seeking induced by either food priming (non-contingent exposure to small amounts of food), cues previously associated with food, or injections of the pharmacological stressor yohimbine. We also address methodological issues related to the use of the reinstatement model to study relapse to food seeking, similarities and differences in mechanisms underlying reinstatement of food seeking versus drug seeking, and the degree to which the reinstatement procedure provides a suitable model for studying relapse in humans. We conclude by discussing implications for medication development and future research. We offer three tentative conclusions: (1)The neuronal mechanisms of food-priming- and cue-induced reinstatement are likely different from those of reinstatement induced by the pharmacological stressor yohimbine. (2)The neuronal mechanisms of reinstatement of food seeking are possibly different from those of ongoing food-reinforced operant responding. (3)The neuronal mechanisms underlying reinstatement of food seeking overlap to some degree with those of reinstatement of drug seeking.

Perineural Infiltration of Cutaneous Squamous Cell Carcinoma and Basal Cell Carcinoma Without Clinical Features

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lin, Charles, E-mail: Charles_Lin@health.qld.gov.au; Tripcony, Lee; Keller, Jacqui

2012-01-01

Purpose: To review the factors that influence outcome and patterns of relapse in patients with cutaneous squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) with perineural infiltration (PNI) without clinical or radiologic features, treated with surgery and radiotherapy. Methods and Materials: Between 1991 and 2004, 222 patients with SCC or BCC with PNI on pathologic examination but without clinical or radiologic PNI features were identified. Charts were reviewed retrospectively and relevant data collected. All patients were treated with curative intent; all had radiotherapy, and most had surgery. The primary endpoint was 5-year relapse-free survival from the time of diagnosis.more » Results: Patients with SCC did significantly worse than those with BCC (5-year relapse-free survival, 78% vs. 91%; p < 0.01). Squamous cell carcinoma with PNI at recurrence did significantly worse than de novo in terms of 5-year local failure (40% vs. 19%; p < 0.01) and regional relapse (29% vs. 5%; p < 0.01). Depth of invasion was also a significant factor. Of the PNI-specific factors for SCC, focal PNI did significantly better than more-extensive PNI, but involved nerve diameter or presence of PNI at the periphery of the tumor were not significant factors. Conclusions: Radiotherapy in conjunction with surgery offers an acceptable outcome for cutaneous SCC and BCC with PNI. This study suggests that focal PNI is not an adverse feature.« less

ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION FOR CHEMOTHERAPY-UNRESPONSIVE MANTLE CELL LYMPHOMA: A COHORT ANALYSIS FROM THE CIBMTR

PubMed Central

Hamadani, Mehdi; Saber, Wael; Ahn, Kwang Woo; Carreras, Jeanette; Cairo, Mitchell S.; Fenske, Timothy S.; Gale, Robert Peter; Gibson, John; Hale, Gregory A.; Hari, Parameswaran N.; Hsu, Jack W.; Inwards, David J.; Kamble, Rammurti T.; Klein, Anderas; Maharaj, Dipnarine; Marks, David I.; Rizzieri, David A.; Savani, Bipin N.; Schouten, Harry C.; Waller, Edmund K.; Wirk, Baldeep; Lazarus, Hillard M.

2013-01-01

Patients with chemorefractory mantle cell lymphoma (MCL) have poor prognosis. We used the CIBMTR database to study the outcome of 202 patients with refractory MCL who underwent allogeneic hematopoietic cell transplantation (allo-HCT) using either myeloablative (MA) or reduced intensity/non-myeloablative conditioning (RIC/NST), during 1998–2010. We analyzed non-relapse mortality (NRM), progression/relapse, progression-free survival (PFS), and overall survival (OS). Seventy-four patients received MA, and 128 underwent RIC/NST. Median ages are 54 and 59 years for MA and RIC/NST allo-HCT recipients, respectively. Median follow-up after MA and RIC/NST allo-HCT is 35 months and 43 months, respectively. At 3 years, comparing MA with RIC/NST allo-HCT, no significant differences were found in terms of NRM (47% vs. 43%; p-value=0.68), relapse/progression (33% vs. 32%; p-value=0.89), PFS (20% vs. 25%; p=0.53), and OS (25% vs. 30%; p-value=0.45). On multivariate analysis no significant differences were observed in NRM, relapse, PFS and OS between MA and RIC/NST allo-HCT; however, receiving a bone marrow or T-cell depleted allograft was associated with an increased risk of NRM and inferior PFS and OS. Despite a refractory disease state, approximately a fourth of MCL patients can attain durable remissions after allo-HCT. Conditioning regimen intensity did not influence the outcomes of patients after allo HCT. PMID:23333532

Treatment and Prognosis of Isolated Local Relapse after Stereotactic Body Radiotherapy for Clinical Stage I Non-Small-Cell Lung Cancer: Importance of Salvage Surgery.

PubMed

Hamaji, Masatsugu; Chen, Fengshi; Matsuo, Yukinori; Ueki, Nami; Hiraoka, Masahiro; Date, Hiroshi

2015-11-01

Many efforts have been made to detect local relapse (LR) in the follow-up after stereotactic body radiotherapy (SBRT) for non-small-cell lung cancer (NSCLC) although limited data are available on its treatment and prognosis. We aimed to characterize treatment options and clarify long-term outcomes of isolated LR after SBRT for patients with clinical stage I NSCLC. We reviewed our institutional database in search of patients with isolated LR after SBRT for clinical stage I NSCLC at our institution between 1999 and 2013. Patient characteristics were compared with Mann-Whitney U test, χ2 test, or Fisher's exact test as appropriate. Survival outcomes were estimated with Kaplan-Meier method. Potential prognostic factors were investigated using Cox proportional hazard model. Of 308 patients undergoing SBRT for clinical stage I NSCLC, 49 patients were identified to have isolated LR. Twelve patients underwent salvage surgery, none underwent radiotherapy, and eight patients received chemotherapy, whereas 29 patients received best supportive care. No patient characteristic except operability was significantly related with patient selection for LR treatments. Five-year overall survival (OS) rate of the whole cohort was 47.9% from SBRT and 25.7% from LR. Salvage surgery was associated with improved OS after LR (p = 0.014), and 5-year OS for patients undergoing salvage surgery was 79.5% from LR. It was confirmed that our patient selection for salvage surgery for isolated LR was associated with favorable survival outcomes. Operability based on multidisciplinary conferences, rather than measurable patient characteristics, is essential for appropriate patient selection for salvage surgery.

Omitting elective nodal irradiation during thoracic irradiation in limited-stage small cell lung cancer--evidence from a phase II trial.

PubMed

Colaco, Rovel; Sheikh, Hamid; Lorigan, Paul; Blackhall, Fiona; Hulse, Paul; Califano, Raffaele; Ashcroft, Linda; Taylor, Paul; Thatcher, Nicholas; Faivre-Finn, Corinne

2012-04-01

Omitting elective nodal irradiation (ENI) in limited-stage disease small cell lung cancer (LD-SCLC) is expected to result in smaller radiation fields. We report on data from a randomised phase II trial that omitted ENI in patients receiving concurrent chemo-radiotherapy for LD-SCLC. 38 patients with LD-SCLC were randomised to receive once-daily (66 Gy in 33 fractions) or twice-daily (45 Gy in 30 fractions) radiotherapy (RT). 3D-conformal RT was given concurrently with cisplatin and etoposide starting with the second cycle of a total of four cycles. The gross tumour volume was defined as primary tumour with involved lymph nodes (nodes ≥1 cm in short axis) identifiable with CT imaging. ENI was not used. Six recurrence patterns were identified: recurrence within planning target volume (PTV) only, recurrence within PTV+regional nodal recurrence and/or distant recurrence, isolated nodal recurrence outside PTV, nodal recurrence outside PTV+distant recurrence, distant metastases only and no recurrence. At median follow-up 16.9 months, 31/38 patients were evaluable and 14/31 patients had relapsed. There were no isolated nodal recurrences. Eight patients relapsed with intra-thoracic disease: 2 within PTV only, 4 within PTV and distantly and 2 with nodal recurrence outside PTV plus distant metastases. Rates of grade 3+ acute oesophagitis and pneumonitis in the 31 evaluable patients were 23 and 3% respectively. In our study of LD-SCLC, omitting ENI based on CT imaging was not associated with a high risk of isolated nodal recurrence, although further prospective studies are needed to confirm this. Routine ENI omission will be further evaluated prospectively in the ongoing phase III CONVERT trial (NCT00433563). Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Friend or foe? Mogamulizumab in allogeneic hematopoietic stem cell transplantation for adult T-cell leukemia/lymphoma

PubMed Central

Shindo, Takero

2016-01-01

Adult T-cell leukemia/lymphoma (ATL/ATLL) is a peripheral T-cell neoplasm associated with human T-lymphotropic virus type-1 (HTLV-1). Even the currently most intensive chemotherapy regimen modified LSG15 (mLSG15, VCAP-AMP-VECP) results in a dismal clinical outcome, with a median overall survival of only around 1 year. Although allogeneic hematopoietic stem cell transplantation (allo-HSCT) may lead to long-term remission in a proportion of patients with aggressive ATL, the clinical outcome in patients with refractory or relapsed ATL is unsatisfactory. The anti-CCR4 antibody mogamulizumab (moga) has been recently approved for ATL in Japan, and it is effective in a significant proportion of patients with refractory or relapsed ATL. However, there are major concerns about the harmful influences of pretransplant moga on the immune reconstitution after allo-HSCT. Specifically, moga depletes regulatory T cells (Tregs) for at least a few months, which may increase the risk of graft-versus-host disease (GVHD) after allo-HSCT. A recent retrospective study from Japan clearly showed that pretransplant moga increased the risk of severe and steroid-refractory GVHD, which led to increases in non-relapse mortality and overall mortality. To improve the overall clinical outcome in patients with relapsed or refractory ATL, more studies are needed to incorporate moga without increasing adverse effects on the clinical outcome after allo-HSCT. In this review, we aim to provide an updated summary of the research related to moga and allo-HSCT. PMID:27868052

Conditioning with Treosulfan and Fludarabine Followed by Allogeneic Hematopoietic Cell Transplantation for High-Risk Hematologic Malignancies

PubMed Central

Nemecek, Eneida R.; Guthrie, Katherine A.; Sorror, Mohamed L.; Wood, Brent L.; Doney, Kristine C.; Hilger, Ralf A.; Scott, Bart L.; Kovacsovics, Tibor J.; Maziarz, Richard T.; Woolfrey, Ann E.; Bedalov, Antonio; Sanders, Jean E.; Pagel, John M.; Sickle, Eileen J.; Witherspoon, Robert; Flowers, Mary E.; Appelbaum, Frederick R.; Deeg, H. Joachim

2010-01-01

In this prospective study 60 patients of median age 46 (range 5–60) years, with acute myeloid leukemia (AML; n=44), acute lymphoblastic leukemia (ALL; n=3), or myelodysplastic syndrome (MDS; n=13) were conditioned for allogeneic hematopoietic cell transplantation with a treosulfan/fludarabine combination. Most patients were considered at high risk for relapse or non-relapse mortality (NRM). Patients received intravenous treosulfan, 12 g/m2/day (n=5) or 14 g/m2/day (n=55) on days -6 to -4, and fludarabine (30 mg/m2/day) on days -6 to -2, followed by infusion of marrow (n=7) or peripheral blood stem cells (n=53) from HLA-identical siblings (n=30) or unrelated donors (n=30). All patients engrafted. NRM was 5% at day 100, and 8% at 2 years. With a median follow-up of 22 months, the 2-year relapse-free survival for all patients was 58% and 88% for patients without high risk cytogenetics. The 2-year cumulative incidence of relapse was 33% (15% for patients with MDS, 34% for AML in first remission, 50% for AML or ALL beyond first remission and 63% for AML in refractory relapse). Thus, a treosulfan/fludarabine regimen was well tolerated and yielded encouraging survival and disease control with minimal NRM. Further trials are warranted to compare treosulfan/fludarabine to other widely used regimens, and to study the impact of using this regimen in more narrowly defined groups of patients. PMID:20685259

Defining a New Prognostic index for Stage I Non-seminomatous Germ Cell Tumors using CXCL12 Expression and Proportion of Embryonal Carcinoma

PubMed Central

Gilbert, Duncan C; Al-Saadi, Reem; Thway, Khin; Chandler, Ian; Berney, Daniel; Gabe, Rhian; Stenning, Sally P; Sweet, Joan; Huddart, Robert; Shipley, Janet M

2015-01-01

Purpose Up to 50% of patients diagnosed with stage I non-seminomatous germ cell tumors (NSGCT) harbor occult metastases. Patients are managed by surveillance with chemotherapy at relapse or adjuvant treatment up-front. Late toxicities from chemotherapy are increasingly recognised. Based on a potential biological role in germ cells/tumors and pilot data, our aim was to evaluate tumor expression of the chemokine CXCL12 alongside previously proposed markers as clinically useful biomarkers of relapse. Experimental design Immunohistochemistry for tumor expression of CXCL12 was assessed as a biomarker of relapse alongside vascular invasion, histology (percentage embryonal carcinoma) and MIB1 staining for proliferationin formalin fixed paraffin-embedded orchidectomy samples from patients enrolled in the Medical Research Council’s TE08/22 prospective trials of surveillance in stage I NSGCT. Results TE08/TE22 trial patients had a 76.4% 2-year relapse free rate (RFR) and both CXCL12 expression and percentage embryonal carcinoma provided prognostic value independently of vascular invasion (stratified log rank test p=0.006 for both). There was no additional prognostic value for MIB1 staining. A model using CXCL12, percentage embryonal carcinoma and VI defines 3 prognostic groups that were independantly validated. Conclusions CXCL12 and percentage embryonal carcinoma both stratify patients’ relapse risk over and above vascular invasion alone. This is anticipated to improve the stratification of patients and identify high-risk cases to be considered for adjuvant therapy. PMID:26453693

Relationship between cytomegalovirus (CMV) reactivation, CMV-driven immunity, overall immune recovery and graft-versus-leukaemia effect in children.

PubMed

Jeljeli, Mohamed; Guérin-El Khourouj, Valérie; Porcher, Raphael; Fahd, Mony; Leveillé, Sandrine; Yakouben, Karima; Ouachée-Chardin, Marie; LeGoff, Jerome; Cordeiro, Debora Jorge; Pédron, Beatrice; Baruchel, Andre; Dalle, Jean-Hugues; Sterkers, Ghislaine

2014-07-01

The interplay between immune recovery, cytomegalovirus (CMV)-reactivation, CMV-driven immunity and graft-versus-leukaemia effect (GVL) was analysed in 108 children (median age: 8 years) who underwent haematopoietic-stem cell transplantation (HSCT) for acute leukaemia. Follow-up was 2 years unless death or relapse occurred. CMV-polymerase chain reaction (PCR) was programmed weekly until month +3 post-HSCT. Immunomonitoring consisted of sequential lymphocyte subset enumerations and analyses of T-cell proliferative and γ-interferon responses to CMV and to adenovirus. In the 108 recipients, the 2-year relapse rate (RR) was 25% (median time to onset 4·5 months; range: 24 d-17 months). CMV reactivation occurrence was 31% (median time to onset 26 d). Donor/recipient CMV serostatus did not influence RR. Among the 89 recipients disease-free after day +120, i) early CMV-reactivation before day +30 was more frequent (P = 0·01) in the relapse recipient group opposed to the non-relapse group. ii) CD8(+) /CD28(-) and CD4(+) CD45RA(-) T-cell expansions induced by CMV did not influence RR, iii) Recovery of anti-CMV and also anti-adenovirus immunity and of naïve CD4(+) T-cells was faster in the non-relapse group (P = 0·008; 0·009 and 0·002 respectively). In contrast to adult acute myeloid leukaemia, CMV reactivation was associated with increased RR in this paediatric series. Accelerated overall immune recovery rather than CMV-driven immunity had a favourable impact on RR. © 2014 John Wiley & Sons Ltd.

Radiation therapy is an effective modality in the treatment of mantle cell lymphoma, even in heavily pretreated patients.

PubMed

Haque, Waqar; Voong, K Ranh; Shihadeh, Ferial; Arzu, Isidora; Pinnix, Chelsea; Mazloom, Ali; Medeiros, L Jeffrey; Romaguera, Jorge; Rodriguez, Alma; Wang, Michael; Allen, Pamela; Dabaja, Bouthaina

2014-12-01

Mantle cell lymphoma has an aggressive clinical course and continuous relapse pattern with a median survival of 3 to 7 years. Multiple courses of chemotherapy are the basis of treatment. Radiotherapy is underutilized in this disease. We undertook this study to assess the role of radiation therapy. A total of 41 consecutive patients with mantle cell lymphoma diagnosed from December, 1999 to January, 2010 who received radiation therapy were reviewed retrospectively. The main endpoint was in-field lymphoma response at each irradiated disease site. There were 39 evaluable patients (68 symptomatic sites). Sites treated included: nodal stations (n = 31), soft tissue (n = 13), mucosal sites (n = 11), central nervous system (n = 10), gastrointestinal tract (n = 2), and bone (n = 1). Median maximum tumor size at presentation was 3.5 cm (range, 1.3 cm-9.6 cm). The median dose of radiation was 30.6 Gy (range 18-40 Gy). Median follow-up post radiation per site was 12.3 months (range, 0.6-80.9 months). Response to treatment was complete in 47 sites (69.1%), partial in 16 sites (23.5%), and 5 sites (7.4%) had stable disease. In 9 (13.2%) sites local relapse occurred (median 7 months; range 2-21). The mean size of lymphoma at time of RT correlated with relapse, with tumors with local relapse larger than those without a local relapse (P = .005). Our data add to accumulating evidence that mantle cell lymphoma is a radio-sensitive disease with excellent responses to relatively low radiation doses, even in patients with chemo-refractory disease. Copyright © 2014 Elsevier Inc. All rights reserved.

Return to work for patients with diffuse large B-cell lymphoma and transformed indolent lymphoma undergoing autologous stem cell transplantation

PubMed Central

Arboe, Bente; Olsen, Maja Halgren; Goerloev, Jette Soenderskov; Duun-Henriksen, Anne Katrine; Johansen, Christoffer; Dalton, Susanne Oksbjerg; Brown, Peter de Nully

2017-01-01

Background Autologous stem cell transplantation (ASCT) is the standard treatment for patients with relapsed diffuse large B-cell lymphoma (DLBCL) or transformed indolent lymphoma (TIL). The treatment is mainly considered for younger patients still available for the work market. In this study, social outcomes after ASCT in terms of return to work (RTW) are described. Patients and methods Information from national administrative registers was combined with clinical information on patients, who received ASCT for relapse of DLBCL or TIL between 2000 and 2012. A total of 164 patients were followed until RTW, disability or old-age pension, death, or December 31, 2015, whichever came first. A total of 205 patients were followed with disability pension as the event of interest. Cox models were used to determine cause-specific hazards. Results During follow-up, 82 (50%) patients returned to work. The rate of returning to work in the first year following ASCT was decreased for patients being on sick leave at the time of relapse (hazard ratio [HR] 0.3 [0.2;0.5]) and increased for patients aged ≥55 years (HR 1.9 [1.1;3.3]). In all, 56 (27%) patients were granted disability pension. Being on sick leave at the time of relapse was positively associated with receiving a disability pension in the first 2 years after ASCT (HR 3.7 [1.8;7.7]). Conclusion Patients on sick leave at the time of relapse have a poorer prognosis regarding RTW and have a higher rate of disability pension. Furthermore, patients >55 are more likely to RTW compared to younger patients. These results indicate an unmet need for focused social rehabilitation. PMID:28652814

Global exosome transcriptome profiling reveals biomarkers for multiple sclerosis.

PubMed

Selmaj, Igor; Cichalewska, Maria; Namiecinska, Magdalena; Galazka, Grazyna; Horzelski, Wojciech; Selmaj, Krzysztof W; Mycko, Marcin P

2017-05-01

Accumulating evidence supports a role for exosomes in immune regulation. In this study, we investigated the total circulating exosome transcriptome in relapsing-remitting multiple sclerosis (RRMS) patients and healthy controls (HC). Next generation sequencing (NGS) was used to define the global RNA profile of serum exosomes in 19 RRMS patients (9 in relapse, 10 in remission) and 10 HC. We analyzed 5 million reads and >50,000 transcripts per sample, including a detailed analysis of microRNAs (miRNAs) differentially expressed in RRMS. The discovery set data were validated by quantification using digital quantitative polymerase chain reaction with an independent cohort of 63 RRMS patients (33 in relapse, 30 in remission) and 32 HC. Exosomal RNA NGS revealed that of 15 different classes of transcripts detected, 4 circulating exosomal sequences within the miRNA category were differentially expressed in RRMS patients versus HC: hsa-miR-122-5p, hsa-miR-196b-5p, hsa-miR-301a-3p, and hsa-miR-532-5p. Serum exosomal expression of these miRNAs was significantly decreased during relapse in RRMS. These miRNAs were also decreased in patients with a gadolinium enhancement on brain magnetic resonance imaging. In vitro secretion of these miRNAs by peripheral blood mononuclear cells was also significantly impaired in RRMS. These data show that circulating exosomes have a distinct RNA profile in RRMS. Because putative targets for these miRNAs include the signal transducer and activator of transcription 3 and the cell cycle regulator aryl hydrocarbon receptor, the data suggest a disturbed cell-to-cell communication in this disease. Thus, exosomal miRNAs might represent a useful biomarker to distinguish multiple sclerosis relapse. Ann Neurol 2017;81:703-717. © 2017 American Neurological Association.

Treatment of Relapsed and/or Chemotherapy Refractory B-cell Malignancy by Tandem CAR T Cells Targeting CD19 and CD22

ClinicalTrials.gov

2017-06-10

Hematopoietic/Lymphoid Cancer; Adult Acute Lymphoblastic Leukemia in Remission; B-cell Adult Acute Lymphoblastic Leukemia; B-Cell Chronic Lymphocytic Leukemia in Relapse (Diagnosis); Prolymphocytic Leukemia; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Refractory Chronic Lymphocytic Leukemia; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Chronic Lymphocytic Leukemia; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Chronic Lymphocytic Leukemia; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma

Perioperative circulating tumor cells in surgical patients with non-small cell lung cancer: does surgical manipulation dislodge cancer cells thus allowing them to pass into the peripheral blood?

PubMed

Sawabata, Noriyoshi; Funaki, Soichiro; Hyakutake, Takeru; Shintani, Yasushi; Fujiwara, Ayako; Okumura, Meinoshin

2016-12-01

We herein evaluated the status of circulating tumor cells (CTC) dislodged from the tumor during surgery in patients who underwent pulmonary resection for non-small cell lung cancer (NSCLC) to assess the clinical implications. Tumor cells in the peripheral arterial blood before surgery (Before) and immediately after lung resection (After) and in the blood from the pulmonary vein of the resected lung were detected using a size selective method. The clinicopathological characteristics and the prognosis were then analyzed according to the CTC status: no tumor cells detected (N), single tumor cell or total number less than 4 cells (S), and existence of clustered cells (C). According to the CTC status, the patients were classified into the following three groups: Before-C and After-C, Group I (n = 6); Before-S or N and After-C, Group II (n = 9); and Before-S or N and After-S or N, Group III (n = 8). Group III showed a high rate of p-stage IA, smaller tumor size, lower CEA level, lower SUVmax level, and a higher relapse-free survival rate than the other groups. CTCs were detected in patients after undergoing lung resection, some of which may have been dislodged by the surgical procedure. The presence of clustered CTCs after the operation indicated an unfavorable outcome.

SncRNA (microRNA & snoRNA) opposite expression pattern found in multiple sclerosis relapse and remission is sex dependent

PubMed Central

Muñoz-Culla, Maider; Irizar, Haritz; Sáenz-Cuesta, Matías; Castillo-Triviño, Tamara; Osorio-Querejeta, Iñaki; Sepúlveda, Lucía; López de Munain, Adolfo; Olascoaga, Javier; Otaegui, David

2016-01-01

Multiple sclerosis (MS) is a common inflammatory and degenerative disease that causes neurological disability. It affects young adults and its prevalence is higher in women. The most common form is manifested as a series of acute episodes of neurological disability (relapses) followed by a recovery phase (remission). Recently, non-coding RNAs have emerged as new players in transcriptome regulation, and in turn, they could have a significant role in MS pathogenesis. In this context, our aim was to investigate the involvement of microRNAs and snoRNAs in the relapse-remission dynamics of MS in peripheral blood leucocytes, to shed light on the molecular and regulatory mechanisms that underlie this complex process. With this approach, we found that a subset of small non-coding RNAs (sncRNA) is altered in relapse and remission, revealing unexpected opposite changes that are sex dependent. Furthermore, we found that a relapse-related miRNA signature regulated general metabolism processes in leucocytes, and miRNA altered in remission are involved in the regulation of innate immunity. We observed that sncRNA dysregulation is different in relapse and remission leading to differences in transcriptome regulation, and that this process is sex dependent. In conclusion, relapse and remission have a different molecular background in men and women. PMID:26831009

Cancer stem cells and drug resistance: the potential of nanomedicine

PubMed Central

Vinogradov, Serguei; Wei, Xin

2012-01-01

Properties of the small group of cancer cells called tumor-initiating or cancer stem cells (CSCs) involved in drug resistance, metastasis and relapse of cancers can significantly affect tumor therapy. Importantly, tumor drug resistance seems to be closely related to many intrinsic or acquired properties of CSCs, such as quiescence, specific morphology, DNA repair ability and overexpression of antiapoptotic proteins, drug efflux transporters and detoxifying enzymes. The specific microenvironment (niche) and hypoxic stability provide additional protection against anticancer therapy for CSCs. Thus, CSC-focused therapy is destined to form the core of any effective anticancer strategy. Nanomedicine has great potential in the development of CSC-targeting drugs, controlled drug delivery and release, and the design of novel gene-specific drugs and diagnostic modalities. This review is focused on tumor drug resistance-related properties of CSCs and describes current nanomedicine approaches, which could form the basis of novel combination therapies for eliminating metastatic and CSCs. PMID:22471722

Cytokine-enhanced vaccine and interferon-β plus suicide gene as combined therapy for spontaneous canine sarcomas.

PubMed

Finocchiaro, Liliana M E; Villaverde, Marcela S; Gil-Cardeza, María L; Riveros, María D; Glikin, Gerardo C

2011-10-01

Eleven soft tissue- and five osteosarcoma canine patients were subjected to: (i) periodic subcutaneous injection of irradiated xenogeneic cells secreting hGM-CSF and hIL-2 mixed with allogeneic or autologous tumor homogenates; and (ii) injections of cIFN-β and HSVtk-carrying lipoplexes and ganciclovir, marginal (after surgery) and/or intratumoral (in the case of partial tumor resection, local relapse or small surface tumors). This treatment alone (4 patients) or as surgery adjuvant (12 patients), was safe and well tolerated. In those patients presenting local disease (6/11), the suicide gene plus cIFN-β treatment induced local antitumor activity evidenced by the objective responses (3 complete, 2 partial) and stable diseases (2). In addition, the treatment prevented or delayed local relapse, regional metastases (lymph nodes developed only in 3/16) and distant metastases (0/16), suggesting a strong systemic antitumor immunity. The most encouraging result was the long survival times of 10 patients (>1 year, with good quality of life). Copyright © 2011 Elsevier Ltd. All rights reserved.

Massive intracerebral Epstein-Barr virus reactivation in lethal multiple sclerosis relapse after natalizumab withdrawal.

PubMed

Serafini, Barbara; Scorsi, Eleonora; Rosicarelli, Barbara; Rigau, Valérie; Thouvenot, Eric; Aloisi, Francesca

2017-06-15

Rebound of disease activity in multiple sclerosis patients after natalizumab withdrawal is a potentially life-threatening event. To verify whether highly destructive inflammation after natalizumab withdrawal is associated with Epstein-Barr virus (EBV) reactivation in central nervous system infiltrating B-lineage cells and cytotoxic immunity, we analyzed post-mortem brain tissue from a patient who died during a fulminating MS relapse following natalizumab withdrawal. Numerous EBV infected B cells/plasma cells and CD8+ T cells infiltrated all white matter lesions; the highest frequency of EBV lytically infected cells and granzyme B+ CD8+ T cells was observed in actively demyelinating lesions. These results may encourage switching to B-cell depleting therapy after natalizumab discontinuation. Copyright © 2017 Elsevier B.V. All rights reserved.

Increased CD8+ T Cell Response to Epstein-Barr Virus Lytic Antigens in the Active Phase of Multiple Sclerosis

PubMed Central

Angelini, Daniela F.; Serafini, Barbara; Piras, Eleonora; Severa, Martina; Coccia, Eliana M.; Rosicarelli, Barbara; Ruggieri, Serena; Gasperini, Claudio; Buttari, Fabio; Centonze, Diego; Mechelli, Rosella; Salvetti, Marco; Borsellino, Giovanna; Aloisi, Francesca; Battistini, Luca

2013-01-01

It has long been known that multiple sclerosis (MS) is associated with an increased Epstein-Barr virus (EBV) seroprevalence and high immune reactivity to EBV and that infectious mononucleosis increases MS risk. This evidence led to postulate that EBV infection plays a role in MS etiopathogenesis, although the mechanisms are debated. This study was designed to assess the prevalence and magnitude of CD8+ T-cell responses to EBV latent (EBNA-3A, LMP-2A) and lytic (BZLF-1, BMLF-1) antigens in relapsing-remitting MS patients (n = 113) and healthy donors (HD) (n = 43) and to investigate whether the EBV-specific CD8+ T cell response correlates with disease activity, as defined by clinical evaluation and gadolinium-enhanced magnetic resonance imaging. Using HLA class I pentamers, lytic antigen-specific CD8+ T cell responses were detected in fewer untreated inactive MS patients than in active MS patients and HD while the frequency of CD8+ T cells specific for EBV lytic and latent antigens was higher in active and inactive MS patients, respectively. In contrast, the CD8+ T cell response to cytomegalovirus did not differ between HD and MS patients, irrespective of the disease phase. Marked differences in the prevalence of EBV-specific CD8+ T cell responses were observed in patients treated with interferon-β and natalizumab, two licensed drugs for relapsing-remitting MS. Longitudinal studies revealed expansion of CD8+ T cells specific for EBV lytic antigens during active disease in untreated MS patients but not in relapse-free, natalizumab-treated patients. Analysis of post-mortem MS brain samples showed expression of the EBV lytic protein BZLF-1 and interactions between cytotoxic CD8+ T cells and EBV lytically infected plasma cells in inflammatory white matter lesions and meninges. We therefore propose that inability to control EBV infection during inactive MS could set the stage for intracerebral viral reactivation and disease relapse. PMID:23592979

Enzalutamide in Treating Patients With Relapsed or Refractory Mantle Cell Lymphoma

ClinicalTrials.gov

2018-03-27

Ann Arbor Stage I Mantle Cell Lymphoma; Ann Arbor Stage II Mantle Cell Lymphoma; Ann Arbor Stage III Mantle Cell Lymphoma; Ann Arbor Stage IV Mantle Cell Lymphoma; Recurrent Mantle Cell Lymphoma; Refractory Mantle Cell Lymphoma

Patterns of relapse in primary central nervous system lymphoma: inferences regarding the role of the neuro-vascular unit and monoclonal antibodies in treating occult CNS disease.

PubMed

Ambady, Prakash; Fu, Rongwei; Netto, Joao Prola; Kersch, Cymon; Firkins, Jenny; Doolittle, Nancy D; Neuwelt, Edward A

2017-06-02

The radiologic features and patterns of primary central nervous system lymphoma (PCNSL) at initial presentation are well described. High response rates can be achieved with first-line high-dose methotrexate (HD-MTX) based regimens, yet many relapse within 2 years of diagnosis. We describe the pattern of relapse and review the potential mechanisms involved in relapse. We identified 78 consecutive patients who attained complete radiographic response (CR) during or after first-line treatment for newly diagnosed PCNSL (CD20+, diffuse large B cell type). Patients were treated with HD-MTX based regimen in conjunction with blood-brain barrier disruption (HD-MTX/BBBD); 44 subsequently relapsed. Images and medical records of these 44 consecutive patients were retrospectively reviewed. The anatomical location of enhancing lesions at initial diagnosis and at the time of relapse were identified and compared. 37/44 patients fulfilled inclusion criteria and had new measureable enhancing lesions at relapse; the pattern and location of relapse of these 37 patients were identified. At relapse, the new enhancement was at a spatially distinct site in 30 of 37 patients. Local relapse was found only in seven patients. Unlike gliomas, the majority of PCNSL had radiographic relapse at spatially distinct anatomical locations within the brain behind a previously intact neurovascular unit (NVU), and in few cases outside, the central nervous system (CNS). This may suggest either (1) reactivation of occult reservoirs behind an intact NVU in the CNS (or ocular) or (2) seeding from bone marrow or other extra CNS sites. Recognizing patterns of relapse is key for early detection and may provide insight into potential mechanisms of relapse as well as help develop strategies to extend duration of complete response.

Haemopoietic stem cell transplantation for acute lymphoblastic leukaemia.

PubMed

Popat, Uday; Carrum, George; Heslop, Helen E

2003-02-01

The majority of children and some adults with acute lymphocytic leukaemia (ALL) can be cured with current intensive chemotherapy regimens. For those patients who relapse or who do not achieve remission, allogeneic haemopoietic stem cell transplantation (HSCT) offers the best chance for long-term disease control. Different sources of haemopoietic stem cells including marrow, peripheral blood, and cord blood are now available and the introduction of subablative regimens has increased the number of patients who are transplant candidates. Relapse remains the major cause of transplant failure and immunotherapy strategies post-transplant to augment the graft versus leukaemia effect are being explored.

Efficacy and Safety of Ibrutinib in Indian Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia and Mantle Cell Lymphoma: Cases from a Named Patient Program.

PubMed

Agarwal, Mohan B; Bhurani, Dinesh; Shah, Chirag; Sood, Nitin; Singhal, Manish; Kamat, Anil; Chezhian, Subash; Mishra, Suryaprakash; Nagrale, Dinesh

2017-01-01

This named patient program evaluated the safety and efficacy of ibrutinib, a selective inhibitor of Bruton's tyrosine kinase in Indian patients with relapsed/refractory chronic lymphocytic leukemia (CLL, with/without chromosome 17 deletion [del17p]) and mantle cell lymphoma (MCL). The eight enrolled patients (relapsed/refractory CLL: n = 6 [4/6 patients with del17p] and relapsed/refractory MCL: n = 2) had median age of 55 years (range, 52-60) and had received a median of 3 (CLL patients) and 4 (MCL patients) prior therapies. Patients received once-daily dose of ibrutinib (420 mg: CLL, 560 mg: MCL). In CLL patients, the median time to response was 3 months (range, 0.5-7) and five of six patients had partial response (PR) whereas one achieved complete response (CR). Median time on treatment was 11.5 months (range, 8-14); five patients continued treatment and one was recommended stem cell transplantation (SCT). Of the two MCL patients, one achieved PR and one showed CR and advanced to SCT. In CLL patients, the median (range) hemoglobin level improved from 9.8 g/dL (7.2-11) at baseline to 12.0 g/dL (9.5-13.2) and median (range) platelet count improved from 150,000 cells/μL (21,000-195,000) at baseline to 190,350 cells/μL (130,000-394,000) at the time of analysis (July 2016). Most adverse events (AEs) reported were infections ( n = 2). No Grade 3-4 or serious AEs, dose reductions, or treatment discontinuation due to AEs were reported. In this first real-world experience in Indian patients, ibrutinib demonstrated therapeutic efficacy in relapsed/refractory CLL (with/without del17p) and MCL. Safety results were consistent with the current known profile of ibrutinib.

Novel anticancer activity of phloroglucinol against breast cancer stem-like cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kim, Rae-Kwon; Uddin, Nizam; Hyun, Jin-Won

Poor prognosis of breast cancer patients is closely associated with metastasis and relapse. There is substantial evidence supporting that cancer stem-like cells (CSCs) are primarily responsible for relapse in breast cancer after anticancer treatment. However, there is a lack of suitable drugs that target breast cancer stem-like cells (BCSCs). Here, we report that phloroglucinol (PG), a natural phlorotannin component of brown algae, suppresses sphere formation, anchorage-independent colony formation and in vivo tumorigenicity. In line with these observations, treatment with PG also decreased CD44{sup +} cancer cell population as well as expression of CSC regulators such as Sox2, CD44, Oct4, Notch2more » and β-catenin. Also, treatment with PG sensitized breast cancer cells to anticancer drugs such as cisplatin, etoposide, and taxol as well as to ionizing radiation. Importantly, PG inhibited KRAS and its downstream PI3K/AKT and RAF-1/ERK signaling pathways that regulate the maintenance of CSCs. Taken together, our findings implicate PG as a good candidate to target BCSCs and to prevent the disease relapse. - Highlights: • Phloroglucinol suppresses in vivo tumor formation. • Phloroglucinol sensitizes breast cancer cells to anticancer agents. • Phloroglucinol inhibits breast cancer stem-like cells. • Phloroglucinol inhibits PI3K/AKT and KRAS/RAF/ERK signaling pathways.« less

Small molecule screening reveals a transcription-independent pro-survival function of androgen receptor in castration-resistant prostate cancer

PubMed Central

Narizhneva, Natalia V.; Tararova, Natalia D.; Ryabokon, Petro; Shyshynova, Inna; Prokvolit, Anatoly; Komarov, Pavel G.; Purmal, Andrei A.; Gudkov, Andrei V.; Gurova, Katerina V.

2010-01-01

In prostate cancer (PCa) patients, initial responsiveness to androgen deprivation therapy is frequently followed by relapse due to development of treatment-resistant androgen-independent PCa. This is typically associated with acquisition of mutations in AR that allow activity as a transcription factor in the absence of ligand, indicating that androgen-independent PCa remains dependent on AR function. Our strategy to effectively target AR in androgen-independent PCa involved using a cell-based readout to isolate small molecules that inhibit AR transactivation function through mechanisms other than modulation of ligand binding. A number of the identified inhibitors were toxic to AR-expressing PCa cells regardless of their androgen dependence. Among these, some only suppressed PCa cell growth (ARTIS), while others induced cell death (ARTIK). ARTIK, but not ARTIS, compounds caused disappearance of AR protein from treated cells. siRNA against AR behaved like ARTIK compounds, while a dominant negative AR mutant that prevents AR-mediated transactivation but does not eliminate the protein showed only a growth suppressive effect. These observations reveal a transcription-independent function of AR that is essential for PCa cell viability and, therefore, is an ideal target for anti-PCa treatment. Indeed, several of the identified AR inhibitors demonstrated in vivo efficacy in mouse models of PCa and are candidates for pharmacologic optimization. PMID:19946220

Durable graft-versus-leukaemia effects without donor lymphocyte infusions - results of a phase II study of sequential T-replete allogeneic transplantation for high-risk acute myeloid leukaemia and myelodysplasia.

PubMed

Davies, Jeff K; Hassan, Sandra; Sarker, Shah-Jalal; Besley, Caroline; Oakervee, Heather; Smith, Matthew; Taussig, David; Gribben, John G; Cavenagh, Jamie D

2018-02-01

Allogeneic haematopoietic stem-cell transplantation remains the only curative treatment for relapsed/refractory acute myeloid leukaemia (AML) and high-risk myelodysplasia but has previously been limited to patients who achieve remission before transplant. New sequential approaches employing T-cell depleted transplantation directly after chemotherapy show promise but are burdened by viral infection and require donor lymphocyte infusions (DLI) to augment donor chimerism and graft-versus-leukaemia effects. T-replete transplantation in sequential approaches could reduce both viral infection and DLI usage. We therefore performed a single-arm prospective Phase II clinical trial of sequential chemotherapy and T-replete transplantation using reduced-intensity conditioning without planned DLI. The primary endpoint was overall survival. Forty-seven patients with relapsed/refractory AML or high-risk myelodysplasia were enrolled; 43 proceeded to transplantation. High levels of donor chimerism were achieved spontaneously with no DLI. Overall survival of transplanted patients was 45% and 33% at 1 and 3 years. Only one patient developed cytomegalovirus disease. Cumulative incidences of treatment-related mortality and relapse were 35% and 20% at 1 year. Patients with relapsed AML and myelodysplasia had the most favourable outcomes. Late-onset graft-versus-host disease protected against relapse. In conclusion, a T-replete sequential transplantation using reduced-intensity conditioning is feasible for relapsed/refractory AML and myelodysplasia and can deliver graft-versus-leukaemia effects without DLI. © 2017 John Wiley & Sons Ltd.

Ixabepilone in Treating Patients With Relapsed or Refractory Aggressive Non-Hodgkin's Lymphoma

ClinicalTrials.gov

2014-05-07

Anaplastic Large Cell Lymphoma; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma

Human central nervous system astrocytes support survival and activation of B cells: implications for MS pathogenesis.

PubMed

Touil, Hanane; Kobert, Antonia; Lebeurrier, Nathalie; Rieger, Aja; Saikali, Philippe; Lambert, Caroline; Fawaz, Lama; Moore, Craig S; Prat, Alexandre; Gommerman, Jennifer; Antel, Jack P; Itoyama, Yasuto; Nakashima, Ichiro; Bar-Or, Amit

2018-04-19

The success of clinical trials of selective B cell depletion in patients with relapsing multiple sclerosis (MS) indicates B cells are important contributors to peripheral immune responses involved in the development of new relapses. Such B cell contribution to peripheral inflammation likely involves antibody-independent mechanisms. Of growing interest is the potential that B cells, within the MS central nervous system (CNS), may also contribute to the propagation of CNS-compartmentalized inflammation in progressive (non-relapsing) disease. B cells are known to persist in the inflamed MS CNS and are more recently described as concentrated in meningeal immune-cell aggregates, adjacent to the subpial cortical injury which has been associated with progressive disease. How B cells are fostered within the MS CNS and how they may contribute locally to the propagation of CNS-compartmentalized inflammation remain to be elucidated. We considered whether activated human astrocytes might contribute to B cell survival and function through soluble factors. B cells from healthy controls (HC) and untreated MS patients were exposed to primary human astrocytes that were either maintained under basal culture conditions (non-activated) or pre-activated with standard inflammatory signals. B cell exposure to astrocytes included direct co-culture, co-culture in transwells, or exposure to astrocyte-conditioned medium. Following the different exposures, B cell survival and expression of T cell co-stimulatory molecules were assessed by flow cytometry, as was the ability of differentially exposed B cells to induce activation of allogeneic T cells. Secreted factors from both non-activated and activated human astrocytes robustly supported human B cell survival. Soluble products of pre-activated astrocytes also induced B cell upregulation of antigen-presenting cell machinery, and these B cells, in turn, were more efficient activators of T cells. Astrocyte-soluble factors could support survival and activation of B cell subsets implicated in MS, including memory B cells from patients with both relapsing and progressive forms of disease. Our findings point to a potential mechanism whereby activated astrocytes in the inflamed MS CNS not only promote a B cell fostering environment, but also actively support the ability of B cells to contribute to the propagation of CNS-compartmentalized inflammation, now thought to play key roles in progressive disease.

ABT-199 (venetoclax) and BCL-2 inhibitors in clinical development.

PubMed

Cang, Shundong; Iragavarapu, Chaitanya; Savooji, John; Song, Yongping; Liu, Delong

2015-11-20

With the advent of new agents targeting CD20, Bruton's tyrosine kinase, and phosphoinositol-3 kinase for chronic lymphoid leukemia (CLL), more treatment options exist than ever before. B-cell lymphoma-2 (BCL-2) plays a major role in cellular apoptosis and is a druggable target. Small molecule inhibitors of BCL-2 are in active clinical studies. ABT-199 (venetoclax, RG7601, GDC-0199) has been granted breakthrough designation by FDA for relapsed or refractory CLL with 17p deletion. In this review, we summarized the latest clinical development of ABT-199/venetoclax and other novel agents targeting the BCL-2 proteins.

Treating relapsed or refractory Philadelphia chromosome-negative acute lymphoblastic leukemia: liposome-encapsulated vincristine

PubMed Central

Davis, Tyler; Farag, Sherif S

2013-01-01

Acute lymphoblastic leukemia (ALL) remains a disease with poor outcomes in adults. While induction chemotherapy achieves a complete remission in almost 90% of patients, the majority will relapse and die of their disease. Relapsed ALL is associated with a high reinduction mortality and chemotherapy resistance, with allogeneic hematopoietic stem cell transplantation offering the only therapy with curative potential. However, there is no efficacious and well tolerated standard regimen accepted as a “bridge” to allogeneic stem cell transplantation or as definitive treatment for patients who are not transplant candidates. Vincristine is an active drug in patients with ALL, but its dose intensity is limited by neurotoxicity, and its full potential as an anticancer drug is thus not realized. Encapsulation of vincristine into sphingomyelin and cholesterol nanoparticle liposomes facilitates dose-intensification and densification to enhanced target tissues with reduced potential for toxicity. Vincristine sulfate liposome injection (VSLI) is associated with significant responses in clinically advanced ALL, and has recently been approved by the US Food and Drug Administration for treatment of relapsed and clinically advanced Philadelphia chromosome-negative ALL. This review provides an overview of the preclinical and clinical studies leading to the approval of VSLI for the treatment of relapsed and refractory ALL, and suggests potential areas of future clinical development. PMID:24072970

Hematopoietic stem cell transplantation for isolated extramedullary relapse of acute lymphoblastic leukemia in children.

PubMed

Gabelli, Maria; Zecca, Marco; Messina, Chiara; Carraro, Elisa; Buldini, Barbara; Rovelli, Attilio Maria; Fagioli, Franca; Bertaina, Alice; Lanino, Edoardo; Favre, Claudio; Rabusin, Marco; Prete, Arcangelo; Ripaldi, Mimmo; Barberi, Walter; Porta, Fulvio; Caniglia, Maurizio; Santarone, Stella; D'Angelo, Paolo; Basso, Giuseppe; Locatelli, Franco

2018-06-13

Relapse of acute lymphoblastic leukemia (ALL) may occur in extramedullary sites, mainly central nervous system (CNS) and testis. Optimal post-remissional treatment for isolated extramedullary relapse (IEMR) is still controversial. We collected data of children treated with hematopoietic stem cell transplantation (HSCT) for ALL IEMR from 1990 to 2015 in Italy. Among 281 patients, 167 had a relapse confined to CNS, 73 to testis, 14 to mediastinum, and 27 to other organs. Ninety-seven patients underwent autologous HSCT, 79 received allogeneic HSCT from a matched family donor, 75 from a matched unrelated donor, and 30 from an HLA-haploidentical donor. The 10-year overall survival was 56% and was not influenced by gender, ALL blast immune-phenotype, age, site of relapse, duration of first remission, and type of HSCT. In multivariable analysis, the only prognostic factors were disease status at HSCT and year of transplantation. Patients transplanted in third or subsequent complete remission (CR) had a risk of death 2.3 times greater than those in CR2. Children treated after 2000 had half the risk of death than those treated before that year. Our results suggest that both autologous and allogeneic HSCT may be considered for the treatment of pediatric ALL IEMR after the achievement of CR2.

Effect of Radiotherapy Dose and Volume on Relapse in Merkel Cell Cancer of the Skin

DOE Office of Scientific and Technical Information (OSTI.GOV)

Foote, Matthew, E-mail: matthew_foote@health.qld.gov.a; Harvey, Jennifer; Porceddu, Sandro

Purpose: To assess the effect of radiotherapy (RT) dose and volume on relapse patterns in patients with Stage I-III Merkel cell carcinoma (MCC). Patients and Methods: This was a retrospective analysis of 112 patients diagnosed with MCC between January 2000 and December 2005 and treated with curative-intent RT. Results: Of the 112 evaluable patients, 88% had RT to the site of primary disease for gross (11%) or subclinical (78%) disease. Eighty-nine percent of patients had RT to the regional lymph nodes; in most cases (71%) this was for subclinical disease in the adjuvant or elective setting, whereas 21 patients (19%)more » were treated with RT to gross nodal disease. With a median follow-up of 3.7 years, the 2-year and 5-year overall survival rates were 72% and 53%, respectively, and the 2-year locoregional control rate was 75%. The in-field relapse rate was 3% for primary disease, and relapse was significantly lower for patients receiving {>=}50Gy (hazard ratio [HR] = 0.22; 95% confidence interval [CI], 0.06-0.86). Surgical margins did not affect the local relapse rate. The in-field relapse rate was 11% for RT to the nodes, with dose being significant for nodal gross disease (HR = 0.24; 95% CI, 0.07-0.87). Patients who did not receive elective nodal RT had a much higher rate of nodal relapse compared with those who did (HR = 6.03; 95% CI, 1.34-27.10). Conclusion: This study indicates a dose-response for subclinical and gross MCC. Doses of {>=}50Gy for subclinical disease and {>=}55Gy for gross disease should be considered. The draining nodal basin should be treated in all patients.« less

A phase II study of high-dose celecoxib and metronomic 'low-dose' cyclophosphamide and methotrexate in patients with relapsed and refractory lymphoma.

PubMed

El Bary, Naser Abd; Hashem, Tarek; Metwally, Hasan; Ghany, Ashraf Abd; El Mageed, Hager Abd

2010-01-01

Relapsed, histologically aggressive non-Hodgkin lymphoma (NHL) has a poor prognosis; relapsed patients who do not respond to second line therapy or are unfit for BMT have a worse prognosis. Angiogenesis is increased in aggressive NHL and could be targeted by selective cyclooxygenase-2 inhibition and metronomic chemotherapy. We assessed the toxicity of metronomic chemotherapy and the response and progression-free survival in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). We prospectively studied 41 patients with a diagnosis of relapsed and/or refractory DLBCL who may have received any number of preceding therapies (as long as one included an anthracycline) and were not candidates for bone marrow transplantation. They received oral cyclophosphamide (50 mg every day), oral methotrexate (2.5 mg 4 times/week) and high-dose oral celecoxib (400 mg twice daily) until there was disease progression or unacceptable toxicity. All 41 patients (median age, 56 years) were evaluable for toxicity and response, with a median follow up of 9.1 months (range, 4-35 months). At relapse, 51.2% had a high international prognostic index. The treatment protocol was well tolerated with no major toxicities. The most common toxicities were fatigue (61%), nausea (22%), neutropenia (19.5%), and anemia (22%). In 31.7% there was a partial response and 48.8% had stable disease. Progression-free survival was 12 months. The median response duration was 10 months. We conclude that metronomic chemotherapy can be used for patients with relapsed and or refractory DLBCL with reasonable outcome and acceptable toxicity. Standard approaches such as hematopoietic stem cell transplantation and chemo-immunotherapy combinations should be explored prior to a decision on metronomic chemotherapy.

The Role of Radiotherapy Alone in Patients With Merkel Cell Carcinoma: Reporting the Australian Experience of 43 Patients

DOE Office of Scientific and Technical Information (OSTI.GOV)

Veness, Michael, E-mail: michael.veness@swahs.health.nsw.gov.a; Foote, Matthew; Gebski, Val

2010-11-01

Purpose: To review the role of radiotherapy (RTx) alone in patients with Merkel cell carcinoma (MCC). Methods and Materials: The records of 43 patients with MCC treated with RTx alone between 1993 and 2007 at the Westmead and Royal Brisbane/Mater Hospitals, Australia, were reviewed. Multivariate analysis was performed by use of Cox regression analysis. Results: The median age was 79 years (range, 48-91 years) in 19 women (44%) and 24 men (56%). All patients were white, and 5 (12%) had immunosuppression. A majority (56%) underwent irradiation at initial diagnosis, with the remainder (44%) treated in the relapse setting. The medianmore » duration of follow-up was 39 months. The head and neck comprised the most frequently treated site (47%). The median maximum lesion size was 30 mm (range, 5-130 mm). Relapse developed in 60% of patients, with most being out-of-field relapses. The in-field control rate was 75%. Most out-of-field relapses were to visceral organs. Relapse developed outside the irradiated field in 53% of patients. On multivariate analysis, only nodal status (negative nodes vs. nodes present) was significantly associated with relapse-free survival, with p = 0.005 (hazard ratio, 0.25; 95% confidence interval, 0.96-0.663). Overall survival at 2 and 5 years was 58% and 37%, respectively. Conclusions: Patients with MCC treated with RTx have a high likelihood of obtaining in-field control. Doses of 50 to 55 Gy in 20 to 25 fractions are recommended. A minority of patients are cured, with many dying of systemic relapse. Lower dose fractionation schedules (e.g., 25 Gy in 5 fractions) may be considered in patients with a very poor performance status.« less

Impact of Early Cytomegalovirus Reactivation in Cord Blood Stem Cell Recipients in the Current Era

PubMed Central

Ramanathan, Muthalagu; Teira, Pierre; Battiwalla, Minoo; Barrett, John; Ahn, Kwang Woo; Chen, Min; Green, Jamie; Laughlin, Mary; Lazarus, Hillard M.; Marks, David; Saad, Ayman; Seftel, Matthew; Saber, Wael; Savani, Bipin; Waller, Edmund; Wingard, John; Auletta, Jeffery J.; Lindemans, Caroline A.; Boeckh, Michael; Riches, Marcie L.

2016-01-01

Several studies have reported an association between cytomegalovirus (CMV) reactivation and a decreased incidence of relapse for acute myeloid leukemia (AML) after adult donor allogeneic hematopoietic cell transplantation (HCT). Limited data, however, are available on the impact of CMV reactivation on relapse after cord blood stem cell (CB) transplantation. The unique combination of higher incidence of CMV reactivation in the seropositive recipient and lower incidence of graft versus host disease (GvHD) in CB HCT allows for a valuable design to analyze the impact of CMV reactivation. Data from 1684 patients transplanted with cord blood (CB) between 2003 and 2010 for AML and acute lymphoblastic leukemia (ALL) were analyzed. The median time to CMV reactivation was 34 days (range: 2 – 287). CMV reactivation and positive CMV serology were associated with increased non-relapse mortality (NRM) amongst both AML and ALL CB recipients [Reactivation, AML: RR 1.41 (1.07–1.85); ALL: 1.60 (1.14 – 2.23); Serology, AML: RR 1.39 (1.05 – 1.85), ALL: RR 1.61 (1.18 – 2.19)]. For patients with ALL, but not those with AML, this yielded inferior overall survival (p<0.005). Risk of relapse was not impacted by CMV reactivation or positive CMV serostatus for either disease. PMID:27042847

Outcome of patients with relapsed diffuse large B-cell lymphoma who fail second-line salvage regimens in the International CORAL study.

PubMed

Van Den Neste, E; Schmitz, N; Mounier, N; Gill, D; Linch, D; Trneny, M; Milpied, N; Radford, J; Ketterer, N; Shpilberg, O; Dührsen, U; Ma, D; Brière, J; Thieblemont, C; Salles, G; Moskowitz, C H; Glass, B; Gisselbrecht, C

2016-01-01

Salvage chemotherapy followed by autologous stem cell transplantation (ASCT) is the standard second-line treatment for relapsed and refractory diffuse large B-cell lymphoma (DLBCL). However, the strategy is less clear in patients who require third-line treatment. Updated outcomes of 203 patients who could not proceed to scheduled ASCT in the Collaborative Trial in Relapsed Aggressive Lymphoma (CORAL) are herein reviewed. In the intent-to-treat analysis, overall response rate to third-line chemotherapy was 39%, with 27% CR or CR unconfirmed, and 12% PR. Among the 203 patients, 64 (31.5%) were eventually transplanted (ASCT 56, allogeneic SCT 8). Median overall survival (OS) of the entire population was 4.4 months. OS was significantly improved in patients with lower tertiary International Prognostic Index (IPI), patients responding to third-line treatment and patients transplanted with a 1-year OS of 41.6% compared with 16.3% for the not transplanted (P<0.0001). In multivariate analysis, IPI at relapse (hazard ratio (HR) 2.409) and transplantation (HR 0.375) independently predicted OS. Third-line salvage chemotherapy can lead to response followed by transplantation and long-term survival in DLBCL patients. However, improvement of salvage efficacy is an urgent need with new drugs.

Exponential Decay Nonlinear Regression Analysis of Patient Survival Curves: Preliminary Assessment in Non-Small Cell Lung Cancer

PubMed Central

Stewart, David J.; Behrens, Carmen; Roth, Jack; Wistuba, Ignacio I.

2010-01-01

Background For processes that follow first order kinetics, exponential decay nonlinear regression analysis (EDNRA) may delineate curve characteristics and suggest processes affecting curve shape. We conducted a preliminary feasibility assessment of EDNRA of patient survival curves. Methods EDNRA was performed on Kaplan-Meier overall survival (OS) and time-to-relapse (TTR) curves for 323 patients with resected NSCLC and on OS and progression-free survival (PFS) curves from selected publications. Results and Conclusions In our resected patients, TTR curves were triphasic with a “cured” fraction of 60.7% (half-life [t1/2] >100,000 months), a rapidly-relapsing group (7.4%, t1/2=5.9 months) and a slowly-relapsing group (31.9%, t1/2=23.6 months). OS was uniphasic (t1/2=74.3 months), suggesting an impact of co-morbidities; hence, tumor molecular characteristics would more likely predict TTR than OS. Of 172 published curves analyzed, 72 (42%) were uniphasic, 92 (53%) were biphasic, 8 (5%) were triphasic. With first-line chemotherapy in advanced NSCLC, 87.5% of curves from 2-3 drug regimens were uniphasic vs only 20% of those with best supportive care or 1 drug (p<0.001). 54% of curves from 2-3 drug regimens had convex rapid-decay phases vs 0% with fewer agents (p<0.001). Curve convexities suggest that discontinuing chemotherapy after 3-6 cycles “synchronizes” patient progression and death. With postoperative adjuvant chemotherapy, the PFS rapid-decay phase accounted for a smaller proportion of the population than in controls (p=0.02) with no significant difference in rapid-decay t1/2, suggesting adjuvant chemotherapy may move a subpopulation of patients with sensitive tumors from the relapsing group to the cured group, with minimal impact on time to relapse for a larger group of patients with resistant tumors. In untreated patients, the proportion of patients in the rapid-decay phase increased (p=0.04) while rapid-decay t1/2 decreased (p=0.0004) with increasing stage, suggesting that higher stage may be associated with tumor cells that both grow more rapidly and have a higher probability of surviving metastatic processes than in early stage tumors. This preliminary assessment of EDNRA suggests that it may be worth exploring this approach further using more sophisticated, statistically rigorous nonlinear modelling approaches. Using such approaches to supplement standard survival analyses could suggest or support specific testable hypotheses. PMID:20627364

Adoptive T-cell therapies for refractory/relapsed leukemia and lymphoma: current strategies and recent advances

PubMed Central

McLaughlin, Lauren; Cruz, C. Russell; Bollard, Catherine M.

2015-01-01

Despite significant advancements in the treatment and outcome of hematologic malignancies, prognosis remains poor for patients who have relapsed or refractory disease. Adoptive T-cell immunotherapy offers novel therapeutics that attempt to utilize the noted graft versus leukemia effect. While CD19 chimeric antigen receptor (CAR)-modified T cells have thus far been the most clinically successful application of adoptive T immunotherapy, further work with antigen specific T cells and CARs that recognize other targets have helped diversify the field to treat a broad spectrum of hematologic malignancies. This article will focus primarily on therapies currently in the clinical trial phase as well as current downfalls or limitations. PMID:26622998

Emergency pancreatoduodenectomy (whipple procedure) for massive upper gastrointestinal bleeding caused by a diffuse B-cell lymphoma of the duodenum: report of a case.

PubMed

Stratigos, Panagiotis; Kouskos, Efstratios; Kouroglou, Maria; Chrisafis, Ioannis; Fois, Lucia; Mavrogiorgis, Anastasios; Axiotis, Efthimios; Zamtrakis, Sotirios

2007-01-01

We herein report a rare case of a massive upper gastrointestinal (GI) bleeding, caused by high-grade diffuse B-cell lymphoma of the duodenum, secondary to immunoproliferative small intestinal disease (IPSID) and treated with an emergency partial pancreatoduodenectomy. A 42-year-old man was admitted to our hospital because of hematemesis. Upper GI endoscopy was unrevealing because of the copious bleeding. Initially, the patient underwent conservative treatment, thus resulting in the temporary cessation of the bleeding. Later, the hemorrhage massively relapsed. An urgent abdominal ultrasound raised the suspicion of a large, possibly bleeding, neoplasm of the duodenum, which was finally confirmed by abdominal computed tomography. The patient underwent an emergency laparotomy, during which a partial pancreatoduodenectomy was performed (Whipple procedure). Histologically, the tumor was a high-grade B-cell lymphoma of the duodenum. The nearby small intestinal mucosa was suggestive of IPSID. A massive upper GI hemorrhage from a high-grade B-cell non-Hodgkin lymphoma of the duodenum, which develops secondary to IPSID, is a very rare clinical demonstration of this disease. Our case is one of the few reports in the English literature, for which the Whipple procedure has been performed as a curative treatment.

Self-Delivering RNAi Targeting PD-1 Improves Tumor-Specific T Cell Functionality for Adoptive Cell Therapy of Malignant Melanoma.

PubMed

Ligtenberg, Maarten A; Pico de Coaña, Yago; Shmushkovich, Taisia; Yoshimoto, Yuya; Truxova, Iva; Yang, Yuan; Betancur-Boissel, Monica; Eliseev, Alexey V; Wolfson, Alexey D; Kiessling, Rolf

2018-06-06

Adoptive cell therapy (ACT) is becoming a prominent alternative therapeutic treatment for cancer patients relapsing on traditional therapies. In parallel, antibodies targeting immune checkpoint molecules, such as cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4) and cell death protein 1 pathway (PD-1), are rapidly being approved for multiple cancer types, including as first line therapy for PD-L1-expressing non-small-cell lung cancer. The combination of ACT and checkpoint blockade could substantially boost the efficacy of ACT. In this study, we generated a novel self-delivering small interfering RNA (siRNA) (sdRNA) that knocked down PD-1 expression on healthy donor T cells as well as patient-derived tumor-infiltrating lymphocytes (TIL). We have developed an alternative chemical modification of RNA backbone for improved stability and increased efficacy. Our results show that T cells treated with sdRNA specific for PD-1 had increased interferon γ (IFN-γ) secreting capacity and that this modality of gene expression interference could be utilized in our rapid expansion protocol for production of TIL for therapy. TIL expanded in the presence of PD-1-specific sdRNA performed with increased functionality against autologous tumor as compared to control TIL. This method of introducing RNAi into T cells to modify the expression of proteins could easily be adopted into any ACT protocol and will lead to the exploration of new combination therapies. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Current Therapy and New Directions in the Treatment of Hairy Cell Leukemia: A Review.

PubMed

Sarvaria, Aditya; Topp, Zheng; Saven, Alan

2016-01-01

Hairy cell leukemia (HCL) is a chronic B-cell leukemia noted for an indolent course that ultimately results in cytopenias and massive splenomegaly. Whereas treatment with the nucleoside purine analogues cladribine and pentostatin results in lengthy remissions in nearly all patients with HCL, most patients will experience relapse while a small percentage of patients' disease fails to respond to therapy in the first place. Retreatment with a purine nucleoside analogue often leads to an effective but limited response. For decades, few other viable therapeutic options were available to these patients who required retreatment. Recently, new insights into the mechanism of disease of HCL have led to research in new potential treatment agents, either alone or with a purine nucleoside analogue. Clinical trials with rituximab, bendamustine, and conjugate immunotoxins will reveal what role these therapies will have in HCL treatment. A better understanding of the BRAF/MEK/ERK pathway and the B-cell signaling pathway has allowed further exploration into the novel drugs vemurafenib, dabrafenib, trametinib, and ibrutinib.

Safety and tolerability of ibrutinib monotherapy in Japanese patients with relapsed/refractory B cell malignancies.

PubMed

Tobinai, Kensei; Ogura, Michinori; Ishizawa, Kenichi; Suzuki, Tatsuya; Munakata, Wataru; Uchida, Toshiki; Aoki, Tomohiro; Morishita, Takanobu; Ushijima, Yoko; Takahara, Satoko

2016-01-01

In this phase I dose-escalation study we evaluated the safety, tolerability, pharmacokinetics, and antitumor activity of ibrutinib, an oral covalent inhibitor of Bruton's tyrosine kinase (BTK, in Japanese patients with relapsed/refractory B cell malignancies (RRBCM). Fifteen patients aged 42-78 years were enrolled to one of three cohorts. Cohort 1 (n = 3) consisted of two phases, a single-dose (140 and 280 mg) phase and a multiple-dose (420 mg) phase of ibrutinib; cohort 2 (n = 6) included multiple doses of ibrutinib 560 mg; and cohort 3 (n = 6) included only patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) dosed at ibrutinib 420 mg. One patient (CLL/SLL cohort) experienced grade 3 pneumonia and sepsis, which were considered dose-limiting toxicities. No deaths were reported. The most common (≥ 20% patients) adverse events were neutropenia, anemia, nasopharyngitis, increased bilirubin, and rash. Dose-dependent increase in maximum plasma concentration and area under the concentration from 0 to the last quantifiable time was observed, while time to reach maximum plasma concentration and elimination half-life was similar between doses. The overall response rate was 73.3% (11/15) for all cohorts combined. Overall, ibrutinib (420 and 560 mg) was tolerable with acceptable safety profiles and effective for Japanese patients with RRBCM including CLL/SLL. NCT01704963.

T helper 17.1 cells associate with multiple sclerosis disease activity: perspectives for early intervention.

PubMed

van Langelaar, Jamie; van der Vuurst de Vries, Roos M; Janssen, Malou; Wierenga-Wolf, Annet F; Spilt, Isis M; Siepman, Theodora A; Dankers, Wendy; Verjans, Georges M G M; de Vries, Helga E; Lubberts, Erik; Hintzen, Rogier Q; van Luijn, Marvin M

2018-05-01

Interleukin-17-expressing CD4+ T helper 17 (Th17) cells are considered as critical regulators of multiple sclerosis disease activity. However, depending on the species and pro-inflammatory milieu, Th17 cells are functionally heterogeneous, consisting of subpopulations that differentially produce interleukin-17, interferon-gamma and granulocyte macrophage colony-stimulating factor. In the current study, we studied distinct effector phenotypes of human Th17 cells and their correlation with disease activity in multiple sclerosis patients. T helper memory populations single- and double-positive for C-C chemokine receptor 6 (CCR6) and CXC chemokine receptor 3 (CXCR3) were functionally assessed in blood and/or cerebrospinal fluid from a total of 59 patients with clinically isolated syndrome, 35 untreated patients and 24 natalizumab-treated patients with relapsing-remitting multiple sclerosis, and nine patients with end-stage multiple sclerosis. Within the clinically isolated syndrome group, 23 patients had a second attack within 1 year and 26 patients did not experience subsequent attacks during a follow-up of >5 years. Low frequencies of T helper 1 (Th1)-like Th17 (CCR6+CXCR3+), and not Th17 (CCR6+CXCR3-) effector memory populations in blood strongly associated with a rapid diagnosis of clinically definite multiple sclerosis. In cerebrospinal fluid of clinically isolated syndrome and relapsing-remitting multiple sclerosis patients, Th1-like Th17 effector memory cells were abundant and showed increased production of interferon-gamma and granulocyte macrophage colony-stimulating factor compared to paired CCR6+ and CCR6-CD8+ T cell populations and their blood equivalents after short-term culturing. Their local enrichment was confirmed ex vivo using cerebrospinal fluid and brain single-cell suspensions. Across all pro-inflammatory T helper cells analysed in relapsing-remitting multiple sclerosis blood, Th1-like Th17 subpopulation T helper 17.1 (Th17.1; CCR6+CXCR3+CCR4-) expressed the highest very late antigen-4 levels and selectively accumulated in natalizumab-treated patients who remained free of clinical relapses. This was not found in patients who experienced relapses during natalizumab treatment. The enhanced potential of Th17.1 cells to infiltrate the central nervous system was supported by their predominance in cerebrospinal fluid of early multiple sclerosis patients and their preferential transmigration across human brain endothelial layers. These findings reveal a dominant contribution of Th1-like Th17 subpopulations, in particular Th17.1 cells, to clinical disease activity and provide a strong rationale for more specific and earlier use of T cell-targeted therapy in multiple sclerosis.

Clinical characteristics of patients with central nervous system relapse in BCR-ABL1-positive acute lymphoblastic leukemia: the importance of characterizing ABL1 mutations in cerebrospinal fluid.

PubMed

Sanchez, Ricardo; Ayala, Rosa; Alonso, Rafael Alberto; Martínez, María Pilar; Ribera, Jordi; García, Olga; Sanchez-Pina, José; Mercadal, Santiago; Montesinos, Pau; Martino, Rodrigo; Barba, Pere; González-Campos, José; Barrios, Manuel; Lavilla, Esperanza; Gil, Cristina; Bernal, Teresa; Escoda, Lourdes; Abella, Eugenia; Amigo, Ma Luz; Moreno, Ma José; Bravo, Pilar; Guàrdia, Ramón; Hernández-Rivas, Jesús-María; García-Guiñón, Antoni; Piernas, Sonia; Ribera, José-María; Martínez-López, Joaquín

2017-07-01

We investigated the frequency, predictors, and evolution of acute lymphoblastic leukemia (ALL) in patients with CNS relapse and introduced a novel method for studying BCR-ABL1 protein variants in cDNA from bone marrow (BM) and cerebrospinal fluid (CSF) blast cells. A total of 128 patients were analyzed in two PETHEMA clinical trials. All achieved complete remission after imatinib treatment. Of these, 30 (23%) experienced a relapse after achieving complete remission, and 13 (10%) had an isolated CNS relapse or combined CNS and BM relapses. We compared the characteristics of patients with and without CNS relapse and further analyzed CSF and BM samples from two of the 13 patients with CNS relapse. In both patients, classical sequencing analysis of the kinase domain of BCR-ABL1 from the cDNA of CSF blasts revealed the pathogenic variant p.L387M. We also performed ultra-deep next-generation sequencing (NGS) in three samples from one of the relapsed patients. We did not find the mutation in the BM sample, but we did find it in CSF blasts with 45% of reads at the time of relapse. These data demonstrate the feasibility of detecting BCR-ABL1 mutations in CSF blasts by NGS and highlight the importance of monitoring clonal evolution over time.

The significance of PIWI family expression in human lung embryogenesis and non-small cell lung cancer

PubMed Central

Navarro, Alfons; Tejero, Rut; Viñolas, Nuria; Cordeiro, Anna; Marrades, Ramon M.; Fuster, Dolors; Caritg, Oriol; Moises, Jorge; Muñoz, Carmen; Molins, Laureano; Ramirez, Josep; Monzo, Mariano

2015-01-01

The expression of Piwi-interacting RNAs, small RNAs that bind to PIWI proteins, was until recently believed to be limited to germinal stem cells. We have studied the expression of PIWI genes during human lung embryogenesis and in paired tumor and normal tissue prospectively collected from 71 resected non-small-cell lung cancer patients. The mRNA expression analysis showed that PIWIL1 was highly expressed in 7-week embryos and downregulated during the subsequent weeks of development. PIWIL1 was expressed in 11 of the tumor samples but in none of the normal tissue samples. These results were validated by immunohistochemistry, showing faint cytoplasmic reactivity in the PIWIL1-positive samples. Interestingly, the patients expressing PIWIL1 had a shorter time to relapse (TTR) (p = 0.006) and overall survival (OS) (p = 0.0076) than those without PIWIL1 expression. PIWIL2 and 4 were downregulated in tumor tissue in comparison to the normal tissue (p < 0.001) and the patients with lower levels of PIWIL4 had shorter TTR (p = 0.048) and OS (p = 0.033). In the multivariate analysis, PIWIL1 expression emerged as an independent prognostic marker. Using 5-Aza-dC treatment and bisulfite sequencing, we observed that PIWIL1 expression could be regulated in part by methylation. Finally, an in silico study identified a stem-cell expression signature associated with PIWIL1 expression. PMID:25742785

A Phase II Study of Single Agent Brentuximab Vedotin in Relapsed/Refractory CD30 Low (<10%) Mature T Cell Lymphoma (TCL)

ClinicalTrials.gov

2018-04-16

T-cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Hepato-splenic T-cell Lymphoma; Adult T-cell Leukemia/Lymphoma; Enteropathy Associated T-cell Lymphoma; NK T-cell Lymphoma; Transformed Mycosis Fungoides

Three-year follow-up of treatment-naïve and previously treated patients with CLL and SLL receiving single-agent ibrutinib.

PubMed

Byrd, John C; Furman, Richard R; Coutre, Steven E; Burger, Jan A; Blum, Kristie A; Coleman, Morton; Wierda, William G; Jones, Jeffrey A; Zhao, Weiqiang; Heerema, Nyla A; Johnson, Amy J; Shaw, Yun; Bilotti, Elizabeth; Zhou, Cathy; James, Danelle F; O'Brien, Susan

2015-04-16

Ibrutinib is an orally administered inhibitor of Bruton tyrosine kinase that antagonizes B-cell receptor, chemokine, and integrin-mediated signaling. In early-phase studies, ibrutinib demonstrated high response rates and prolonged progression-free survival (PFS) in chronic lymphocytic leukemia (CLL). The durable responses observed with ibrutinib relate in part to a modest toxicity profile that allows the majority of patients to receive continuous therapy for an extended period. We report on median 3-year follow-up of 132 patients with symptomatic treatment-naïve and relapsed/refractory CLL or small lymphocytic lymphoma. Longer treatment with ibrutinib was associated with improvement in response quality over time and durable remissions. Toxicity with longer follow-up diminished with respect to occurrence of grade 3 or greater cytopenias, fatigue, and infections. Progression remains uncommon, occurring primarily in some patients with relapsed del(17)(p13.1) and/or del(11)(q22.3) disease. Treatment-related lymphocytosis remains largely asymptomatic even when persisting >1 year and does not appear to alter longer-term PFS and overall survival compared with patients with partial response or better. Collectively, these data provide evidence that ibrutinib controls CLL disease manifestations and is well tolerated for an extended period; this information can help direct potential treatment options for different subgroups to diminish the long-term risk of relapse. © 2015 by The American Society of Hematology.

Complete molecular remission in relapsed and refractory acute myeloid leukaemia with MLL-AF9 treated with chidamide-based chemotherapy.

PubMed

Lun, Y; Yang, J-J; Wu, Y

2017-12-01

The mixed lineage leukaemia (MLL) gene translocations are found in approximately 10% of adults with acute myeloid leukaemia (AML) and are markers of poor prognosis. As the best reported response in relapsed and refractory MLL-rearranged AML is around 40%, reinduction treatment is very challenging for those patients. We report a case of relapsed and refractory AML with MLL-AF9, who did not respond to FLAG (fludarabine, cytarabine, granulocyte colony stimulating factor) regimen reinduction treatment, but achieved complete response and molecular remission after chidamide-based chemotherapy. Chidamide (CS055/HBI-8000) is a new histone deacetylase (HDAC) inhibitor that is clinically active in relapsed and refractory peripheral T-cell lymphomas. To the best of our knowledge, successful reinduction treatment on relapsed MLL-AF9 by chidamide-based regimen has not been previously reported. © 2017 John Wiley & Sons Ltd.

Long-term survival of sorafenib-treated FLT3-ITD-positive acute myeloid leukaemia patients relapsing after allogeneic stem cell transplantation.

PubMed

Metzelder, S K; Schroeder, T; Lübbert, M; Ditschkowski, M; Götze, K; Scholl, S; Meyer, R G; Dreger, P; Basara, N; Fey, M F; Salih, H R; Finck, A; Pabst, T; Giagounidis, A; Kobbe, G; Wollmer, E; Finke, J; Neubauer, A; Burchert, A

2017-11-01

Fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD)-positive acute myeloid leukaemia (AML) relapsing after allogeneic stem cell transplantation (allo-SCT) has a dismal prognosis with limited therapeutic options. FLT3-ITD kinase inhibition is a reasonable but palliative experimental treatment alternative in this situation. Information on long-term outcome is not available. We performed a long-term follow-up analysis of a previously reported cohort of 29 FLT3-ITD-positive AML patients, which were treated in relapse after allo-SCT with sorafenib monotherapy. With a median follow-up of 7.5 years, 6 of 29 patients (21%) are still alive. Excluding one patient who received a second allo-SCT, five patients (17%) achieved sustained complete remissions with sorafenib. Four of these patients are in treatment-free remission for a median of 4.4 years. Sorafenib may enable cure of a proportion of very poor risk FLT3-ITD-positive AML relapsing after allo-SCT. Copyright © 2017 Elsevier Ltd. All rights reserved.

Performance evaluation of 4 measuring methods of ground-glass opacities for predicting the 5-year relapse-free survival of patients with peripheral nonsmall cell lung cancer: a multicenter study.

PubMed

Kakinuma, Ryutaro; Kodama, Ken; Yamada, Kouzo; Yokoyama, Akira; Adachi, Shuji; Mori, Kiyoshi; Fukuyama, Yasuro; Fukuda, Yasuro; Kuriyama, Keiko; Oda, Junichi; Oda, Junji; Noguchi, Masayuki; Matsuno, Yoshihiro; Yokose, Tomoyuki; Ohmatsu, Hironobu; Nishiwaki, Yutaka

2008-01-01

To evaluate the performance of 4 methods of measuring the extent of ground-glass opacities as a means of predicting the 5-year relapse-free survival of patients with peripheral nonsmall cell lung cancer (NSLC). Ground-glass opacities on thin-section computed tomographic images of 120 peripheral NSLCs were measured at 7 medical institutions by the length, area, modified length, and vanishing ratio (VR) methods. The performance (Az) of each method in predicting the 5-year relapse-free survival was evaluated using receiver operating characteristic analysis. The mean Az value obtained by the length, area, modified length, and VR methods in the receiver operating characteristic analyses was 0.683, 0.702, 0.728, and 0.784, respectively. The differences between the mean Az value obtained by the VR method and by the other 3 methods were significant. Vanishing ratio method was the most accurate predictor of the 5-year relapse-free survival of patients with peripheral NSLC.

Lorenz system in the thermodynamic modelling of leukaemia malignancy.

PubMed

Alexeev, Igor

2017-05-01

The core idea of the proposed thermodynamic modelling of malignancy in leukaemia is entropy arising within normal haematopoiesis. Mathematically its description is supposed to be similar to the Lorenz system of ordinary differential equations for simplified processes of heat flow in fluids. The hypothetical model provides a description of remission and relapse in leukaemia as two hierarchical and qualitatively different states of normal haematopoiesis with their own phase spaces. Phase space transition is possible through pitchfork bifurcation, which is considered the common symmetrical scenario for relapse, induced remission and the spontaneous remission of leukaemia. Cytopenia is regarded as an adaptive reaction of haematopoiesis to an increase in entropy caused by leukaemia clones. The following predictions are formulated: a) the percentage of leukaemia cells in marrow as a criterion of remission or relapse is not necessarily constant but is a variable value; b) the probability of remission depends upon normal haematopoiesis reaching bifurcation; c) the duration of remission depends upon the eradication of leukaemia cells through induction or consolidation therapies; d) excessively high doses of chemotherapy in consolidation may induce relapse. Copyright © 2017 Elsevier Ltd. All rights reserved.

High non-relapse mortality and low relapse incidence in gender-mismatched allogeneic hematopoietic stem cell transplantation from a parous female donor with a male child.

PubMed

Shinohara, Akihito; Inamoto, Yoshihiro; Kurosawa, Saiko; Hiramoto, Nobuhiro; Ueda, Ryosuke; Tanaka, Takashi; Tada, Kohei; Kobayashi, Yujin; Morikawa, Noriyuki; Okinaka, Keiji; Kim, Sung-Won; Tajima, Kinuko; Fukuda, Takahiro

2017-03-01

To clarify the influence of exposure to a male fetus during a female donor's (FD) pregnancy in allogeneic hematopoietic stem cell transplantation (HSCT), we retrospectively examined 292 HSCT patients. The 5-year non-relapse mortality (NRM) was 33.5% among 31 male recipients who had HSCT from FD with a male child (MC), 23.0% among 40 male recipients who had HSCT from FD without MC and 19.6% among 221 other recipients. The 5-year relapse incidence (RI) was 22.6%, 42.0%, and 43.1% for the respective group. In multivariate analysis, male recipients who had HSCT from FD with MC had an increased risk of NRM (hazard ratio [HR] 1.92, 95% CI 1.08-3.42, p = .03), a reduced risk of RI (HR 0.42, 95% CI 0.18-0.96, p = .04), resulting in no significant difference regarding overall survival. Male child of FD is suggested to influence NRM and RI in gender-mismatched HSCT.

Failure Rates and Patterns of Recurrence in Patients With Resected N1 Non-Small-Cell Lung Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Varlotto, John M., E-mail: jvarlotto@hmc.psu.edu; Medford-Davis, Laura Nyshel; Recht, Abram

2011-10-01

Purpose: To examine the local and distant recurrence rates and patterns of failure in patients undergoing potentially curative resection of N1 non-small-cell lung cancer. Methods and Materials: The study included 60 consecutive unirradiated patients treated from 2000 to 2006. Median follow-up was 30 months. Failure rates were calculated by the Kaplan-Meier method. A univariate Cox proportional hazard model was used to assess factors associated with recurrence. Results: Local and distant failure rates (as the first site of failure) at 2, 3, and 5 years were 33%, 33%, and 46%; and 26%, 26%, and 32%, respectively. The most common site ofmore » local failure was in the mediastinum; 12 of 18 local recurrences would have been included within proposed postoperative radiotherapy fields. Patients who received chemotherapy were found to be at increased risk of local failure, whereas those who underwent pneumonectomy or who had more positive nodes had significantly increased risks of distant failure. Conclusions: Patients with resected non-small-cell lung cancer who have N1 disease are at substantial risk of local recurrence as the first site of relapse, which is greater than the risk of distant failure. The role of postoperative radiotherapy in such patients should be revisited in the era of adjuvant chemotherapy.« less

Alisertib added to rituximab and vincristine is synthetic lethal and potentially curative in mice with aggressive DLBCL co-overexpressing MYC and BCL2.

PubMed

Mahadevan, Daruka; Morales, Carla; Cooke, Laurence S; Manziello, Ann; Mount, David W; Persky, Daniel O; Fisher, Richard I; Miller, Thomas P; Qi, Wenqing

2014-01-01

Pearson correlation coefficient for expression analysis of the Lymphoma/Leukemia Molecular Profiling Project (LLMPP) demonstrated Aurora A and B are highly correlated with MYC in DLBCL and mantle cell lymphoma (MCL), while both Auroras correlate with BCL2 only in DLBCL. Auroras are up-regulated by MYC dysregulation with associated aneuploidy and resistance to microtubule targeted agents such as vincristine. Myc and Bcl2 are differentially expressed in U-2932, TMD-8, OCI-Ly10 and Granta-519, but only U-2932 cells over-express mutated p53. Alisertib [MLN8237 or M], a highly selective small molecule inhibitor of Aurora A kinase, was synergistic with vincristine [VCR] and rituximab [R] for inhibition of cell proliferation, abrogation of cell cycle checkpoints and enhanced apoptosis versus single agent or doublet therapy. A DLBCL (U-2932) mouse model showed tumor growth inhibition (TGI) of ∼ 10-20% (p = 0.001) for M, VCR and M-VCR respectively, while R alone showed ∼ 50% TGI (p = 0.001). M-R and VCR-R led to tumor regression [TR], but relapsed 10 days after discontinuing therapy. In contrast, M-VCR-R demonstrated TR with no relapse >40 days after stopping therapy with a Kaplan-Meier survival of 100%. Genes that are modulated by M-VCR-R (CENP-C, Auroras) play a role in centromere-kinetochore function in an attempt to maintain mitosis in the presence of synthetic lethality. Together, our data suggest that the interaction between alisertib plus VCR plus rituximab is synergistic and synthetic lethal in Myc and Bcl-2 co-expressing DLBCL. Alisertib plus vincristine plus rituximab [M-VCR-R] may represent a new strategy for DLBCL therapy.

The regulatory BCL2 promoter polymorphism (-938C>A) is associated with relapse and survival of patients with oropharyngeal squamous cell carcinoma.

PubMed

Lehnerdt, G F; Franz, P; Bankfalvi, A; Grehl, S; Kelava, A; Nückel, H; Lang, S; Schmid, K W; Siffert, W; Bachmann, H S

2009-06-01

Expression of the antiapoptotic and antiproliferative protein B-cell lymphoma 2 (Bcl-2) has been repeatedly shown to be associated with better locoregional control and patients' survival in oropharyngeal squamous cell carcinoma (OSCC). A regulatory (-938C>A) single-nucleotide polymorphism (SNP) in the inhibitory P2 BCL2 gene promoter generates significantly different BCL2 promoter activities and has been associated with outcome in different malignancies. The aim of the present study was to analyze the possible influence of the (-938C>A) SNP on survival of patients suffering from OSCC. One hundred and thirty-three patients with primary OSCC were retrospectively investigated. Bcl-2 expression of tumor cells was demonstrated by means of immunohistochemistry. Both the Bcl-2 expression and the (-938C>A) genotypes were correlated with the patients' survival. The (-938C>A) SNP was significantly related to Bcl-2 expression (P = 0.008). Kaplan-Meier curves revealed a significant association of the -938 SNP with relapse-free (P = 0.0283) and overall survival (P = 0.0247). Multiple Cox regression identified the BCL2 (-938CC) genotype as an independent prognostic factor for relapse [hazard ratio (HR) 1.898, P = 0.021] as well as for death in OSCC patients (HR 1.897, P = 0.013). The (-938C>A) SNP represents a potential novel prognostic marker in patients with OSCC that could help to identify a group of patients at high risk for relapse and death.

Higher Donor Apheresis Blood Volumes Are Associated with Reduced Relapse Risk and Improved Survival in Reduced-Intensity Allogeneic Transplantations with Unrelated Donors.

PubMed

Crisalli, Lisa M; Hinkle, Joanne T; Walling, Christopher C; Sell, Mary; Frey, Noelle V; Hexner, Elizabeth O; Loren, Alison W; Luger, Selina M; Stadtmauer, Edward A; Porter, David L; Reshef, Ran

2018-06-01

Allogeneic hematopoietic stem cell transplantation (HSCT) with reduced-intensity conditioning (RIC) offers a curative option for patients with hematologic malignancies who are unable to undergo myeloablative conditioning, but its success is limited by high rates of relapse. Several studies have suggested a role for T cell doses in peripheral blood stem cell grafts in RIC HSCT. Because T cell dose is typically not known until after the collection, and apheresis blood volume is easily modifiable, we hypothesized that higher donor apheresis blood volumes would improve transplantation outcomes through an effect on graft composition. Thus, we analyzed the relationships between apheresis volume, graft composition, and transplantation outcomes in 142 consecutive patients undergoing unrelated donor allogeneic RIC HSCT. We found that apheresis volume ≥15 L was associated with a significantly decreased risk of relapse (adjusted hazard ratio [aHR], .48; 95% confidence interval [CI], .28 to .84]; P = .01) and improved relapse-free survival (aHR, .56; 95% CI, .35 to .89; P = .02) and overall survival (aHR, .55; 95% CI, .34 to .91; P = .02). A high apheresis volume was not associated with increased rates of acute or chronic graft-versus-host disease. These results demonstrate that an apheresis volume of at least 15 L is independently predictive of improved transplantation outcomes after RIC allogeneic HSCT. Copyright © 2018 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Management of relapsed multiple myeloma: recommendations of the International Myeloma Working Group.

PubMed

Laubach, J; Garderet, L; Mahindra, A; Gahrton, G; Caers, J; Sezer, O; Voorhees, P; Leleu, X; Johnsen, H E; Streetly, M; Jurczyszyn, A; Ludwig, H; Mellqvist, U-H; Chng, W-J; Pilarski, L; Einsele, H; Hou, J; Turesson, I; Zamagni, E; Chim, C S; Mazumder, A; Westin, J; Lu, J; Reiman, T; Kristinsson, S; Joshua, D; Roussel, M; O'Gorman, P; Terpos, E; McCarthy, P; Dimopoulos, M; Moreau, P; Orlowski, R Z; Miguel, J S; Anderson, K C; Palumbo, A; Kumar, S; Rajkumar, V; Durie, B; Richardson, P G

2016-05-01

The prognosis for patients multiple myeloma (MM) has improved substantially over the past decade with the development of new, more effective chemotherapeutic agents and regimens that possess a high level of anti-tumor activity. In spite of this important progress, however, nearly all MM patients ultimately relapse, even those who experience a complete response to initial therapy. Management of relapsed MM thus represents a vital aspect of the overall care for patients with MM and a critical area of ongoing scientific and clinical research. This comprehensive manuscript from the International Myeloma Working Group provides detailed recommendations on management of relapsed disease, with sections dedicated to diagnostic evaluation, determinants of therapy, and general approach to patients with specific disease characteristics. In addition, the manuscript provides a summary of evidence from clinical trials that have significantly impacted the field, including those evaluating conventional dose therapies, as well as both autologous and allogeneic stem cell transplantation. Specific recommendations are offered for management of first and second relapse, relapsed and refractory disease, and both autologous and allogeneic transplant. Finally, perspective is provided regarding new agents and promising directions in management of relapsed MM.

Activated mesenchymal stem cell administration inhibits chronic alcohol drinking and suppresses relapse-like drinking in high-alcohol drinker rats.

PubMed

Ezquer, Fernando; Quintanilla, María Elena; Morales, Paola; Ezquer, Marcelo; Lespay-Rebolledo, Carolyne; Herrera-Marschitz, Mario; Israel, Yedy

2017-10-18

Neuroinflammation has been reported to follow chronic ethanol intake and may perpetuate alcohol consumption. Present studies determined the effect of human mesenchymal stem cells (hMSCs), known for their anti-inflammatory action, on chronic ethanol intake and relapse-like ethanol intake in a post-deprivation condition. Rats were allowed 12-17 weeks of chronic voluntary ethanol (10% and 20% v/v) intake, after which a single dose of activated hMSCs (5 × 10 5 ) was injected into a brain lateral ventricle. Control animals were administered vehicle. After assessing the effect of hMSCs on chronic ethanol intake for 1 week, animals were deprived of ethanol for 2 weeks and thereafter an ethanol re-access of 60 min was allowed to determine relapse-like intake. A single administration of activated hMSCs inhibited chronic alcohol consumption by 70% (P < 0.001), an effect seen within the first 24 hours of hMSCs administration, and reduced relapse-like drinking by 80% (P < 0.001). In the relapse-like condition, control animals attain blood ethanol ('binge-like') levels >80 mg/dl. The single hMSC administration reduced relapse-like blood ethanol levels to 20 mg/dl. Chronic ethanol intake increased by 250% (P < 0.001) the levels of reactive oxygen species in hippocampus, which were markedly reduced by hMSC administration. Astrocyte glial acidic fibrillary protein immunoreactivity, a hallmark of neuroinflammation, was increased by 60-80% (P < 0.001) by chronic ethanol intake, an effect that was fully abolished by the administration of hMSCs. This study supports the neuroinflammation-chronic ethanol intake hypothesis and suggest that mesenchymal stem cell administration may be considered in the treatment of alcohol use disorders. © 2017 Society for the Study of Addiction.

Standard-Dose Combination Chemotherapy or High-Dose Combination Chemotherapy and Stem Cell Transplant in Treating Patients With Relapsed or Refractory Germ Cell Tumors

ClinicalTrials.gov

2018-06-08

Germ Cell Tumor; Teratoma; Choriocarcinoma; Germinoma; Mixed Germ Cell Tumor; Yolk Sac Tumor; Childhood Teratoma; Malignant Germ Cell Neoplasm; Extragonadal Seminoma; Non-seminomatous Germ Cell Tumor; Seminoma

Anaplastic lymphoma kinase inhibition in metastatic non-small cell lung cancer: clinical impact of alectinib

PubMed Central

Muller, Ittai B; de Langen, Adrianus J; Giovannetti, Elisa; Peters, Godefridus J

2017-01-01

A subset of non-small cell lung cancer (NSCLC) tumors (5%) harbors an anaplastic lymphoma kinase (ALK) translocation that drives tumorigenesis. The clinically approved first-line treatment crizotinib specifically inhibits ALK and improves progression-free survival (PFS) in treated and untreated patients by 4 months compared to standard chemotherapy. While some patients relapse after crizotinib treatment due to resistance mutations in ALK, second-generation ALK inhibitors effectively induce tumor response and prolong PFS. Alectinib, a second-generation ALK inhibitor, has recently been approved for ALK-rearranged NSCLC after patients progressed on crizotinib. Alectinib is able to inhibit several crizotinib- and ceritinib-resistant ALK mutations in vitro. Furthermore, alectinib is a more potent tyrosine kinase inhibitor (TKI), with favorable safety profile, and has increased penetration into the central nervous system, inhibiting crizotinib-resistant brain metastases. The discovery of effective personalized therapies to combat ALK-rearranged NSCLC such as alectinib is an example of the importance of genomic profiling of NSCLC and provides an excellent template for future discoveries in managing these tumors. PMID:28979145

Anaplastic lymphoma kinase inhibition in metastatic non-small cell lung cancer: clinical impact of alectinib.

PubMed

Muller, Ittai B; de Langen, Adrianus J; Giovannetti, Elisa; Peters, Godefridus J

2017-01-01

A subset of non-small cell lung cancer (NSCLC) tumors (5%) harbors an anaplastic lymphoma kinase (ALK) translocation that drives tumorigenesis. The clinically approved first-line treatment crizotinib specifically inhibits ALK and improves progression-free survival (PFS) in treated and untreated patients by 4 months compared to standard chemotherapy. While some patients relapse after crizotinib treatment due to resistance mutations in ALK, second-generation ALK inhibitors effectively induce tumor response and prolong PFS. Alectinib, a second-generation ALK inhibitor, has recently been approved for ALK-rearranged NSCLC after patients progressed on crizotinib. Alectinib is able to inhibit several crizotinib- and ceritinib-resistant ALK mutations in vitro. Furthermore, alectinib is a more potent tyrosine kinase inhibitor (TKI), with favorable safety profile, and has increased penetration into the central nervous system, inhibiting crizotinib-resistant brain metastases. The discovery of effective personalized therapies to combat ALK-rearranged NSCLC such as alectinib is an example of the importance of genomic profiling of NSCLC and provides an excellent template for future discoveries in managing these tumors.

Atezolizumab, Gemcitabine, Oxaliplatin, and Rituximab in Treating Patients With Relapsed or Refractory Transformed Diffuse Large B-Cell Lymphoma

ClinicalTrials.gov

2018-06-06

Recurrent Diffuse Large B-Cell Lymphoma; Refractory Diffuse Large B-Cell Lymphoma; Refractory Transformed Indolent Non-Hodgkin Lymphoma; Transformed Follicular Lymphoma to Diffuse Large B-Cell Lymphoma

Alisertib in Treating Patients With Relapsed or Refractory Peripheral T-Cell Non-Hodgkin Lymphoma

ClinicalTrials.gov

2016-02-09

Adult Nasal Type Extranodal NK/T-Cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-Cell Lymphoma; Hepatosplenic T-Cell Lymphoma; Mature T-Cell and NK-Cell Non-Hodgkin Lymphoma; Recurrent Adult Non-Hodgkin Lymphoma; Recurrent Adult T-Cell Leukemia/Lymphoma

Long-term outcome of antineutrophil cytoplasmic antibody-associated small vessel vasculitis after renal transplantation.

PubMed

Marco, Helena; Mirapeix, Eduard; Arcos, Emma; Comas, Jordi; Ara, Jordi; Gil-Vernet, Salvador; Puig, Josep; Vinyas, Odette; Perello, Manel; Oppenheimer, Federico; Poveda, Rafael; Ibernón, Meritxell; Díaz, Montserrat; Ballarin, Jose

2013-01-01

The survival after renal transplantation of patients with antineutrophil cytoplasmic antibody (ANCA)-associated to systemic vasculitis is as good as in other diseases, although most of the reports are based on small numbers of patients. Furthermore, it is not known whether comorbidities (cardiovascular [CV] disease and cancer) are more frequent than in general population. We report our experience and the analysis of the published data on this topic. The outcome after transplantation in 49 patients with ANCA-associated small vessel vasculitis was compared with a control group. The relapse rate of vasculitis was 0.01 per patient per year. Comparison with the control patients revealed no difference in long-term outcome, CV mortality or incidence of malignancies. In the published literature, patients with ANCA at transplantation and with Wegener's granulomatosis are at greater risk of relapse. Taking our own results together with the review of the literature, we conclude that patient and graft survival rates compare favorably with those in control group that the recurrence rate is very low and that there is no increase in the incidence of cancer or in CV mortality. Patients with ANCA at transplantation and with Wegener's granulomatosis have a higher relapse rate. © 2013 John Wiley & Sons A/S.

Value of Surveillance Studies for Patients With Stage I to II Diffuse Large B-Cell Lymphoma in the Rituximab Era

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hiniker, Susan M.; Pollom, Erqi L.; Khodadoust, Michael S.

2015-05-01

Background: The role of surveillance studies in limited-stage diffuse large B-cell lymphoma (DLBCL) in the rituximab era has not been well defined. We sought to evaluate the use of imaging (computed tomography [CT] and positron emission tomography [PET]-CT) scans and lactate dehydrogenase (LDH) in surveillance of patients with stage I to II DLBCL. Methods: A retrospective analysis was performed of patients who received definitive treatment between 2000 and 2013. Results: One hundred sixty-two consecutive patients with stage I to II DLBCL were treated with chemotherapy +/− rituximab, radiation, or combined modality therapy. The 5-year rates of overall survival (OS) and freedommore » from progression (FFP) were 81.2% and 80.8%, respectively. Of the 162 patients, 124 (77%) were followed up with at least 1 surveillance PET scan beyond end-of-treatment scans; of those, 94 of 124 (76%) achieved a complete metabolic response on PET scan after completion of chemotherapy, and this was associated with superior FFP (P=.01, HR=0.3) and OS (P=.01, HR 0.3). Eighteen patients experienced relapse after initial response to therapy. Nine relapses were initially suspected by surveillance imaging studies (8 PET, 1 CT), and 9 were suspected clinically (5 by patient-reported symptoms and 4 by symptoms and physical examination). No relapses were detected by surveillance LDH. The median duration from initiation of treatment to relapse was 14.3 months among patients with relapses suspected by imaging, and 59.8 months among patients with relapses suspected clinically (P=.077). There was no significant difference in OS from date of first therapy or OS after relapse between patients whose relapse was suspected by imaging versus clinically. Thirteen of 18 patients underwent successful salvage therapy after relapse. Conclusions: A complete response on PET scan immediately after initial chemotherapy is associated with superior FFP and OS in stage I to II DLBCL. The use of PET scans as posttreatment surveillance is not associated with a survival advantage. LDH is not a sensitive marker for relapse. Our results argue for limiting the use of posttreatment surveillance in patients with limited-stage DLBCL.« less

Onalespib in Treating Patients With Relapsed or Refractory Anaplastic Large Cell Lymphoma, Mantle Cell Lymphoma, or Diffuse Large B-Cell Lymphoma

ClinicalTrials.gov

2018-05-23

ALK Positive; BCL6 Positive; Recurrent Anaplastic Large Cell Lymphoma; Recurrent Diffuse Large B-Cell Lymphoma; Recurrent Mantle Cell Lymphoma; Refractory Anaplastic Large Cell Lymphoma; Refractory Diffuse Large B-Cell Lymphoma; Refractory Mantle Cell Lymphoma

Intracellular Survival of Staphylococcus aureus in Endothelial Cells: A Matter of Growth or Persistence

PubMed Central

Rollin, Guillaume; Tan, Xin; Tros, Fabiola; Dupuis, Marion; Nassif, Xavier; Charbit, Alain; Coureuil, Mathieu

2017-01-01

The Gram-positive human pathogen Staphylococcus aureus is a leading cause of severe bacterial infections. Recent studies have shown that various cell types could readily internalize S. aureus and infected cells have been proposed to serve as vehicle for the systemic dissemination of the pathogen. Here we focused on the intracellular behavior of the Community-Associated Methicillin-Resistant S. aureus strain USA300. Supporting earlier observations, we found that wild-type S. aureus strain USA300 persisted for longer period within endothelial cells than within macrophages and that a mutant displaying the small colony variant phenotype (ΔhemDBL) had increased intracellular persistence. Time-lapse microscopy revealed that initial persistence of wild-type bacteria in endothelial cells corresponded to distinct single cell events, ranging from active intracellular bacterial proliferation, leading to cell lysis, to non-replicating bacterial persistence even 1 week after infection. In sharp contrast, ΔhemDBL mutant bacteria were essentially non-replicating up to 10 days after infection. These findings suggest that internalization of S. aureus in endothelial cells triggers its persistence and support the notion that endothelial cells might constitute an intracellular persistence niche responsible for reported relapse of infection after antibiotic therapy. PMID:28769913

Simvastatin With Topotecan and Cyclophosphamide in Relapsed and/or Refractory Pediatric Solid and CNS Tumors

ClinicalTrials.gov

2018-05-29

Retinoblastoma; Clear Cell Sarcoma; Renal Cell Carcinoma; Rhabdoid Tumor; Wilms Tumor; Hepatoblastoma; Neuroblastoma; Germ Cell Tumors; Ewings Sarcoma; Non-rhabdomyosarcoma Soft Tissue Sarcoma; Osteosarcoma; Rhabdomyosarcoma

Predictive significance of the European LeukemiaNet classification of genetic aberrations in patients with acute myeloid leukaemia undergoing allogeneic stem cell transplantation.

PubMed

Hemmati, Philipp G; Vuong, Lam G; Terwey, Theis H; Jehn, Christian F; le Coutre, Philipp; Penack, Olaf; Na, Il-Kang; Dörken, Bernd; Arnold, Renate

2017-02-01

The purpose of this study was to evaluate the predictive capacity of the European LeukemiaNet (ELN) classification of genetic risk in patients with acute myeloid leukaemia (AML) undergoing allogeneic stem cell transplantation (alloSCT). We retrospectively analysed 274 patients transplanted at our centre between 2004 and 2014. The ELN grouping is comparable to the Southwest Oncology Group/Eastern Cooperative Oncology Group (SWOG/ECOG) stratification in predicting the outcome after alloSCT [overall P = 0.0064 for disease-free survival (DFS), overall P = 0.003 for relapse]. Patients with an intermediate-1 profile have a significantly elevated 5-yr relapse incidence as compared to favourable risk patients, that is 40% vs. 15%, [hazard ratio (HR) 2.58, P = 0.048]. An intermediate-1 risk profile is an independent predictor for relapse as determined by multivariate Cox regression analysis (HR 3.05, P = 0.023). In intermediate-1 patients, the presence of an FLT3 internal tandem duplication (FLT3-ITD) is associated with a significantly increased relapse incidence (P = 0.0323), and a lower DFS (P = 0.0465). FLT3-ITD is an independent predictor for overall survival, DFS and relapse incidence in the intermediate-1 subgroup. The ELN stratification of genetic risk predicts the outcome of patients with AML undergoing alloSCT. Patients with an intermediate-1 profile have a high risk for treatment failure due to relapse, which prompts the development of alternative treatment strategies. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

The what, when and how of CAR T cell therapy for ALL.

PubMed

Frey, Noelle

2017-09-01

Chimeric Antigen Receptor (CAR) T cells that have been engineered to target CD19 have shown great promise in patients with relapsed and refractory B cell acute lymphocytic leukemia with remission rates of 70-90%. Some remissions have successfully bridged patients to a curable allogeneic stem cell transplant, some responses have been durable without further treatment, and some patients have achieved durable remissions for relapsed ALL after allogeneic stem cell transplant. Cytokine release syndrome, correlating with the in vivo activation and expansion of T cells, and neurologic toxicity are the most significant side effects and approaches to better understand and manage these events are the subject of ongoing clinical trials. The decision to intervene with CARTs requires an individualized approach taking into consideration patient, disease and therapy related factors. Copyright © 2017 Elsevier Ltd. All rights reserved.

Early indicators of relapses vs pseudorelapses in neuromyelitis optica spectrum disorder

PubMed Central

Kessler, Remi A.; Mealy, Maureen A.

2016-01-01

Objective: The purpose of this study was to review cases of neuromyelitis optica spectrum disorder (NMOSD) relapses and pseudorelapses to identify early features that differentiate between them at onset of symptoms. Methods: This was a retrospective analysis of 74 hospitalizations of patients with NMOSD who were admitted to the Johns Hopkins Hospital for workup and treatment of a presumed relapse. Standard workup included MRI and blood and urine testing for metabolic and infectious etiologies. The gold standard for a relapse was defined as new or worsening symptoms and a change in neurologic examination correlating with a new or enhancing MRI lesion. A pseudorelapse was a clinical exacerbation with similar symptoms and signs but the MRI was negative, and workup identified an alternative cause for the symptoms that, when treated, resulted in the improvement of neurologic symptoms. Factors considered to be early predictors of relapses vs pseudorelapses were analyzed using the Fisher test. Results: Among 74 NMOSD hospitalizations for presumed relapse, 57 were confirmed relapses while 17 had a negative MRI and an identifiable cause of pseudorelapse. The most common causes of pseudorelapse were infection, pain, and dysautonomia. The only early predictor that reliably differentiated relapse from pseudorelapse among this NMOSD patient population was vision loss (p = 0.039). Race, sex, presentations of weakness, numbness, and bowel/bladder dysfunction, white blood cell count, and urinary tract infection were not different among patients with relapses vs pseudorelapses. Conclusions: Vision loss in NMOSD is strongly suggestive of a true relapse vs a pseudorelapse. Pseudorelapses localized to the spinal cord in patients with previous myelitis presented similarly to true relapses and could only be ruled out by a negative MRI. PMID:27508210

Osteoclasts control reactivation of dormant myeloma cells by remodelling the endosteal niche

PubMed Central

Lawson, Michelle A.; McDonald, Michelle M.; Kovacic, Natasa; Hua Khoo, Weng; Terry, Rachael L.; Down, Jenny; Kaplan, Warren; Paton-Hough, Julia; Fellows, Clair; Pettitt, Jessica A.; Neil Dear, T.; Van Valckenborgh, Els; Baldock, Paul A.; Rogers, Michael J.; Eaton, Colby L.; Vanderkerken, Karin; Pettit, Allison R.; Quinn, Julian M. W.; Zannettino, Andrew C. W.; Phan, Tri Giang; Croucher, Peter I.

2015-01-01

Multiple myeloma is largely incurable, despite development of therapies that target myeloma cell-intrinsic pathways. Disease relapse is thought to originate from dormant myeloma cells, localized in specialized niches, which resist therapy and repopulate the tumour. However, little is known about the niche, and how it exerts cell-extrinsic control over myeloma cell dormancy and reactivation. In this study, we track individual myeloma cells by intravital imaging as they colonize the endosteal niche, enter a dormant state and subsequently become activated to form colonies. We demonstrate that dormancy is a reversible state that is switched ‘on' by engagement with bone-lining cells or osteoblasts, and switched ‘off' by osteoclasts remodelling the endosteal niche. Dormant myeloma cells are resistant to chemotherapy that targets dividing cells. The demonstration that the endosteal niche is pivotal in controlling myeloma cell dormancy highlights the potential for targeting cell-extrinsic mechanisms to overcome cell-intrinsic drug resistance and prevent disease relapse. PMID:26632274

Fludarabine Phosphate, Low-Dose Total Body Irradiation, and Donor Stem Cell Transplant in Treating Patients With Hematologic Malignancies or Kidney Cancer

ClinicalTrials.gov

2017-10-09

Accelerated Phase Chronic Myelogenous Leukemia; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); B-cell Chronic Lymphocytic Leukemia; Childhood Acute Lymphoblastic Leukemia in Remission; Childhood Acute Myeloid Leukemia in Remission; Childhood Chronic Myelogenous Leukemia; Childhood Myelodysplastic Syndromes; Childhood Renal Cell Carcinoma; Chronic Phase Chronic Myelogenous Leukemia; Clear Cell Renal Cell Carcinoma; de Novo Myelodysplastic Syndromes; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Nodal Marginal Zone B-cell Lymphoma; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Hodgkin Lymphoma; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Recurrent/Refractory Childhood Hodgkin Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Refractory Multiple Myeloma; Relapsing Chronic Myelogenous Leukemia; Splenic Marginal Zone Lymphoma; Stage III Renal Cell Cancer; Stage IV Renal Cell Cancer; T-cell Large Granular Lymphocyte Leukemia; Type 1 Papillary Renal Cell Carcinoma; Type 2 Papillary Renal Cell Carcinoma; Waldenström Macroglobulinemia

Outcome of treatment after first relapse in younger adults with acute myeloid leukemia initially treated by the ALFA-9802 trial.

PubMed

Thomas, Xavier; Raffoux, Emmanuel; Renneville, Aline; Pautas, Cécile; de Botton, Stéphane; de Revel, Thierry; Reman, Oumedaly; Terré, Christine; Gardin, Claude; Chelghoum, Youcef; Boissel, Nicolas; Quesnel, Bruno; Cordonnier, Catherine; Bourhis, Jean-Henri; Elhamri, Mohamed; Fenaux, Pierre; Preudhomme, Claude; Socié, Gérard; Michallet, Mauricette; Castaigne, Sylvie; Dombret, Hervé

2012-09-01

Forty-seven percent of adults with acute myeloid leukemia (AML) who entered the ALFA-9802 trial and achieved a first complete remission (CR) experienced a first relapse. We examined the outcome of these 190 adult patients. Eighty-four patients (44%) achieved a second CR. The median overall survival (OS) after relapse was 8.9 months with a 2-year OS at 25%. Factors predicting a better outcome after relapse were stem cell transplant (SCT) performed in second CR and a first CR duration >1 year. Risk groups defined at the time of diagnosis and treatment received in first CR also influenced the outcome after relapse. The best results were obtained in patients with core binding factor (CBF)-AML, while patients initially defined as favorable intermediate risk showed a similar outcome after relapse than those initially entering the poor risk group. We conclude that most adult patients with recurring AML could not be rescued using current available therapies, although allogeneic SCT remains the best therapeutic option at this stage of the disease. Copyright © 2012 Elsevier Ltd. All rights reserved.

Brentuximab Vedotin and Lenalidomide in Treating Patients With Relapsed or Refractory T-Cell Lymphomas

ClinicalTrials.gov

2018-06-15

CD30-Positive Neoplastic Cells Present; Folliculotropic Mycosis Fungoides; Recurrent Mycosis Fungoides; Recurrent Primary Cutaneous T-Cell Non-Hodgkin Lymphoma; Refractory Mycosis Fungoides; Refractory Primary Cutaneous T-Cell Non-Hodgkin Lymphoma; Sezary Syndrome

A Study of CD45RA+ Depleted Haploidentical Stem Cell Transplantation in Children With Relapsed or Refractory Solid Tumors and Lymphomas

ClinicalTrials.gov

2017-08-17

Ewing Sarcoma; Gastrointestinal Tumor; Germ Cell Tumor; Hepatic Tumor; Lymphoma; Wilms Tumor; Rhabdoid Tumor; Clear Cell Carcinoma; Renal Cell Carcinoma; Melanoma; Neuroblastoma; Rhabdomyosarcoma; Non-rhabdomyosarcoma

Ibrutinib in Treating Patients With Refractory or Relapsed Lymphoma After Donor Stem Cell Transplant

ClinicalTrials.gov

2017-10-03

Blastoid Variant Mantle Cell Lymphoma; Recurrent Chronic Lymphocytic Leukemia; Recurrent Follicular Lymphoma; Recurrent Hodgkin Lymphoma; Recurrent Mantle Cell Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Follicular Lymphoma; Refractory Hodgkin Lymphoma; Refractory Mantle Cell Lymphoma

Relapse prevention interventions for smoking cessation.

PubMed

Hajek, P; Stead, L F; West, R; Jarvis, M

2005-01-25

Several treatments can help smokers make a successful quit attempt, but many initially successful quitters relapse over time. There are interventions designed to help prevent relapse. To assess whether specific interventions for relapse prevention reduce the proportion of recent quitters who return to smoking. We searched the Cochrane Tobacco Addiction group trials register in September 2004 for studies mentioning relapse prevention or maintenance in title, abstracts or keywords. Randomized or quasi-randomized controlled trials of relapse prevention interventions with a minimum follow up of six months. We included smokers who quit on their own, or were undergoing enforced abstinence, or who were participating in treatment programmes. We included trials that compared relapse prevention interventions to a no intervention control, or that compared a cessation programme with additional relapse prevention components to a cessation programme alone. Studies were screened and data extracted by one author and checked by a second. Disagreements were resolved by discussion or referral to a third author. Forty studies met inclusion criteria, but were heterogeneous in terms of populations and interventions. We considered studies that randomized abstainers separately from studies that randomized participants prior to their quit date. We detected no benefit of brief and 'skills-based' relapse prevention interventions for women who had quit smoking due to pregnancy, or for smokers undergoing a period of enforced abstinence. We also failed to detect significant effects in trials in other smokers who had quit on their own or with a formal programme. Amongst trials recruiting smokers and evaluating the effect of additional relapse prevention components we also found no evidence of benefit in any subgroup. We did not find that providing training in skills thought to be needed for relapse avoidance reduced relapse, but most studies did not use experimental designs best suited to the task, and had limited power to detect expected small differences between interventions. At the moment there is insufficient evidence to support the use of any specific intervention for helping smokers who have successfully quit for a short time to avoid relapse. The verdict is strongest for interventions focusing on identifying and resolving tempting situations, as most studies were concerned with these. There is very little research available regarding other approaches. Until more evidence becomes available it may be more efficient to focus resources on supporting the initial cessation attempt rather than on additional relapse prevention efforts.

Genomic complexity and dynamics of clonal evolution in childhood acute myeloid leukemia studied with whole-exome sequencing.

PubMed

Masetti, Riccardo; Castelli, Ilaria; Astolfi, Annalisa; Bertuccio, Salvatore Nicola; Indio, Valentina; Togni, Marco; Belotti, Tamara; Serravalle, Salvatore; Tarantino, Giuseppe; Zecca, Marco; Pigazzi, Martina; Basso, Giuseppe; Pession, Andrea; Locatelli, Franco

2016-08-30

Despite significant improvement in treatment of childhood acute myeloid leukemia (AML), 30% of patients experience disease recurrence, which is still the major cause of treatment failure and death in these patients. To investigate molecular mechanisms underlying relapse, we performed whole-exome sequencing of diagnosis-relapse pairs and matched remission samples from 4 pediatric AML patients without recurrent cytogenetic alterations. Candidate driver mutations were selected for targeted deep sequencing at high coverage, suitable to detect small subclones (0.12%). BiCEBPα mutation was found to be stable and highly penetrant, representing a separate biological and clinical entity, unlike WT1 mutations, which were extremely unstable. Among the mutational patterns underlying relapse, we detected the acquisition of proliferative advantage by signaling activation (PTPN11 and FLT3-TKD mutations) and the increased resistance to apoptosis (hyperactivation of TYK2). We also found a previously undescribed feature of AML, consisting of a hypermutator phenotype caused by SETD2 inactivation. The consequent accumulation of new mutations promotes the adaptability of the leukemia, contributing to clonal selection. We report a novel ASXL3 mutation characterizing a very small subclone (<1%) present at diagnosis and undergoing expansion (60%) at relapse. Taken together, these findings provide molecular clues for designing optimal therapeutic strategies, in terms of target selection, adequate schedule design and reliable response-monitoring techniques.

Lenalidomide and Ibrutinib in Treating Patients With Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma

ClinicalTrials.gov

2018-03-02

Recurrent Diffuse Large B-Cell Lymphoma; Recurrent Follicular Lymphoma; Recurrent Lymphoplasmacytic Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Refractory Diffuse Large B-Cell Lymphoma; Refractory Follicular Lymphoma; Refractory Lymphoplasmacytic Lymphoma; Refractory Mantle Cell Lymphoma

International reference analysis of outcomes in adults with B-precursor Ph-negative relapsed/refractory acute lymphoblastic leukemia

PubMed Central

Gökbuget, Nicola; Dombret, Hervè; Ribera, Jose-Maria; Fielding, Adele K.; Advani, Anjali; Bassan, Renato; Chia, Victoria; Doubek, Michael; Giebel, Sebastian; Hoelzer, Dieter; Ifrah, Norbert; Katz, Aaron; Kelsh, Michael; Martinelli, Giovanni; Morgades, Mireia; O’Brien, Susan; Rowe, Jacob M.; Stieglmaier, Julia; Wadleigh, Martha; Kantarjian, Hagop

2016-01-01

Adults with relapsed/refractory acute lymphoblastic leukemia have an unfavourable prognosis, which is influenced by disease and patient characteristics. To further evaluate these characteristics, a retrospective analysis of 1,706 adult patients with Ph-negative relapsed/refractory B-precursor acute lymphoblastic leukemia diagnosed between 1990–2013 was conducted using data reflecting the standard of care from 11 study groups and large centers in Europe and the United States. Outcomes included complete remission, overall survival, and realization of stem cell transplantation after salvage treatment. The overall complete remission rate after first salvage was 40%, ranging from 35%–41% across disease status categories (primary refractory, relapsed with or without prior transplant), and was lower after second (21%) and third or greater (11%) salvage. The overall complete remission rate was higher for patients diagnosed from 2005 onward (45%, 95% CI: 39%–50%). One- and three-year survival rates after first, second, and third or greater salvage were 26% and 11%, 18% and 6%, and 15% and 4%, respectively, and rates were 2%–5% higher among patients diagnosed from 2005. Prognostic factors included younger age, longer duration of first remission, and lower white blood cell counts at primary diagnosis. This large dataset can provide detailed reference outcomes for patients with relapsed/refractory Ph-negative B-precursor acute lymphoblastic leukemia. clinicaltrials.gov identifier: 02003612 PMID:27587380

Alemtuzumab, Fludarabine Phosphate, and Low-Dose Total Body Irradiation Before Donor Stem Cell Transplantation in Treating Patients With Hematological Malignancies

ClinicalTrials.gov

2018-05-24

Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Nasal Type Extranodal NK/T-cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Childhood Burkitt Lymphoma; Childhood Chronic Myelogenous Leukemia; Childhood Diffuse Large Cell Lymphoma; Childhood Immunoblastic Large Cell Lymphoma; Childhood Nasal Type Extranodal NK/T-cell Lymphoma; Chronic Phase Chronic Myelogenous Leukemia; Contiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Contiguous Stage II Grade 1 Follicular Lymphoma; Contiguous Stage II Grade 2 Follicular Lymphoma; Contiguous Stage II Marginal Zone Lymphoma; Contiguous Stage II Small Lymphocytic Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Hepatosplenic T-cell Lymphoma; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Nodal Marginal Zone B-cell Lymphoma; Noncontiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Noncontiguous Stage II Grade 1 Follicular Lymphoma; Noncontiguous Stage II Grade 2 Follicular Lymphoma; Noncontiguous Stage II Marginal Zone Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Peripheral T-cell Lymphoma; Previously Treated Myelodysplastic Syndromes; Progressive Hairy Cell Leukemia, Initial Treatment; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Childhood Anaplastic Large Cell Lymphoma; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Small Noncleaved Cell Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Recurrent/Refractory Childhood Hodgkin Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Refractory Multiple Myeloma; Relapsing Chronic Myelogenous Leukemia; Splenic Marginal Zone Lymphoma; Stage I Adult Diffuse Small Cleaved Cell Lymphoma; Stage I Childhood Anaplastic Large Cell Lymphoma; Stage I Childhood Large Cell Lymphoma; Stage I Cutaneous T-cell Non-Hodgkin Lymphoma; Stage I Grade 1 Follicular Lymphoma; Stage I Grade 2 Follicular Lymphoma; Stage I Mantle Cell Lymphoma; Stage I Marginal Zone Lymphoma; Stage I Mycosis Fungoides/Sezary Syndrome; Stage I Small Lymphocytic Lymphoma; Stage II Childhood Anaplastic Large Cell Lymphoma; Stage II Childhood Large Cell Lymphoma; Stage II Cutaneous T-cell Non-Hodgkin Lymphoma; Stage II Mycosis Fungoides/Sezary Syndrome; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Small Cleaved Cell Lymphoma; Stage III Childhood Anaplastic Large Cell Lymphoma; Stage III Childhood Large Cell Lymphoma; Stage III Cutaneous T-cell Non-Hodgkin Lymphoma; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage III Marginal Zone Lymphoma; Stage III Mycosis Fungoides/Sezary Syndrome; Stage III Small Lymphocytic Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Small Cleaved Cell Lymphoma; Stage IV Childhood Anaplastic Large Cell Lymphoma; Stage IV Childhood Large Cell Lymphoma; Stage IV Cutaneous T-cell Non-Hodgkin Lymphoma; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma; Stage IV Marginal Zone Lymphoma; Stage IV Mycosis Fungoides/Sezary Syndrome; Stage IV Small Lymphocytic Lymphoma; T-cell Large Granular Lymphocyte Leukemia; Waldenström Macroglobulinemia

The impact of coexisting lung diseases on outcomes in patients with pathological Stage I non-small-cell lung cancer.

PubMed

Tao, Hiroyuki; Onoda, Hideko; Okabe, Kazunori; Matsumoto, Tsuneo

2018-06-01

Cigarette smoking is a well-known cause of interstitial lung disease (ILD), pulmonary emphysema and lung cancer. Coexisting pulmonary disease can affect prognosis in patients with lung cancer. The aim of this study was to determine the influence of pulmonary disease on outcomes in patients with a smoking history who had undergone surgery for pathological Stage I non-small-cell lung cancer. Medical records of 257 patients with a smoking history who underwent surgery for pathological Stage I non-small-cell lung cancer between June 2009 and December 2014 were reviewed. Coexisting ILDs were evaluated using high-resolution computed tomography. The degree of pulmonary emphysema was determined using image analysis software according to the Goddard classification. The impact of clinicopathological factors on outcome was evaluated. Among the 257 patients, ILDs were detected via high-resolution computed tomography in 60 (23.3%) patients; of these, usual interstitial pneumonia (UIP) patterns and non-UIP patterns were seen in 25 (9.7%) and 35 (13.6%) patients, respectively. The degree of pulmonary emphysema was classified as none, mild and moderate and included 50 (19.5%), 162 (63.0%) and 45 (17.5%) patients, respectively. The 5-year overall survival, cancer-specific survival and relapse-free survival were 80.7%, 88.0% and 74.9%, respectively, during a median follow-up period of 50.5 months. In multivariate analysis, the presence of a UIP pattern was shown to be an independent risk factor for poor outcome. The presence of a UIP-pattern ILD on high-resolution computed tomography images was shown to be a risk factor for poor outcome in patients with a smoking history who had undergone surgery for pathological Stage I non-small-cell lung cancer.

Targeting Mutant BRAF with Vemurafenib in Relapsed or Refractory Hairy Cell Leukemia

PubMed Central

Tiacci, Enrico; Park, Jae H.; De Carolis, Luca; Chung, Stephen S.; Broccoli, Alessandro; Scott, Sasinya; Zaja, Francesco; Devlin, Sean; Pulsoni, Alessandro; Chung, Young Rock; Cimminiello, Michele; Kim, Eunhee; Rossi, Davide; Stone, Richard M.; Motta, Giovanna; Saven, Alan; Varettoni, Marzia; Altman, Jessica K.; Anastasia, Antonella; Grever, Michael R.; Ambrosetti, Achille; Rai, Kanti R.; Fraticelli, Vincenzo; Lacouture, Mario E.; Carella, Angelo Michele; Levine, Ross L.; Leoni, Pietro; Rambaldi, Alessandro; Falzetti, Franca; Ascani, Stefano; Capponi, Monia; Martelli, Maria Paola; Park, Christopher Y.; Pileri, Stefano Aldo; Rosen, Neal; Foà, Robin; Berger, Michael F.; Zinzani, Pier Luigi; Abdel-Wahab, Omar; Falini, Brunangelo; Tallman, Martin S.

2016-01-01

BACKGROUND BRAF-V600E is the genetic lesion underlying hairy cell leukemia. We assessed the safety and activity of the oral BRAF inhibitor vemurafenib in patients with hairy cell leukemia who relapsed after or were refractory to purine analogues. METHODS We conducted in Italy and USA two phase-2 single-arm multicenter studies of vemurafenib (960 mg twice daily) given for a median of 16 and 18 weeks, respectively. Primary endpoints were complete remission rate and overall response rate. Patient enrollment was completed (n=28) in the Italian trial in April 2013 and is still open (n=26/36) in the American trial. RESULTS Drug-related adverse events were usually of grade 1-2, and those most frequently requiring dose reductions were rash and arthralgia/arthritis; secondary cutaneous tumors (treated with simple excision) developed in 6/50 patients. Overall response rates were 96% (25/26 evaluable Italian patients) and 100% (24/24 evaluable American patients), obtained after a median of 8 weeks and 12 weeks, respectively. Complete response rates were 34.6% (9/26) and 41.7% (10/24), respectively. In the Italian trial, after a median follow-up of 23 months, the median relapse-free and treatment-free survivals were respectively 19 and 25 months in complete responders, and 6 and 18 months in partial responders. In the American trial, 1-year progression-free and overall survival were 73% and 91%, respectively. Frequent persistence of phospho-ERK+ bone marrow leukemic cells at the end of treatment suggests bypass MEK-ERK reactivation as a resistance mechanism. CONCLUSIONS A short oral course of vemurafenib proved safe and highly effective in relapsed/refractory hairy cell leukemia patients (Funded by AIRC, ERC, Roche/Genentech and others; EudractCT number: 2011-005487-13, ClinicalTrials.gov number NCT01711632). PMID:26352686

Ibrutinib (Imbruvica). Relapsed chronic lymphocytic leukaemia and mantle cell lymphoma: uncertain impact on survival.

PubMed

January

2016-04-01

codynamic interactions are also likely in view of its adverse effect profile. There is no consensus on the treatment of patients with refractory or relapsed mantle cell lymphoma, or for patients with relapsed or possibly refractory chronic lymphocytic leukaemia. Ibrutinib inhibits an enzyme involved in regulating B lymphocyte activity. It has been authorised in the European Union for these conditions. Clinical evaluation of ibrutinib in mantle cell lymphoma is based on a single non-comparative trial in 111 patients, in which the median overall survival time was 22.5 months. Clinical evaluation of ibrutinib in chronic lymphocytic leukaemia is based on two randomised trials. One unblinded trial compared ibrutinib versus ofatumumab and involved 391 patients, most of whom were sufficiently fit to receive anticancer combination therapy. Ibrutinib was more effective than ofatumumab, but the choice of this comparator might not have been appropriate for most of the patients who received it. The other double-blind, placebo-controlled trial involved 578 patients with relapsed or refractory chronic lymphocytic leukaemia. Ibrutinib was added to the bendamustine + rituximab combination. No significant difference in mortality was observed between the two groups. The main adverse effects of ibrutinib were: gastrointestinal disorders such as diarrhoea; life-threatening infections and bleeding disorders; and cardiac disorders, including atrial fibrillation. Ibrutinib carries a risk of multiple pharmacokinetic interactions. Pharmacodynamic interactions are also likely in view of its adverse effect profile.

Preventing relapse after haematopoietic stem cell transplantation for acute leukaemia: the role of post-transplantation minimal residual disease (MRD) monitoring and MRD-directed intervention.

PubMed

Mo, Xiao-Dong; Lv, Meng; Huang, Xiao-Jun

2017-10-01

Relapse is the main cause of treatment failure after allogeneic haematopoietic stem cell transplantation (allo-HSCT) for acute leukaemia (AL). Post-transplantation minimal residual disease (MRD) monitoring enables risk stratification and identifies AL patients at higher risk of relapse. MRD assessment primarily involves the determination of leukaemia-associated immunophenotypic patterns using multiparameter flow cytometry, and the polymerase chain reaction (PCR)-based evaluation of expression levels of leukaemia-related genes (specific reciprocal gene rearrangements and other mutation types). In addition, next generation sequencing and digital PCR may further enrich current MRD detection. Several MRD-directed interventions have demonstrated the ability to reduce the risk of relapse with acceptable treatment-related toxicities. Donor lymphocyte infusion (DLI) is the most important intervention for MRD-positive patients, while several modified strategies, such as granulocyte colony-stimulating factor-mobilized peripheral blood cells followed by short term immune suppression and escalating dose regimen, further improve the safety and efficacy of DLI. Interferon therapy, targeted drugs, and hypomethylating agents have also been introduced for MRD-directed interventions. Referring to the issues of whether and who would benefit from pre-emptive intervention according to MRD, in this review, we summarized this rapidly evolving area of MRD monitoring and MRD-directed interventions in AL patients after allo-HSCT. © 2017 John Wiley & Sons Ltd.

Tumor suppressors BTG1 and IKZF1 cooperate during mouse leukemia development and increase relapse risk in B-cell precursor acute lymphoblastic leukemia patients.

PubMed

Scheijen, Blanca; Boer, Judith M; Marke, René; Tijchon, Esther; van Ingen Schenau, Dorette; Waanders, Esmé; van Emst, Liesbeth; van der Meer, Laurens T; Pieters, Rob; Escherich, Gabriele; Horstmann, Martin A; Sonneveld, Edwin; Venn, Nicola; Sutton, Rosemary; Dalla-Pozza, Luciano; Kuiper, Roland P; Hoogerbrugge, Peter M; den Boer, Monique L; van Leeuwen, Frank N

2017-03-01

Deletions and mutations affecting lymphoid transcription factor IKZF1 (IKAROS) are associated with an increased relapse risk and poor outcome in B-cell precursor acute lymphoblastic leukemia. However, additional genetic events may either enhance or negate the effects of IKZF1 deletions on prognosis. In a large discovery cohort of 533 childhood B-cell precursor acute lymphoblastic leukemia patients, we observed that single-copy losses of BTG1 were significantly enriched in IKZF1 -deleted B-cell precursor acute lymphoblastic leukemia ( P =0.007). While BTG1 deletions alone had no impact on prognosis, the combined presence of BTG1 and IKZF1 deletions was associated with a significantly lower 5-year event-free survival ( P =0.0003) and a higher 5-year cumulative incidence of relapse ( P =0.005), when compared with IKZF1 -deleted cases without BTG1 aberrations. In contrast, other copy number losses commonly observed in B-cell precursor acute lymphoblastic leukemia, such as CDKN2A/B, PAX5, EBF1 or RB1 , did not affect the outcome of IKZF1 -deleted acute lymphoblastic leukemia patients. To establish whether the combined loss of IKZF1 and BTG1 function cooperate in leukemogenesis, Btg1 -deficient mice were crossed onto an Ikzf1 heterozygous background. We observed that loss of Btg1 increased the tumor incidence of Ikzf1 +/- mice in a dose-dependent manner. Moreover, murine B cells deficient for Btg1 and Ikzf1 +/- displayed increased resistance to glucocorticoids, but not to other chemotherapeutic drugs. Together, our results identify BTG1 as a tumor suppressor in leukemia that, when deleted, strongly enhances the risk of relapse in IKZF1 -deleted B-cell precursor acute lymphoblastic leukemia, and augments the glucocorticoid resistance phenotype mediated by the loss of IKZF1 function. Copyright© Ferrata Storti Foundation.

Quantification of Acute Lymphoblastic Leukemia Clonotypes in Leukapheresed Peripheral Blood Progenitor Cells Predicts Relapse Risk after Autologous Hematopoietic Stem Cell Transplantation.

PubMed

Mannis, Gabriel N; Martin, Thomas G; Damon, Lloyd E; Andreadis, Charalambos; Olin, Rebecca L; Kong, Katherine A; Faham, Malek; Hwang, Jimmy; Ai, Weiyun Z; Gaensler, Karin M L; Sayre, Peter H; Wolf, Jeffrey L; Logan, Aaron C

2016-06-01

Since the incorporation of tyrosine kinase inhibitors into the treatment of Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL), the notion that all patients with "high-risk" ALL uniformly require allogeneic (allo) hematopoietic cell transplantation (HCT) has received increasing scrutiny. Although multiple studies have shown superiority of alloHCT over autologous (auto) hematopoietic cell transplantation for high-risk patients, these findings may be explained, in part, by contamination of the peripheral blood progenitor cell (PBPC) leukapheresis product by residual leukemic cells in patients undergoing autoHCT. We retrospectively evaluated minimal residual disease (MRD) using next-generation sequencing (NGS) in the PBPC leukapheresis product of 32 ALL patients who underwent autoHCT. Twenty-eight patients (88%) had diagnostic samples with quantifiable immunoreceptor rearrangements to follow for MRD. Twelve (38%) patients had Ph+ B-ALL, 12 (38%) had Philadelphia chromosome-negative (Ph-) B-ALL, and 4 (14%) had T cell ALL. With a median follow-up of 41 months (range, 3 to 217), median relapse-free survival (RFS) and overall survival for the entire cohort were 3.2 and 4.2 years, respectively; at 5 years after transplantation, 42% of patients remain alive and relapse free. Using MRD detection at a threshold of ≥ 1 × 10(-6), median RFS for patients with detectable MRD was 6.5 months and was not reached for patients without detectable disease (P = .0005). In multivariate analysis, the only factor significantly associated with relapse was the presence of MRD ≥1 × 10(-6) (odds ratio, 23.8; confidence interval, 1.8 to 312.9; P = .0158). Our findings suggest that NGS for MRD detection can predict long-term RFS in patients undergoing autoHCT for high-risk ALL. Copyright © 2016 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Lyme disease and relapsing fever Borrelia elongate through zones of peptidoglycan synthesis that mark division sites of daughter cells.

PubMed

Jutras, Brandon Lyon; Scott, Molly; Parry, Bradley; Biboy, Jacob; Gray, Joe; Vollmer, Waldemar; Jacobs-Wagner, Christine

2016-08-16

Agents that cause Lyme disease, relapsing fever, leptospirosis, and syphilis belong to the phylum Spirochaetae-a unique lineage of bacteria most known for their long, spiral morphology. Despite the relevance to human health, little is known about the most fundamental aspects of spirochete growth. Here, using quantitative microscopy to track peptidoglycan cell-wall synthesis, we found that the Lyme disease spirochete Borrelia burgdorferi displays a complex pattern of growth. B. burgdorferi elongates from discrete zones that are both spatially and temporally regulated. In addition, some peptidoglycan incorporation occurs along the cell body, with the notable exception of a large region at the poles. Newborn cells inherit a highly active zone of peptidoglycan synthesis at midcell that contributes to elongation for most of the cell cycle. Concomitant with the initiation of nucleoid separation and cell constriction, second and third zones of elongation are established at the 1/4 and 3/4 cellular positions, marking future sites of division for the subsequent generation. Positioning of elongation zones along the cell is robust to cell length variations and is relatively precise over long distances (>30 µm), suggesting that cells ‟sense" relative, as opposed to absolute, cell length to establish zones of peptidoglycan synthesis. The transition from one to three zones of peptidoglycan growth during the cell cycle is also observed in relapsing fever Borrelia. However, this mode of growth does not extend to representative species from other spirochetal genera, suggesting that this distinctive growth mode represents an evolutionary divide in the spirochete phylum.

Nodular lymphocyte-predominant Hodgkin lymphoma: a unique disease deserving unique management.

PubMed

Eichenauer, Dennis A; Engert, Andreas

2017-12-08

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare lymphoma entity with an incidence of 0.1 to 0.2/100 000/y. Compared with the more common subtypes of classical Hodgkin lymphoma, NLPHL is characterized by distinct pathological and clinical features. Histologically, the disease-defining lymphocyte predominant cells consistently express CD20 but lack CD30. Clinically, NLPHL mostly has a rather indolent course, and patients usually are diagnosed in early stages. The prognosis of early-stage NLPHL is excellent, with progression-free survival and overall survival rates exceeding 90% after involved-field radiotherapy (IF-RT) alone (stage IA) or combined modality treatment consisting of a brief chemotherapy with 2 cycles of ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) chemotherapy followed by IF-RT (early stages other than stage IA). In contrast, patients with advanced disease at diagnosis tend to relapse either with NLPHL histology or with histological transformation into aggressive B-cell non-Hodgkin lymphoma despite more aggressive first-line treatment with 6 to 8 cycles of multiagent chemotherapy. However, even NLPHL patients with multiple relapses successfully respond to salvage therapy in many cases. Salvage therapies range from single-agent anti-CD20 antibody treatment to high-dose chemotherapy followed by autologous stem cell transplantation. Treatment at disease recurrence should be chosen on the basis of various factors, including histology at relapse, time to relapse, extent of disease at relapse, and prior treatment. Because death among NLPHL patients is more often caused by therapy-related late effects than lymphoma-related complications, optimizing the risk-benefit ratio of treatment by decreasing toxicity whenever possible is the major goal of clinical research in this disease. © 2016 by The American Society of Hematology. All rights reserved.

Autologous transplantation versus allogeneic transplantation in patients with follicular lymphoma experiencing early treatment failure.

PubMed

Smith, Sonali M; Godfrey, James; Ahn, Kwang Woo; DiGilio, Alyssa; Ahmed, Sairah; Agrawal, Vaibhav; Bachanova, Veronika; Bacher, Ulrike; Bashey, Asad; Bolaños-Meade, Javier; Cairo, Mitchell; Chen, Andy; Chhabra, Saurabh; Copelan, Edward; Dahi, Parastoo B; Aljurf, Mahmoud; Farooq, Umar; Ganguly, Siddhartha; Hertzberg, Mark; Holmberg, Leona; Inwards, David; Kanate, Abraham S; Karmali, Reem; Kenkre, Vaishalee P; Kharfan-Dabaja, Mohamed A; Klein, Andreas; Lazarus, Hillard M; Mei, Matthew; Mussetti, Alberto; Nishihori, Taiga; Ramakrishnan Geethakumari, Praveen; Saad, Ayman; Savani, Bipin N; Schouten, Harry C; Shah, Nirav; Urbano-Ispizua, Alvaro; Vij, Ravi; Vose, Julie; Sureda, Anna; Hamadani, Mehdi

2018-06-15

Early treatment failure (ETF) in follicular lymphoma (FL), defined as relapse or progression within 2 years of frontline chemoimmunotherapy, is a newly recognized marker of poor survival and identifies a high-risk group of patients with an expected 5-year overall survival (OS) rate of approximately 50%. Transplantation is an established option for relapsed FL, but its efficacy in this specific ETF FL population has not been previously evaluated. This study compared autologous hematopoietic stem cell transplantation (auto-HCT) with either matched sibling donor (MSD) or matched unrelated donor (MUD) allogeneic hematopoietic cell transplantation (allo-HCT) as the first transplantation approach for patients with ETF FL (age ≥ 18 years) undergoing auto-HCT or allo-HCT between 2002 and 2014. The primary endpoint was OS. The secondary endpoints were progression-free survival, relapse, and nonrelapse mortality (NRM). Four hundred forty FL patients had ETF (auto-HCT, 240; MSD hematopoietic stem cell transplantation [HCT], 105; and MUD HCT, 95). With a median follow-up of 69 to 73 months, the adjusted probability of 5-year OS was significantly higher after auto-HCT (70%) or MSD HCT (73%) versus MUD HCT (49%; P = .0008). The 5-year adjusted probability of NRM was significantly lower for auto-HCT (5%) versus MSD (17%) or MUD HCT (33%; P < .0001). The 5-year adjusted probability of disease relapse was lower with MSD (31%) or MUD HCT (23%) versus auto-HCT (58%; P < .0001). Patients with high-risk FL, as defined by ETF, undergoing auto-HCT for FL have low NRM and a promising 5-year OS rate (70%). MSD HCT has lower relapse rates than auto-HCT but similar OS. Cancer 2018;124:2541-51. © 2018 American Cancer Society. © 2018 American Cancer Society.

Survival outcomes of patients with germ cell tumors treated with high-dose chemotherapy for refractory or relapsing disease.

PubMed

Zschäbitz, Stefanie; Distler, Florian A; Krieger, Benjamin; Wuchter, Patrick; Schäfer-Eckart, Kerstin; Jenzer, Maximilian; Hohenfellner, Markus; Dreger, Peter; Haag, Georg Martin; Jäger, Dirk; Pahernik, Sascha; Grüllich, Carsten

2018-04-27

Male patients with metastatic germ cell tumors can be cured in up to 96% of cases depending on stage and IGCCCG prognosis group. Treatment in relapse consists of conventional or high-dose chemotherapy (HDCT) with autologous stem cell transplantation (ASCT) combined with local treatment modalities. Most patients were classified as poor risk according to IGCCCG ( n = 24; 52%) and as intermediate ( n = 12), high ( n = 16), or very high risk ( n = 9) at time of first relapse according to IPFSG criteria. In 67% of patients ( n = 31) HDCT/ASCT was performed as first salvage treatment in relapse or for primary refractory disease following first line chemotherapy. In 46% of patients ( n = 21) progressive disease was documented after mobilization and prior to HDCT/ASCT. Median progression free survival (mPFS) was 7.4 months (95% confidence interval (CI): 1.3-13.6) while median overall survival (mOS) was 22.2 months (95% CI: 8.9-35.5). When stratified for IPFSG risk group, mPFS ( p < 0.001) and mOS ( p = 0.009) differed significantly between risk groups (very low vs. low vs. intermediate vs. high vs. very high). Metastases to liver/bone/brain and platinum refractory disease were independent risk factors for inferior PFS ( p = 0.024; p = 0.008) but not OS. Forty-six patients treated with HDCT/ASCT at the university clinics in Heidelberg and Nuremberg between 2000-2016 were identified and analyzed. Data was collected retrospectively. HDCT/ASCT offers a potential curative strategy for patients with relapsed GCT. Improvement is still needed in patients with intermediate, high, and very high IPFSG risk group.

Gemcitabine, dexamethasone, and cisplatin (GDP) as salvage chemotherapy for patients with relapsed or refractory peripheral T cell lymphoma-not otherwise specified.

PubMed

Qi, Fei; Dong, Mei; He, Xiaohui; Li, Yexiong; Wang, Weihu; Liu, Peng; Yang, Jianliang; Gui, Lin; Zhang, Changgong; Yang, Sheng; Zhou, Shengyu; Shi, Yuankai

2017-02-01

Standard therapeutic options for patients with relapsed or refractory peripheral T cell lymphoma-not otherwise specified (PTCL-NOS) remain unclear. There are few large cohort studies specifically focused on gemcitabine-based chemotherapy for PTCL-NOS. We retrospectively reviewed patients with relapsed or refractory PTCL-NOS who received salvage GDP (gemcitabine, dexamethasone, and cisplatin) chemotherapy at the Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Beijing, China, from May 2008 to August 2014. Twenty-five patients were enrolled and analyzed. The median number of cycles of GDP chemotherapy per patient was four (range, 2-8 cycles). Overall response rate was 64.0% (16/25) with five achieved complete remission or complete remission unconfirmed. After a median follow-up of 9 months, median overall survival (OS) and progression-free survival after relapse or progression (second-PFS) were 9.3 and 5.4 months. One-year PFS rate and 1-year OS rate were 27.4% and 43.9%, respectively. Median second-PFS was significantly longer in patients sensitive to GDP than the ones resistant to the treatment (10.3 vs. 2.8 months, p < .01). In addition, the low International Prognostic Index, low Prognostic Index for T cell lymphoma, or normal level of LDH in serum was associated with favorable prognosis. Grade 3/4 adverse effect was observed in 10 of 25 patients treated with GDP including neutropenia (8/25), thrombocytopenia (5/25), and anemia (4/25). Taken together, our study suggests that GDP is an effective and optional salvage regimen for relapsed or refractory PTCL-NOS.

Comparison of Newly Diagnosed and Relapsed Patients with Acute Promyelocytic Leukemia Treated with Arsenic Trioxide: Insight into Mechanisms of Resistance

PubMed Central

Chendamarai, Ezhilarasi; Ganesan, Saravanan; Alex, Ansu Abu; Kamath, Vandana; Nair, Sukesh C.; Nellickal, Arun Jose; Janet, Nancy Beryl; Srivastava, Vivi; Lakshmi, Kavitha M.; Viswabandya, Auro; Abraham, Aby; Aiyaz, Mohammed; Mullapudi, Nandita; Mugasimangalam, Raja; Padua, Rose Ann; Chomienne, Christine; Chandy, Mammen; Srivastava, Alok; George, Biju; Balasubramanian, Poonkuzhali; Mathews, Vikram

2015-01-01

There is limited data on the clinical, cellular and molecular changes in relapsed acute promyeloytic leukemia (RAPL) in comparison with newly diagnosed cases (NAPL). We undertook a prospective study to compare NAPL and RAPL patients treated with arsenic trioxide (ATO) based regimens. 98 NAPL and 28 RAPL were enrolled in this study. RAPL patients had a significantly lower WBC count and higher platelet count at diagnosis. IC bleeds was significantly lower in RAPL cases (P=0.022). The ability of malignant promyelocytes to concentrate ATO intracellularly and their in-vitro IC50 to ATO was not significantly different between the two groups. Targeted NGS revealed PML B2 domain mutations in 4 (15.38%) of the RAPL subset and none were associated with secondary resistance to ATO. A microarray GEP revealed 1744 genes were 2 fold and above differentially expressed between the two groups. The most prominent differentially regulated pathways were cell adhesion (n=92), cell survival (n=50), immune regulation (n=74) and stem cell regulation (n=51). Consistent with the GEP data, immunophenotyping revealed significantly increased CD34 expression (P=0.001) in RAPL cases and there was in-vitro evidence of significant microenvironment mediated innate resistance (EM-DR) to ATO. Resistance and relapse following treatment with ATO is probably multi-factorial, mutations in PML B2 domain while seen only in RAPL may not be the major clinically relevant cause of subsequent relapses. In RAPL additional factors such as expansion of the leukemia initiating compartment along with EM-DR may contribute significantly to relapse following treatment with ATO based regimens. PMID:25822503

Avelumab, Utomilumab, Rituximab, Ibrutinib, and Combination Chemotherapy in Treating Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma or Mantle Cell Lymphoma

ClinicalTrials.gov

2018-06-13

CCND1 Positive; CD20 Positive; Recurrent Diffuse Large B-Cell Lymphoma; Recurrent Mantle Cell Lymphoma; Refractory Diffuse Large B-Cell Lymphoma; Refractory Mantle Cell Lymphoma; Transformed Follicular Lymphoma to Diffuse Large B-Cell Lymphoma

Plasminogen activator inhibitor-2 in patients with monocytic leukemia.

PubMed

Scherrer, A; Kruithof, E K; Grob, J P

1991-06-01

Plasma and tumor cells from 103 patients with leukemia or lymphoma at initial presentation were investigated for the presence of plasminogen activator inhibitor-2 (PAI-2) antigen, a potent inhibitor of urokinase. PAI-2 was detected in plasma and leukemic cells of the 21 patients with leukemia having a monocytic component [acute myelomonocytic (M4), acute monoblastic (M5), and chronic myelomonocytic leukemias], and in the three patients with acute undifferentiated myeloblastic leukemia (M0). In contrast, this serine protease inhibitor was undetectable in 79 patients with other subtypes of acute myeloid leukemia or other hematological malignancies. Serial serum PAI-2 determinations in 16 patients with acute leukemia at presentation, during therapy, remission, and relapse revealed that in the five patients with M4-M5, elevated PAI-2 levels rapidly normalized under therapy and during remission, but increased again in the patients with a relapse associated with an M4-M5 phenotype. Thus, PAI-2 seems to be a marker highly specific for the active stages of monocytic leukemia, i.e. presentation and relapse. The presence of PAI-2 in the plasma and cells of patients with M0 may give a clue to a monocytic origin of these cells.

Genomic tissue typing and optimal antithymocyte globuline dose using unrelated donors results in similar survival and relapse as HLA-identical siblings in haematopoietic stem-cell transplantation for leukaemia.

PubMed

Remberger, Mats; Mattsson, Jonas; Hausenberger, Dan; Schaffer, Marie; Svahn, Britt-Marie; Ringdén, Olle

2008-05-01

Sixty-one leukaemia patients treated with haematopoietic stem cell transplantation (HSCT) from a genomic human leucocyte antigen (HLA)-A, -B and -DRbeta1 matched unrelated donor (MUD) were compared with 121 patients with an HLA-identical sibling donor. All patients received conventional conditioning. We selected all patients with unrelated donors who received optimal antithymocyte globuline (ATG) dose, 6 mg/kg. One hundred and seven patients received stem cells from peripheral blood and 75 patients received bone marrow (BM) cells. The incidences of acute graft-versus-host disease (GVHD) grades II-IV were 33.4% and 34.7% in the MUD and sibling group, respectively. After year 2001, the incidence of chronic GVHD was similar in the two groups (27.8% vs. 25.8%). There was no difference in overall survival (60% vs. 60%), transplant-related mortality (18.6% vs. 16.6%) and relapse (23% vs. 26.4%) between the two groups. Haematopoietic stem cell transplantation with unrelated donors results in similar GVHD, relapse and survival as compared to using sibling donors. Reasons for this may be improved tissue-typing techniques and supportive care and optimisation of the ATG dose.

Natural Killer Cell Immunotherapy Targeting Cancer Stem Cells

PubMed Central

Luna, Jesus I; Grossenbacher, Steven K.; Murphy, William J; Canter, Robert J

2017-01-01

Introduction Standard cytoreductive cancer therapy, such as chemotherapy and radiotherapy, are frequently resisted by a small portion of cancer cells with “stem-cell” like properties including quiescence and repopulation. Immunotherapy represents a breakthrough modality for improving oncologic outcomes in cancer patients. Since the success of immunotherapy is not contingent on target cell proliferation, it may also be uniquely suited to address the problem of resistance and repopulation exerted by cancer stem cells (CSCs). Areas covered Natural killer (NK) cells have long been known for their ability to reject allogeneic hematopoietic stem cells, and there are increasing data demonstrating that NK cells can selectively identify and lyse CSCs. In this report, we review the current knowledge of CSCs and NK cells and highlight recent studies that support the concept that NK cells are capable of targeting CSC in solid tumors, especially in the context of combination therapy simultaneously targeting non-CSCs and CSCs. Expert Opinion Unlike cytotoxic cancer treatments, NK cells are able to target and eliminate quiescent/non-proliferating cells such as CSCs, and these enigmatic cells are an important source of relapse and metastasis. NK targeting of CSCs represents a novel and potentially high impact method to capitalize on the intrinsic therapeutic potential of NK cells. PMID:27960589

Donor-Recipient Matching for KIR Genotypes Reduces Chronic GVHD and Missing Inhibitory KIR Ligands Protect against Relapse after Myeloablative, HLA Matched Hematopoietic Cell Transplantation

PubMed Central

Faridi, Rehan Mujeeb; Kemp, Taylor J.; Dharmani-Khan, Poonam; Lewis, Victor; Rajalingam, Raja; Berka, Noureddine; Storek, Jan; Masood Khan, Faisal

2016-01-01

Background Allogeneic hematopoietic cell transplantation (HCT) can be curative for many hematologic diseases. However, complications such as graft-versus-host disease (GVHD) and relapse of primary malignancy remain significant and are the leading causes of morbidity and mortality. Effects of killer Ig-like receptors (KIR)-influenced NK cells on HCT outcomes have been extensively pursued over the last decade. However, the relevance of the reported algorithms on HLA matched myeloablative HCT with rabbit antithymocyte globulin (ATG) is used for GVHD prophylaxis remains elusive. Here we examined the role of KIR and KIR-ligands of donor-recipient pairs in modifying the outcomes of ATG conditioned HLA matched sibling and unrelated donor HCT Methods and Findings The study cohort consisted of 281 HLA matched sibling and unrelated donor-recipient pairs of first allogeneic marrow or blood stem cell transplantation allocated into ‘discovery’ (135 pairs) and ‘validation’ (146 pairs) cohorts. High resolution HLA typing was obtained from the medical charts and KIR gene repertoires were obtained by a Luminex® based SSO method. All surviving patients were followed-up for a minimum of two years. KIR and HLA class I distributions of HCT pairs were stratified as per applicable definitions and were tested for their association with cause specific outcomes [acute GVHD grade II-IV (aGVHD), chronic GVHD needing systemic therapy (cGVHD) and relapse] using a multivariate competing risks regression model as well as with survival outcomes [relapse-free survival (RFS), cGVHD & relapse free survival (cGRFS) and overall survival (OS)] by multivariate Cox proportional hazards regression model. A significant association between KIR genotype mismatching (KIR-B/x donor into KIR-AA recipient or vice versa) and cGVHD was found in both discovery (p = 0.001; SHR = 2.78; 95%CI: 1.50–5.17) and validation cohorts (p = 0.005; SHR = 2.61; 95%CI: 1.33–5.11). High incidence of cGVHD associated with KIR genotype mismatching was applicable to both sibling and unrelated donors and was specific to recipients who had one or two C1 bearing HLA-C epitopes (HLA-C1/x, p = 0.001; SHR = 2.40; 95%CI: 1.42–4.06). When compared with KIR genotype mismatched transplants, HLA-C1/x patients receiving grafts from KIR genotype matched donors had a significantly improved cGRFS (p = 0.013; HR = 1.62; 95%CI: 1.11–2.39). Although there was no effect of KIR genotype matching on survival outcomes, a significantly reduced incidence of relapse (p = 0.001; SHR = 0.22; 95%CI: 0.10–0.54) and improved relapse-free survival (p = 0.038; HR = 0.40; 95%CI: 0.17–0.95) was observed with one or more missing ligands for donor inhibitory KIR among the recipients of unrelated donor transplants. Conclusions The present study for the first time presents the beneficial effects of KIR genotype matching in reducing cGVHD in myeloablative transplant setting using HLA matched (sibling and unrelated) donors. The findings offer a clinically applicable donor selection strategy that can help control cGVHD without affecting the risk of relapse and/or identify patients at a high risk of developing cGVHD as potential candidates for preemptive therapy. The findings also affirm the beneficial effect of one or more missing inhibitory KIR ligands in the recipient in reducing relapse and improving a relapse free survival in unrelated donor transplants. PMID:27341514

Donor-Recipient Matching for KIR Genotypes Reduces Chronic GVHD and Missing Inhibitory KIR Ligands Protect against Relapse after Myeloablative, HLA Matched Hematopoietic Cell Transplantation.

PubMed

Faridi, Rehan Mujeeb; Kemp, Taylor J; Dharmani-Khan, Poonam; Lewis, Victor; Tripathi, Gaurav; Rajalingam, Raja; Daly, Andrew; Berka, Noureddine; Storek, Jan; Masood Khan, Faisal

2016-01-01

Allogeneic hematopoietic cell transplantation (HCT) can be curative for many hematologic diseases. However, complications such as graft-versus-host disease (GVHD) and relapse of primary malignancy remain significant and are the leading causes of morbidity and mortality. Effects of killer Ig-like receptors (KIR)-influenced NK cells on HCT outcomes have been extensively pursued over the last decade. However, the relevance of the reported algorithms on HLA matched myeloablative HCT with rabbit antithymocyte globulin (ATG) is used for GVHD prophylaxis remains elusive. Here we examined the role of KIR and KIR-ligands of donor-recipient pairs in modifying the outcomes of ATG conditioned HLA matched sibling and unrelated donor HCT. The study cohort consisted of 281 HLA matched sibling and unrelated donor-recipient pairs of first allogeneic marrow or blood stem cell transplantation allocated into 'discovery' (135 pairs) and 'validation' (146 pairs) cohorts. High resolution HLA typing was obtained from the medical charts and KIR gene repertoires were obtained by a Luminex® based SSO method. All surviving patients were followed-up for a minimum of two years. KIR and HLA class I distributions of HCT pairs were stratified as per applicable definitions and were tested for their association with cause specific outcomes [acute GVHD grade II-IV (aGVHD), chronic GVHD needing systemic therapy (cGVHD) and relapse] using a multivariate competing risks regression model as well as with survival outcomes [relapse-free survival (RFS), cGVHD & relapse free survival (cGRFS) and overall survival (OS)] by multivariate Cox proportional hazards regression model. A significant association between KIR genotype mismatching (KIR-B/x donor into KIR-AA recipient or vice versa) and cGVHD was found in both discovery (p = 0.001; SHR = 2.78; 95%CI: 1.50-5.17) and validation cohorts (p = 0.005; SHR = 2.61; 95%CI: 1.33-5.11). High incidence of cGVHD associated with KIR genotype mismatching was applicable to both sibling and unrelated donors and was specific to recipients who had one or two C1 bearing HLA-C epitopes (HLA-C1/x, p = 0.001; SHR = 2.40; 95%CI: 1.42-4.06). When compared with KIR genotype mismatched transplants, HLA-C1/x patients receiving grafts from KIR genotype matched donors had a significantly improved cGRFS (p = 0.013; HR = 1.62; 95%CI: 1.11-2.39). Although there was no effect of KIR genotype matching on survival outcomes, a significantly reduced incidence of relapse (p = 0.001; SHR = 0.22; 95%CI: 0.10-0.54) and improved relapse-free survival (p = 0.038; HR = 0.40; 95%CI: 0.17-0.95) was observed with one or more missing ligands for donor inhibitory KIR among the recipients of unrelated donor transplants. The present study for the first time presents the beneficial effects of KIR genotype matching in reducing cGVHD in myeloablative transplant setting using HLA matched (sibling and unrelated) donors. The findings offer a clinically applicable donor selection strategy that can help control cGVHD without affecting the risk of relapse and/or identify patients at a high risk of developing cGVHD as potential candidates for preemptive therapy. The findings also affirm the beneficial effect of one or more missing inhibitory KIR ligands in the recipient in reducing relapse and improving a relapse free survival in unrelated donor transplants.

Donor Vδ1+ γδ T cells expand after allogeneic hematopoietic stem cell transplantation and show reactivity against CMV-infected cells but not against progressing B-CLL.

PubMed

Prinz, Immo; Thamm, Kristina; Port, Matthias; Weissinger, Eva M; Stadler, Michael; Gabaev, Ildar; Jacobs, Roland; Ganser, Arnold; Koenecke, Christian

2013-05-11

γδ T lymphocytes play an important role in immune reactions towards infections and malignancies. In particular, Vγ9-Vδ1+ T lymphocytes are thought to play protective antiviral roles in human CMV infection. Recently, Vδ1+ T lymphocytes were proposed to also have anti- B-CLL reactivity. Here we report a case of 48-year-old man who received allogeneic stem cell transplantation for progressive B-CLL. Within one year after transplantation, lymphoma relapsed despite a dramatic increase of Vδ1+ T cells in the patient's blood. In vitro killing assays revealed activity of patient's γδ cells against CMV target cells, but not against the relapsing lymphoma-cells. This argues for a contribution of Vδ1+ cells in the immune reaction against CMV reactivation, but does not support a strong correlation of expanded Vδ1+ T cells and favorable disease outcome in B-CLL patients.

Monocyte to macrophage differentiation-associated (MMD) targeted by miR-140-5p regulates tumor growth in non-small cell lung cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, Weina, E-mail: liweina228@163.com; He, Fei, E-mail: hesili1027@163.com

2014-07-18

Highlights: • Expression of MMD is increased in lung cancer tissues. • Knockdown of MMD inhibits growth of A549 and LLC cells in vitro and in vivo. • MMD is a direct functional target of miR-140-5p. • MiR-140-5p/MMD axis regulates Erk1/2 signaling. - Abstract: Monocyte to macrophage differentiation-associated (MMD) is identified in macrophages as a gene associated with the differentiation from monocytes to macrophages. Recent microarray analysis for non-small cell lung cancer (NSCLC) suggests that MMD is an important signature associated with relapse and survival among patients with NSCLC. Therefore, we speculate that MMD likely plays a role in lungmore » cancer. In this study, we found that the protein level of MMD was increased in lung cancer compared to benign lung tissues, and knockdown of MMD inhibited the growth of A549 and Lewis lung cancer cells (LLC) in vitro and in vivo. Integrated analysis demonstrated that MMD was a direct functional target of miR-140-5p. Furthermore, we found that miR-140-5p/MMD axis could affect the cell proliferation of lung cancer cells by regulating Erk signaling. Together, our results highlight the significance of miR-140-5p/MMD axis in lung cancer, and miR-140-5p/MMD axis could serve as new molecular targets for the therapy against lung cancer.« less

Highly elevated serum lactate dehydrogenase is associated with central nervous system relapse in patients with diffuse large B-cell lymphoma: Results of a multicenter prospective cohort study.

PubMed

Kim, Seok Jin; Hong, Jun Sik; Chang, Myung Hee; Kim, Jeong-A; Kwak, Jae-Yong; Kim, Jin Seok; Yoon, Dok Hyun; Lee, Won Sik; Do, Young Rok; Kang, Hye Jin; Eom, Hyeon-Seok; Park, Yong; Won, Jong-Ho; Mun, Yeung-Chul; Kim, Hyo Jung; Kwon, Jung Hye; Kong, Jee Hyun; Oh, Sung Yong; Lee, Sunah; Bae, Sung Hwa; Yang, Deok-Hwan; Jun, Hyun Jung; Kim, Yang Soo; Yun, Hwan Jung; Lee, Soon Il; Kim, Min Kyoung; Park, Eun Kyung; Kim, Won Seog; Suh, Cheolwon

2016-11-01

Central nervous system involvement remains a challenging issue in the treatment of patients with diffuse large B-cell lymphoma. We conducted a prospective cohort study with newly diagnosed diffuse large B-cell lymphoma patients receiving rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone to identify incidence and risk factors for central nervous system involvement. Among 595 patients, 279 patients received pre-treatment central nervous system evaluation, and 14 patients had central nervous system involvement at diagnosis (2.3% out of entire patients and 5.0% out of the 279 patients). For those patients, median follow-up duration was 38.2 months and some of them achieved long-term survival. Out of 581 patients who did not have central nervous system involvement at diagnosis, 26 patients underwent secondary central nervous system relapse with a median follow-up of 35 months, and the median time to central nervous system involvement was 10.4 months (range: 3.4-29.2). Serum lactate dehydrogenase > ×3 upper limit of normal range, the Eastern Cooperative Oncology Group performance status ≥ 2, and involvement of sinonasal tract or testis, were independent risk factors for central nervous system relapse in multivariate analysis. Our study suggests that enhanced stratification of serum lactate dehydrogenase according to the National Comprehensive Cancer Network-International Prognostic Index may contribute to better prediction for central nervous system relapse in patients with diffuse large B-cell lymphoma. This trial was registered at clinicaltrials.gov identifier: 01202448.

Highly elevated serum lactate dehydrogenase is associated with central nervous system relapse in patients with diffuse large B-cell lymphoma: Results of a multicenter prospective cohort study

PubMed Central

Kim, Seok Jin; Hong, Jun Sik; Chang, Myung Hee; Kim, Jeong-A; Kwak, Jae-Yong; Kim, Jin Seok; Yoon, Dok Hyun; Lee, Won Sik; Do, Young Rok; Kang, Hye Jin; Eom, Hyeon-Seok; Park, Yong; Won, Jong-Ho; Mun, Yeung-Chul; Kim, Hyo Jung; Kwon, Jung Hye; Kong, Jee Hyun; Oh, Sung Yong; Lee, Sunah; Bae, Sung Hwa; Yang, Deok-Hwan; Jun, Hyun Jung; Kim, Yang Soo; Yun, Hwan Jung; Il Lee, Soon; Kim, Min Kyoung; Park, Eun Kyung; Kim, Won Seog; Suh, Cheolwon

2016-01-01

Central nervous system involvement remains a challenging issue in the treatment of patients with diffuse large B-cell lymphoma. We conducted a prospective cohort study with newly diagnosed diffuse large B-cell lymphoma patients receiving rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone to identify incidence and risk factors for central nervous system involvement. Among 595 patients, 279 patients received pre-treatment central nervous system evaluation, and 14 patients had central nervous system involvement at diagnosis (2.3% out of entire patients and 5.0% out of the 279 patients). For those patients, median follow-up duration was 38.2 months and some of them achieved long-term survival. Out of 581 patients who did not have central nervous system involvement at diagnosis, 26 patients underwent secondary central nervous system relapse with a median follow-up of 35 months, and the median time to central nervous system involvement was 10.4 months (range: 3.4–29.2). Serum lactate dehydrogenase > ×3 upper limit of normal range, the Eastern Cooperative Oncology Group performance status ≥ 2, and involvement of sinonasal tract or testis, were independent risk factors for central nervous system relapse in multivariate analysis. Our study suggests that enhanced stratification of serum lactate dehydrogenase according to the National Comprehensive Cancer Network-International Prognostic Index may contribute to better prediction for central nervous system relapse in patients with diffuse large B-cell lymphoma. This trial was registered at clinicaltrials.gov identifier: 01202448. PMID:27713132

Bruton tyrosine kinase inhibition in chronic lymphocytic leukemia.

PubMed

Maddocks, Kami; Jones, Jeffrey A

2016-04-01

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia and remains incurable outside of the setting of allogeneic stem cell transplant. While the standard therapy for both initial and relapsed CLL has traditionally included monoclonal antibody therapy in combination with chemotherapy, there are patients with high-risk disease features including unmutated IgVH, del(11q22) and del(17p13) that are associated with poor overall responses to these therapies with short time to relapse and shortened overall survival. Additionally, many of these therapies have a high rate of infectious toxicity in a population already at increased risk. Targeting the B-cell receptor (BCR) signaling pathway has emerged as a promising therapeutic advance in a variety of B-cell malignancies, including CLL. Bruton agammaglobulinemia tyrosine kinase (Btk) is a tyrosine kinase in the BCR pathway critical to the survival of both normal and malignant B cells and inhibition of this kinase has shown to block the progression of CLL. Ibrutinib, a first in class oral inhibitor of Btk, has shown promise as a very effective agent in the treatment of CLL-in both relapsed and upfront therapy, alone and in combination with other therapies, and in patients of all-risk disease-which has led to its approval in relapsed CLL and as frontline therapy in patients with the high-risk del(17p13) disease. Several studies are ongoing to evaluate the efficacy and safety of ibrutinib in combination with chemotherapy as frontline treatment for CLL and investigation into newer-generation Btk inhibitors is also underway. Copyright © 2016 Elsevier Inc. All rights reserved.

[Ibrutinib: A new drug of B-cell malignancies].

PubMed

Thieblemont, Catherine

2015-06-01

Ibrutinib (Imbruvica®) is a first-in-class, orally administered once-daily, that inhibits B-cell antigen receptor signaling downstream of Bruton's tyrosine kinase (BTK). Ibrutinib has been approved in USA in February 2014 and in France in October 2014 for the treatment of patients with relapsed/refractory mantle cell lymphoma (MCL) or chronic lymphocytic leukaemia (CLL) and for the treatment of patients with CLL and a chromosome 17 deletion (del 17p) or TP53 mutation. In clinical studies, ibrutinib induced an impressive overall response rate (68%) in patients with relapsed/refractory MCL (phase II study). In CLL, ibrutinib has shown to significantly improve progression-free survival, response rate and overall survival in patients with relapsed/refractory CLL, including in those with del 17p. Ibrutinib had an acceptable tolerability profile. Less than 10% of patients discontinued their treatment because of adverse events. Results are pending in other B-cell lymphomas subtypes such as in diffuse large B-cell lymphoma and in follicular lymphoma. An approval extension has already been enregistered for Waldenström disease in USA in January 2015. Given its efficacy and tolerability, ibrutinib is an emerging treatment option for patients with B-cell malignancies. Copyright © 2015 Société Françise du Cancer. Publié par Elsevier Masson SAS. Tous droits réservés. Published by Elsevier Masson SAS. All rights reserved.

Rituximab after lymphoma-directed conditioning and allogeneic stem-cell transplantation for relapsed and refractory aggressive non-Hodgkin lymphoma (DSHNHL R3): an open-label, randomised, phase 2 trial.

PubMed

Glass, Bertram; Hasenkamp, Justin; Wulf, Gerald; Dreger, Peter; Pfreundschuh, Michael; Gramatzki, Martin; Silling, Gerda; Wilhelm, Christian; Zeis, Matthias; Görlitz, Anke; Pfeiffer, Sebastian; Hilgers, Reinhard; Truemper, Lorenz; Schmitz, Norbert

2014-06-01

Allogeneic stem-cell transplantation has had limited success for patients with refractory and relapsed aggressive B-cell or T-cell lymphoma. We investigated the effect of adding rituximab to standard prophylaxis for graft-versus-host disease after transplantation and estimated overall survival when using a lymphoma-directed myeloablative conditioning regimen. We did this randomised, open-label, phase 2 study at seven German transplantation centres. We enrolled patients with aggressive B-cell or T-cell lymphoma and primary refractory disease, early relapse (<12 months after first-line treatment), or relapse after autologous transplantation. Conditioning with fludarabine (125 mg/m(2)), busulfan (12 mg/kg oral or 9·6 mg/kg intravenous), and cyclophosphamide (120 mg/kg) was followed by allogeneic stem-cell transplantation. Patients were randomly assigned (1:1) to receive rituximab (375 mg/m(2) on days 21, 28, 35, 42, 175, 182, 189, and 196) or not. Allocation was done with a centralised computer-generated procedure; patients were stratified by histological subtype (B-cell vs T-cell lymphoma) and donor match (HLA-identical vs non-identical). Neither investigators nor patients were masked to allocation. The primary endpoints were the incidence of acute graft-versus-host disease grade 2-4 in each treatment group and overall survival at 1 year in both groups combined. All analyses were done for the intention-to-treat population. The study is registered with ClinicalTrials.gov, number NCT00785330. Between June 16, 2004, and March 24, 2009, we screened 86 patients and enrolled 84; 42 were randomly assigned to each group. The cumulative incidence of grade 2-4 acute graft-versus-host disease was 46% (95% CI 32-62) in the rituximab group and 42% (95% CI 29-59) in the no rituximab group (hazard ratio [HR] 0·91, 95% CI 0·52-1·60; p=0·74). Overall survival at 1 year for the whole study population was 52% (95% CI 41-62). Grade 4 haematological toxic effects and grade 3 alopecia occurred in all patients. The most common non-haematological grade 5 toxic effects were pneumonia (nine in the no rituximab group vs ten in the rituximab group) and other infections (seven vs four). The lymphoma-directed myeloablative conditioning regimen developed here is promising for patients with refractory and relapsed aggressive B-cell and T-cell lymphomas. However, the addition of rituximab did not affect the incidence of graft-versus-host disease or overall survival. Hoffmann-La Roche, Amgen, Astellas Pharma. Copyright © 2014 Elsevier Ltd. All rights reserved.

Nivolumab With or Without Varlilumab in Treating Patients With Relapsed or Refractory Aggressive B-cell Lymphomas

ClinicalTrials.gov

2018-06-11

ALK-Positive Large B-Cell Lymphoma; Atypical Burkitt/Burkitt-Like Lymphoma; Burkitt-Like Lymphoma With 11q Aberration; Diffuse Large B-Cell Lymphoma Activated B-Cell Type; Diffuse Large B-Cell Lymphoma Associated With Chronic Inflammation; Diffuse Large B-Cell Lymphoma Germinal Center B-Cell Type; Diffuse Large B-Cell Lymphoma, Not Otherwise Specified; EBV-Positive Diffuse Large B-Cell Lymphoma, Not Otherwise Specified; EBV-Positive Mucocutaneous Ulcer; High-Grade B-Cell Lymphoma With MYC, BCL2, and BCL6 Rearrangements; Human Herpesvirus 8-Positive Neoplastic Cells Present; Intravascular Large B-Cell Lymphoma; Large B-Cell Lymphoma With IRF4 Rearrangement; Plasmablastic Lymphoma; Primary Cutaneous Diffuse Large B-Cell Lymphoma; Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type; Primary Diffuse Large B-Cell Lymphoma of the Central Nervous System; Primary Effusion Lymphoma; Recurrent B-Cell Lymphoma, Unclassifiable, With Features Intermediate Between Diffuse Large B-Cell Lymphoma and Classic Hodgkin Lymphoma; Recurrent Burkitt Lymphoma; Recurrent Diffuse Large B-Cell Lymphoma; Recurrent Lymphomatoid Granulomatosis; Recurrent Primary Mediastinal (Thymic) Large B-Cell Cell Lymphoma; Refractory B-Cell Lymphoma, Unclassifiable, With Features Intermediate Between Diffuse Large B-Cell Lymphoma and Classic Hodgkin Lymphoma; Refractory Burkitt Lymphoma; Refractory Diffuse Large B-Cell Lymphoma; Refractory Primary Mediastinal (Thymic) Large B-Cell Cell Lymphoma; Small Intestinal High Grade B-Cell Lymphoma, Not Otherwise Specified; T-Cell/Histiocyte-Rich Large B-Cell Lymphoma

High-Dose Y-90-Ibritumomab Tiuxetan Added to Reduced-Intensity Allogeneic Stem Cell Transplant Regimen for Relapsed or Refractory Aggressive B-Cell Lymphoma

ClinicalTrials.gov

2017-12-04

Post-Transplant Lymphoproliferative Disorder; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent B-Cell Non-Hodgkin Lymphoma; Recurrent Burkitt Lymphoma; Refractory B-Cell Non-Hodgkin Lymphoma; Refractory Burkitt Lymphoma; Refractory Diffuse Large B-Cell Lymphoma

Ibrutinib Before and After Stem Cell Transplant in Treating Patients With Relapsed or Refractory Diffuse Large B-cell Lymphoma

ClinicalTrials.gov

2018-06-25

Diffuse Large B-Cell Lymphoma Activated B-Cell Type; Diffuse Large B-Cell Lymphoma, Not Otherwise Specified; High Grade B-Cell Lymphoma, Not Otherwise Specified; Recurrent Burkitt Lymphoma; Recurrent Diffuse Large B-Cell Lymphoma; Refractory Burkitt Lymphoma; Refractory Diffuse Large B-Cell Lymphoma

Deciphering KRAS and NRAS mutated clone dynamics in MLL-AF4 paediatric leukaemia by ultra deep sequencing analysis.

PubMed

Trentin, Luca; Bresolin, Silvia; Giarin, Emanuela; Bardini, Michela; Serafin, Valentina; Accordi, Benedetta; Fais, Franco; Tenca, Claudya; De Lorenzo, Paola; Valsecchi, Maria Grazia; Cazzaniga, Giovanni; Kronnie, Geertruy Te; Basso, Giuseppe

2016-10-04

To induce and sustain the leukaemogenic process, MLL-AF4+ leukaemia seems to require very few genetic alterations in addition to the fusion gene itself. Studies of infant and paediatric patients with MLL-AF4+ B cell precursor acute lymphoblastic leukaemia (BCP-ALL) have reported mutations in KRAS and NRAS with incidences ranging from 25 to 50%. Whereas previous studies employed Sanger sequencing, here we used next generation amplicon deep sequencing for in depth evaluation of RAS mutations in 36 paediatric patients at diagnosis of MLL-AF4+ leukaemia. RAS mutations including those in small sub-clones were detected in 63.9% of patients. Furthermore, the mutational analysis of 17 paired samples at diagnosis and relapse revealed complex RAS clone dynamics and showed that the mutated clones present at relapse were almost all originated from clones that were already detectable at diagnosis and survived to the initial therapy. Finally, we showed that mutated patients were indeed characterized by a RAS related signature at both transcriptional and protein levels and that the targeting of the RAS pathway could be of beneficial for treatment of MLL-AF4+ BCP-ALL clones carrying somatic RAS mutations.

Case report: retroperitoneal fibrosis simulating local relapse of sarcomatoid renal cell carcinoma.

PubMed

Esquena, Salvador; Abascal, José Maria; Trilla, Enrique; De Torres, Inés; Morote, Juan

2006-01-01

Generally, retroperitoneal fibrosis is an idiopathic process that envelopes and displaces ureters, causing hydronefrosis and renal failure. CT scan is the best choice for diagnosis. Other aetiologies described are malignancies, drugs, aorta aneurisms and immunological or rheumatological diseases. A 53-year-old male with hypertension and diabetes was operated on radical nephrectomy for renal mass. Pathological examination showed sarcomatoid renal cell carcinoma, Fürhman 3 grade, pT2 N0. Within 6 months of surgery, control CT scan demonstrated a left retroperitoneal mass, without separation with pancreas queue and spleen hilium, suggesting local relapse. Resection of the mass with splenectomy and partial pancreatectomy en bloc was performed. Microscopic evaluation revealed a dense collagenic tissue with a prominent inflammatory infiltrate, and the immunohistochemical study was negative for cytokeratin AE1-AE3. There was no evidence of malignancy in the histological examination. All these findings aided to diagnose a retroperitoneal fibrosis. Sometimes retroperitoneal fibrosis can simulate or is associated to malignancies. Presentation of a retroperitoneal fibrosis simulating local relapse of sarcomatoid renal cell carcinoma has not been previously reported in the English literature.

[Use of alternative donors for allogeneic haematopoietic cell transplantation in lymphoid neoplasms: Guidelines from the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC)].

PubMed

Gauthier, Jordan; Chantepie, Sylvain; Bouabdallah, Krimo; Jost, Edgar; Nguyen, Stéphanie; Gac, Anne-Claire; Damaj, Gandhi; Duléry, Rémy; Michallet, Mauricette; Delage, Jérémy; Lewalle, Philippe; Morschhauser, Franck; Salles, Gilles; Yakoub-Agha, Ibrahim; Cornillon, Jérôme

2017-12-01

Despite great improvements in the outcome of patients with lymphoma, some may still relapse or present with primary refractory disease. In these situations, allogeneic haematopoietic cell transplantation (allo-HCT) is a potentially curative option, in particular in the case of relapse after autologous stem cell transplantation. Recently, novel agents such as anti-PD1 and BTK inhibitors have started to challenge the use of allo-HCT for relapsed or refractory lymphoma. During the 2016 annual workshop of the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC), we performed a comprehensive review of the literature published in the last 10 years and established guidelines to clarify the indications and transplant modalities in this setting. This manuscript reports on general considerations regarding allo-HCT for lymphoma and elaborates on the use of alternative donors in this setting. Copyright © 2017 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.

Lymphocyte Infusion in Treating Patients With Relapsed Cancer After Bone Marrow or Peripheral Stem Cell Transplantation

ClinicalTrials.gov

2011-11-28

Breast Cancer; Chronic Myeloproliferative Disorders; Gestational Trophoblastic Tumor; Kidney Cancer; Leukemia; Lymphoma; Multiple Myeloma and Plasma Cell Neoplasm; Myelodysplastic Syndromes; Neuroblastoma; Ovarian Cancer; Sarcoma; Testicular Germ Cell Tumor

High expression of long non-coding RNA MALAT1 in breast cancer is associated with poor relapse-free survival.

PubMed

Wang, Zhanwei; Katsaros, Dionyssios; Biglia, Nicoletta; Shen, Yi; Fu, Yuanyuan; Loo, Lenora W M; Jia, Wei; Obata, Yuki; Yu, Herbert

2018-05-29

Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) has been identified as a prognostic marker for the metastasis of early-stage non-small cell lung cancer (NSCLCs). We studied MALAT1 expression in breast cancer in relation to disease features and patient survival. Quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) was used to measure MALAT1 expression in tumor samples of 509 breast cancer patients. Hazards ratios (HRs) and 95% confidence intervals (CIs) were calculated to assess the association between MALAT1 expression and breast cancer survival using the Cox proportional hazards regression model, and the analysis was adjusted for age at surgery, tumor grade, disease stage, and hormone receptor status. Meta-analysis of multiple microarray datasets from online databases and our own study was performed to evaluate the association of MALAT1 with breast cancer survival. Patients with low-grade or ER-positive tumors had higher expression of MALAT1 compared to those with high-grade (p = 0.013) or ER-negative (p = 0.0002) tumors. Patients with PR-positive tumors also had higher MALAT1 expression than those with PR-negative tumors (p < 0.0001). In patients with positive hormone receptors or low tumor grade, tumors with high MALAT1 expression were more likely to recur. Survival analysis showed that patients with high expression of MALAT1 had a twofold increase in risk of relapse (p = 0.0083) compared to those with low expression. This association remained significant after adjustment for age at surgery, disease stage, tumor grade, and hormone receptor status. Meta-analysis showed that high MALAT1 expression was associated with poor relapse-free survival in patients with hormone receptor-positive tumors (HR 1.44, 95% CI 1.08-1.92). High expression of lncRNA MALAT1 is associated with breast cancer relapse and may play a role in tumor progression.

Recent Developments in Cellular Immunotherapy for HSCT-Associated Complications

PubMed Central

Reis, Monica; Ogonek, Justyna; Qesari, Marsela; Borges, Nuno M.; Nicholson, Lindsay; Preußner, Liane; Dickinson, Anne Mary; Wang, Xiao-nong; Weissinger, Eva M.; Richter, Anne

2016-01-01

Allogeneic hematopoietic stem cell transplantation is associated with serious complications, and improvement of the overall clinical outcome of patients with hematological malignancies is necessary. During the last decades, posttransplant donor-derived adoptive cellular immunotherapeutic strategies have been progressively developed for the treatment of graft-versus-host disease (GvHD), infectious complications, and tumor relapses. To date, the common challenge of all these cell-based approaches is their implementation for clinical application. Establishing an appropriate manufacturing process, to guarantee safe and effective therapeutics with simultaneous consideration of economic requirements is one of the most critical hurdles. In this review, we will discuss the recent scientific findings, clinical experiences, and technological advances for cell processing toward the application of mesenchymal stromal cells as a therapy for treatment of severe GvHD, virus-specific T cells for targeting life-threating infections, and of chimeric antigen receptors-engineered T cells to treat relapsed leukemia. PMID:27895644

[Allogeneic haematopoietic cell transplantation for diffuse large B cell lymphoma: Guidelines from the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC)].

PubMed

Gauthier, Jordan; Chantepie, Sylvain; Bouabdallah, Krimo; Jost, Edgar; Nguyen, Stéphanie; Gac, Anne-Claire; Damaj, Gandhi; Duléry, Rémy; Michallet, Mauricette; Delage, Jérémy; Lewalle, Philippe; Morschhauser, Franck; Salles, Gilles; Yakoub-Agha, Ibrahim; Cornillon, Jérôme

2017-12-01

Despite great improvements in the outcome of patients with lymphoma, some may still relapse or present with primary refractory disease. In these situations, allogeneic hematopoietic cell transplantation is a potentially curative option, this is true particularly in the case of after autologous stem cell transplantation if remission can be achieved. Recently, novel agents such as anti-PD1 and BTK inhibitors have started to challenge the use of allogeneic hematopoietic cell transplantation for relapsed or refractory lymphoma. During the 2016 annual workshop of the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC), we performed a comprehensive review of the literature published in the last 10 years and established guidelines to clarify the indications and transplant modalities in this setting. This section specifically reports on our conclusions regarding diffuse large B cell lymphoma. Copyright © 2017. Published by Elsevier Masson SAS.

CNS Plasmacytoid Dendritic Cells Regulate the Severity of Relapsing Experimental Autoimmune Encephalomyelitis1

PubMed Central

Bailey-Bucktrout, Samantha L.; Caulkins, Sarah C.; Goings, Gwendolyn; Fischer, Jens A. A.; Dzionek, Andrzej; Miller, Stephen D.

2010-01-01

Plasmacytoid dendritic cells (pDC) have both stimulatory and regulatory effects on T cells. pDCs are a major CNS-infiltrating DC population during experimental autoimmune encephalomyelitis (EAE), but unlike myeloid DCs (mDC) have a minor role in T cell activation and epitope spreading. We show that depletion of pDCs during either the acute or relapse phases of EAE resulted in exacerbation of disease severity. pDC depletion significantly enhanced CNS but not peripheral CD4+ T cell activation, as well as IL-17 and IFN-γ production. Moreover, CNS pDCs suppressed CNS mDC-driven production of IL-17, IFN-γ and IL-10 in an IDO-independent manner. The data demonstrate that pDCs play a critical regulatory role in negatively regulating pathogenic CNS CD4+ T cell responses highlighting a new role for pDCs in inflammatory autoimmune disease. PMID:18453561

A Review of Autologous Stem Cell Transplantation in Lymphoma.

PubMed

Zahid, Umar; Akbar, Faisal; Amaraneni, Akshay; Husnain, Muhammad; Chan, Onyee; Riaz, Irbaz Bin; McBride, Ali; Iftikhar, Ahmad; Anwer, Faiz

2017-06-01

Chemotherapy remains the first-line therapy for aggressive lymphomas. However, 20-30% of patients with non-Hodgkin lymphoma (NHL) and 15% with Hodgkin lymphoma (HL) recur after initial therapy. We want to explore the role of high-dose chemotherapy (HDT) and autologous stem cell transplant (ASCT) for these patients. There is some utility of upfront consolidation for-high risk/high-grade B-cell lymphoma, mantle cell lymphoma, and T-cell lymphoma, but there is no role of similar intervention for HL. New conditioning regimens are being investigated which have demonstrated an improved safety profile without compromising the myeloablative efficiency for relapsed or refractory HL. Salvage chemotherapy followed by HDT and rescue autologous stem cell transplant remains the standard of care for relapsed/refractory lymphoma. The role of novel agents to improve disease-related parameters remains to be elucidated in frontline induction, disease salvage, and high-dose consolidation or in the maintenance setting.

MiR-9-5p and miR-106a-5p dysregulated in CD4+ T-cells of multiple sclerosis patients and targeted essential factors of T helper17/regulatory T-cells differentiation

PubMed Central

Majd, Maryam; Hosseini, Aref; Ghaedi, Kamran; Kiani-Esfahani, Abbas; Tanhaei, Somayeh; Shiralian-Esfahani, Hanieh; Rahnamaee, Seyed Yahya; Mowla, Seyed Javad; Nasr-Esfahani, Mohammad Hossein

2018-01-01

Objective(s): Multiple sclerosis (MS) is considered as a chronic type of an inflammatory disease characterized by loss of myelin of CNS. Recent evidence indicates that Interleukin 17 (IL-17)-producing T helper cells (Th17 cells) population are increased and regulatory T cells (Treg cells) are decreased in MS. Despite extensive research in understanding the mechanism of Th17 and Treg differentiation, the role of microRNAs in MS is not completely understood. Thereby, as a step closer, we analyzed the expression profile of miR-9-5p and miR-106a-5p, and protein level of retinoic acid receptor (RAR)-related orphan receptor C (RORC; Th17 master transcription factor) as direct target of miR-106a-5p and forkhead box P3 (FOXP3; Treg master transcription factor) as indirect target of miR-9-5p in CD4+ T cells in two groups of relapsing and remitting in our relapsing-remitting MS (RR-MS) patients. Materials and Methods: Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was utilized to assess the expression of miRNAs and mRNAs, in 40 RR-MS patients and 11 healthy individuals. Thus, FOXP3 and RAR-related orphan receptor γt (RORγt) was assessed in CD4+T-cells by flow cytometry. We also investigated the role of these miRNAs in Th17/Treg differentiation pathway through bioinformatics tools. Results: An up-regulation of miR-9-5p and down-regulation of miR-106a-5p in relapsing phase of MS patients were observed compared to healthy controls. RORC and FOXP3 were up-regulated in relapsing and remitting phases of MS, respectively. Conclusion: Expression pattern of miR-9-5p and miR-106a-5p and their targets suggest a possible inducing role of miR-9-5p and suppressing role of miR-106a-5p in differentiation pathway of Th17 cells during MS pathogenesis. PMID:29511494

Autologous hematopoietic stem cell transplantation in peripheral T-cell lymphoma using a uniform high-dose regimen.

PubMed

Smith, S D; Bolwell, B J; Rybicki, L A; Brown, S; Dean, R; Kalaycio, M; Sobecks, R; Andresen, S; Hsi, E D; Pohlman, B; Sweetenham, J W

2007-08-01

The role of high-dose therapy and autologous stem cell transplantation (ASCT) for patients with peripheral T-cell lymphoma (PTCL) is poorly defined. Comparisons of outcomes between PTCL and B-cell non-Hodgkin's lymphoma (NHL) have yielded conflicting results, in part due to the rarity and heterogeneity of PTCL. Some retrospective studies have found comparable survival rates for patients with T- and B-cell NHL. In this study, we report our single-center experience of ASCT over one decade using a uniform chemotherapy-only high-dose regimen. Thirty-two patients with PTCL-unspecified (PTCL-u; 11 patients) and anaplastic large-cell lymphoma (21 patients) underwent autologous stem cell transplant, mostly for relapsed or refractory disease. The preparative regimen consisted of busulfan, etoposide and cyclophosphamide. Kaplan-Meier 5-year overall survival (OS) and relapse-free survival (RFS) are 34 and 18%, respectively. These results suggest a poor outcome for patients with PTCL after ASCT, and new therapies for T-cell lymphoma are needed.

Outcome of patients with intracranial non-germinomatous germ cell tumors-lessons from the SIOP-CNS-GCT-96 trial.

PubMed

Calaminus, Gabriele; Frappaz, Didier; Kortmann, Rolf Dieter; Krefeld, Barbara; Saran, Frank; Pietsch, Torsten; Vasiljevic, Alexandre; Garre, Maria Luisa; Ricardi, Umberto; Mann, Jillian R; Göbel, Ulrich; Alapetite, Claire; Murray, Matthew J; Nicholson, James C

2017-11-29

Following promising results to increase survival and reduce treatment burden in intracranial non-germinomatous germ cell tumors (NGGCTs), we conducted a European study using dose-intense chemotherapy followed by risk-adapted radiotherapy. All patients received 4 courses of cisplatin/etoposide/ifosfamide. Non-metastatic patients then received focal radiotherapy only (54 Gy); metastatic patients received 30 Gy craniospinal radiotherapy with 24 Gy boost to primary tumor and macroscopic metastatic sites. Patients with localized malignant NGGCT (n = 116) demonstrated 5-year progression-free survival (PFS) and overall survival (OS) of 0.72 ± 0.04 and 0.82 ± 0.04, respectively. Primary tumor sites were: 67 pineal, 35 suprasellar, 5 bifocal, 9 others. One patient died postsurgery in clinical remission; 3 patients progressed during treatment and 27 (23%) relapsed afterward. Fourteen were local, 6 combined, and 7 distant relapses (outside radiation field). Seventeen of the 27 relapsed patients died of disease. Patients with metastatic disease (n = 33) demonstrated 5-year PFS and OS of 0.68 ± 0.09 and 0.75 ± 0.08, respectively; 1 patient died following progression on treatment and 9 (27%) relapsed afterward (5 local, 1 combined, 3 distant). Only one metastatic patient with recurrence was salvaged. Multivariate analysis identified diagnostic alpha-fetoprotein level (serum and/or cerebrospinal fluid level >1000 ng/mL, 19/149 patients, of whom 11 relapsed; P < 0.0003) and residual disease following treatment, including after second-look surgery (n = 52/145 evaluable patients, 26 relapsed; P = 0.0002) as significant prognostic indicators in this cohort. In localized malignant NGGCT, craniospinal radiotherapy could be avoided without increased relapses outside the radiotherapy field. Chemotherapy and craniospinal radiotherapy remain the gold standard for metastatic disease. © The Author(s) 2017. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

Long-Term Outcomes and Patterns of Relapse of Early-Stage Extranodal Marginal Zone Lymphoma Treated With Radiation Therapy With Curative Intent

DOE Office of Scientific and Technical Information (OSTI.GOV)

Teckie, Sewit; Qi, Shunan; Lovie, Shona

Purpose: To report the long-term outcome and patterns of relapse of a large cohort of marginal zone lymphoma (MZL) patients treated with curative-intent radiation therapy (RT) alone. Patients and Methods: We reviewed the charts of 490 consecutive patients with stage IE or IIE MZL referred between 1992 and 2012 to our institution. Of those, 244 patients (50%) were treated with RT alone. Pathology was confirmed by hematopathologists at our institution. Patient and disease factors were analyzed for association with relapse-free survival (RFS) and overall survival (OS). Results: Median age of the cohort was 59 years, and median follow-up was 5.2 years. Annmore » Arbor stage was IE in 92%. Most common disease sites were stomach (50%), orbit (18%), non-thyroid head-and-neck (8%), skin (8%), and breast (5%). Median RT dose was 30 Gy. Five-year OS and RFS were 92% and 74%, respectively. Cumulative incidence of disease-specific death was just 1.1% by 5 years. Sixty patients (24%) developed relapse of disease; 10 were in the RT field. Crude rate of transformation to pathologically confirmed large-cell lymphoma was 1.6%. On multivariable analysis, primary disease site (P=.007) was independently associated with RFS, along with age (P=.04), presence of B-symptoms (P=.02), and International Prognostic Index risk group (P=.03). All disease sites except for head-and-neck had worse RFS relative to stomach. Conclusion: Overall and cause-specific survival are high in early-stage extra-nodal MZL treated with curative RT alone. In this large cohort of 244 patients, most patients did not experience relapse of MZL after curative RT; when relapses did occur, the majority were in distant sites. Stomach cases were less likely to relapse than other anatomic sites. Transformation to large-cell lymphoma was rare.« less

Controversies in autologous and allogeneic hematopoietic cell transplantation in peripheral T/NK-cell lymphomas.

PubMed

Shustov, Andrei

2013-03-01

Peripheral T-cell and NK-cell lymphomas (PT/NKCL) are a heterogeneous group of lymphoid neoplasms with poor outcomes. There is no consensus on the best front line therapy or management of relapsed/refractory disease. The use of autologous and allogeneic hematopoietic cell transplantation (HCT) has been studied in both settings to improve outcomes. Multiple retrospective and several prospective trials were reported. While at first sight the outcomes in the relapsed/refractory setting appear similar in B-cell and T-cell lymphomas when treated with high dose therapy (HDT) and autologous HCT, it is becoming obvious that only specific subtypes of PTCL benefit from this approach (i.e. anaplastic large cell lymphoma [ALCL] and angioimmunoblastic lymphoma [AITL] in second CR). In less favorable histologies, HDT seems to provide limited benefit, with the majority of patients experiencing post-transplant relapse. The use of autologous HCT to consolidate first remission has been evaluated in several prospective trials. Again, the best results were observed in ALCL, but the superiority of this approach over chemotherapy alone needs confirmation in randomized trials. In less favorable histologies, high-dose consolidation resulted in low survival rates comparable to those obtained with chemotherapy alone, and without randomized trials it is hard to recommend this strategy to all patients with newly diagnosed PT/NKCL. Allogeneic HCT might provide potent and potentially curative graft-vs-lymphoma effect and overcome chemotherapy resistance. Only a few studies have been reported to date on allogeneic HCT in PT/NKCL. Based on available data, eligible patients benefit significantly from this approach, with 50% or more patients achieving long-term disease control or cure, although at the expense of significant treatment related mortality (TRM). Reduced-intensity conditioning regimens appear to have lower TRM and might extend this approach to older patients. With the recent approval of several novel agents for relapsed/refractory PT/NKCL and their impact on survival of patients after relapse, it is becoming even more difficult to assess the benefit of HCT on overall survival and apply the results of non-randomized studies to clinical practice. Development of effective clinico-pathologic prognostic models might provide the opportunity to better define the role of HCT for patients with various subtypes of PT/NKCL. The first randomized trial comparing upfront autologous and allogeneic HCT was initiated by the German High-Grade Non-Hodgkin Lymphoma Study Group, and the results of this study might help answer some of the controversies for the first time. Copyright © 2013. Published by Elsevier Ltd.

Iodine I 131 Monoclonal Antibody BC8 Before Autologous Stem Cell Transplant in Treating Patients With Relapsed or Refractory Hodgkin Lymphoma or Non-Hodgkin Lymphoma

ClinicalTrials.gov

2017-11-15

Recurrent B-Cell Non-Hodgkin Lymphoma; Recurrent Hodgkin Lymphoma; Recurrent T-Cell Non-Hodgkin Lymphoma; Refractory B-Cell Non-Hodgkin Lymphoma; Refractory Hodgkin Lymphoma; Refractory T-Cell Non-Hodgkin Lymphoma

Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study.

PubMed

Topp, Max S; Gökbuget, Nicola; Stein, Anthony S; Zugmaier, Gerhard; O'Brien, Susan; Bargou, Ralf C; Dombret, Hervé; Fielding, Adele K; Heffner, Leonard; Larson, Richard A; Neumann, Svenja; Foà, Robin; Litzow, Mark; Ribera, Josep-Maria; Rambaldi, Alessandro; Schiller, Gary; Brüggemann, Monika; Horst, Heinz A; Holland, Chris; Jia, Catherine; Maniar, Tapan; Huber, Birgit; Nagorsen, Dirk; Forman, Stephen J; Kantarjian, Hagop M

2015-01-01

Adults with relapsed or refractory B-precursor acute lymphoblastic leukaemia have an unfavourable prognosis. Blinatumomab is a bispecific T-cell engager antibody construct targeting CD19, an antigen consistently expressed on B-lineage acute lymphoblastic leukaemia cells. We aimed to confirm the activity and safety profile of blinatumomab for acute lymphoblastic leukaemia. In a multicentre, single-arm, open-label phase 2 study, we enrolled adult patients with Philadelphia-chromosome-negative, primary refractory or relapsed (first relapse within 12 months of first remission, relapse within 12 months after allogeneic haemopoietic stem-cell transplantation [HSCT], or no response to or relapse after first salvage therapy or beyond) leukaemia. Patients received blinatumomab (9 μg/day for the first 7 days and 28 μg/day thereafter) by continuous intravenous infusion over 4 weeks every 6 weeks (up to five cycles), per protocol. The primary endpoint was complete remission (CR) or CR with partial haematological recovery of peripheral blood counts (CRh) within the first two cycles. Analysis was by intention to treat. This trial is registered at ClinicalTrials.gov, number NCT01466179. Between Jan 13, 2012, and Oct 10, 2013, 189 patients were enrolled and treated with blinatumomab. After two cycles, 81 (43%, 95% CI 36-50) patients had achieved a CR or CRh: 63 (33%) patients had a CR and 18 (10%) patients had a CRh. 32 (40%) of patients who achieved CR/CRh underwent subsequent allogeneic HSCT. The most frequent grade 3 or worse adverse events were febrile neutropenia (48 patients, 25%), neutropenia (30 patients, 16%), and anaemia (27 patients, 14%). Three (2%) patients had grade 3 cytokine release syndrome. Neurologic events of worst grade 3 or 4 occurred in 20 (11%) and four (2%) patients, respectively. Three deaths (due to sepsis, Escherichia coli sepsis, and Candida infection) were thought to be treatment-related by the investigators. Single-agent blinatumomab showed antileukaemia activity in adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia characterised by negative prognostic factors. Further assessment of blinatumomab treatment earlier in the course of the disease and in combination with other treatment approaches is warranted. Amgen. Copyright © 2015 Elsevier Ltd. All rights reserved.

Adult primary angiitis of the central nervous system: isolated small-vessel vasculitis represents distinct disease pattern.

PubMed

de Boysson, Hubert; Boulouis, Grégoire; Aouba, Achille; Bienvenu, Boris; Guillevin, Loïc; Zuber, Mathieu; Touzé, Emmanuel; Naggara, Olivier; Pagnoux, Christian

2017-03-01

We aimed to identify whether presentations and outcomes in adult patients with isolated small-vessel primary angiitis of the CNS (PACNS) would differ from other patients with large/medium-vessel involvement. In the French PACNS cohort, we compared the characteristics, treatments and outcomes of patients with isolated small-vessel disease (normal CT, MR and/or conventional angiograms, brain biopsy positive for vasculitis) with other patients who had large/medium-vessel involvement (vessel abnormalities on CT, MR or conventional angiograms). A good functional outcome was defined as a modified Rankin scale ⩽2 at last follow-up, regardless of the occurrence of relapse. Among the 102 patients in the cohort, 26 (25%) had isolated small-vessel PACNS, whereas the 76 others demonstrated large/medium-vessel involvement. Patients with isolated small-vessel PACNS had more seizures (P < 0.0001), cognitive (P = 0.02) or consciousness impairment (P = 0.03) and more dyskinesias (P = 0.002) but less focal deficits (P = 0.0002) than other PACNS patients. They also had more abnormal cerebrospinal fluid analysis (P = 0.008) and gadolinium enhancements on MRI (P = 0.001) but less frequent acute ischaemic lesions (P < 0.0001) than patients with large/medium-vessel involvement. Treatments and modified Rankin scale at last follow-up did not differ between groups. Thirty-two (31%) patients relapsed; 14 (54%) with isolated small-vessel PACNS vs 18 (24%) with large/medium-vessel involvement (P = 0.004). Eight patients died, with no difference between the groups (P = 0.97). In our cohort, adult patients with isolated small-vessel PACNS presented some distinct disease features and relapsed more often than other PACNS patients who had large/medium-vessel involvement. Functional outcomes and mortality did not differ. © The Author 2016. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com

Incidence and Outcomes of Central Nervous System Hemophagocytic Lymphohistiocytosis Relapse after Reduced-Intensity Conditioning Hematopoietic Stem Cell Transplantation.

PubMed

Lounder, Dana T; Khandelwal, Pooja; Chandra, Sharat; Jordan, Michael B; Kumar, Ashish R; Grimley, Michael S; Davies, Stella M; Bleesing, Jack J; Marsh, Rebecca A

2017-05-01

Hemophagocytic lymphohistiocytosis (HLH) is an immune regulatory disorder that commonly presents with central nervous system (CNS) involvement. The only cure for genetic HLH is hematopoietic stem cell transplantation (HSCT), typically treated with reduced-intensity conditioning (RIC) regimens. We sought to estimate the incidence of CNS relapse after RIC HSCT, determine risk factors, and evaluate outcomes. We performed a retrospective chart review of 94 consecutive children and young adults with primary HLH who received RIC HSCT. CNS relapse within 1 year after transplantation was diagnosed by review of clinical symptoms, cerebral spinal fluid (CSF), and radiologic findings. Four (4.25%) patients developed symptoms of possible CNS HLH after HSCT and 3 patients were diagnosed. Eight patients underwent screening lumbar puncture because of history of active CNS disease at the onset of the conditioning regimen and 4 had evidence of continued disease. The overall incidence of CNS relapse and continued CNS disease after RIC HSCT was 8%. All patients with CNS disease after HSCT responded to CNS-directed therapy. Whole blood donor chimerism at the time of CNS relapse was low at 1% to 34%, but it remained high at 88% to 100% for patients with continued CNS disease. Overall survival for patients with CNS relapse was 50%, compared with 75% for patients without CNS disease (P = .079). Our data suggest that a low level of donor chimerism or active CNS disease at the time of transplantation increase the risk of CNS HLH after HSCT. Surveillance CSF evaluation after allogeneic RIC HSCT should be considered in patients with risk factors and CNS-directed treatment should be initiated if appropriate. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Effects of Disasters on Smoking and Relapse: An Exploratory Study of Hurricane Katrina Victims.

PubMed

Lanctot, Jennifer Q; Stockton, Michelle B; Mzayek, Fawaz; Read, Mary; McDevitt-Murphy, Meghan; Ward, Kenneth

2008-01-01

Psychosocial stress maintains cigarette use and precipitates relapse, but little is known about how natural disasters in particular affect smoking. To determine the feasibility of recruiting victims soon after a natural disaster for a survey study, and to assess the types and determinants of changes in smoking behavior resulting from exposure to the disaster. A convenience sample of 35 Hurricane Katrina refugees who had smoked more than 100 cigarettes in their lifetime were surveyed one month after the storm to evaluate changes in smoking behavior. Among a small sample of former smokers, more than half relapsed after Katrina, citing stress, urge, and sadness. Among current smokers, 52% increased their smoking after Katrina by more than half a pack per day on average. Most individuals who increased their smoking or relapsed expressed interest in receiving cessation assistance within the next month. Stress-related increases in smoking and relapse may be common after a natural disaster. Health education professionals have an important role to play in responding to changes in tobacco use in the aftermath of disasters. Educational interventions to discourage tobacco use as a coping strategy may be especially warranted given the high level of interest expressed in smoking cessation.

Plerixafor and Filgrastim For Mobilization of Donor Peripheral Blood Stem Cells Before A Donor Peripheral Blood Stem Cell Transplant in Treating Patients With Hematologic Malignancies

ClinicalTrials.gov

2017-06-26

Accelerated Phase Chronic Myelogenous Leukemia; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Atypical Chronic Myeloid Leukemia, BCR-ABL Negative; Blastic Phase Chronic Myelogenous Leukemia; Chronic Phase Chronic Myelogenous Leukemia; de Novo Myelodysplastic Syndromes; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Nodal Marginal Zone B-cell Lymphoma; Noncontiguous Stage II Adult Burkitt Lymphoma; Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Noncontiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Noncontiguous Stage II Adult Lymphoblastic Lymphoma; Noncontiguous Stage II Grade 1 Follicular Lymphoma; Noncontiguous Stage II Grade 2 Follicular Lymphoma; Noncontiguous Stage II Grade 3 Follicular Lymphoma; Noncontiguous Stage II Mantle Cell Lymphoma; Noncontiguous Stage II Marginal Zone Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Refractory Multiple Myeloma; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes; Splenic Marginal Zone Lymphoma; Stage I Multiple Myeloma; Stage II Multiple Myeloma; Stage III Adult Burkitt Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Mixed Cell Lymphoma; Stage III Adult Diffuse Small Cleaved Cell Lymphoma; Stage III Adult Hodgkin Lymphoma; Stage III Adult Immunoblastic Large Cell Lymphoma; Stage III Adult Lymphoblastic Lymphoma; Stage III Chronic Lymphocytic Leukemia; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage III Marginal Zone Lymphoma; Stage III Multiple Myeloma; Stage III Small Lymphocytic Lymphoma; Stage IV Adult Burkitt Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Mixed Cell Lymphoma; Stage IV Adult Diffuse Small Cleaved Cell Lymphoma; Stage IV Adult Hodgkin Lymphoma; Stage IV Adult Immunoblastic Large Cell Lymphoma; Stage IV Adult Lymphoblastic Lymphoma; Stage IV Chronic Lymphocytic Leukemia; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma; Stage IV Marginal Zone Lymphoma; Stage IV Small Lymphocytic Lymphoma

Irinotecan in patients with relapsed or cisplatin-refractory germ cell cancer: a phase II study of the German Testicular Cancer Study Group.

PubMed

Kollmannsberger, C; Rick, O; Klaproth, H; Kubin, T; Sayer, H G; Hentrich, M; Welslau, M; Mayer, F; Kuczyk, M; Spott, C; Kanz, L; Bokemeyer, C

2002-09-23

Despite generally high cure rates in patients with metastatic germ cell cancer, patients with progressive disease on first-line cisplatin-based chemotherapy or with relapsed disease following high-dose salvage therapy exhibit a very poor prognosis. Irinotecan has shown antitumour activity in human testicular tumour xenografts in nude mice. We have performed a phase II study examining the single agent activity of irinotecan in patients with metastatic relapsed or cisplatin-refractory germ cell cancer. Refractory disease was defined as progression or relapse within 4 weeks after cisplatin-based chemotherapy or relapse after salvage high-dose chemotherapy with autologous stem cell support. Irinotecan was administered at a dose of 300 (-350) mg m(-2) every 3 weeks. Response was evaluated every 4 weeks. Fifteen patients have been enrolled. Median age was 35 (19-53) years. Primary tumour localisation was gonadal/mediastinal in 12/3 patients. Patients had been pretreated with a median of six (4-12) cisplatin-containing cycles and 13 out of 15 patients had previously failed high-dose chemotherapy with blood stem cell support. Median number of irinotecan applications was two (1-3). Fourteen patients are assessable for response and all for toxicity. In one patient, no adequate response evaluation was performed. Toxicity was generally acceptable and consisted mainly of haematological side effects with common toxicity criteria 3 degrees anaemia (two patients), common toxicity criteria 3 degrees leukocytopenia (one patient) and common toxicity criteria 3 degrees thrombocytopenia (three patients). Common toxicity criteria 3/4 degrees non-haematological toxicity occurred in five patients (33%): 1 x diarrhoea, 2 x alopecia, 1 x fever and in one patient worsening of pre-existing peripheral polyneuropathy from 1 degrees to 4 degrees. No response was observed to irinotecan therapy. Currently, 13 patients have died of the disease and two patients are alive with the disease. The patients included in our study exhibit similar prognostic characteristics as patients treated in previous trials evaluating new drugs in this setting. Irinotecan at a dose of 300-350 mg m(-2) every 3 weeks appears to have no antitumour activity in patients with cisplatin-refractory germ cell cancer and, thus, further investigation in this disease is not justified.

Real-world data on Len/Dex combination at second-line therapy of multiple myeloma: treatment at biochemical relapse is a significant prognostic factor for progression-free survival.

PubMed

Katroditou, Eirini; Kyrtsonis, Marie-Christine; Delimpasi, Sosana; Kyriakou, Despoina; Symeonidis, Argiris; Spanoudakis, Emmanouil; Vasilopoulos, Georgios; Anagnostopoulos, Achilles; Kioumi, Anna; Zikos, Panagiotis; Aktypi, Anthi; Briasoulis, Evangelos; Megalakaki, Aikaterini; Repousis, Panayiotis; Adamopoulos, Ioannis; Gogos, Dimitrios; Kotsopoulou, Maria; Pappa, Vassiliki; Papadaki, Eleni; Fotiou, Despoina; Nikolaou, Eftychia; Giannopoulou, Evlambia; Hatzimichael, Eleftheria; Giannakoulas, Nikolaos; Douka, Vassiliki; Kokoviadou, Kyriaki; Timotheatou, Despoina; Terpos, Evangelos

2018-05-13

We evaluated progression-free survival (PFS) rate of patients treated with lenalidomide/dexamethasone (Len/Dex), the efficacy of the combination, and the prognostic significance of treatment at biochemical vs. clinical relapse on PFS in 207 consecutive myeloma patients treated with Len/Dex in second line, according to routine clinical practice in Greece. First-line treatment included bortezomib-based (63.3%) or immunomodulatory drug-based (34.8%) therapies; 25% of patients underwent autologous stem cell transplantation. Overall response rate was 73.4% (17.8% complete response and 23.7% very good partial response); median time to best response was 6.7 months. Overall, median PFS and 12-month PFS rate was 19.2 months and 67.6%, respectively. 67.5% of patients had biochemical relapse and 32.5% had clinical relapse prior to initiation of Len/Dex. Median PFS was 24 months for patients treated at biochemical relapse vs. 13.2 months for those treated at clinical relapse (HR:0.63, p = 0.006) and the difference remained significant after adjustment for other prognostic factors. Type of relapse was the strongest prognostic factor for PFS in multivariate analysis. These real-world data confirm the efficacy of Len/Dex combination at first relapse; more importantly, it is demonstrated for the first time outside a clinical trial setting that starting therapy with Len/Dex at biochemical, rather than at clinical relapse, is a significant prognostic factor for PFS, inducing a 37% reduction of the probability of disease progression or death.

Single agent and synergistic combinatorial efficacy of first-in-class small molecule imipridone ONC201 in hematological malignancies.

PubMed

Prabhu, Varun V; Talekar, Mala K; Lulla, Amriti R; Kline, C Leah B; Zhou, Lanlan; Hall, Junior; Van den Heuvel, A Pieter J; Dicker, David T; Babar, Jawad; Grupp, Stephan A; Garnett, Mathew J; McDermott, Ultan; Benes, Cyril H; Pu, Jeffrey J; Claxton, David F; Khan, Nadia; Oster, Wolfgang; Allen, Joshua E; El-Deiry, Wafik S

2018-01-01

ONC201, founding member of the imipridone class of small molecules, is currently being evaluated in advancer cancer clinical trials. We explored single agent and combinatorial efficacy of ONC201 in preclinical models of hematological malignancies. ONC201 demonstrated (GI50 1-8 µM) dose- and time-dependent efficacy in acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Burkitt's lymphoma, anaplastic large cell lymphoma (ALCL), cutaneous T-cell lymphoma (CTCL), Hodgkin's lymphoma (nodular sclerosis) and multiple myeloma (MM) cell lines including cells resistant to standard of care (dexamethasone in MM) and primary samples. ONC201 induced caspase-dependent apoptosis that involved activation of the integrated stress response (ATF4/CHOP) pathway, inhibition of Akt phosphorylation, Foxo3a activation, downregulation of cyclin D1, IAP and Bcl-2 family members. ONC201 synergistically reduced cell viability in combination with cytarabine and 5-azacytidine in AML cells. ONC201 combined with cytarabine in a Burkitt's lymphoma xenograft model induced tumor growth inhibition that was superior to either agent alone. ONC201 synergistically combined with bortezomib in MM, MCL and ALCL cells and with ixazomib or dexamethasone in MM cells. ONC201 combined with bortezomib in a Burkitt's lymphoma xenograft model reduced tumor cell density and improved CHOP induction compared to either agent alone. These results serve as a rationale for ONC201 single-agent trials in relapsed/refractory acute leukemia, non-Hodgkin's lymphoma, MM and combination trial with dexamethasone in MM, provide pharmacodynamic biomarkers and identify further synergistic combinatorial regimens that can be explored in the clinic.

Massage Therapy Given by Caregiver in Treating Quality of Life of Young Patients Undergoing Treatment for Cancer

ClinicalTrials.gov

2018-05-24

Accelerated Phase Chronic Myelogenous Leukemia; Acute Undifferentiated Leukemia; Angioimmunoblastic T-cell Lymphoma; Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative; Blastic Phase Chronic Myelogenous Leukemia; Burkitt Lymphoma; Childhood Acute Lymphoblastic Leukemia in Remission; Childhood Acute Myeloid Leukemia in Remission; Childhood Chronic Myelogenous Leukemia; Childhood Diffuse Large Cell Lymphoma; Childhood Grade III Lymphomatoid Granulomatosis; Childhood Immunoblastic Large Cell Lymphoma; Childhood Myelodysplastic Syndromes; Childhood Nasal Type Extranodal NK/T-cell Lymphoma; Chronic Eosinophilic Leukemia; Chronic Myelomonocytic Leukemia; Chronic Neutrophilic Leukemia; Chronic Phase Chronic Myelogenous Leukemia; Contiguous Stage II Mantle Cell Lymphoma; Cutaneous B-cell Non-Hodgkin Lymphoma; Essential Thrombocythemia; Extramedullary Plasmacytoma; Intraocular Lymphoma; Isolated Plasmacytoma of Bone; Juvenile Myelomonocytic Leukemia; Mast Cell Leukemia; Meningeal Chronic Myelogenous Leukemia; Noncontiguous Stage II Mantle Cell Lymphoma; Polycythemia Vera; Post-transplant Lymphoproliferative Disorder; Primary Myelofibrosis; Primary Systemic Amyloidosis; Progressive Hairy Cell Leukemia, Initial Treatment; Prolymphocytic Leukemia; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Childhood Anaplastic Large Cell Lymphoma; Recurrent Childhood Grade III Lymphomatoid Granulomatosis; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Small Noncleaved Cell Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent/Refractory Childhood Hodgkin Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Refractory Multiple Myeloma; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia; Stage 0 Chronic Lymphocytic Leukemia; Stage I Childhood Anaplastic Large Cell Lymphoma; Stage I Childhood Hodgkin Lymphoma; Stage I Childhood Large Cell Lymphoma; Stage I Childhood Lymphoblastic Lymphoma; Stage I Childhood Small Noncleaved Cell Lymphoma; Stage I Chronic Lymphocytic Leukemia; Stage I Cutaneous T-cell Non-Hodgkin Lymphoma; Stage I Multiple Myeloma; Stage I Mycosis Fungoides/Sezary Syndrome; Stage II Childhood Anaplastic Large Cell Lymphoma; Stage II Childhood Hodgkin Lymphoma; Stage II Childhood Large Cell Lymphoma; Stage II Childhood Lymphoblastic Lymphoma; Stage II Childhood Small Noncleaved Cell Lymphoma; Stage II Chronic Lymphocytic Leukemia; Stage II Cutaneous T-cell Non-Hodgkin Lymphoma; Stage II Multiple Myeloma; Stage II Mycosis Fungoides/Sezary Syndrome; Stage III Childhood Anaplastic Large Cell Lymphoma; Stage III Childhood Hodgkin Lymphoma; Stage III Childhood Large Cell Lymphoma; Stage III Childhood Lymphoblastic Lymphoma; Stage III Childhood Small Noncleaved Cell Lymphoma; Stage III Chronic Lymphocytic Leukemia; Stage III Cutaneous T-cell Non-Hodgkin Lymphoma; Stage III Multiple Myeloma; Stage III Mycosis Fungoides/Sezary Syndrome; Stage IV Childhood Anaplastic Large Cell Lymphoma; Stage IV Childhood Hodgkin Lymphoma; Stage IV Childhood Large Cell Lymphoma; Stage IV Childhood Lymphoblastic Lymphoma; Stage IV Childhood Small Noncleaved Cell Lymphoma; Stage IV Chronic Lymphocytic Leukemia; Stage IV Cutaneous T-cell Non-Hodgkin Lymphoma; Stage IV Mycosis Fungoides/Sezary Syndrome; T-cell Large Granular Lymphocyte Leukemia; Unspecified Childhood Solid Tumor, Protocol Specific

The European Medicines Agency Review of Brentuximab Vedotin (Adcetris) for the Treatment of Adult Patients With Relapsed or Refractory CD30+ Hodgkin Lymphoma or Systemic Anaplastic Large Cell Lymphoma: Summary of the Scientific Assessment of the Committee for Medicinal Products for Human Use.

PubMed

Gravanis, Iordanis; Tzogani, Kyriaki; van Hennik, Paula; de Graeff, Pieter; Schmitt, Petra; Mueller-Berghaus, Jan; Salmonson, Tomas; Gisselbrecht, Christian; Laane, Edward; Bergmann, Lothar; Pignatti, Francesco

2016-01-01

On October 25, 2012, a conditional marketing authorization valid throughout the European Union (EU) was issued for brentuximab vedotin for the treatment of adult patients with relapsed or refractory CD30+ Hodgkin lymphoma (HL) and for the treatment of adult patients with relapsed or refractory systemic anaplastic large cell lymphoma (sALCL). For HL, the indication is restricted to treatment after autologous stem cell transplantation (ASCT) or after at least two previous therapies when ASCT or multiagent chemotherapy is not a treatment option. Brentuximab vedotin is an antibody-drug conjugate (ADC) composed of a CD30-directed monoclonal antibody (recombinant chimeric IgG1) that is covalently linked to the antimicrotubule agent monomethyl auristatin E (MMAE). Binding of the ADC to CD30 on the cell surface initiates internalization of the MMAE-CD30 complex, followed by proteolytic cleavage that releases MMAE. The recommended dose is 1.8 mg/kg administered as an intravenous infusion over 30 minutes every 3 weeks. Brentuximab vedotin as a single agent was evaluated in two single-arm studies. Study SG035-003 included 102 patients with relapsed or refractory HL. An objective response was observed in 76 patients (75%), with complete remission in 34 (33%). Study SG035-004 included 58 patients with relapsed or refractory sALCL. An objective response was observed in 50 patients (86%), with complete remission in 34 (59%). The most frequently observed toxicities were peripheral sensory neuropathy, fatigue, nausea, diarrhea, neutropenia, vomiting, pyrexia, and upper respiratory tract infection. The present report summarizes the scientific review of the application leading to approval in the EU. The detailed scientific assessment report and product information, including the summary of the product characteristics, are available on the European Medicines Agency website (http://www.ema.europa.eu). Brentuximab vedotin was approved in the European Union for the treatment of adult patients with relapsed or refractory CD30+ Hodgkin lymphoma or systemic anaplastic large cell lymphoma. For Hodgkin lymphoma, brentuximab vedotin should only be used after autologous stem cell transplantation or following at least two prior therapies when transplantation or multiagent chemotherapy is not a treatment option. In two studies involving 160 patients, partial or complete responses were observed in the majority of patients. Although there was no information on the survival of patients treated in the studies at the time of approval, the responses were considered a clinically relevant benefit. ©AlphaMed Press.

The European Medicines Agency Review of Brentuximab Vedotin (Adcetris) for the Treatment of Adult Patients With Relapsed or Refractory CD30+ Hodgkin Lymphoma or Systemic Anaplastic Large Cell Lymphoma: Summary of the Scientific Assessment of the Committee for Medicinal Products for Human Use

PubMed Central

Tzogani, Kyriaki; van Hennik, Paula; de Graeff, Pieter; Schmitt, Petra; Mueller-Berghaus, Jan; Salmonson, Tomas; Gisselbrecht, Christian; Laane, Edward; Bergmann, Lothar; Pignatti, Francesco

2016-01-01

Background. On October 25, 2012, a conditional marketing authorization valid throughout the European Union (EU) was issued for brentuximab vedotin for the treatment of adult patients with relapsed or refractory CD30+ Hodgkin lymphoma (HL) and for the treatment of adult patients with relapsed or refractory systemic anaplastic large cell lymphoma (sALCL). For HL, the indication is restricted to treatment after autologous stem cell transplantation (ASCT) or after at least two previous therapies when ASCT or multiagent chemotherapy is not a treatment option. Materials and Methods. Brentuximab vedotin is an antibody-drug conjugate (ADC) composed of a CD30-directed monoclonal antibody (recombinant chimeric IgG1) that is covalently linked to the antimicrotubule agent monomethyl auristatin E (MMAE). Binding of the ADC to CD30 on the cell surface initiates internalization of the MMAE-CD30 complex, followed by proteolytic cleavage that releases MMAE. The recommended dose is 1.8 mg/kg administered as an intravenous infusion over 30 minutes every 3 weeks. Results. Brentuximab vedotin as a single agent was evaluated in two single-arm studies. Study SG035-003 included 102 patients with relapsed or refractory HL. An objective response was observed in 76 patients (75%), with complete remission in 34 (33%). Study SG035-004 included 58 patients with relapsed or refractory sALCL. An objective response was observed in 50 patients (86%), with complete remission in 34 (59%). The most frequently observed toxicities were peripheral sensory neuropathy, fatigue, nausea, diarrhea, neutropenia, vomiting, pyrexia, and upper respiratory tract infection. Conclusion. The present report summarizes the scientific review of the application leading to approval in the EU. The detailed scientific assessment report and product information, including the summary of the product characteristics, are available on the European Medicines Agency website (http://www.ema.europa.eu). Implications for Practice: Brentuximab vedotin was approved in the European Union for the treatment of adult patients with relapsed or refractory CD30+ Hodgkin lymphoma or systemic anaplastic large cell lymphoma. For Hodgkin lymphoma, brentuximab vedotin should only be used after autologous stem cell transplantation or following at least two prior therapies when transplantation or multiagent chemotherapy is not a treatment option. In two studies involving 160 patients, partial or complete responses were observed in the majority of patients. Although there was no information on the survival of patients treated in the studies at the time of approval, the responses were considered a clinically relevant benefit. PMID:26621039

Prostate cancer stem cells: from theory to practice.

PubMed

Adamowicz, Jan; Pakravan, Katayoon; Bakhshinejad, Babak; Drewa, Tomasz; Babashah, Sadegh

2017-04-01

None of the generally accepted theories on prostate cancer development can fully explain many distinguishing features of the disease, such as intratumoral heterogeneity, metastatic growth, drug resistance and tumor relapse. Prostate stem cells are a heterogeneous and small subpopulation of self-renewing cells which can actively proliferate in response to changes in the androgen level and give rise to all the cell lineages that build the prostate epithelium. According to the cancer stem cell hypothesis, prostate cancer could be a stem cell disease. Prostate cancer stem cells, which represent only a minimal percentage of the tumor mass, are characterized by a markedly increased clonogenicity and therapeutic resistance. These tumor-initiating cells reside in dynamic niches distributed within the prostate but at a higher concentration in proximal regions of the prostatic ducts. Several markers have been used to identify prostate cancer stem cells. Nevertheless, a definitive profile has not yet been established owing to specificity issues. As cancer stem cells play determining roles in the birth and burst of prostate malignancy, strategies that selectively target them have gained huge clinical attention. Unraveling the mechanisms underlying the physiological functions of cancer stem cells and gaining fundamental insights into their putative involvement in the pathogenesis of prostate tumors provide novel opportunities for the development of efficient and sophisticated therapeutic strategies in the future.

R-ICE and Lenalidomide in Treating Patients With First-Relapse/Primary Refractory Diffuse Large B-Cell Lymphoma

ClinicalTrials.gov

2018-06-25

CD20 Positive; Recurrent B-Cell Non-Hodgkin Lymphoma; Recurrent Diffuse Large B-Cell Lymphoma; Recurrent Mediastinal (Thymic) Large B-Cell Cell Lymphoma; Refractory B-Cell Non-Hodgkin Lymphoma; Refractory Diffuse Large B-Cell Lymphoma; Refractory Mediastinal (Thymic) Large B-Cell Cell Lymphoma; Transformed Recurrent Non-Hodgkin Lymphoma

Autologous peripheral blood haematopoietic stem cell transplantation for systemic lupus erythematosus: the observation of long-term outcomes in a Chinese centre.

PubMed

Cao, Can; Wang, Menglei; Sun, Jing; Peng, Xuebiao; Liu, Qifa; Huang, Liang; Chai, Yanyan; Lai, Kuan; Chen, Pingjiao; Liu, Qingxiu; Li, Qian; Peng, Yusheng; Xiong, Hao; Zhang, Jing; Chen, Minghua; Zeng, Kang

2017-01-01

We aimed to evaluate the safety and long-term efficacy of autologous peripheral blood haematopoietic stem cell transplantation (APHSCT). We did not want to evaluate the efficacy of antibodies but rather the clinical response by investigating progression-free survival and serologic response by assessing autoantibody titres and complement levels. Overall, 22 patients with SLE (17 females; median age, 23 years) undergoing APHSCT were included. The 3-year progression-free survival (PFS) was 77.27% at our centre. We found that all the patients survived over three years. The 5-year PFS and overall survival (OS) rate was 67.90% and 95.20%. The titres of antinuclear antibody (ANA), anti-double-stranded deoxyribonucleic acid antibody (anti-dsDNA), anti-Sm antibody, and 24-h urinary protein significantly decreased, while complements 3 (C3) and C4 normalised at 100 days after transplantation (p<0.05). Kidney re-biopsy revealed a decrease in immune complex deposits in patients with remission. The incidence of CMV reactivation was 59.09% after transplantation in 3 years. Pregnancy and childbirth were reported in three female patients after transplantation. The risk of post-transplantation complications persisted for many years. Immunoablation followed by APHSCT has the potential to induce long-term clinical and serologic remissions despite withdrawal of immunosuppressive maintenance therapy. While relapses may occur, in our small cohort of patients we found no predictive markers for relapse development by analysing antibody and complement levels and urinary proteinuria.

Ondansetron in Preventing Nausea and Vomiting in Patients Undergoing Stem Cell Transplant

ClinicalTrials.gov

2017-04-20

Accelerated Phase Chronic Myelogenous Leukemia; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Atypical Chronic Myeloid Leukemia, BCR-ABL Negative; Blastic Phase Chronic Myelogenous Leukemia; Chronic Eosinophilic Leukemia; Chronic Myelomonocytic Leukemia; Chronic Neutrophilic Leukemia; Chronic Phase Chronic Myelogenous Leukemia; de Novo Myelodysplastic Syndromes; Disseminated Neuroblastoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Nodal Marginal Zone B-cell Lymphoma; Noncontiguous Stage II Adult Burkitt Lymphoma; Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Noncontiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Noncontiguous Stage II Adult Lymphoblastic Lymphoma; Noncontiguous Stage II Grade 1 Follicular Lymphoma; Noncontiguous Stage II Grade 2 Follicular Lymphoma; Noncontiguous Stage II Grade 3 Follicular Lymphoma; Noncontiguous Stage II Mantle Cell Lymphoma; Noncontiguous Stage II Marginal Zone Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Poor Prognosis Metastatic Gestational Trophoblastic Tumor; Previously Treated Myelodysplastic Syndromes; Primary Myelofibrosis; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Small Noncleaved Cell Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Malignant Testicular Germ Cell Tumor; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Neuroblastoma; Recurrent Ovarian Epithelial Cancer; Recurrent Ovarian Germ Cell Tumor; Recurrent Small Lymphocytic Lymphoma; Recurrent/Refractory Childhood Hodgkin Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes; Splenic Marginal Zone Lymphoma; Stage I Multiple Myeloma; Stage II Multiple Myeloma; Stage II Ovarian Epithelial Cancer; Stage III Adult Burkitt Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Mixed Cell Lymphoma; Stage III Adult Diffuse Small Cleaved Cell Lymphoma; Stage III Adult Hodgkin Lymphoma; Stage III Adult Immunoblastic Large Cell Lymphoma; Stage III Adult Lymphoblastic Lymphoma; Stage III Chronic Lymphocytic Leukemia; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Malignant Testicular Germ Cell Tumor; Stage III Mantle Cell Lymphoma; Stage III Marginal Zone Lymphoma; Stage III Multiple Myeloma; Stage III Ovarian Epithelial Cancer; Stage III Small Lymphocytic Lymphoma; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Stage IV Adult Burkitt Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Mixed Cell Lymphoma; Stage IV Adult Diffuse Small Cleaved Cell Lymphoma; Stage IV Adult Hodgkin Lymphoma; Stage IV Adult Immunoblastic Large Cell Lymphoma; Stage IV Adult Lymphoblastic Lymphoma; Stage IV Breast Cancer; Stage IV Chronic Lymphocytic Leukemia; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma; Stage IV Marginal Zone Lymphoma; Stage IV Ovarian Epithelial Cancer; Stage IV Small Lymphocytic Lymphoma

Fludarabine Phosphate, Melphalan, Total-Body Irradiation, Donor Stem Cell Transplant in Treating Patients With Hematologic Cancer or Bone Marrow Failure Disorders

ClinicalTrials.gov

2017-11-29

Accelerated Phase Chronic Myelogenous Leukemia; Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Nasal Type Extranodal NK/T-cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Aplastic Anemia; Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative; Childhood Acute Lymphoblastic Leukemia in Remission; Childhood Acute Myeloid Leukemia in Remission; Childhood Chronic Myelogenous Leukemia; Childhood Diffuse Large Cell Lymphoma; Childhood Immunoblastic Large Cell Lymphoma; Childhood Myelodysplastic Syndromes; Childhood Nasal Type Extranodal NK/T-cell Lymphoma; Chronic Eosinophilic Leukemia; Chronic Myelomonocytic Leukemia; Chronic Neutrophilic Leukemia; Chronic Phase Chronic Myelogenous Leukemia; de Novo Myelodysplastic Syndromes; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Fanconi Anemia; Juvenile Myelomonocytic Leukemia; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Nodal Marginal Zone B-cell Lymphoma; Noncontiguous Stage II Adult Burkitt Lymphoma; Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Noncontiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Noncontiguous Stage II Adult Lymphoblastic Lymphoma; Noncontiguous Stage II Grade 1 Follicular Lymphoma; Noncontiguous Stage II Grade 2 Follicular Lymphoma; Noncontiguous Stage II Grade 3 Follicular Lymphoma; Noncontiguous Stage II Mantle Cell Lymphoma; Noncontiguous Stage II Marginal Zone Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Paroxysmal Nocturnal Hemoglobinuria; Previously Treated Myelodysplastic Syndromes; Primary Myelofibrosis; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Childhood Anaplastic Large Cell Lymphoma; Recurrent Childhood Grade III Lymphomatoid Granulomatosis; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Small Noncleaved Cell Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Recurrent/Refractory Childhood Hodgkin Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Multiple Myeloma; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes; Splenic Marginal Zone Lymphoma; Stage III Adult Diffuse Small Cleaved Cell Lymphoma; Stage III Adult Immunoblastic Large Cell Lymphoma; Stage III Adult Lymphoblastic Lymphoma; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage III Marginal Zone Lymphoma; Stage III Small Lymphocytic Lymphoma; Stage IV Adult Burkitt Lymphoma; Stage IV Adult Diffuse Small Cleaved Cell Lymphoma; Stage IV Adult Immunoblastic Large Cell Lymphoma; Stage IV Adult Lymphoblastic Lymphoma; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma; Stage IV Marginal Zone Lymphoma; Stage IV Small Lymphocytic Lymphoma; Waldenström Macroglobulinemia

Ascorbic Acid and Combination Chemotherapy in Treating Patients With Relapsed or Refractory Lymphoma

ClinicalTrials.gov

2018-03-23

High Grade B-Cell Lymphoma With MYC and BCL2 or BCL6 Rearrangements; Recurrent Diffuse Large B-Cell Lymphoma; Recurrent Hodgkin Lymphoma; Recurrent Lymphoma; Refractory Diffuse Large B-Cell Lymphoma; Refractory Lymphoma

Increasing the treatment motivation of patients with somatic symptom disorder: applying the URICA-S scale.

PubMed

Mander, Johannes; Schaller, Georg; Bents, Hinrich; Dinger, Ulrike; Zipfel, Stephan; Junne, Florian

2017-07-03

Therapeutic intervention programs for somatic symptom disorder (SSD) show only small-to-moderate effect sizes. These effects are partly explained by the motivational problems of SSD patients. Hence, fostering treatment motivation could increase treatment success. One central aspect in SSD patients might be damage to motivation because of symptomatic relapses. Consequently, the aim of the present study was to investigate associations between motivational relapse struggle and therapeutic outcome in SSD patients. We assessed 84 inpatients diagnosed with SSD in the early, middle and late stages of their inpatient treatment. The maintenance subscale of the University of Rhode Island Change Assessment-Short (URICA-S) was applied as a measure to assess motivational relapse struggle. Additionally, patients completed measures of treatment outcome that focus on clinical symptoms, stress levels and interpersonal functioning. The results from multiple regression analyses indicate that higher URICA-S maintenance scores assessed in early stages of inpatient treatment were related to more negative treatment outcomes in SSD patients. SSD patients with ambivalent treatment motivation may fail in their struggle against relapse over the course of therapy. The URICA-S maintenance score assessed at therapy admission facilitated early identification of SSD patients who are at greater risk of relapse. Future studies should incorporate randomized controlled trials to investigate whether this subgroup could benefit from motivational interventions that address relapse.

Ibrutinib-associated tumor lysis syndrome in a patient with mantle cell lymphoma: A case report.

PubMed

Kaur, Varinder; Swami, Arjun

2017-04-01

Mantle cell lymphoma accounts for 5-7% of all non-Hodgkin's lymphomas. Under the current WHO classification, it is categorized as an indolent B cell lymphoma, but has an aggressive clinical course. New insights into leukemogenic molecular pathways of mantle cell lymphoma have uncovered unique therapeutic targets. Ibrutinib, a Bruton's tyrosine kinase inhibitor, is the newest drug in the arsenal that has shown promising efficacy in relapsed mantle cell lymphoma. Long-term studies have shown that grade 3 or 4 adverse events are infrequent. Asymptomatic lymphocytosis is frequently seen with ibrutinib use in mantle cell lymphoma; however, tumor lysis syndrome is an extremely rare complication. To date, only two patients with ibrutinib-associated tumor lysis syndrome in mantle cell lymphoma have been described in a long-term follow-up study. Both patients met laboratory criteria for tumor lysis syndrome, however, but did not develop clinical tumor lysis syndrome. We, here describe a patient with relapsed mantle cell lymphoma who developed clinical tumor lysis syndrome with ibrutinib monotherapy.

Comparison of intermediate-dose methotrexate with cranial irradiation for the post-induction treatment of acute lymphocytic leukemia in children

DOE Office of Scientific and Technical Information (OSTI.GOV)

Freeman, A.I.; Weinberg, V.; Brecher, M.L.

1983-03-03

The authors compared two regimens with respect to their ability to prolong disease-free survival in 506 children and adolescents with acute lymphocytic leukemia. All responders to induction therapy were randomized to treatment with 2400 rad of cranial irradiation plus intrathecal methotrexate or to treatment with intermediate-dose methotrexate plus intrathecal methotrexate, as prophylaxis for involvement of the central nervous system and other sanctuary areas. Complete responders were stratified into either standard-risk or increased-risk groups on the basis of age and white-cell count at presentation. Among patients with standard risk, hematologic relapses occurred in 9 of 117 given methotrexate and 24 ofmore » 120 given irradiation. The rate of central-nervous-system relapse was higher in the methotrexate group (23 of 117) than in the irradiation group. Among patients with increased risk, radiation offered greater protection to the central nervous system than methotrexate; there was no difference in the rate of hematologic relapse. Methotrexate offered better protection against systemic relapse in standard-risk patients and better protection against testicular relapse overall, but it offered less protection against relapses in the central nervous system than cranial irradiation.« less

[Relapse of acute promyelocytic leukemia in the central nervous system revealed by isolated dementia].

PubMed

Colin, O; Julian, A; Puyade, M; Bouyer, S; Meurin, E; Blondeau, S; Houeto, J L; Neau, J P

2016-12-01

Approximately 1.5% of dementia is due to curable aetiology. We report an isolated dementia syndrome due to a meningeal relapse of acute promyelocytic leukaemia with favourable outcome after appropriate treatment. A 72-year-old woman, in remission of an acute promyelocytic leukaemia, presented a loss of autonomy for several months due to corticosubcortical dementia. Lumbar puncture showed blast cells indicating meningeal relapse of leukaemia. Intrathecal chemotherapy and arsenic trioxide obtained biological and molecular remission as well as restoration of normal cognitive functions. In patients with hematologic past history such as acute promyelocytic leukaemia, an isolated cognitive impairment should alert physicians to search for an isolated neuromeningeal relapse. Copyright © 2016 Société nationale française de médecine interne (SNFMI). Published by Elsevier SAS. All rights reserved.

Comparison of clinical outcomes of patients with relapsed acute promyelocytic leukemia induced with arsenic trioxide and consolidated with either an autologous stem cell transplant or an arsenic trioxide-based regimen.

PubMed

Thirugnanam, Rajasekar; George, Biju; Chendamarai, Ezhil; Lakshmi, Kavitha M; Balasubramanian, Poonkuzhali; Viswabandya, Auro; Srivastava, Alok; Chandy, Mammen; Mathews, Vikram

2009-11-01

In patients with relapsed acute promyelocytic leukemia (APL), the best consolidation regimen following induction of remission with arsenic trioxide (ATO) remains to be defined. Since January 2000, 37 patients with relapsed APL were treated at our center. The median age was 34 years (range, 6-57 years), and there were 20 males (54.1%). The median duration of first remission was 20.3 months (range, 2.9-81.2 months). Relapse was treated with single-agent ATO in 22 patients (59.5%), ATO+ATRA in 5 patients (13.5%), and ATO+ATRA + anthracycline in 10 patients (27%). Thirty-three patients (89%) achieved molecular remission after induction and a consolidation course. Fourteen patients opted to undergo autologous stem cell transplantation (SCT), and the remaining 19 patients received monthly cycles of ATO as a single agent (n=13) or ATO+ATRA (n=6) for 6 months. At a median follow-up of 32 months, the 5-year Kaplan-Meier estimate of event-free survival (EFS) was 83.33% +/- 15.21% in those who underwent autologous SCT versus 34.45% +/- 11.24% in those who did not (P=.001; log-rank test). Following remission induction with ATO-based regimens in patients with relapsed APL, consolidation with autologous SCT is associated with a significantly superior clinical outcome compared with ATO- and ATO+ATRA-based maintenance regimens.

Genomic analysis of adult B-ALL identifies potential markers of shorter survival.

PubMed

Patel, Shiven; Mason, Clinton C; Glenn, Martha J; Paxton, Christian N; South, Sara T; Cessna, Melissa H; Asch, Julie; Cobain, Erin F; Bixby, Dale L; Smith, Lauren B; Reshmi, Shalini; Gastier-Foster, Julie M; Schiffman, Joshua D; Miles, Rodney R

2017-05-01

B lymphoblastic leukemia (B-ALL) in adults has a higher risk of relapse and lower long-term survival than pediatric B-ALL, but data regarding genetic prognostic biomarkers are much more limited for adult patients. We identified 70 adult B-ALL patients from three institutions and performed genome-wide analysis via single nucleotide polymorphism (SNP) arrays on DNA isolated from their initial diagnostic sample and, when available, relapse bone marrow specimens to identify recurring copy number alterations (CNA). As B-cell developmental genes play a crucial role in this leukemia, we assessed such for recurrent deletions in diagnostic and relapse samples. We confirmed previous findings that the most prevalent deletions of these genes occur in CDKN2A, IKZF1, and PAX5, with several others at lower frequencies. Of the 16 samples having paired diagnostic and relapse samples, 5 showed new deletions in these recurrent B-cell related genes and 8 showed abolishment. Deletion of EBF1 heralded a significant negative prognostic impact on relapse free survival in univariate and multivariate analyses. The combination of both a CDKN2A/B deletion and an IKZF1 alteration (26% of cases) also showed a trend toward predicting worse overall survival compared to having only one or neither of these deletions. These findings add to the understanding of genomic influences on this comparably understudied disease cohort that upon further validation may help identify patients who would benefit from upfront treatment intensification. Copyright © 2017 Elsevier Ltd. All rights reserved.

Conditional Risk of Relapse in Surveillance for Clinical Stage I Testicular Cancer.

PubMed

Nayan, Madhur; Jewett, Michael A S; Hosni, Ali; Anson-Cartwright, Lynn; Bedard, Philippe L; Moore, Malcolm; Hansen, Aaron R; Chung, Peter; Warde, Padraig; Sweet, Joan; O'Malley, Martin; Atenafu, Eshetu G; Hamilton, Robert J

2017-01-01

Patients on surveillance for clinical stage I (CSI) testicular cancer are counseled regarding their baseline risk of relapse. The conditional risk of relapse (cRR), which provides prognostic information on patients who have survived for a period of time without relapse, have not been determined for CSI testicular cancer. To determine cRR in CSI testicular cancer. We reviewed 1239 patients with CSI testicular cancer managed with surveillance at a tertiary academic centre between 1980 and 2014. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: cRR estimates were calculated using the Kaplan-Meier method. We stratified patients according to validated risk factors for relapse. We used linear regression to determine cRR trends over time. At orchiectomy, the risk of relapse within 5 yr was 42.4%, 17.3%, 20.3%, and 12.2% among patients with high-risk nonseminomatous germ cell tumor (NSGCT), low-risk NSGCT, seminoma with tumor size ≥3cm, and seminoma with tumor size <3cm, respectively. However, for patients without relapse within the first 2 yr of follow-up, the corresponding risk of relapse within the next 5 yr in the groups was 0.0%, 1.0% (95% confidence interval [CI] 0.3-1.7%), 5.6% (95% CI 3.1-8.2%), and 3.9% (95% CI 1.4-6.4%). Over time, cRR decreased (p≤0.021) in all models. Limitations include changes to surveillance protocols over time and few late relapses. After 2 yr, the risk of relapse on surveillance for CSI testicular cancer is very low. Consideration should be given to adapting surveillance protocols to individualized risk of relapse based on cRR as opposed to static protocols based on baseline factors. This strategy could reduce the intensity of follow-up for the majority of patients. Our study is the first to provide data on the future risk of relapse during surveillance for clinical stage I testicular cancer, given a patient has been without relapse for a specified period of time. Copyright © 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Evaluation of a Treatment Approach Combining Nicotine Gum with Self-Guided Behavioral Treatments for Smoking Relapse Prevention.

ERIC Educational Resources Information Center

Killen, Joel D.; And Others

1990-01-01

Randomly assigned 1,218 smokers to cells in 4 (nicotine gum delivered ad lib, fixed regimen nicotine gum, placebo gum, no gum) x 3 (self-selected relapse prevention modules, randomly administered modules, no modules) design. Subjects receiving nicotine gum were more likely to be abstinent at 2- and 6-month followups. Fixed regimen accounted for…

Is adjuvant chemotherapy indicated in ovarian immature teratomas? A combined data analysis from the Malignant Germ Cell Tumor International Collaborative.

PubMed

Pashankar, Farzana; Hale, Juliet P; Dang, Ha; Krailo, Mark; Brady, William E; Rodriguez-Galindo, Carlos; Nicholson, James C; Murray, Matthew J; Bilmire, Deborah F; Stoneham, Sara; Arul, G Suren; Olson, Thomas A; Stark, Daniel; Shaikh, Furqan; Amatruda, James F; Covens, Allan; Gershenson, David M; Frazier, A Lindsay

2016-01-15

There is a debate regarding the management of ovarian immature teratomas (ITs). In adult women, postoperative chemotherapy is standard except for stage I, grade 1 disease, whereas surgery alone is standard in pediatric patients. To determine the role of chemotherapy, a pooled analysis of pediatric and adult clinical trials was conducted. Data from 7 pediatric trials and 2 adult trials were merged in the Malignant Germ Cell International Collaborative data set. Four trials included patients with newly diagnosed pure ovarian ITs and were selected (Pediatric Oncology Group/Children's Cancer Group Intergroup Study (INT 0106), Second UKCCSG Germ Cell Tumor Study (GC2), Gynecologic Oncology Group (GOG 0078 and GOG 0090). Adult and pediatric trials were analyzed separately. The primary outcome measures were event-free survival (EFS) and overall survival (OS). One hundred seventy-nine patients were included (98 pediatric patients and 81 adult patients). Ninety pediatric patients were treated with surgery alone, whereas all adult patients received chemotherapy. The 5-year EFS and OS were 91% and 99%, respectively, for the pediatric cohort and 87% and 93%, respectively, for the adults. There were no relapses in grade 1 patients, regardless of the stage or age. Only 1 adult patient with a grade 2 IT relapsed. Among grade 3 patients, the 5-year EFS was 0.92 (0.72-0.98) for stage I/II and 0.52 (0.22-0.75) for stage III in the pediatric cohort (P = .005) and 0.91 (0.69-0.98) for stage I/II and 0.65 (0.39-0.83) for stage III/IV in the adult cohort (P = .01). Postoperative chemotherapy did not decrease relapses in the pediatric cohort. The grade was the most important risk factor for relapse in ovarian ITs. Among grade 3 patients, the stage was significantly associated with relapse. Adjuvant chemotherapy did not decrease relapses in the pediatric cohort; its role in adults remains unresolved. Cancer 2016;122:230-237. © 2015 American Cancer Society. © 2015 American Cancer Society.

Dermatitis herpetiformis: a cutaneous manifestation of coeliac disease.

PubMed

Collin, Pekka; Salmi, Teea T; Hervonen, Kaisa; Kaukinen, Katri; Reunala, Timo

2017-02-01

Dermatitis herpetiformis (DH) is an itchy blistering skin disease with predilection sites on elbows, knees, and buttocks. Diagnosis is confirmed by showing granular immunoglobulin A deposits in perilesional skin. DH is one manifestation of coeliac disease; the skin symptoms heal with gluten free diet (GFD) and relapse on gluten challenge. Of the first-degree relatives, 5% may be affected by either condition. Tissue transglutaminase (TG2) is the autoantigen in coeliac disease and epidermal transglutaminase (TG3) in DH. Both diseases conditions exhibit TG2-specific autoantibodies in serum and small bowel mucosa; patients with DH have IgA-TG3 in the skin. There are some divergencies between these two phenotypes. One-fourth of DH patients do not have small bowel mucosal villous atrophy, but virtually all have coeliac-type inflammatory changes. The skin symptoms respond slowly to GFD. The incidence of coeliac disease is increasing, whereas the opposite is true for DH. A female predominance is evident in coeliac disease, while DH may be more common in males. Coeliac disease carries the risk of small intestinal T-cell lymphoma; in DH B-cell lymphomas at any site may prevail. Adult coeliac disease carries a slightly increased elevated mortality risk, whereas in DH, the relative mortality rate is significantly decreased. Key messages Dermatitis herpetiformis is a cutaneous manifestation of coeliac disease; both conditions are genetically determined and gluten-dependent. Gastrointestinal symptoms and the degree of villous atrophy are less obvious in dermatitis herpetiformis than in coeliac disease. Both show tissue transglutaminase (TG2) specific autoantibodies in serum and small bowel mucosa. In addition, TG3-targeted IgA antibodies are found in the skin of DH patients Both conditions carry an increased elevated risk of lymphoma, in coeliac disease small intestinal T-cell lymphoma, in dermatitis herpetiformis mainly B-cell lymphoma at various sites. Coeliac disease is currently eight times more common that DH; the incidence of DH is decreasing in contrast to that of coeliac disease, where it is increasing.

Recent advances in acute myeloid leukemia stem cell biology.

PubMed

Horton, Sarah J; Huntly, Brian J P

2012-07-01

The existence of cancer stem cells has long been postulated, but was proven less than 20 years ago following the demonstration that only a small sub-fraction of leukemic cells from acute myeloid leukemia patients were able to propagate the disease in xenografts. These cells were termed leukemic stem cells since they exist at the apex of a loose hierarchy, possess extensive self-renewal and the ability to undergo limited differentiation into leukemic blasts. Acute myeloid leukemia is a heterogeneous condition at both the phenotypic and molecular level with a variety of distinct genetic alterations giving rise to the disease. Recent studies have highlighted that this heterogeneity extends to the leukemic stem cell, with this dynamic compartment evolving to overcome various selection pressures imposed upon it during disease progression. The result is a complex situation in which multiple pools of leukemic stem cells may exist within individual patients which differ both phenotypically and molecularly. Since leukemic stem cells are thought to be resistant to current chemotherapeutic regimens and mediate disease relapse, their study also has potentially profound clinical implications. Numerous studies have generated important recent advances in the field, including the identification of novel leukemic stem cell-specific cell surface antigens and gene expression signatures. These tools will no doubt prove invaluable for the rational design of targeted therapies in the future.

Hematologic Response to Vorinostat Treatment in Relapsed Myeloid Leukemia of Down Syndrome.

PubMed

Scheer, Carina; Kratz, Christian; Witt, Olaf; Creutzig, Ursula; Reinhardt, Dirk; Klusmann, Jan-Henning

2016-09-01

Children with Down syndrome are at high risk to develop myeloid leukemia (ML-DS). Despite their excellent prognosis, children with ML-DS particularly suffer from severe therapy-related toxicities and for relapsed ML-DS the cure rates are very poor. Here we report the clinical course of one child with ML-DS treated with the histone deacetylase (HDAC) inhibitor vorinostat (suberoylanilide hydroxamic acid) after second relapse. The child had previously received conventional chemotherapy and stem cell transplantation, yet showed a remarkable clinical and hematologic response. Thus, HDAC inhibitor may represent an effective class of drugs for the treatment of ML-DS. © 2016 Wiley Periodicals, Inc.

Multiple myeloma with extramedullary disease.

PubMed

Oriol, Albert

2011-11-01

Plasmacytoma is a tumor mass consisting of atypical plasma cells. Incidence of plasmacytomas associated with multiple myeloma range from 7% to 17% at diagnosis and from 6% to 20% during the course of the disease. In both situations, occurrence of extramedullary disease has been consistently associated with a poorer prognosis of myeloma. Extramedullary relapse or progression occurs in a variety of clinical circumstances and settings, and therefore requires individualization of treatment. Alkylating agents, bortezomib, and immunomodulatory drugs, along with corticoids, have been used to treat extramedullary relapse but, because of the relatively low frequency or detection rate of extramedullary relapse, no efficacy data are available from controlled studies in this setting.

The combination of bortezomib with chemotherapy to treat relapsed/refractory acute lymphoblastic leukaemia of childhood.

PubMed

Bertaina, Alice; Vinti, Luciana; Strocchio, Luisa; Gaspari, Stefania; Caruso, Roberta; Algeri, Mattia; Coletti, Valentina; Gurnari, Carmelo; Romano, Mariateresa; Cefalo, Maria Giuseppina; Girardi, Katia; Trevisan, Valentina; Bertaina, Valentina; Merli, Pietro; Locatelli, Franco

2017-02-01

Achieving complete remission (CR) in childhood relapsed/refractory acute lymphoblastic leukaemia (ALL) is a difficult task. Bortezomib, a proteasome inhibitor, has in vitro activity against ALL blasts. A phase I-II trial, reported by the Therapeutic Advances in Childhood Leukaemia and Lymphoma (TACL) consortium, demonstrated that bortezomib with chemotherapy has acceptable toxicity and remarkable activity in patients with relapsed ALL failing 2-3 previous regimens. We evaluated bortezomib in combination with chemotherapy in 30 and 7 children with B-cell precursor (BCP) and T-cell ALL, respectively. Bortezomib (1·3 mg/m 2 /dose) was administered intravenously on days 1, 4, 8, and 11. Chemotherapy agents were the same as those used in the TACL trial, consisting of dexamethasone, doxorubicin, vincristine and pegylated asparaginase. Three patients (8·1%) died due to infections. Twenty-seven patients (72·9%) achieved CR or CR with incomplete platelet recovery (CRp). Fourteen had minimal residual disease (MRD) lower than 0·1%. Twenty-two of 30 BCP-ALL patients (73·3%) and 5/7 patients (71%) with T-cell ALL achieved CR/CRp. The 2-year overall survival (OS) is 31·3%; CR/CRp patients with an MRD response had a remarkable 2-year OS of 68·4%. These data confirm that the combination of bortezomib with chemotherapy is a suitable/effective option for childhood relapsed/refractory ALL. © 2017 John Wiley & Sons Ltd.

Consensus guidelines for the diagnosis and management of patients with classic hairy cell leukemia.

PubMed

Grever, Michael R; Abdel-Wahab, Omar; Andritsos, Leslie A; Banerji, Versha; Barrientos, Jacqueline; Blachly, James S; Call, Timothy G; Catovsky, Daniel; Dearden, Claire; Demeter, Judit; Else, Monica; Forconi, Francesco; Gozzetti, Alessandro; Ho, Anthony D; Johnston, James B; Jones, Jeffrey; Juliusson, Gunnar; Kraut, Eric; Kreitman, Robert J; Larratt, Loree; Lauria, Francesco; Lozanski, Gerard; Montserrat, Emili; Parikh, Sameer A; Park, Jae H; Polliack, Aaron; Quest, Graeme R; Rai, Kanti R; Ravandi, Farhad; Robak, Tadeusz; Saven, Alan; Seymour, John F; Tadmor, Tamar; Tallman, Martin S; Tam, Constantine; Tiacci, Enrico; Troussard, Xavier; Zent, Clive S; Zenz, Thorsten; Zinzani, Pier Luigi; Falini, Brunangelo

2017-02-02

Hairy cell leukemia is an uncommon hematologic malignancy characterized by pancytopenia and marked susceptibility to infection. Tremendous progress in the management of patients with this disease has resulted in high response rates and improved survival, yet relapse and an appropriate approach to re-treatment present continuing areas for research. The disease and its effective treatment are associated with immunosuppression. Because more patients are being treated with alternative programs, comparison of results will require general agreement on definitions of response, relapse, and methods of determining minimal residual disease. The development of internationally accepted, reproducible criteria is of paramount importance in evaluating and comparing clinical trials to provide optimal care. Despite the success achieved in managing these patients, continued participation in available clinical trials in the first-line and particularly in the relapse setting is highly recommended. The Hairy Cell Leukemia Foundation convened an international conference to provide common definitions and structure to guide current management. There is substantial opportunity for continued research in this disease. In addition to the importance of optimizing the prevention and management of the serious risk of infection, organized evaluations of minimal residual disease and treatment at relapse offer ample opportunities for clinical research. Finally, a scholarly evaluation of quality of life in the increasing number of survivors of this now manageable chronic illness merits further study. The development of consensus guidelines for this disease offers a framework for continued enhancement of the outcome for patients.

Consensus guidelines for the diagnosis and management of patients with classic hairy cell leukemia

PubMed Central

Abdel-Wahab, Omar; Andritsos, Leslie A.; Banerji, Versha; Barrientos, Jacqueline; Blachly, James S.; Call, Timothy G.; Catovsky, Daniel; Dearden, Claire; Demeter, Judit; Else, Monica; Forconi, Francesco; Gozzetti, Alessandro; Ho, Anthony D.; Johnston, James B.; Jones, Jeffrey; Juliusson, Gunnar; Kraut, Eric; Kreitman, Robert J.; Larratt, Loree; Lauria, Francesco; Lozanski, Gerard; Montserrat, Emili; Parikh, Sameer A.; Park, Jae H.; Polliack, Aaron; Quest, Graeme R.; Rai, Kanti R.; Ravandi, Farhad; Robak, Tadeusz; Saven, Alan; Seymour, John F.; Tadmor, Tamar; Tallman, Martin S.; Tam, Constantine; Tiacci, Enrico; Troussard, Xavier; Zent, Clive S.; Zenz, Thorsten; Zinzani, Pier Luigi; Falini, Brunangelo

2017-01-01

Hairy cell leukemia is an uncommon hematologic malignancy characterized by pancytopenia and marked susceptibility to infection. Tremendous progress in the management of patients with this disease has resulted in high response rates and improved survival, yet relapse and an appropriate approach to re-treatment present continuing areas for research. The disease and its effective treatment are associated with immunosuppression. Because more patients are being treated with alternative programs, comparison of results will require general agreement on definitions of response, relapse, and methods of determining minimal residual disease. The development of internationally accepted, reproducible criteria is of paramount importance in evaluating and comparing clinical trials to provide optimal care. Despite the success achieved in managing these patients, continued participation in available clinical trials in the first-line and particularly in the relapse setting is highly recommended. The Hairy Cell Leukemia Foundation convened an international conference to provide common definitions and structure to guide current management. There is substantial opportunity for continued research in this disease. In addition to the importance of optimizing the prevention and management of the serious risk of infection, organized evaluations of minimal residual disease and treatment at relapse offer ample opportunities for clinical research. Finally, a scholarly evaluation of quality of life in the increasing number of survivors of this now manageable chronic illness merits further study. The development of consensus guidelines for this disease offers a framework for continued enhancement of the outcome for patients. PMID:27903528

Significance of Ethnicity in the Risk of Acute Graft-versus-Host Disease and Leukemia Relapse after Unrelated Donor Hematopoietic Stem Cell Transplantation

PubMed Central

Morishima, Yasuo; Kawase, Takakazu; Malkki, Mari; Morishima, Satoko; Spellman, Stephen; Kashiwase, Koichi; Kato, Shunichi; Cesbron, Anne; Tiercy, Jean-Marie; Senitzer, David; Velardi, Andrea; Petersdorf, Effie W.

2014-01-01

The significance of patient and donor ethnicity on risk of acute graft-versus-host disease (GVHD) and disease relapse after unrelated donor hematopoietic cell transplantation (HCT) is not known. A total of 4335 patient/donor pairs from the International Histocompatibility Working Group in HCT met the following three criteria: (1) HLA-A, B, C, DRB1 and DQB1 allele matched donor; (2) diagnosis of leukemia, and (3) non-T cell depleted GVHD prophylaxis. Post-transplant risks of acute GVHD and leukemia relapse were defined in Asian/Pacific Islander, Caucasian, African American, Hispanic, and Native American patients transplanted from donors with the same self-described background. Asian patients had a significantly lower incidence of acute GVHD (Japanese patients: 40.0% grades II-IV and 15.3% grades III-IV; non-Japanese Asian patients: 42.1% grades II-IV and 15.7% grades III-IV) compared to Caucasian patients (56.5% grades II-IV and 22.6% grades III-IV) (p< 0.001). The hazard ratio (HR) of acute GVHD for Caucasian patients was significantly higher than for Japanese patients. Unexpectedly, the HR of leukemia relapse in Caucasian patients with early disease status was also significantly higher than that in Japanese patients. These results provide a platform for future investigation into the genetic factors for unrelated donor HCT and clinical implications of diverse ethnic background. PMID:23747601

A phase I study of amrubicin and fixed dose of irinotecan (CPT-11) in relapsed small cell lung cancer: Japan multinational trial organization LC0303.

PubMed

Kawahara, Masaaki; Kubo, Akihito; Komuta, Kiyoshi; Fujita, Yuka; Sasaki, Yoshiaki; Fukushima, Masanori; Daimon, Takashi; Furuse, Kiyoyuki; Mishima, Michiaki; Mio, Tadashi

2012-12-01

To determine the maximum tolerated dose of amrubicin (AMR) with a fixed dose of irinotecan (CPT-11). Patients having pathologically proven small cell lung cancer (SCLC) relapsed after one or two chemotherapies, and Eastern Cooperative Oncology Group performance status of 0 to 2 were eligible for the study. CPT-11 was delivered as 50 mg/m2 on days 1 and 8, every 21 days. AMR was delivered on day 1. Doses of AMR were level 1: 80 mg/m2, level 2: 90 mg/m2, and level 3: 100 mg/m2. Dose elevation was determined using the modified continuous reassessment method. Tolerability was assessed after the first cycle. Another two cycles were conducted when disease progression or unacceptable toxicities were not observed. Eighteen patients (mean age: 66.3 years) were enrolled. A total of 40 courses were conducted. Grade 3/4 toxicities of the first cycle were leukocytopenia: 11 (61%, grade 3/4: 8/3); neutropenia: 15 (83%, grade 3/4: 6/9); and thrombocytopenia: three (17%, grade 3/4: 2/1). Other grade 3 toxicities observed were febrile neutropenia, one; infection, three; diarrhea, one; and dyspnea, one. Dose-limiting toxicity was observed in two of six patients at level 2 (neutropenia and febrile neutropenia) and in one of six at level 3 (thrombocytopenia and infection). The maximum tolerated dose was level 3, and so, the recommended dose for phase II trials was judged to be 90 mg/m2. Objective response was obtained in four of eight patients who were able to evaluate responses. Median survival time was 13 months, with 68% at 1-year survival rate. This combination was well tolerated and showed encouraging activities in SCLC. Randomized phase II trials are being planned in chemonaive SCLC.

Two novel ALK mutations mediate acquired resistance to the next-generation ALK inhibitor alectinib.

PubMed

Katayama, Ryohei; Friboulet, Luc; Koike, Sumie; Lockerman, Elizabeth L; Khan, Tahsin M; Gainor, Justin F; Iafrate, A John; Takeuchi, Kengo; Taiji, Makoto; Okuno, Yasushi; Fujita, Naoya; Engelman, Jeffrey A; Shaw, Alice T

2014-11-15

The first-generation ALK tyrosine kinase inhibitor (TKI) crizotinib is a standard therapy for patients with ALK-rearranged non-small cell lung cancer (NSCLC). Several next-generation ALK-TKIs have entered the clinic and have shown promising activity in crizotinib-resistant patients. As patients still relapse even on these next-generation ALK-TKIs, we examined mechanisms of resistance to the next-generation ALK-TKI alectinib and potential strategies to overcome this resistance. We established a cell line model of alectinib resistance, and analyzed a resistant tumor specimen from a patient who had relapsed on alectinib. We developed Ba/F3 models harboring alectinib-resistant ALK mutations and evaluated the potency of other next-generation ALK-TKIs in these models. We tested the antitumor activity of the next-generation ALK-TKI ceritinib in the patient with acquired resistance to alectinib. To elucidate structure-activity relationships of ALK mutations, we performed computational thermodynamic simulation with MP-CAFEE. We identified a novel V1180L gatekeeper mutation from the cell line model and a second novel I1171T mutation from the patient who developed resistance to alectinib. Both ALK mutations conferred resistance to alectinib as well as to crizotinib, but were sensitive to ceritinib and other next-generation ALK-TKIs. Treatment of the patient with ceritinib led to a marked response. Thermodynamics simulation suggests that both mutations lead to distinct structural alterations that decrease the binding affinity with alectinib. We have identified two novel ALK mutations arising after alectinib exposure that are sensitive to other next-generation ALK-TKIs. The ability of ceritinib to overcome alectinib-resistance mutations suggests a potential role for sequential therapy with multiple next-generation ALK-TKIs. ©2014 American Association for Cancer Research.

Biology and Clinical Relevance of Acute Myeloid Leukemia Stem Cells.

PubMed

Reinisch, Andreas; Chan, Steven M; Thomas, Daniel; Majeti, Ravindra

2015-07-01

Evidence for the cancer stem cell model was first demonstrated in xenotransplanted blood and bone marrow samples from patients with acute myeloid leukemia (AML) almost two decades ago, supporting the concept that a rare clonal and mutated leukemic stem cell (LSC) population is sufficient to drive leukemic growth. The inability to eliminate LSCs with conventional therapies is thought to be the primary cause of disease relapse in AML patients, and as such, novel therapies with the ability to target this population are required to improve patient outcomes. An important step towards this goal is the identification of common immunophenotypic surface markers and biological properties that distinguish LSCs from normal hematopoietic stem and progenitor cells (HSPCs) across AML patients. This work has resulted in the development of a large number of potential LSC-selective therapies that target cell surface molecules, intracellular signaling pathways, and the bone marrow microenvironment. Here, we will review the basic biology, immunophenotypic detection, and clinical relevance of LSCs, as well as emerging biological and small-molecule strategies that either directly target LSCs or indirectly target these cells through modulation of their microenvironment. Copyright © 2015 Elsevier Inc. All rights reserved.

Trichuris suis ova therapy in relapsing multiple sclerosis is safe but without signals of beneficial effect.

PubMed

Voldsgaard, A; Bager, P; Garde, E; Åkeson, P; Leffers, A M; Madsen, C G; Kapel, C; Roepstorff, A; Thamsborg, S M; Melbye, M; Siebner, H; Søndergaard, H B; Sellebjerg, F; Sørensen, P Soelberg

2015-11-01

An observational study has suggested that relapsing-remitting multiple sclerosis patients with helminth infections have lower disease activity and progression than uninfected multiple sclerosis patients. To evaluate the safety and efficacy on MRI activity of treatment with TSO in relapsing MS. The study was an open-label, magnetic resonance imaging assessor-blinded, baseline-to-treatment study including ten patients with relapsing forms of multiple sclerosis. Median (range) age was 41 (24-55) years, disease duration 9 (4-34) years, Expanded Disability Status Scale score 2.5 (1-5.0), and number of relapses within the last two years 3 (2-5). Four patients received no disease modifying therapy, while six patients received IFN-β. After an observational period of 8 weeks, patients received 2500 ova from the helminth Trichuris suis orally every second week for 12 weeks. Patients were followed with serial magnetic resonance imaging, neurological examinations, laboratory safety tests and expression of immunological biomarker genes. Treatment with Trichuris suis orally was well-tolerated apart from some gastrointestinal symptoms. Magnetic resonance imaging revealed 6 new or enlarged T2 lesions in the run-in period, 7 lesions in the early period and 21 lesions in the late treatment period. Two patients suffered a relapse before treatment and two during treatment. Eight patients developed eosinophilia. The expression of cytokines and transcription factors did not change. In a small group of relapsing multiple sclerosis patients, Trichuris suis oral therapy was well tolerated but without beneficial effect. © The Author(s), 2015.

Immunologic prediction of relapse in patients with pemphigus vulgaris (PV) in clinical remission.

PubMed

Daneshpazhooh, Maryam; Zafarmand Sedigh, Vahid; Balighi, Kamran; Hosseini, S Hamed; Ramezani, Ali; Kalantari, Mohammad-Sadegh; Ghandi, Narges; Ghiasi, Maryam; Nikoo, Azita; Chams-Davatchi, Cheyda

2016-06-01

Pemphigus vulgaris (PV) is characterized by multiple relapses, occurring especially in patients on minimal therapy or off therapy. To identify immunologic predictors (anti-desmoglein [Dsg] 1 and 3 antibodies; direct immunofluorescence [DIF]) for relapse in PV patients. Eighty-nine patients in complete clinical remission for at least 6 months and receiving less than or equal to 10 mg prednisolone daily and no immunosuppressive drugs were evaluated using DIF (n=89) and Dsg ELISA (n=46). They were followed until relapse or for at least 18 months. DIF was positive in 44 of 89 patients (49.5%); anti-Dsg 3 antibodies were detected in 18 of 46 patients (39.1%) and anti-Dsg 1 antibodies were detected in 4 of 46 patients (8.7%). Relapse occurred in 38 patients (42.7%). Mean relapse-free time was significantly shorter in anti-Dsg 3-positive patients compared to anti-Dsg 3- negative patients (P = .015) and in DIF-positive patients compared to DIF-negative patients (P = .047), but not in anti-Dsg 1- positive patients compared to anti-Dsg 1-negative patients (P = .501). Sensitivity and predictive values of neither of these tests were high. Small number of anti-Dsg 1-positive patients and use of conventional ELISA. Positive anti-Dsg 3 ELISA and, to a lesser degree, positive DIF are predictors of relapse in PV patients in clinical remission. Decision on discontinuing treatment should be based on the results of these tests as well as on clinical findings. Copyright © 2015 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

STAT3 inhibition as a therapeutic strategy for leukemia.

PubMed

Kanna, Rubashruti; Choudhary, Gaurav; Ramachandra, Nandini; Steidl, Ulrich; Verma, Amit; Shastri, Aditi

2017-11-22

Leukemia is characterized by selective overgrowth of malignant hematopoietic stem cells (HSC's) that interfere with HSC differentiation. Cytoreductive chemotherapy can kill rapidly dividing cancerous cells but cannot eradicate the malignant HSC pool leading to relapses. Leukemic stem cells have several dysregulated pathways and the Janus kinases (JAKs) and signal transducer and activator of transcription (STAT) pathway are prominent among them. STAT3 is an important transcription factor that regulates cell growth, proliferation, and inhibits apoptosis. High STAT3 expression in leukemia has been associated with an increased risk for relapse and decreased overall survival. Multiple strategies for interfering with STAT3 activity in leukemic cells include inhibition of STAT3 phosphorylation, interfering with STAT3 interactions, preventing nuclear transfer, inhibiting transcription and causing interference in STAT: DNA binding. A better understanding of key interactions and upstream mediators of STAT3 activity will help facilitate the development of effective cancer therapies and may result in durable remissions.

Folic acid functionalized surface highlights 5-methylcytosine-genomic content within circulating tumor cells.

PubMed

Malara, Natalia; Coluccio, Maria Laura; Limongi, Tania; Asande, Monica; Trunzo, Valentina; Cojoc, Gheorghe; Raso, Cinzia; Candeloro, Patrizio; Perozziello, Gerardo; Raimondo, Raffaella; De Vitis, Stefania; Roveda, Laura; Renne, Maria; Prati, Ubaldo; Mollace, Vincenzo; Di Fabrizio, Enzo

2014-11-12

Although the detection of methylated cell free DNA represents one of the most promising approaches for relapse risk assessment in cancer patients, the low concentration of cell-free circulating DNA constitutes the biggest obstacle in the development of DNA methylation-based biomarkers from blood. This paper describes a method for the measurement of genomic methylation content directly on circulating tumor cells (CTC), which could be used to deceive the aforementioned problem. Since CTC are disease related blood-based biomarkers, they result essential to monitor tumor's stadiation, therapy, and early relapsing lesions. Within surface's bio-functionalization and cell's isolation procedure standardization, the presented approach reveals a singular ability to detect high 5-methylcytosine CTC-subset content in the whole CTC compound, by choosing folic acid (FA) as transducer molecule. Sensitivity and specificity, calculated for FA functionalized surface (FA-surface), result respectively on about 83% and 60%. FA-surface, allowing the detection and characterization of early metastatic dissemination, provides a unique advance in the comprehension of tumors progression and dissemination confirming the presence of CTC and its association with high risk of relapse. This functionalized surface identifying and quantifying high 5-methylcytosine CTC-subset content into the patient's blood lead significant progress in cancer risk assessment, also providing a novel therapeutic strategy. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

The combination of bendamustine, bortezomib, and rituximab for patients with relapsed/refractory indolent and mantle cell non-Hodgkin lymphoma

PubMed Central

Vose, Julie M.; Kelly, Jennifer L.; Young, Faith; Bernstein, Steven H.; Peterson, Derick; Rich, Lynn; Blumel, Susan; Proia, Nicole K.; Liesveld, Jane; Fisher, Richard I.; Armitage, James O.; Grant, Steven; Leonard, John P.

2011-01-01

Given the significant activity and tolerability of bendamustine, rituximab, and bortezomib in patients with relapsed indolent and mantle cell non-Hodgkin lymphoma, and laboratory studies suggesting synergistic activity, we conducted a multicenter phase 2 study of the bendamustine/bortezomib/rituximab combination. Patients with relapsed or refractory indolent and mantle cell lymphoma with adequate organ function were treated with bendamustine 90 mg/m2 days 1 and 4; rituximab 375 mg/m2 day 1, and bortezomib 1.3 mg/m2 days 1, 4, 8, 11. Six 28-day cycles were planned. Thirty patients (7 with mantle cell lymphoma) were enrolled and treated. Eight patients experienced serious adverse events, including one event of grade 5 sepsis. Common nonhematologic adverse events were generally grade 1 or grade 2 and included nausea (50%), neuropathy (47%), fatigue (47%), constipation (40%), and fever (40%). Of 29 patients evaluable for efficacy, 24 (83%) achieved an objective response (including 15 with complete response). With median follow-up of 24 months, 2-year progression-free survival is 47% (95% confidence interval, 25%-69%). On the basis of these promising results, the US cooperative groups have initiated randomized trials to evaluate this regimen in follicular and mantle cell lymphoma. This trial was registered at www.clinicaltrials.gov as #NCT00547534. PMID:21239695

Immunohistochemical CD271 expression correlates with melanoma progress in a case-control study.

PubMed

Nielsen, Patricia Switten; Riber-Hansen, Rikke; Steiniche, Torben

2018-06-01

Putative cancer stem cell (CSC) markers have arisen from melanoma mouse and in vitro models, but their expression in paraffin embedded patient samples relative to clinical outcome remains largely unexplored. Rather than cells of the tumour bulk, conceivably, CSC drive tumour progression. Accordingly, complete eradication may prevent melanoma relapse. Because elevated tumour-cell proliferation is an established indicator of aggressive disease, this study aimed to investigate the correlation between melanoma recurrence and proliferation of putative CSC that express CD271, CD166, or CD20. Additionally, the expression of these markers was studied in naevi, melanomas, and their recurrence. In melanoma patients, 30 with relapse (cases) and 30 without (controls) were matched for tumour thickness, ulceration, Clark level, subtype, site, gender, and age. One paraffin-embedded section of the patients' primary melanoma (n = 60), relapse (n = 21), and naevus (n = 17) were immunohistochemically double-stained for Ki-67/MART1 and single-stained for CD271, CD166, and CD20. Their whole slide images were aligned as virtual quadruple stains. Image analysis established proliferation indices of each putative stem cell marker and the tumour bulk in addition to the markers' percentage level in tumour areas and the epidermis. In cases vs controls, median dermal proliferation indices (no./mm 2 ) were 211 vs 103 (p = 0.04) for CD271, 512 vs 227 (p = 0.3) for CD166, 184 vs 97 (p = 0.3) for CD20, and 95 vs 103 (p = 0.6) for the tumour bulk. Of additional interest, epidermal CD271 + keratinocytes totalled 8.8% in naevi and 0.98% in melanomas (p = 0.0007). Even though differences between naevi and melanomas also were observed for CD166 in both the epidermis (p = 0.002) and dermis (p = 0.006), they were visually less apparent. CD20 + MART1 + cells were absent in half of the melanomas, and all naevi and relapses. In conclusion, high levels of CD271 + Ki-67 + MART1 + cells were linked to melanoma relapse as opposed to common Ki-67 indices in this particular case-control study. With further investigation, such cells could be potential targets of therapy. Especially, loss of epidermal CD271 + keratinocytes seemed necessary for melanoma development; hence, identification may serve as a diagnostic tool with additional research. Copyright © 2018 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.

Bendamustine in Combination With Gemcitabine and Vinorelbine Is an Effective Regimen As Induction Chemotherapy Before Autologous Stem-Cell Transplantation for Relapsed or Refractory Hodgkin Lymphoma: Final Results of a Multicenter Phase II Study.

PubMed

Santoro, Armando; Mazza, Rita; Pulsoni, Alessandro; Re, Alessandro; Bonfichi, Maurizio; Zilioli, Vittorio Ruggero; Salvi, Flavia; Merli, Francesco; Anastasia, Antonella; Luminari, Stefano; Annechini, Giorgia; Gotti, Manuel; Peli, Annalisa; Liberati, Anna Marina; Di Renzo, Nicola; Castagna, Luca; Giordano, Laura; Carlo-Stella, Carmelo

2016-09-20

This multicenter, open-label, phase II study evaluated the combination of bendamustine, gemcitabine, and vinorelbine (BeGEV) as induction therapy before autologous stem-cell transplantation (ASCT) in patients with relapsed or refractory Hodgkin lymphoma (HL). Patients with HL who were refractory to or had relapsed after one previous chemotherapy line were eligible. The primary end point was complete response (CR) rate after four cycles of therapy. Secondary end points were: overall response rate, stem-cell mobilization activity, and toxicity. Progression-free and overall survival were also evaluated. In total, 59 patients were enrolled. After four cycles of therapy, 43 patients (73%) achieved CR, and six (10%) achieved partial response, for an overall response rate of 83%. The most common grade 3 to 4 nonhematologic toxicities included febrile neutropenia (n = 7) and infection (n = 4). Regarding hematologic toxicities, grade 3 to 4 thrombocytopenia and neutropenia were each experienced by eight patients (13.5%). CD34+ cells were successfully harvested in 55 of 57 evaluable patients, and 43 of 49 responding patients underwent ASCT. With a median follow-up of 29 months, the 2-year progression-free and overall survival rates for the total population were 62.2% and 77.6%, respectively. The same figures for patients undergoing autograft were 80.8% and 89.3%, respectively. This phase II study demonstrates that BeGEV is an effective salvage regimen able to induce CR in a high proportion of patients with relapsed or refractory HL before ASCT. These data provide a strong rationale for further development of the BeGEV regimen. © 2016 by American Society of Clinical Oncology.

Evaluation of CD4+ CD25+ FoxP3+ regulatory T cells during treatment of patients with brucellosis.

PubMed

Hasanjani Roushan, M R; Bayani, M; Soleimani Amiri, S; Mohammadnia-Afrouzi, M; Nouri, H R; Ebrahimpour, S

2016-01-01

Cell-mediated immunity (CMI) plays a critical role in the control of brucellosis. Regulatory T cells (Tregs) have a functional character in modulating the balance between host immune response and tolerance, which can eventually lead to chronic infection or relapse. The aim of this study was to assess the alteration of Tregs in cases of brucellosis before and after treatment. Thirty cases of acute brucellosis with the mean age of 41.03±15.15 years (case group) and 30 healthy persons with the mean age of 40.63±13.95 years (control group) were selected and assessed. Peripheral blood mononuclear cells (PBMCs) were isolated from peripheral blood of all individuals. We analyzed the alteration of Treg cell count using flow cytometry for CD4, CD25, and FoxP3 markers. The level of CD4+ CD25+ FoxP3+ Treg cells was increased in active patients compared with controls (2.5±0.99% vs 1.6±0.84%, p= 0.0004), but it had declined in the treated cases (1.83±0.73%, p=0.02). The level of Tregs was elevated in three relapsed cases. The frequency of Tregs and Treg/Teff (effector T cell) ratio was correlated with inverse serum agglutination test (SAT) and, 2-mercaptoethanol (2-ME) titers as markers of treatment in brucellosis. Based on our findings, we suggest that regulatory cells, such as CD4+ CD25+ FoxP3+ Treg cells, may contribute to the development of infection processes involving immune responses in brucellosis, and evaluation of regulatory T-cell levels may be a potential diagnostic strategy for the treatment outcome in chronic and relapsed cases of brucellosis.

CD30 downregulation, MMAE resistance, and MDR1 upregulation are all associated with resistance to brentuximab vedotin

PubMed Central

Chen, Robert; Hou, Jessie; Newman, Edward; Kim, Young; Donohue, Cecile; Liu, Xueli; Thomas, Sandra H.; Forman, Stephen J.; Kane, Susan E.

2015-01-01

Brentuximab vedotin (BV) is an antibody-drug conjugate that specifically delivers the potent cytotoxic drug MMAE to CD30-positive cells. BV is FDA-approved for treatment of relapsed/refractory Hodgkin lymphoma (HL) and anaplastic large cell lymphoma (ALCL); however, many patients do not achieve complete remission and develop BV resistant disease. We selected for BV-resistant HL (L428) and ALCL (Karpas-299) cell lines using either constant (ALCL) or pulsatile (HL) exposure to BV. We confirmed drug resistance by MTS assay, and analyzed CD30 expression in resistant cells by flow cytometry, qRT-PCR, and Western blotting. We also measured drug exporter expression, MMAE resistance, and intracellular MMAE concentrations in BV-resistant cells. Additionally, tissue biopsy samples from 10 HL and 5 ALCL patients who had relapsed or progressed after BV treatment were analyzed by immunohistocytochemistry for CD30 expression. The resistant ALCL cell line, but not the HL cell line, demonstrated downregulated CD30 expression compared to the parental cell line. In contrast, the HL cell line, but not the ALCL cell line, exhibited MMAE resistance and increased expression of the MDR1 drug exporter compared to the parental line. For both HL and ALCL, samples from patients relapsed/resistant on BV persistently expressed CD30 by immunohistocytochemistry. One HL patient sample expressed MDR1 by immunohistocytochemistry. Although loss of CD30 expression is a possible mode of BV resistance in ALCL in vitro models, this has not been confirmed in patients. MMAE resistance and MDR1 expression are possible modes of BV resistance for HL both in vitro and in patients. PMID:25840583

Different Subcellular Localization of ALCAM Molecules in Neuroblastoma: Association with Relapse

PubMed Central

Corrias, Maria Valeria; Gambini, Claudio; Gregorio, Andrea; Croce, Michela; Barisione, Gaia; Cossu, Claudia; Rossello, Armando; Ferrini, Silvano; Fabbi, Marina

2010-01-01

Background: The Activated Leukocyte Cell Adhesion Molecule (ALCAM/CD), involved in nervous system development, has been linked to tumor progression and metastasis in several tumors. No information is available on ALCAM expression in neuroblastoma, a childhood neoplasia originating from the sympathetic nervous system. Methods: ALCAM expression was analysed by immunofluorescence and immunohistochemistry on differentiated neuroblastoma cell lines and on archival specimens of stroma-poor, not MYCN amplified, resectable neuroblastoma tumors, respectively. Results: ALCAM is variously expressed in neuroblastoma cell lines, is shed by metalloproteases and is cleaved by ADAM17/TACE in vitro. ALCAM is expressed in neuroblastoma primary tumors with diverse patterns of subcellular localization and is highly expressed in the neuropil area in a subgroup of cases. Tumor specimens showing high expression of ALCAM at the membrane of the neuroblast body or low levels in the neuropil area are associated with relapse (P = 0.044 and P < 0.0001, respectively). In vitro differentiated neuroblastoma cells show strong ALCAM expression on neurites, suggesting that ALCAM expression in the neuropil is related to a differentiated phenotype. Conclusions: Assessment of ALCAM localization by immunohistochemistry may help to identify patients who, in the absence of negative prognostic factors, are at risk of relapse and require a more careful follow-up. PMID:20208136

Towards a Therapeutic Reduction of Imatinib Refractory Myeloproliferative Neoplasm-Initiating Cells

PubMed Central

Philips, Steven T.; Hildenbrand, Zacariah L.; Oravecz-Wilson, Katherine I.; Foley, S. Blake; Mgbemena, Victoria E.; Ross, Theodora S.

2014-01-01

Myeloproliferative neoplasms (MPNs) such as chronic myelogenous (CML) and chronic myelomonocytic leukemias (CMML) are frequently induced by tyrosine kinase oncogenes. Although these MPNs are sensitive to tyrosine kinase inhibitors such as imatinib, patients often relapse upon withdrawal of therapy. We used a model of MPN, which is induced by co-expression of the oncoproteins HIP1/PDGFβR (H/P) and AML1/ETO (A/E) from their endogenous loci, to examine the mechanisms of disease development and recurrence following imatinib withdrawal. Although the MPN displayed a full hematologic response to imatinib, 100% of the diseased mice relapsed upon drug withdrawal. MPN persistence was not due to imatinib resistance mutations in the H/P oncogene or massive gene expression changes. Within one week of imatinib treatment, more than 98% of gene expression changes induced by the oncogenes in isolated hematopoietic stem and progenitor cells (LSKs) normalized. Supplementation of imatinib with G-CSF or arsenic trioxide reduced MPN-initiating cell frequencies and the combination of imatinib with arsenic trioxide cured a large fraction of mice with MPNs. In contrast, no mice in the imatinib-treated control cohorts were cured. These data suggest that treatment with a combination of arsenic trioxide and imatinib can eliminate refractory MPN-initiating cells and reduce disease relapse. PMID:24240679