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Sample records for chronic lymphocytic leukemia a

  1. What Is Chronic Lymphocytic Leukemia?

    MedlinePlus

    ... About Chronic Lymphocytic Leukemia What Is Chronic Lymphocytic Leukemia? Cancer starts when cells in the body begin ... the lymph nodes, liver, and spleen. What is leukemia? Leukemia is a cancer that starts in the ...

  2. Supportive Care for Chronic Lymphocytic Leukemia

    MedlinePlus

    ... Chronic Lymphocytic Leukemia Supportive Care for Chronic Lymphocytic Leukemia Supportive care for chronic lymphocytic leukemia (CLL) is ... Treating Hairy Cell Leukemia More In Chronic Lymphocytic Leukemia About Chronic Lymphocytic Leukemia Causes, Risk Factors, and ...

  3. Obinutuzumab in chronic lymphocytic leukemia.

    PubMed

    Dupuis, Jehan

    2015-09-01

    Obinutuzumab is the second next-generation monoclonal anti-CD20 antibody (after ofatumumab) to enter clinical practice in chronic lymphocytic leukemia. Its superiority in association with chlorambucil as compared with chlorambucil alone has led to its approval as a first-line treatment for chronic lymphocytic leukemia, for patients who are not candidates for a more intensive treatment.

  4. What Are the Risk Factors for Chronic Lymphocytic Leukemia?

    MedlinePlus

    ... What Are the Risk Factors for Chronic Lymphocytic Leukemia? A risk factor is something that affects a ... Lymphocytic Leukemia Be Prevented? More In Chronic Lymphocytic Leukemia About Chronic Lymphocytic Leukemia Causes, Risk Factors, and ...

  5. Leukemia cutis in a patient with chronic lymphocytic leukemia presenting as bilateral helical nodules

    PubMed Central

    Raufi, Ali; Alsharedi, Mohamed; Khelfa, Yousef; Griswold, Doreen C; Lebowicz, Yehuda

    2016-01-01

    Chronic lymphocytic leukemia, the most common adult leukemia worldwide, is considered an indolent but incurable non-Hodgkin lymphoma. Leukemia cutis is an uncommon manifestation of chronic lymphocytic leukemia. We present a case of an adult patient who presented with skin lesion of bilateral ears, which led to the diagnosis of chronic lymphocytic leukemia. We also reviewed the cases of auricular involvement in chronic lymphocytic leukemia patients reported in the literature. Local treatment is indicated in case of leukemia cutis; however, systemic treatment is recommended when there are systemic signs and symptoms. Better awareness of disease evolution and prompt diagnosis of this leukemia cutis of chronic lymphocytic leukemia will improve the effectiveness and outcome of its management. PMID:28228955

  6. Chronic lymphocytic leukemia: a changing natural history?

    PubMed

    Rozman, C; Bosch, F; Montserrat, E

    1997-06-01

    There are some data suggesting that the natural history of chronic lymphocytic leukemia (CLL) may be changing, but a systematic analysis of this topic is lacking. To address this issue, we examined two cohorts of CLL patients in whom the diagnosis was established in 1960-1979 (group I) and in 1980-1989 (group II), respectively. Striking differences were observed between both cohorts. The diagnosis in the second group was established at higher age (65.8 vs 61.3 years; P = 0.0001), both in males (63.8 vs 59.1 years; P = 0.004) and females (68.3 vs 64.2 years; P = 0.01); the proportion of patients in whom the diagnosis was established in low-risk clinical stage (Binet's A) was significantly higher in group II (65.7% vs 42.6%; P < 0.001), and the survival was more than double in group II (median of 11.1 vs 5.3 years; P < 0.0001). Moreover, the impact of the disease on life expectancy was much lower in the more recent cohort. These differences may be due, at least in part, to changes in the natural history of the disease.

  7. Treatment of Chronic Lymphocytic Leukemia by Risk Group

    MedlinePlus

    ... Chronic Lymphocytic Leukemia Typical Treatment of Chronic Lymphocytic Leukemia Treatment options for chronic lymphocytic leukemia (CLL) vary ... Treating Hairy Cell Leukemia More In Chronic Lymphocytic Leukemia About Chronic Lymphocytic Leukemia Causes, Risk Factors, and ...

  8. Expanding the armamentarium for chronic lymphocytic leukemia: A review of novel agents in the management of chronic lymphocytic leukemia.

    PubMed

    Marini, Bernard L; Samanas, Lisa; Perissinotti, Anthony J

    2016-06-29

    Treatment options for chronic lymphocytic leukemia, the most common leukemia in the United States, have expanded rapidly in recent years. While traditional chemoimmunotherapy still remains a mainstay for young, fit patients, a number of novel targeted therapies have emerged that have changed the therapeutic landscape. Two innovative anti-CD20 monoclonal antibodies, obinutuzumab and ofatumomamab, have demonstrated activity in chronic lymphocytic leukemia and represent well-tolerated options in upfront management of elderly patients or in those with significant comorbidities. Agents targeting the B-cell receptor pathway, ibrutinib and idelalisib, have excellent activity in chronic lymphocytic leukemia, particularly in those patients with 17p deletions, in which responses to chemoimmunotherapy are traditionally dismal. Venetoclax (ABT-199), the recently FDA-approved BCL2 inhibitor, as well as several other agents and therapy combinations in the pipeline offer great promise for patients with chronic lymphocytic leukemia, particularly in the relapsed/refractory setting. This article comprehensively reviews the data for novel agents in chronic lymphocytic leukemia, including the pharmacology of therapies, unique toxicities, and other practical management considerations for clinicians.

  9. Chronic Lymphocytic Leukemia

    PubMed Central

    Motta, Marina; Wierda, William G.; Ferrajoli, Alessandra

    2015-01-01

    Patients with purine analogue-refractory chronic lymphocytic leukemia (CLL) have short survival and limited treatment options. Defining the best salvage strategies for this population is challenging, because limited data are available from clinical trials, and because studies have enrolled mixed populations (patients with recurrent and refractory disease or patients with refractory disease and Richter transformation). Moreover, patients with refractory CLL have a high incidence of unfavorable molecular and clinical features, such as high-risk genomic profiles, unmutated immunoglobulin heavy-chain genes, expression of zeta-chain-associated protein kinase 70, and bulky lymphadenopathies. These patients are also severely immunosuppressed because of the underlying disease and the treatments received, and experience a high rate of infectious complications that pose an additional difficulty in selecting treatment. Despite these challenges, in parallel with better characterizations of the biologic features of refractory CLL, the number of available treatment modalities for this population has increased. Several chemoimmunotherapy combinations have been developed, and novel agents with a different mechanism of action are being investigated in clinical trials. Furthermore, allogeneic stem cell transplantation with nonmyeloablative conditioning regimens is a therapeutic strategy that is increasingly offered to patients with refractory CLL. PMID:19536902

  10. Lenalidomide and Vaccine Therapy in Treating Patients With Early-Stage Asymptomatic Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

    ClinicalTrials.gov

    2016-12-26

    Chronic Lymphocytic Leukemia; Stage 0 Chronic Lymphocytic Leukemia; Stage I Chronic Lymphocytic Leukemia; Stage I Small Lymphocytic Lymphoma; Stage II Chronic Lymphocytic Leukemia; Stage II Small Lymphocytic Lymphoma

  11. Obatoclax, Fludarabine, and Rituximab in Treating Patients With Previously Treated Chronic Lymphocytic Leukemia

    ClinicalTrials.gov

    2013-09-27

    B-cell Chronic Lymphocytic Leukemia; Leukemia; Prolymphocytic Leukemia; Refractory Chronic Lymphocytic Leukemia; Stage I Chronic Lymphocytic Leukemia; Stage II Chronic Lymphocytic Leukemia; Stage III Chronic Lymphocytic Leukemia; Stage IV Chronic Lymphocytic Leukemia

  12. Cryptococcal prostatitis in a patient with chronic lymphocytic leukemia.

    PubMed

    Sharma, N; Varma, S; Varma, N; Kumari, S; Chakraborty, A

    2000-10-01

    Cryptococcosis is a systemic mycosis usually affecting patients of immunodeficiency i.e. transplants recipients, patients on chemotherapy for neoplastic diseases and in those suffering from human immunodeficiency virus infection. We report a 52-year old male suffering from chronic lymphocytic leukemia (CLL) on chemotherapy who presented with fever and features of prostatism. Cryptococcus neoformans infection (CN) was diagnosed on aspiration of a prostatic nodule. Subsequent investigations revealed a disseminated involvement by cryptococcus. The case represents an unusual presentation of disseminated cryptococcosis.

  13. Ofatumumab, Pentostatin, and Cyclophosphamide in Treating Patients With Untreated Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

    ClinicalTrials.gov

    2014-10-30

    Hematopoietic/Lymphoid Cancer; B-cell Chronic Lymphocytic Leukemia; Contiguous Stage II Small Lymphocytic Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Stage 0 Chronic Lymphocytic Leukemia; Stage I Chronic Lymphocytic Leukemia; Stage I Small Lymphocytic Lymphoma; Stage II Chronic Lymphocytic Leukemia; Stage III Chronic Lymphocytic Leukemia; Stage III Small Lymphocytic Lymphoma; Stage IV Chronic Lymphocytic Leukemia; Stage IV Small Lymphocytic Lymphoma

  14. What Should You Ask Your Doctor about Chronic Lymphocytic Leukemia?

    MedlinePlus

    ... Should You Ask Your Doctor About Chronic Lymphocytic Leukemia? As you cope with cancer and cancer treatment, ... About Chronic Lymphocytic Leukemia? More In Chronic Lymphocytic Leukemia About Chronic Lymphocytic Leukemia Causes, Risk Factors, and ...

  15. Do We Know What Causes Chronic Lymphocytic Leukemia?

    MedlinePlus

    ... Prevention Do We Know What Causes Chronic Lymphocytic Leukemia? The exact cause of most cases of chronic ... Lymphocytic Leukemia Be Prevented? More In Chronic Lymphocytic Leukemia About Chronic Lymphocytic Leukemia Causes, Risk Factors, and ...

  16. Fludarabine Phosphate and Total-Body Irradiation Before Donor Peripheral Blood Stem Cell Transplant in Treating Patients With Chronic Lymphocytic Leukemia or Small Lymphocytic Leukemia

    ClinicalTrials.gov

    2016-07-18

    B-Cell Prolymphocytic Leukemia; Chronic Lymphocytic Leukemia; Prolymphocytic Leukemia; Recurrent Chronic Lymphocytic Leukemia; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; T-Cell Prolymphocytic Leukemia

  17. What Are the Key Statistics for Chronic Lymphocytic Leukemia?

    MedlinePlus

    ... What Are the Key Statistics for Chronic Lymphocytic Leukemia? The American Cancer Society's estimates for leukemia in ... Leukemia Research and Treatment? More In Chronic Lymphocytic Leukemia About Chronic Lymphocytic Leukemia Causes, Risk Factors, and ...

  18. What's New in Chronic Lymphocytic Leukemia Research and Treatment?

    MedlinePlus

    ... Lymphocytic Leukemia (CLL) About Chronic Lymphocytic Leukemia What's New in Chronic Lymphocytic Leukemia Research and Treatment? Many ... person's outlook and whether they will need treatment. New drugs for chronic lymphocytic leukemia Dozens of new ...

  19. Treatment of chronic lymphocytic leukemia.

    PubMed

    Ferrajoli, Alessandra; O'Brien, Susan M

    2004-04-01

    Treatment options for patients with chronic lymphocytic leukemia have changed over the past two decades. This article reviews the experience accumulated with the use of alkylating agents alone and in combination; purine analogues alone and in combination and monoclonal antibodies such as rituximab, and alemtuzumab alone and in combination. The results obtained with different treatment strategies are summarized, compared, and reviewed.

  20. Transplantation in chronic lymphocytic leukemia.

    PubMed

    Le Dieu, Rifca; Gribben, John G

    2007-02-01

    Although there have been no randomized trials comparing the outcome of stem cell transplantation (SCT) with standard chemotherapy for patients with chronic lymphocytic leukemia (CLL), increasingly, both autologous and allogeneic SCT approaches are being explored in this disease. Clinical trials have demonstrated that these approaches are feasible, but current data suggest that autologous transplantation is not curative and myeloablative SCT, although offering the potential for cure, is associated with high treatment-related mortality. There is a clear demonstration of a graft-versus-leukemia effect in CLL, with encouraging results seen after SCT with reduced-intensity conditioning. Because no other treatment modalities are currently capable of improving survival in this disease, the treatment of choice for younger patients with poor-risk CLL may well be SCT, but continued enrollment of appropriate patients into well-designed clinical trials is vital to compare advances in SCT with the advances occurring in chemoimmunotherapy in CLL.

  1. Monoclonal antibodies in chronic lymphocytic leukemia.

    PubMed

    Ferrajoli, Alessandra; Faderl, Stefan; Keating, Michael J

    2006-09-01

    Multiple options are now available for the treatment of chronic lymphocytic leukemia. Over the last 10 years, monoclonal antibodies have become an integral part of the management of this disease. Alemtuzumab has received approval for use in patients with fludarabine-refractory chronic lymphocytic leukemia. Rituximab has been investigated extensively in chronic lymphocytic leukemia both as a single agent and in combination with chemotherapy and other monoclonal antibodies. Epratuzumab and lumiliximab are newer monoclonal antibodies in the early phase of clinical development. This article will review the monoclonal antibodies more commonly used to treat chronic lymphocytic leukemia, the results obtained with monoclonal antibodies as single agents and in combination with chemotherapy, and other biological agents and newer compounds undergoing clinical trials.

  2. Chronic Lymphocytic Leukemia

    MedlinePlus

    Leukemia is cancer of the white blood cells. White blood cells help your body fight infection. Your blood cells form in your bone marrow. In leukemia, the bone marrow produces abnormal white blood cells. ...

  3. Alvocidib in Treating Patients With B-Cell Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

    ClinicalTrials.gov

    2013-07-01

    B-cell Chronic Lymphocytic Leukemia; Contiguous Stage II Small Lymphocytic Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Stage I Chronic Lymphocytic Leukemia; Stage I Small Lymphocytic Lymphoma; Stage II Chronic Lymphocytic Leukemia; Stage III Chronic Lymphocytic Leukemia; Stage III Small Lymphocytic Lymphoma; Stage IV Chronic Lymphocytic Leukemia; Stage IV Small Lymphocytic Lymphoma

  4. [Apoptosis in chronic lymphocytic leukemia].

    PubMed

    Giordano, M

    2000-01-01

    Chronic lymphocytic leukemia of B cells (B-CLL) is the most prevalent leukemia in the Occidental Hemisphere. It is characterized by a progressive accumulation of monoclonal CD5+ B lymphocytes, with low amounts of surface Ig. Most B-CLL cells are arrested in the G0 phase of the cell cycle; therefore their accumulation in vivo appears to result from the inhibition of apoptosis which has been attributed to over-expression of the anti-apoptotic protein Bcl-2. When cultured in vitro, spontaneous apoptosis occurs, suggesting the existence in vivo of survival-promoting factors. We here show that non-malignant leukocytes, particularly monocytes and NK cells, are able to inhibit B-CLL cells apoptosis, at least in part, through the release of soluble factors. Neutralizing antibodies directed to interferon-gamma or IL-4 only partially abolish the protecting effects of accessory cells suggesting that they are not the main cytokines involved. Increased apoptosis of B-CLL cells is not associated with modifications in the expression of Bcl-2, Fas or Fas ligand. Considering that B-CLL is associated to autoimmune phenomena and recurrent infections due to hypogammaglobulinemia, it should be interesting to correlate the activation of immune responses with disease progression.

  5. Cyclophosphamide, Alvocidib, and Rituximab in Treating Patients With High Risk B-Cell Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

    ClinicalTrials.gov

    2015-11-10

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

  6. Epigenetic alterations in a murine model for chronic lymphocytic leukemia.

    PubMed

    Chen, Shih-Shih; Sherman, Mara H; Hertlein, Erin; Johnson, Amy J; Teitell, Michael A; Byrd, John C; Plass, Christoph

    2009-11-15

    Early stages in the development of chronic lymphocytic leukemia (CLL) have not been explored mainly due to the inability to study normal B-cells en route to transformation. In order to determine such early events of leukemogenesis, we have used a well established mouse model for CLL. Over-expression of human TCL1, a known CLL oncogene in murine B-cells leads to the development of mature CD19+/CD5+/IgM+ clonal leukemia with a disease phenotype similar to that seen in human CLL. Herein, we review our recent study using this TCL1-driven mouse model for CLL and corresponding human CLL samples in a cross-species epigenomics approach to address the timing and relevance of epigenetic events occurring during leukemogenesis. We demonstrated that the mouse model recapitulates the epigenetic events that have been reported for human CLL, affirming the power and validity of this mouse model to study early epigenetic events in cancer progression. Epigenetic alterations are detected as early as three months after birth, far before disease manifests at about 11 months of age. These mice undergo NFkappaB repressor complex mediated inactivation of the transcription factor Foxd3, whose targets become aberrantly methylated and silenced in mouse and human CLL. Overall, our data suggest the accumulated epigenetic alterations during CLL pathogenesis as a consequence of gene silencing through TCL1 and NFkappaB repressor complex, suggesting the relevance for NFkappaB as a therapeutic target in CLL.

  7. Epigenetic alterations in a murine model for chronic lymphocytic leukemia

    PubMed Central

    Chen, Shih-Shih; Sherman, Maura H; Hertlein, Erin; Johnson, Amy J; Teitell, Michael A.; Byrd, John C.; Plass, Christoph

    2010-01-01

    Early stages in the development of chronic lymphocytic leukemia (CLL) have not been explored mainly due to the inability to study normal B-cells in route to transformation. In order to determine such early events of leukemogenesis, we have used a well established mouse model for CLL. Over-expression of human TCL1, a known CLL oncogene, in murine B-cells leads to the development of mature CD19+/CD5+/IgM+ clonal leukemia with a similar disease phenotype seen in human CLL. Herein, we review our recent study using this TCL1 murine model for CLL and corresponding human CLL samples in a cross-species epigenomics approach to address the timing and relevance of epigenetic events occurring during leukemogenesis. We were able to demonstrate that the mouse model recapitulates epigenetic events very similar to what has been reported for human CLL and thus provides an exciting new tool to study early epigenetic events. Epigenetic alterations are seen at a time of three month after birth, much earlier than the phenotypically visible disease which occurs around 11 month of age. An early event in gene silencing is the inactivation of transcription factor Foxd3 expression through an NF-κB mediated process in animals with one month of age. PMID:19901553

  8. Chronic lymphocytic leukemia (CLL)

    MedlinePlus

    ... Complications of CLL and its treatment may include: Autoimmune hemolytic anemia Bleeding from low platelet count Hypogammaglobulinemia, a condition ... used during any medical emergency or for the diagnosis or treatment of any medical condition. A licensed ...

  9. Management of chronic lymphocytic leukemia.

    PubMed

    Stilgenbauer, Stephan; Furman, Richard R; Zent, Clive S

    2015-01-01

    Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) is usually diagnosed in asymptomatic patients with early-stage disease. The standard management approach is careful observation, irrespective of risk factors unless patients meet the International Workshop on CLL (IWCLL) criteria for "active disease," which requires treatment. The initial standard therapy for most patients combines an anti-CD20 antibody (such as rituximab, ofatumumab, or obinutuzumab) with chemotherapy (fludarabine/cyclophosphamide [FC], bendamustine, or chlorambucil) depending on multiple factors including the physical fitness of the patient. However, patients with very high-risk CLL because of a 17p13 deletion (17p-) with or without mutation of TP53 (17p-/TP53mut) have poor responses to chemoimmunotherapy and require alternative treatment regimens containing B-cell receptor (BCR) signaling pathway inhibitors. The BCR signaling pathway inhibitors (ibrutinib targeting Bruton's tyrosine kinase [BTK] and idelalisib targeting phosphatidyl-inositol 3-kinase delta [PI3K-delta], respectively) are currently approved for the treatment of relapsed/refractory CLL and all patients with 17p- (ibrutinib), and in combination with rituximab for relapsed/refractory patients (idelalisib). These agents offer great efficacy, even in chemotherapy refractory CLL, with increased tolerability, safety, and survival. Ongoing studies aim to determine the best therapy combinations with the goal of achieving long-term disease control and the possibility of developing a curative regimen for some patients. CLL is associated with a wide range of infectious, autoimmune, and malignant complications. These complications result in considerable morbidity and mortality that can be minimized by early detection and aggressive management. This active monitoring requires ongoing patient education, provider vigilance, and a team approach to patient care.

  10. Obinutuzumab for chronic lymphocytic leukemia.

    PubMed

    Rioufol, Catherine; Salles, Gilles

    2014-10-01

    Chronic lymphocytic leukemia (CLL) is a frequent hematological malignancy that is incurable using standard approaches. Two anti-CD20 monoclonal antibodies (mAb), rituximab and ofatumumab, have been approved for CLL treatment. A new glycoengineered type II humanized anti-CD20 mAb, obinutuzumab (GA101), has been developed and demonstrates increased activity against B-cell malignancies by inducing direct cell death and better antibody-dependent cellular cytotoxicity. In a recent randomized Phase III study in patients with newly diagnosed CLL and coexisting conditions, obinutuzumab plus chlorambucil demonstrated significant improvement in progression-free survival and several other outcome parameters, in contrast to rituximab plus chlorambucil. Grade 3-4 infusion-related reactions and neutropenia occurred more frequently in patients who received obinutuzumab compared with those who received rituximab; however, the rate of serious infections was similar. Obinutuzumab represents a promising new option for patients with CLL and must be investigated with other chemotherapy regimens or with new targeted agents.

  11. Fludarabine in the treatment of chronic lymphocytic leukemia: a review

    PubMed Central

    Ricci, Francesca; Tedeschi, Alessandra; Morra, Enrica; Montillo, Marco

    2009-01-01

    Fludarabine (FAMP) is the most effective and most extensively studied purine analog in indolent B-cell malignancies. Its use is indicated for first-and second-line treatment of B-cell chronic lymphocytic leukemia (B-CLL). FAMP as a single agent has produced superior response rates and progression-free survival than standard therapy with chlorambucil and alkylator-based regimen. Efficacy of FAMP may be increased by combining this purine analog with other chemotherapeutic and non-chemotherapeutic agents. FAMP and cyclophosphamide combination (FC) has shown promising results with higher overall response and complete response rates than FAMP in monotherapy, although no difference has been detected in survival. Quality of response and eradication of minimal residual disease (MRD) have been reported to be associated with prolonged survival. Eradication of MRD has been achieved by combining FC with mitoxantrone or monoclonal antibody including alemtuzumab or rituximab or both. FAMP has been widely used in non-myeloablative conditioning regimens, often combined with a variety of other cytotoxic agents, with the aim of inducing enough immunosuppression to allow successful engraftment and to exert some pretransplant anti-tumor activity. The current paper provides an overview of use of FAMP as a single agent or as a cornerstone of different therapeutic strategies for treatment of B-CLL patients. PMID:19436622

  12. Lenalidomide and Chronic Lymphocytic Leukemia

    PubMed Central

    González-Rodríguez, Ana Pilar; Payer, Angel R.; Acebes-Huerta, Andrea; Huergo-Zapico, Leticia; Villa-Alvarez, Monica; Gonzalez-García, Esther; Gonzalez, Segundo

    2013-01-01

    Lenalidomide is an oral immunomodulatory drug used in multiple myeloma and myelodysplastic syndrome and most recently it has shown to be effective in the treatment of various lymphoproliferative disorders such as chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma. The mechanism of action of lenalidomide varies depending on the pathology, and in the case of CLL, it appears to primarily act by restoring the damaged mechanisms of tumour immunosurveillance. This review discusses the potential mechanism of action and efficacy of lenalidomide, alone or in combination, in treatment of CLL and its toxic effects such as tumor lysis syndrome (TLS) and tumor flare reaction (TFR), that make its management different from other hematologic malignancies. PMID:24163824

  13. Novel Therapies for Chronic Lymphocytic Leukemia: A Canadian Perspective.

    PubMed

    Owen, Carolyn; Assouline, Sarit; Kuruvilla, John; Uchida, Cassandra; Bellingham, Catherine; Sehn, Laurie

    2015-11-01

    Chronic lymphocytic leukemia (CLL) is the most common adult lymphoproliferative disorder in Western countries. The current standard of care for CLL is chemoimmunotherapy, typically with fludarabine, cyclophosphamide, and rituximab (FCR). However, most patients with CLL are elderly with comorbidities and are unable to tolerate FCR. In order to choose the best treatment for each individual patient, physicians must balance efficacy with toxicity. In addition, most currently available treatments are ineffective in CLL patients with loss of TP53. Two groups of novel therapeutic agents-anti-CD20 monoclonal antibodies and small molecule inhibitors-are attempting to address these issues, and 5 of these agents have progressed to phase 3 trials: obinutuzumab, idelalisib, ibrutinib, venetoclax (ABT-199), and duvelisib (IPI-145). We present the current evidence for these novel agents in the treatment of CLL, along with the perspectives of 4 Canadian oncology experts.

  14. Chylothorax Associated with Chronic Lymphocytic Leukemia

    PubMed Central

    Kohmoto, Osamu; Kawabe, Kazumi; Ono, Hideya; Yanagimoto, Ryuta; Arimoto, Junji; Hatada, Atsutoshi; Suruda, Tadatoshi; Minakata, Yoshiaki

    2016-01-01

    An 80-year-old man who had suffered from chronic lymphocytic leukemia (CLL) and achieved complete remission was admitted to our hospital due to right pleural effusion. Thoracentesis revealed that the effusion was chyle. Lymphoscintigraphy showed an obstruction of the thoracic duct below the sternum. CD45-gated flow cytometry of the pleural effusion showed elevated numbers of CD5- and CD23-positive lymphocytes and a high serum level of soluble interleukin-2 receptor. These results suggested that the chylothorax was caused by the obstruction of the thoracic duct by the sludging of either abnormal lymphocytes of CLL or transformed malignant lymphoma cells. PMID:27980266

  15. 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

  16. Chronic Lymphocytic Leukemia and Other Lymphoproliferative Disorders.

    PubMed

    Wall, Sarah; Woyach, Jennifer A

    2016-02-01

    Chronic lymphocytic leukemia affects less than 1% of US adults but is the most common leukemia and primarily affects older patients. Non-Hodgkin lymphomas are the seventh most common cancers in the United States and also primarily affect older patients. In general, older patients should be treated differently than their younger, fitter counterparts. Fitness level and comorbidities should be taken into account when planning treatment. First-line treatment of most of these B-cell lymphoproliferative disorders consists of chemoimmunotherapy. In relapsed and refractory disease, there is a growing role for therapies targeting the B-cell receptor signaling pathway.

  17. SnapShot: chronic lymphocytic leukemia.

    PubMed

    Ciccone, Maria; Ferrajoli, Alessandra; Keating, Michael J; Calin, George A

    2014-11-10

    Chronic lymphocytic leukemia (CLL) is the most common leukemia among adults in western countries. This SnapShot depicts the origins and evolution of this B cell malignancy, describes prognostic factors and CLL animal models, and illustrates therapies in preclinical and clinical development against CLL.

  18. Entospletinib and Obinutuzumab in Treating Patients With Relapsed Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma, or Non-Hodgkin Lymphoma

    ClinicalTrials.gov

    2017-03-24

    Anemia; B-Cell Prolymphocytic Leukemia; Fatigue; Fever; Grade 1 Follicular Lymphoma; Grade 2 Follicular Lymphoma; Grade 3a Follicular Lymphoma; Hairy Cell Leukemia; Lymphadenopathy; Lymphocytosis; Lymphoplasmacytic Lymphoma; Mantle Cell Lymphoma; Marginal Zone Lymphoma; Night Sweats; Recurrent Chronic Lymphocytic Leukemia; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Small Lymphocytic Lymphoma; Richter Syndrome; Splenomegaly; Thrombocytopenia; Weight Loss

  19. [Morphometric analysis of lymphocyte nuclei in chronic lymphocytic leukemia].

    PubMed

    Ostapenko, V A; Kruchinskiĭ, N G; Smirnova, L A; Cherednik, A B; Nesterov, V N; Tepliakov, A I

    1994-01-01

    This work is dedicated to the study of use of quantitative analysis of cell nucleus structure for the analysis of peripheral blood lymphocytes in patients with chronic lymphocytic leukaemia. The structure of lymphocytic nuclei of healthy donors was evaluated by means of staining by toluidine blue purified cell suspensions smears. The preparations were analysed on the television measuring system "omnicon" with measurements of the following parameters: square of the nucleus, euchromatin, heterochromatin, and the ratio of heterochromatin and euchromatin squares. Actuarial analysis and nuclei classification of the previously mentioned parameters showed, that in peripheral blood of patients with chronic lymphocytic leukemia a large amount of atypical lymphocytes is present with reduced nucleus sizes. Atypical cells retain the ratio of structural components of chromatine, characteristic to normal cells, which show their low proliferative activity.

  20. Chronic lymphocytic leukemia: a clinical review including Korean cohorts

    PubMed Central

    Jeon, Young-Woo; Cho, Seok-Goo

    2016-01-01

    Only 5th decade ago, chronic lymphocytic leukemia (CLL) was only recognized as disease group of presenting features like peripheral lymphocytosis, organomegaly including of splenomegaly. As understanding of disease biology and molecular diagnostic tools are getting improved gradually, characterization of variation in CLL’s clinical courses was facilitated, resulting in better risk stratification and targeted treatments. Consequently multiple new targeted agents have been used in treatment of CLL, it makes improved clinical outcome. Rituximab containing chemoimmunotherapy (combination of rituximab, fludarabine, and cyclophosphamide) have shown better overall response rate and progression-free survival on fit patients’ group in front-line setting, result in standard first-line therapeutic option for CLL. Furthermore, after introducing that the B-cell receptor is crucial for the evolution and progression of CLL, emerging treatments targeting highly activated surface antigens and oncogenic signaling pathways have been associated with several successes in recent decades. These include new anti-CD 20 monoclonal antibody (obinutuzumab), the bruton tyrosine kinase inhibitor (ibrutinib), the phosphatidylinositol 3-kinase inhibitor (idelalisib), and B-cell CLL/lymphoma 2 inhibitor (ABT-199 and ABT-263). So, we discuss not only general pathophysiology of CLL, but also rapidly advancing treatment strategies that are being studied or approved for treatment of CLL. PMID:27044858

  1. Development and characterization of a physiologically relevant model of lymphocyte migration in chronic lymphocytic leukemia.

    PubMed

    Walsby, Elisabeth; Buggins, Andrea; Devereux, Stephen; Jones, Ceri; Pratt, Guy; Brennan, Paul; Fegan, Chris; Pepper, Chris

    2014-06-05

    There is growing evidence that lymphocyte trafficking contributes to the clinical course of chronic lymphocytic leukemia (CLL), but to date, only static in vitro cultures have been used to study these phenomena. To address this lack of data, we have developed a dynamic in vitro model in which CLL cells experience shear forces equivalent to those in capillary beds and are made to flow through capillary-like hollow fibers lined with endothelial cells. CLL cells treated in this way increased their expression of CD62L and CXCR4 (both P < .0001) and of CD49d and CD5 (both P = .003) directly as a result of the shear force. Furthermore, CLL cells migrated through the endothelium into the "extravascular" space (mean migration, 1.37% ± 2.14%; n = 21). Migrated CLL cells had significantly higher expression of CD49d (P = .02), matrix metallopeptidase-9 (P = .004), CD38 (P = .009), CD80 (P = .04), and CD69 (P = .04) compared with CLL cells that remained in the circulation. The degree of migration observed strongly correlated with CD49d expression (r(2), 0.47; P = .01), and treatment with the CD49d-blocking antibody natalizumab resulted in significantly decreased migration (P = .01). Taken together, our data provide evidence for a novel, dynamic, and tractable in vitro model of lymphocyte migration and confirm that CD49d is a critical regulator of this process in CLL.

  2. Curcumin and Cholecalciferol in Treating Patients With Previously Untreated Stage 0-II Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

    ClinicalTrials.gov

    2016-10-04

    Contiguous Stage II Small Lymphocytic Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Stage 0 Chronic Lymphocytic Leukemia; Stage I Chronic Lymphocytic Leukemia; Stage I Small Lymphocytic Lymphoma; Stage II Chronic Lymphocytic Leukemia

  3. Metabolism pathways in chronic lymphocytic leukemia.

    PubMed

    Rozovski, Uri; Hazan-Halevy, Inbal; Barzilai, Merav; Keating, Michael J; Estrov, Zeev

    2016-01-01

    Alterations in chronic lymphocytic leukemia (CLL) cell metabolism have been studied by several investigators. Unlike normal B lymphocytes or other leukemia cells, CLL cells, like adipocytes, store lipids and utilize free fatty acids (FFA) to produce chemical energy. None of the recently identified mutations in CLL directly affects metabolic pathways, suggesting that genetic alterations do not directly contribute to CLL cells' metabolic reprogramming. Conversely, recent data suggest that activation of STAT3 or downregulation of microRNA-125 levels plays a crucial role in the utilization of FFA to meet the CLL cells' metabolic needs. STAT3, known to be constitutively activated in CLL, increases the levels of lipoprotein lipase (LPL) that mediates lipoprotein uptake and shifts the CLL cells' metabolism towards utilization of FFA. Herein, we review the evidence for altered lipid metabolism, increased mitochondrial activity and formation of reactive oxygen species (ROS) in CLL cells, and discuss the possible therapeutic strategies to inhibit lipid metabolism pathways in patient with CLL.

  4. Decreased deformability of lymphocytes in chronic lymphocytic leukemia

    NASA Astrophysics Data System (ADS)

    Zheng, Yi; Wen, Jun; Nguyen, John; Cachia, Mark A.; Wang, Chen; Sun, Yu

    2015-01-01

    This paper reports the first study of stiffness/deformability changes of lymphocytes in chronic lymphocytic leukemia (CLL) patients, demonstrating that at the single cell level, leukemic metastasis progresses are accompanied by biophysical property alterations. A microfluidic device was utilized to electrically measure cell volume and transit time of single lymphocytes from healthy and CLL patients. The results from testing thousands of cells reveal that lymphocytes from CLL patients have higher stiffness (i.e., lower deformability), as compared to lymphocytes in healthy samples, which was also confirmed by AFM indentation tests. This observation is in sharp contrast to the known knowledge on other types of metastatic cells (e.g., breast and lung cancer cells) whose stiffness becomes lower as metastasis progresses.

  5. T-cell chronic lymphocytic leukemia in a double yellow-headed Amazon parrot (Amazona ochrocephala oratrix).

    PubMed

    Osofsky, Anna; Hawkins, Michelle G; Foreman, Oded; Kent, Michael S; Vernau, William; Lowenstine, Linda J

    2011-12-01

    An adult, male double yellow-headed Amazon parrot (Amazona ochrocephala oratrix) was diagnosed with chronic lymphocytic leukemia based on results of a complete blood cell count and cytologic examination of a bone marrow aspirate. Treatment with oral chlorambucil was attempted, but no response was evident after 40 days. The bird was euthanatized, and the diagnosis of chronic lymphocytic leukemia was confirmed on gross and microscopic examination of tissues. Neoplastic lymphocytes were found in the bone marrow, liver, kidney, testes, and blood vessels. Based on CD3-positive immunocytochemical and immunohistochemical immunophenotyping, the chronic lymphocytic leukemia was determined to be of T-cell origin.

  6. Chronic lymphocytic leukemia in African Americans.

    PubMed

    Coombs, Catherine C; Falchi, Lorenzo; Weinberg, J Brice; Ferrajoli, Alessandra; Lanasa, Mark C

    2012-11-01

    Chronic lymphocytic leukemia (CLL) is the most prevalent leukemia in the United States with almost 4390 attributable deaths per year. Epidemiologic data compiled by the Surveillance, Epidemiology and End Results (SEER) program identifies important differences in incidence and survival for African Americans with CLL. Although the incidence of CLL is lower among African Americans than among Caucasians (4.6 and 6.2 per 100 000 men, respectively), age-adjusted survival is inferior. African American patients with CLL are almost twice as likely to die from a CLL-related complication in the first 5 years after diagnosis as are Caucasian patients with CLL. The biologic basis for these observations is almost entirely unexplored, and a comprehensive clinical analysis of African American patients with CLL is lacking. This is the subject of the present review.

  7. Animal models for chronic lymphocytic leukemia.

    PubMed

    Pekarsky, Yuri; Zanesi, Nicola; Aqeilan, Rami I; Croce, Carlo M

    2007-04-01

    B-cell chronic lymphocytic leukemia (B-CLL), the most common leukemia in the Western world, results from an expansion of a rare population of CD5+ mature B-lymphocytes. Although clinical features and genomic abnormalities in B-CLL have been studied in considerable detail, the molecular mechanisms underlying disease development has remained unclear until recently. In the last 4 years, several transgenic mouse models for B-CLL were generated. Investigations of these mouse models revealed that deregulation of three pathways, Tcl1-Akt pathway, TNF-NF-kB pathway, and Bcl2-mediated anti-apoptotic pathway, result in the development of B-CLL. While deregulation of TCL1 alone caused a B-CLL phenotype in mice, overexpression of Bcl2 required aberrantly activated TNF-NF-kB pathway signaling to yield the disease phenotype. In this article, we present what has been learned from mice with B-CLL phenotype and how these mouse models of B-CLL were used to test therapeutic treatments for this common leukemia.

  8. Obinutuzumab for previously untreated chronic lymphocytic leukemia.

    PubMed

    Abraham, Jame; Stegner, Mark

    2014-04-01

    Obinutuzumab was approved by the Food and Drug Administration in late 2013 for use in combination with chlorambucil for the treatment of patients with previously untreated chronic lymphocytic leukemia (CLL). The approval was based on results of an open-label phase 3 trial that showed improved progression-free survival (PFS) with the combination of obinutuzumab plus chlorambucil compared with chlorambucil alone. Obinutuzumab is a monoclonal antibody that targets CD20 antigen expressed on the surface of pre B- and mature B-lymphocytes. After binding to CD20, obinutuzumab mediates B-cell lysis by engaging immune effector cells, directly activating intracellular death signaling pathways, and activating the complement cascade. Immune effector cell activities include antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis.

  9. Fludarabine Phosphate, Radiation Therapy, and Rituximab in Treating Patients Who Are Undergoing Donor Stem Cell Transplant Followed by Rituximab for High-Risk Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

    ClinicalTrials.gov

    2017-03-27

    Chronic Lymphocytic Leukemia; Prolymphocytic Leukemia; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Stage III Chronic Lymphocytic Leukemia; Stage III Small Lymphocytic Lymphoma; Stage IV Chronic Lymphocytic Leukemia; Stage IV Small Lymphocytic Lymphoma; T-Cell Large Granular Lymphocyte Leukemia

  10. Current concepts in diagnosis and treatment of chronic lymphocytic leukemia

    PubMed Central

    Roliński, Jacek

    2015-01-01

    Chronic lymphocytic leukemia (CLL) is the most commonly diagnosed type of leukemia in Western Europe and North America, and represents about 30% of all leukemias in adults. Chronic lymphocytic leukemia is a disease of the elderly, who are often in poorer general health and burdened with multiple comorbidities. These factors affect the decision making when choosing an appropriate method of treatment. In recent years there has been significant progress in the treatment of chronic lymphocytic leukemia, first due to the introduction of immunochemotherapy with monoclonal antibodies and latterly small molecules, like tyrosine kinase inhibitors targeting B-cell receptor signaling. This article discusses the current diagnostic principles, the most important prognostic factors and therapeutic options, available in first-line treatment and in refractory/resistant disease, including high-risk CLL, both for patients with good and those with poor performance status. It also presents important novel molecules which have been evaluated in clinical trials. PMID:26793019

  11. Combined chronic lymphocytic leukemia and prolactinoma: a rare occurrence in a patient presenting with pituitary apoplexy.

    PubMed

    Krisht, Khaled M; Palmer, Cheryl A; Couldwell, William T

    2013-10-01

    The authors describe a rare case of combined pituitary chronic lymphocytic leukemia (CLL) and prolactinoma in a 77-year-old man presenting with apoplexy. This case highlights the importance of evaluating the pituitary gland in patients with CLL who present with clinical manifestations of apoplexy as well as the need to carefully evaluate pathological specimens from the gland for the presence of lymphocytic cells in those patients. This is the first reported case of a combined CLL-prolactinoma pituitary lesion presenting with apoplexy.

  12. Central nervous system expression of a monoclonal paraprotein in a chronic lymphocytic leukemia patient.

    PubMed

    Ruiz, P; Moezzi, M; Chamizo, W; Ganjei, P; Whitcomb, C C; Rey, L C

    1992-01-01

    An unusual complication of chronic lymphocytic leukemia (CLL) is reported. The patient, a 79-year-old man, had a long standing history of CLL, that had been complicated by the development of a Guillain-Barré-like syndrome and a peripheral biclonal gammopathy. The biclonal immunoglobulins identified in the serum were IgM lambda and IgG lambda. The patient's condition progressed and he eventually developed ophthalmologic complications. Cerebrospinal fluid (CSF) obtained during evaluation of his visual dysfunction contained numerous small, mature lymphocytes consistent with the presence of CLL cells in the central nervous system (CNS); immunoperoxidase staining of these cells revealed a monoclonal population. Protein electrophoretic evaluation of the patient's CSF showed a single monoclonal band and immunofixation electrophoresis of the CSF revealed that the immunoglobulin present was IgG lambda. No evidence for the monoclonal IgM paraprotein identified in serum could be appreciated in the CSF by immunofixation. Taken together, these findings strongly implied that there was CNS involvement by the leukemia and this process caused the patient's neurologic symptoms. Furthermore, this study demonstrates that chronic lymphocytic leukemia should also be considered as one of the hematopoietic malignancies associated with monoclonal gammopathies involving the CNS.

  13. Chronic lymphocytic leukemia B cells contain anomalous Lyn tyrosine kinase, a putative contribution to defective apoptosis

    PubMed Central

    Contri, Antonella; Brunati, Anna Maria; Trentin, Livio; Cabrelle, Anna; Miorin, Marta; Cesaro, Luca; Pinna, Lorenzo A.; Zambello, Renato; Semenzato, Gianpietro; Donella-Deana, Arianna

    2005-01-01

    B cell chronic lymphocytic leukemia (B-CLL) is a neoplastic disorder characterized by accumulation of B lymphocytes due to uncontrolled growth and resistance to apoptosis. Analysis of B cells freshly isolated from 40 patients with chronic lymphocytic leukemia demonstrated that the Src kinase Lyn, the switch molecule that couples the B cell receptor to downstream signaling, displays anomalous properties. Lyn is remarkably overexpressed at the protein level in leukemic cells as compared with normal B lymphocytes, with a substantial aliquot of the kinase anomalously present in the cytosol. Whereas in normal B lymphocytes Lyn activation is dependent on B cell–receptor stimulation, in resting malignant cells, the constitutive activity of the kinase accounts for high basal protein tyrosine phosphorylation and low responsiveness to IgM ligation. Addition of the Lyn inhibitors PP2 and SU6656 to leukemic cell cultures restores cell apoptosis, and treatment of malignant cells with drugs that induce cell apoptosis decreases both activity and amount of the tyrosine kinase. These findings suggest a direct correlation between high basal Lyn activity and defects in the induction of apoptosis in leukemic cells. They also support a critical role for Lyn in B-CLL pathogenesis and identify this tyrosine kinase as a potential therapeutic target. PMID:15650771

  14. Role of angiogenesis in chronic lymphocytic leukemia.

    PubMed

    Letilovic, Tomislav; Vrhovac, Radovan; Verstovsek, Srdan; Jaksic, Branimir; Ferrajoli, Alessandra

    2006-09-01

    Angiogenesis is a physiologic process of new blood vessels formation mediated by various cytokines called angiogenic and angiostatic factors. Although its potential pathophysiologic role in solid tumors has been extensively studied for more than 3 decades, enhancement of angiogenesis in chronic lymphocytic leukemia (CLL) and other malignant hematological disorders has been recognized more recently. An increased level of angiogenesis has been documented by various experimental methods both in bone marrow and lymph nodes of patients with CLL. Although the role of angiogenesis in the pathophysiology of this disease remains to be fully elucidated, experimental data suggest that several angiogenic factors play a role in the disease progression. Biologic markers of angiogenesis were also shown to be of prognostic relevance in CLL. The current findings provide the rationale for investigating antiangiogenic agents in CLL. In the current review angiogenesis in CLL is discussed and its potential diagnostic and therapeutic applications.

  15. Targeted treatment for chronic lymphocytic leukemia

    PubMed Central

    Masood, Aisha; Sher, Taimur; Paulus, Aneel; Miller, Kena C; Chitta, Kasyapa S; Chanan-Khan, Asher

    2011-01-01

    The treatment of chronic lymphocytic leukemia (CLL) has evolved over the last few decades. Recognition has increased of several key components of CLL biology currently manipulated for therapeutics. A milestone in the treatment of CLL was reached with the incorporation of immunotherapy with conventional chemotherapy. The fludarabine/cyclophosphamide/rituximab combination has demonstrated survival advantage for the first time in the treatment of CLL. Several other biological compounds are being explored with the hope of improving responses, impacting survival, and ultimately curing CLL. Important agents being tested are targeted on CLL surface molecules and their ligands, signal transduction protein and oncogenes. This review provides a brief summary of the recent advances made in preclinical and clinical investigation of selected promising therapeutic agents, which lead the target-directed therapeutic approach. PMID:22162923

  16. Ofatumumab in poor-prognosis chronic lymphocytic leukemia: a Phase IV, non-interventional, observational study from the European Research Initiative on Chronic Lymphocytic Leukemia

    PubMed Central

    Moreno, Carol; Montillo, Marco; Panayiotidis, Panayiotis; Dimou, Maria; Bloor, Adrian; Dupuis, Jehan; Schuh, Anna; Norin, Stefan; Geisler, Christian; Hillmen, Peter; Doubek, Michael; Trněný, Marek; Obrtlikova, Petra; Laurenti, Luca; Stilgenbauer, Stephan; Smolej, Lukas; Ghia, Paolo; Cymbalista, Florence; Jaeger, Ulrich; Stamatopoulos, Kostas; Stavroyianni, Niki; Carrington, Patrick; Zouabi, Hamadi; Leblond, Veronique; Gomez-Garcia, Juan C.; Rubio, Martin; Marasca, Roberto; Musuraca, Gerardo; Rigacci, Luigi; Farina, Lucia; Paolini, Rossella; Pospisilova, Sarka; Kimby, Eva; Bradley, Colm; Montserrat, Emili

    2015-01-01

    We report the largest retrospective, phase IV non-interventional, observational study of ofatumumab therapy in heavily pre-treated patients with poor-prognosis chronic lymphocytic leukemia. Total number of patients was 103; median age was 65 years (range 39–85). Median number of prior lines of therapy was 4 (range 1–13), including, in most cases, rituximab-, fludarabine- and alemtuzumab-based regimens; 13 patients had been allografted. Of 113 adverse events, 28 (29%) were considered to be directly related to ofatumumab. Grade 3–4 toxicities included neutropenia (10%), thrombocytopenia (5%), anemia (3%), pneumonia (17%), and fever (3%). Two heavily pre-treated patients developed progressive multifocal leukoencephalopathy. On an intention-to-treat analysis, the overall response rate was 22% (3 complete response, 1 incomplete complete response). Median progression-free and overall survival times were 5 and 11 months, respectively. This study confirms in a daily-life setting the feasibility and acceptable toxicity of ofatumumab treatment in advanced chronic lymphocytic leukemia. The complete response rate, however, was low. Therefore, treatment with ofatumumab should be moved to earlier phases of the disease. Ideally, this should be done in combination with other agents, as recently approved for ofatumumab plus chlorambucil as front-line treatment for patients unfit for fludarabine. This study is registered at clinicaltrials.gov identifier:01453062. PMID:25596264

  17. A review of supportive care and recommended preventive approaches for patients with chronic lymphocytic leukemia.

    PubMed

    Randhawa, Jasleen K; Ferrajoli, Alessandra

    2016-03-01

    Chronic lymphocytic leukemia (CLL) is the most prevalent type of adult leukemia encountered in the western world. Patients with CLL are typically older, with a median age in the 70s, and are at risk for certain complications due to the disease itself and due to the therapies imparted for this. Patients with CLL are at a higher risk of infections, partly due to disease and partly due to the immune dysfunction induced by treatment, such as purine analogous-based chemoimmunotherapy, which leads to lymphocyte depletion. Infections are a leading cause of complications and death in CLL patients. Also, CLL patients have been shown to have a higher incidence of other malignancies. Despite this knowledge, there are no definite guidelines as to what is the best approach to manage or prevent these associated complications of CLL. In this review, the authors discuss the data available and outline recommendations as to the best way to approach this issue in daily practice.

  18. AMD3100 disrupts the cross-talk between chronic lymphocytic leukemia cells and a mesenchymal stromal or nurse-like cell-based microenvironment: pre-clinical evidence for its association with chronic lymphocytic leukemia treatments

    PubMed Central

    Stamatopoulos, Basile; Meuleman, Nathalie; De Bruyn, Cécile; Pieters, Karlien; Mineur, Philippe; Le Roy, Christine; Saint-Georges, Stéphane; Varin-Blank, Nadine; Cymbalista, Florence; Bron, Dominique; Lagneaux, Laurence

    2012-01-01

    Background Interactions with the microenvironment, such as bone marrow mesenchymal stromal cells and nurse-like cells, protect chronic lymphocytic leukemia cells from spontaneous and drug-induced apoptosis. This protection is partially mediated by the chemokine SDF-1α (CXCL12) and its receptor CXCR4 (CD184) present on the chronic lymphocytic leukemia cell surface. Design and Methods Here, we investigated the ability of AMD3100, a CXCR4 antagonist, to sensitize chronic lymphocytic leukemia cells to chemotherapy in a chronic lymphocytic leukemia/mesenchymal stromal cell based or nurse-like cell based microenvironment co-culture model. Results AMD3100 decreased CXCR4 expression signal (n=15, P=0.0078) and inhibited actin polymerization/migration in response to SDF-1α (n=8, P<0.01) and pseudoemperipolesis (n=10, P=0.0010), suggesting that AMD3100 interferes with chronic lymphocytic leukemia cell trafficking. AMD3100 did not have a direct effect on apoptosis when chronic lymphocytic leukemia cells were cultured alone (n=10, P=0.8812). However, when they were cultured with SDF-1α, mesenchymal stromal cells or nurse-like cells (protecting them from apoptosis, P<0.001), chronic lymphocytic leukemia cell pre-treatment with AMD3100 significantly inhibited these protective effects (n=8, P<0.01) and decreased the expression of the anti-apoptotic proteins MCL-1 and FLIP. Furthermore, combining AMD3100 with various drugs (fludarabine, cladribine, valproïc acid, bortezomib, flavopiridol, methylprednisolone) in our mesenchymal stromal cell co-culture model enhanced drug-induced apoptosis (n=8, P<0.05) indicating that AMD3100 could mobilize chronic lymphocytic leukemia cells away from their protective microenvironment, making them more accessible to conventional therapies. Conclusions Taken together, these data demonstrate that interfering with the SDF-1α/CXCR4 axis by using AMD3100 inhibited chronic lymphocytic leukemia cell trafficking and microenvironment

  19. Chronic lymphocytic-leukemia with pleomorphic lymphocytes (cll-pleo) - a comparative-study with typical cll.

    PubMed

    Batata, A; Shen, B; Batata, S

    1994-05-01

    Cell suspensions from the peripheral brood of 21 cases of chronic lymphocytic leukemia with pleomorphic lymphocytes (CLL-pleo) and 155 cases of typical CLL were analyzed to define the phenotype of the former and compare it with the phenotype of the latter. CLL-pleo was characterized by weak fluorescence intensity of surface immunoglobulin (mean channel number on flow cytometry <200), positive mouse rosettes and CD5, and negative CD22 and tartrate resistant acid phosphatase. Comparison of the positive rates of the markers and of the mean percentages of marker-expressing cells showed no statistical difference between CLL-pleo and typical CLL. CLL-pleo constitutes a morphological variant of typical CLL bearing the same membrane phenotype as typical CLL, although the mean absolute lymphocyte count in CLL-pleo was significantly higher than that of typical CLL.

  20. Chronic T-cell Lymphocytic Leukemia in a Black Swan ( Cygnus atratus ): Diagnosis, Treatment, and Pathology.

    PubMed

    Sinclair, Kristin M; Hawkins, Michelle G; Wright, Lewis; Chin, Richard P; Owens, Sean D; Guzman, David Sanchez-Migallon; Kent, Michael S; BVSc, H L Shivaprasad

    2015-12-01

    An asymptomatic 14-year old, male black swan ( Cygnus atratus ) housed at a zoological institution was presented for routine preshipment examination. Hematologic findings indicated that the bird had a severe lymphocytic leukocytosis, consistent with chronic lymphocytic leukemia. Radiographs showed the presence of multiple soft tissue masses within the caudal coelomic cavity; ultrasound showed one mass to be an enlarged spleen, a cystic mass near the gonads, and a mass suspected to be associated with the ventriculus. Results of further antemortem diagnostics, including bone marrow aspiration, fine-needle aspirate cytology of the coelomic masses, and immunohistochemical staining confirmed T-cell leukemia with infiltration of the bone marrow and the spleen. The bird showed partial response to treatment with chlorambucil, lomustine, prednisone, l-asparaginase, and whole-body radiation, with neither evidence of adverse effects nor clinical signs of disease. Although the leukemia showed response, there was no evidence of remission at any point. The swan died 433 days after initial evaluation and initiation of therapy. Necropsy, histopathologic findings, and immunohistochemistry results confirmed extensive infiltration of multiple organs, including the liver, spleen, heart, lungs, and kidneys with neoplastic T-cell lymphocytes.

  1. Leptomeningeal disease in chronic lymphocytic leukemia.

    PubMed

    Lange, C P E; Brouwer, R E; Brooimans, R; Vecht, Ch J

    2007-12-01

    Chronic lymphocytic leukemia (CLL) is the most common lymphoproliferative disorder in the western hemisphere, with an annual incidence of 3:100000. Commonly patients are asymptomatic but not rarely disease progression occurs in the setting of lymphadenopathy and extensive leukemic burden. Leptomeningeal involvement in patients with CLL is infrequent, with presenting symptoms of headache (23%), acute or chronic changes in mental status (28%), cranial nerve abnormalities (54%) including optic neuropathy (28%), weakness of lower extremities (23%) and cerebellar signs (18%). In this report, we discuss a CLL patient with leptomeningeal involvement, who presented with neurological symptoms as the first clinical sign, and a diagnosis of leptomeningeal was made based on CSF cytology and flow cytometry. Treatment consisted of radiation therapy and intrathecal chemotherapy with arabinoside-cytosine and systemic chemotherapy. On the basis of this patient-report together with 37 other previously reported cases, the clinical characteristics together with treatment options and outcome of leptomeningeal involvement in CLL are reviewed. Our case together with data from the literature indicate that a timely diagnosis and intensive treatment of leptomeningeal disease of CLL may lead to longstanding and complete resolution of neurological symptoms.

  2. Establishment of a cell line from leucocytes of a cow with chronic lymphocytic leukemia.

    PubMed

    Adomaitiene, D; Tamosiunas, V; Mauricas, M; Surovas, V; Markevicius, A

    1983-07-01

    A cell line was established from blood leucocytes of a cow with chronic lymphocytic leukemia. The leucocytes were cultured with conditioned medium (culture fluid of mouse cell line L). In vitro cell transformation was demonstrated by adaptation to permanent growth, modification of cell morphology, the alteration of cell surface phenotype, kinetic behaviour and the loss of the euploid stability of the cell karyotype. Ultrastructural studies showed rather a uniform cell pattern in a culture population heterogeneous for degree of cell vacuolization. A wide variation in the expression of surface markers in cells was demonstrated by E-, EA- and EAC-rosetting. In suspension culture the cell population was found to be sIg negative. Expression of leukemia-associated antigens by a fraction of the cultured cells was evidenced by a cytotoxic technique using complement and heterologous antisera against bovine leukemic lymphocytes, absorbed with normal lymphoid cells. Virus-like particles and BLV antigens were not identified. Culture cells failed to show spontaneous or antibody-dependent killer cytotoxicity. Comparison with blood lymphocytes of healthy and leukemic cattle was done. The established culture should be useful as a model for experimental immunology and oncology.

  3. Chronic lymphocytic leukemia monitoring with a lamprey idiotope-specific antibody

    PubMed Central

    Nakahara, Hirotomo; Herrin, Brantley R; Alder, Matthew N; Catera, Rosa; Yan, Xiao-Jie; Chiorazzi, Nicholas; Cooper, Max D

    2013-01-01

    For antigen recognition, lampreys use leucine-rich repeats (LRR) instead of immunoglobulin V-(D)-J domains to generate variable lymphocyte receptors (VLR) of three types, VLRA, VLRB, and VLRC. VLRB-bearing lymphocytes respond to immunization with proliferation and differentiation into plasmacytes that secrete multivalent VLRB antibodies. Here we immunized lampreys with B cells from patients with chronic lymphocytic leukemia (CLL) to generate recombinant monoclonal VLRB antibodies, one of which, VLR39, was specific for the donor CLL cells. The target epitope of VLR39 was shown to be the complementarity determining region 3 (CDR3) of the heavy chain variable region (VH) of the B cell receptor. Using this antibody to monitor the CLL donor after chemo-immunotherapy-induced remission, we detected VLR39+ B cells in the patient 51 months later, before significant increase in lymphocyte count or CD5+ B cells. This indication of reemergence of the leukemic clone was verified by VH sequencing. Lamprey antibodies can exhibit exquisite specificity for a protein epitope, a CLL signature VH CDR3 sequence in this case, and offer a rapid strategy for generating anti-idiotype antibodies for early detection of leukemia recurrence. PMID:24432304

  4. Chronic lymphocytic leukemia monitoring with a Lamprey idiotope-specific antibody.

    PubMed

    Nakahara, Hirotomo; Herrin, Brantley R; Alder, Matthew N; Catera, Rosa; Yan, Xiao-Jie; Chiorazzi, Nicholas; Cooper, Max D

    2013-10-01

    For antigen recognition, lampreys use leucine-rich repeats (LRR) instead of immunoglobulin V-(D)-J domains to generate variable lymphocyte receptors (VLR) of three types, VLRA, VLRB, and VLRC. VLRB-bearing lymphocytes respond to immunization with proliferation and differentiation into plasmacytes that secrete multivalent VLRB antibodies. Here we immunized lampreys with B cells from patients with chronic lymphocytic leukemia (CLL) to generate recombinant monoclonal VLRB antibodies, one of which, VLR39, was specific for the donor CLL cells. The target epitope of VLR39 was shown to be the complementarity determining region 3 (CDR3) of the heavy chain variable region (VH) of the B cell receptor. Using this antibody to monitor the CLL donor after chemo-immunotherapy-induced remission, we detected VLR39(+) B cells in the patient 51 months later, before significant increase in lymphocyte count or CD5(+) B cells. This indication of reemergence of the leukemic clone was verified by VH sequencing. Lamprey antibodies can exhibit exquisite specificity for a protein epitope, a CLL signature VH CDR3 sequence in this case, and offer a rapid strategy for generating anti-idiotype antibodies for early detection of leukemia recurrence.

  5. Idelalisib for the Treatment of Chronic Lymphocytic Leukemia

    PubMed Central

    Khan, Maliha

    2014-01-01

    Chronic lymphocytic leukemia is the most common leukemia in the United States. It is a slowly progressive disease, with an 82% five-year survival rate. The treatment strategies are highly individualized with patients in the early and stable stages typically not requiring treatment. However, those with progressive or clinically advanced disease will require treatment. Cytotoxic drugs, such as the alkylating agents, purine nucleoside antagonists, and immunotherapeutic agents, have been the mainstay of chemotherapeutic treatment in CLL. However, given the lack of therapeutic specificity, these medications (especially older ones) have limited tolerability due to side effects. In this paper, we will discuss the data on the use of phosphatidylinositol 3 kinase inhibitor Idelalisib in the management of patients with chronic lymphocytic leukemia. The preclinical and clinical data thus far demonstrate that Idelalisib produces a dramatic and durable response in patients with chronic lymphocytic leukemia and without causing significant toxicity. Moving forward, the ongoing clinical trials will help address the various questions currently being raised regarding the long-term application and safety of Idelalisib. With greater clinical experience following more widespread use of Idelalisib, we will be able to determine the optimal combination therapies in treatment-naïve and relapsed/refractory patients, resulting in more individualized therapeutic strategies for patients with chronic lymphocytic leukemia. PMID:25093123

  6. Cat scratch disease mimicking Richter's Syndrome in a patient with chronic lymphocytic leukemia.

    PubMed

    Razaq, Mohammad; Godkar, Darshan; Mankan, Nagander; Sridhar, Sundara; Hussain, Shafkat; Ohri, Anju

    2005-03-01

    Richter's Syndrome is a highly refractory and usually fatal condition. It occurs as a result of transformation of chronic lymphocytic leukemia (CLL) or low grade lymphoma into highly aggressive lymphoma. Patients usually present with rapidly enlarging lymph nodes and systemic symptoms like night sweats, fever and weight loss. We are reporting a case of CLL presenting with similar symptoms. Initial suspicion of Richter's Syndrome proved wrong when lymph node biopsy did not reveal evidence of high grade lymphoma. Instead it showed findings consistent with cat scratch disease (CSD), later confirmed by serology. To our knowledge this is the first reported case of CSD in a patient with CLL.

  7. Fludarabine Treatment of Patient with Chronic Lymphocytic Leukemia Induces a Digital Ischemia

    PubMed Central

    Soyaltin, Utku Erdem; Yuce Yildirim, Deniz; Yildirim, Mustafa; Ceylan, Cengiz; Akar, Harun

    2016-01-01

    We report a 63-year-old man with a history of chronic lymphocytic leukemia (CLL) who presented with asymmetrical Raynaud's phenomenon of sudden onset which progressed to acral gangrene rapidly in a week. These symptoms began approximately one week after the fourth cycle of fludarabine and cyclophosphamide chemotherapy and were accompanied by pain, numbness, and cyanosis in the fingers of his right hand except the first finger. Fludarabine may play a role in acral vascular syndrome. The treatment with fludarabine in patients with evolving digital ischemia should be carried out with caution. PMID:27885347

  8. Legionella lansingensis sp. nov. isolated from a patient with pneumonia and underlying chronic lymphocytic leukemia.

    PubMed Central

    Thacker, W L; Dyke, J W; Benson, R F; Havlichek, D H; Robinson-Dunn, B; Stiefel, H; Schneider, W; Moss, C W; Mayberry, W R; Brenner, D J

    1992-01-01

    A Legionella-like organism, strain 1677-MI-H, was isolated from the bronchoscopy washings of a patient with pneumonia who had a 2-year history of progressive, chronic lymphocytic leukemia. The growth characteristics, cellular fatty acids, and ubiquinone content of the isolate were consistent with those for Legionella spp. The isolate was serologically distinct in the slide agglutination test with absorbed antisera. DNA hybridization studies showed that strain 1677-MI-H (ATCC 49751) represents a new Legionella species which is named Legionella lansingensis. PMID:1401005

  9. The biology behind B-cell lymphoma 2 as a target in chronic lymphocytic leukemia

    PubMed Central

    Ortíz-Maldonado, Valentín; Mozas, Pablo; Delgado, Julio

    2016-01-01

    B-cell lymphoma 2 (BCL2)-type proteins are key regulators of the intrinsic or mitochondrial pathway for apoptosis. Since escape from apoptosis is one the main ‘hallmarks of cancer’, BCL2 inhibitors have emerged as promising therapeutic agents for diverse lymphoid malignancies, particularly chronic lymphocytic leukemia (CLL). Multiple clinical trials have shown efficacy of these agents in patients with relapsed/refractory disease with a favorable toxicity profile. Moreover, some clinical trials indicate that combination with monoclonal antibodies and other novel agents may enhance their effect. PMID:27904736

  10. Ionizing Radiation and Chronic Lymphocytic Leukemia

    PubMed Central

    Richardson, David B.; Wing, Steve; Schroeder, Jane; Schmitz-Feuerhake, Inge; Hoffmann, Wolfgang

    2005-01-01

    The U.S. government recently implemented rules for awarding compensation to individuals with cancer who were exposed to ionizing radiation while working in the nuclear weapons complex. Under these rules, chronic lymphocytic leukemia (CLL) is considered to be a nonradiogenic form of cancer. In other words, workers who develop CLL automatically have their compensation claim rejected because the compensation rules hold that the risk of radiation-induced CLL is zero. In this article we review molecular, clinical, and epidemiologic evidence regarding the radiogenicity of CLL. We note that current understanding of radiation-induced tumorigenesis and the etiology of lymphatic neoplasia provides a strong mechanistic basis for expecting that ionizing radiation exposure increases CLL risk. The clinical characteristics of CLL, including prolonged latency and morbidity periods and a low case fatality rate, make it relatively difficult to evaluate associations between ionizing radiation and CLL risk via epidemiologic methods. The epidemiologic evidence of association between external exposure to ionizing radiation and CLL is weak. However, epidemiologic findings are consistent with a hypothesis of elevated CLL mortality risk after a latency and morbidity period that spans several decades. Our findings in this review suggest that there is not a persuasive basis for the conclusion that CLL is a nonradiogenic form of cancer. PMID:15626639

  11. Isochromosome 17q in Chronic Lymphocytic Leukemia

    PubMed Central

    Alhourani, Eyad; Rincic, Martina; Melo, Joana B.; Carreira, Isabel M.; Glaser, Anita; Pohle, Beate; Schlie, Cordula; Liehr, Thomas

    2015-01-01

    In chronic lymphocytic leukemia (CLL), presence of acquired cytogenetic abnormalities may help to estimate prognosis. However, deletion of TP53 gene, which is associated with an aggressive course of the disease and poor prognosis along with a lack of response to treatment, is one of the alterations which may escape cytogenetic diagnoses in CLL. Thus, other techniques have emerged such as interphase fluorescence in situ hybridization (iFISH). Deletion of TP53 may but must not go together with the formation of an isochromosome i(17q); surprisingly this subgroup of patients was not in the focus of CLL studies yet. This study was about if presence of i(17q) could be indicative for a new subgroup in CLL with more adverse prognosis. As a result, TP53 deletion was detected in 18 out of 150 (12%) here studied CLL cases. Six of those cases (~33%) had the TP53 deletion accompanied by an i(17q). Interestingly, the cases with i(17q) showed a tendency towards more associated chromosomal aberrations. These findings may be the bases for follow-up studies in CLL patients with TP53 deletion with and without i(17q); it may be suggested that the i(17q) presents an even more adverse prognostic marker than TP53 deletion alone. PMID:26697230

  12. Cytogenetic investigations of chronic lymphocytic leukemia.

    PubMed

    Wren, Catherine; Moriarty, Helen; Marsden, Katherine; Tegg, Elizabeth

    2010-04-15

    This study aimed to determine which culture method would yield the highest culture success rate, mitotic index, banding resolution, and abnormality rate in investigation of patients with chronic lymphocytic leukemia (CLL). A range of culture techniques for conventional cytogenetic (CC) analyses was compared: 24-hour unstimulated, 72 hours incubation with additional fetal calf serum, 72 hours stimulation with interleukin 4, 72 hours stimulation with lipopolysaccharide (LPS), 72 hours stimulation with TPA (12-O-tetradecanoylphorbol 13-acetate), and 72 hours stimulation with CpG-oligonucleotide DSP30 + Interleukin-2 (IL-2). CC abnormality rates were also compared to fluorescence in situ hybridization (FISH) results using probes for CLL (LSI D13S319/13q34/CEP 12: LSI ATM/p53). Forty-five samples from 24 patients (consisting of 11 newly diagnosed and 13 previously diagnosed patients) were included. For CC, a 100.0% culture success rate was achieved (n = 45) by means of an EDTA (ethylenediaminetetraacetic acid) peripheral blood sample with an associated 62.5% CC abnormality rate (n = 24). FISH detected an abnormality rate of 75.0% (n = 24). The combined CC and FISH abnormality rate was 87.5% (n = 24). This study demonstrates that CC that uses TPA and DSP30 + IL-2 on EDTA peripheral blood is effective in the investigation of CLL and may be used as a supplement to FISH studies.

  13. Richter Syndrome in Chronic Lymphocytic Leukemia.

    PubMed

    Vitale, Candida; Ferrajoli, Alessandra

    2016-02-01

    The term Richter syndrome (RS) indicates the transformation of chronic lymphocytic leukemia (CLL) into an aggressive lymphoma. RS is a rare complication with an aggressive clinical course, bearing an unfavorable prognosis. In the majority of cases, CLL transforms into RS as diffuse large B cell lymphoma (DLBCL), and a clonal relation between the two processes can be found. However, clonally unrelated RS can occur and transformations to other histologies beside DLBCL have been described. Recent data have shed some light on genetic characteristics that can influence and drive the transformation from CLL to RS. This molecular information has not been translated yet into significant treatment advances, and currently the therapy regimens for RS continue to rely on intensive chemotherapy combinations followed by stem cell transplant in suitable candidates. Based on the rapid pace of discoveries in the field of hematological malignancies and on the recent revolution in the therapeutic landscape for CLL and B cell lymphomas, new therapeutic options for RS might be available in the upcoming years.

  14. Gene mutations in chronic lymphocytic leukemia.

    PubMed

    Amin, Nisar A; Malek, Sami N

    2016-04-01

    The recent discovery of genes mutated in chronic lymphocytic leukemia (CLL) has stimulated new research into the role of these genes in CLL pathogenesis. CLL cases carry approximately 5-20 mutated genes per exome, a lower number than detected in many human tumors. Of the recurrently mutated genes in CLL, all are mutated in 10% or less of patients when assayed in unselected CLL cohorts at diagnosis. Mutations in TP53 are of major clinical relevance, are often associated with del17p and gain in frequency over time. TP53 mutated and associated del17p states substantially lower response rates, remission duration, and survival in CLL. Mutations in NOTCH1 and SF3B1 are recurrent, often associated with progressive CLL that is also IgVH unmutated and ZAP70-positive and are under investigation as targets for novel therapies and as factors influencing CLL outcome. There are an estimated 20-50 additional mutated genes with frequencies of 1%-5% in CLL; more work is needed to identify these and to study their significance. Finally, of the major biological aberration categories influencing CLL as a disease, gene mutations will need to be placed into context with regard to their ultimate role and importance. Such calibrated appreciation necessitates studies incorporating multiple CLL driver aberrations into biological and clinical analyses.

  15. Update on Therapy of Chronic Lymphocytic Leukemia

    PubMed Central

    Gribben, John G.; O'Brien, Susan

    2011-01-01

    There have been tremendous advances in the treatment of chronic lymphocytic leukemia (CLL) over the past decade, with the goal of therapy no longer being just to palliate symptoms but now to achieve complete remission, eradicate minimal residual disease, and improve survival. During this period, there have also been major advances in identification of molecular factors associated with increased risk of progression. The clinical utility of these factors is being explored to determine whether we can identify groups of patients who should be treated earlier in their disease course and whether we can tailor therapy for groups of patients with specific molecular markers of disease. First-line chemoimmunotherapy approaches now offer prolonged survival, and there is a need to identify patients who are suitable candidates for allogeneic stem-cell transplantation that uses reduced-intensity conditioning regimens. The vast majority of CLL patients are either too old or do not have sufficiently high-risk disease to warrant these approaches, and effective therapies that can be tolerated by the more frail elderly patients with this disease are urgently needed. Numerous novel agents are being developed, and their role in the first-line treatment of frail patients or those who relapse after previous treatment is being explored in clinical trials. PMID:21220603

  16. Sequencing of chronic lymphocytic leukemia therapies.

    PubMed

    Barrientos, Jacqueline C

    2016-12-02

    It is an unprecedented time for the treatment of patients with chronic lymphocytic leukemia (CLL) with the recent approval of several targeted agents for use in frontline, relapsed, refractory, and high-risk disease. Traditionally, frontline management of CLL has been a combination of chemotherapy (fludarabine, cyclophosphamide, bendamustine, or chlorambucil) with an anti-CD20 monoclonal antibody (rituximab, ofatumumab, obinutuzumab). The current landscape is rapidly evolving with the advent of therapies that demonstrate selective inhibition of important pathways necessary for CLL proliferation and survival. Despite considerable progress, much is still unknown and optimal treatment selection and sequence is still debatable. None of the new agents have been compared against each other and the impact of adding an additional agent to monotherapy is not yet fully elucidated. In routine clinical practice, the choice of therapy is based on nonrandomized comparisons, presence of comorbidities, and toxicity considerations. These recently approved drugs (ibrutinib, idelalisib, and venetoclax) are reporting excellent outcomes, including patients with high-risk disease such as 17p deletion (17p-) or TP53 mutations (TP53mut). Ibrutinib and venetoclax have been approved for use in 17p- patients (frontline and relapsed, respectively). Ibrutinib is currently moving into the frontline space given recent regulatory approvals. This review will summarize and interpret the limited therapeutic sequencing data available, highlighting the need for additional studies to optimize combination strategies and treatments after failure or discontinuation of these novel agents.

  17. Romidepsin Controls Chronic Lymphocytic Leukemia in a Patient with Mycosis Fungoides

    PubMed Central

    Lemchak, David. M.; Akilov, Oleg. E.

    2016-01-01

    Romidepsin belongs to a class of medications called histone deacetylase inhibitors and is currently approved for treatment of cutaneous and peripheral T-cell lymphomas. Romidepsin was previously investigated for the treatment of chronic lymphocytic leukemia (CLL), and demonstrated potential benefit, but interest in its use declined following phase I clinical trials that showed poor tolerance of a significant side effect profile. We presented a patient with a history of stage II CLL, referred to dermatology for treatment of new-onset of mycosis fungoides (MF), who was treated with romidepsin over seven months. The patient achieved a partial response with 50% decrease in body surface area occupied by MF, thinning of remaining plaques, and near complete response in his CLL. His absolute lymphocyte count remained within the normal range for four months following discontinuation of romidepsin. Side effects were well-tolerated and did not limit therapy. Current literature on romidepsin is reviewed and compared to existing treatments for CLL. PMID:27994839

  18. A phase I study of escalated dose subcutaneous alemtuzumab given weekly with rituximab in relapsed chronic lymphocytic leukemia/small lymphocytic lymphoma.

    PubMed

    Brown, Jennifer R; Messmer, Bradley; Werner, Lillian; Davids, Matthew S; Mikler, Evgeny; Supko, Jeffrey G; Fisher, David C; LaCasce, Ann S; Armand, Philippe; Jacobsen, Eric; Dalton, Virginia; Tesar, Bethany; Fernandes, Stacey M; McDonough, Sean; Ritz, Jerome; Rassenti, Laura; Kipps, Thomas J; Neuberg, Donna; Freedman, Arnold S

    2013-06-01

    This study assessed the safety and preliminary efficacy of escalated dose subcutaneous alemtuzumab in combination with rituximab in chronic lymphocytic leukemia. Twenty-eight patients with relapsed refractory chronic lymphocytic leukemia were treated on four dosing cohorts of weekly rituximab at 375 mg/m(2) and alemtuzumab doses that started at 30 mg three times per week and escalated to weekly dosing over four weeks, culminating with 90 mg weekly. One dose limiting toxicity of a rituximab infusion reaction was seen in cohort 2, but the regimen was otherwise well tolerated without evidence of differential toxicity by cohort. The overall response rate by National Cancer Institute-Working Group criteria was 61%, and the rate of complete bone marrow response was 43%, most of whom were negative for minimal residual disease. The addition of CT scan evaluation per International Workshop on Chronic Lymphocytic Leukemia 2008 criteria reduced the overall response rate to 14%. Median overall survival was 35 months, with 12 patients able to proceed to stem cell transplantation. Pharmacokinetic studies showed that chronic lymphocytic leukemia involving more than 80% of the bone marrow at study start was associated with lower trough concentrations of alemtuzumab and rituximab, and that higher trough serum concentrations of alemtuzumab were associated with complete bone marrow clearance. We conclude that escalated subcutaneous doses of alemtuzumab given weekly are well tolerated and result in excellent bone marrow clearance of chronic lymphocytic leukemia, helping patients to proceed to stem cell transplantation. This study is registered at ClinicalTrials.gov (Identifier:00330252).

  19. Lipoprotein Lipase as a Prognostic Marker in Chronic Lymphocytic Leukemia.

    PubMed

    Mátrai, Zoltán; Andrikovics, Hajnalka; Szilvási, Anikó; Bors, András; Kozma, András; Ádám, Emma; Halm, Gabriella; Karászi, Éva; Tordai, Attila; Masszi, Tamás

    2017-01-01

    The marked clinical heterogeneity of CLL makes early prognosis assessment important. Lipoprotein lipase (LPL) has been shown to confer adverse prognosis in CLL, recent data indicating it might also contribute to CLL cell survival and metabolism. We determined LPL mRNA expression in unselected peripheral blood of 84 CLL patients by RT PCR. Results were correlated with other prognostic markers and outcome. 30/84 (40 %) of cases were LPL positive based on the cutoff established by ROC analysis. In LPL positive patients significantly shorter median survival (136 vs 258 months, p < 0.0001) and time to first treatment intervals (36 vs 144 months, p < 0.002) were documented. LPL values correlated with male gender, higher stages, more treatment requirement, CD38 positivity and unmutated IgVH genes. Among cases with 13q deletion, LPL positivity identified a subcohort with poor outcome (median survival 108 months vs NR, p < 0.0001). In multivariate analysis, cytogenetic aberrations and LPL had significant impact on survival. Our results confirm that LPL is a strong predictor of outcome in CLL, able to improve prognostic accuracy in good risk cytogenetic subgroups. The relationship between its prognostic and functional role in CLL needs to be explored further.

  20. miR-181b is a biomarker of disease progression in chronic lymphocytic leukemia.

    PubMed

    Visone, Rosa; Veronese, Angelo; Rassenti, Laura Z; Balatti, Veronica; Pearl, Dennis K; Acunzo, Mario; Volinia, Stefano; Taccioli, Cristian; Kipps, Thomas J; Croce, Carlo M

    2011-09-15

    MicroRNAs play a crucial role in chronic lymphocytic leukemia. We investigated whether microRNAs can discriminate patients with a progressive disease from patients with a stable disease. We analyzed microRNA expression on leukemic cells isolated from 358 sequential samples of 114 patients with either stable or progressive disease. We found that during the course of the disease the expression values of miR-181b, the most dysregulated microRNA, decreased in samples of patients with a progressive (P < .001, training and validation sets) but not in samples of patients with a stable disease (P = .3, training set; P = .2, validation set) over time. A drop of ≥ 50% between sequential samples and/or a miR-181b value ≤ 0.005 at the starting time point were significant to differentiate progressive from stable disease (P = .004, training set; P < .001, validation set). These parameters were associated with high risk of requiring treatment (risk ratio, 5.8; 95% confidence interval, 2.5-14.9). We also observed that miR-181b targets Mcl-1 protein and that the decrease of its expression inversely correlated with increased protein levels of MCL1 and BCL2 target genes. We conclude that parameters defined on the basis of the miR-181b expression values specify disease progression in chronic lymphocytic leukemia and are associated with clinical outcome.

  1. Apparent feline leukemia virus-induced chronic lymphocytic leukemia and response to treatment.

    PubMed

    Kyle, Kristy N; Wright, Zachary

    2010-04-01

    Chylothorax secondary to chronic lymphocytic leukemia (CLL) was diagnosed in a feline leukemia virus (FeLV)-positive 8-year-old castrated male domestic shorthair feline. The leukemia resolved following therapy with chlorambucil, prednisone, cyclophosphamide, doxorubicin, and lomustine. To our knowledge, this is the first reported case of CLL in an FeLV-positive cat. Although a causative relationship cannot be proven, patients diagnosed with either disease may benefit from diagnostics to rule out the presence of the other concurrent condition.

  2. The B lineage transcription factor E2A regulates apoptosis in chronic lymphocytic leukemia (CLL) cells.

    PubMed

    Kardava, Lela; Yang, Qi; St Leger, Anthony; Foon, Kenneth A; Lentzsch, Suzanne; Vallejo, Abbe N; Milcarek, Christine; Borghesi, Lisa

    2011-06-01

    Chronic lymphocytic leukemia (CLL) is a common malignancy characterized by the accumulation of B lymphocytes with an antigen-experienced activated CD19(+)CD5(+) clonal phenotype. Clinically, ∼50% of cases will behave more aggressively. Here, we investigate the role of the major B-cell transcription factor E2A, a known regulator of B-cell survival and proliferation, to CLL persistence. We show that E2A is elevated at the mRNA and protein levels relative to normal B-cell subsets. E2A silencing in primary CLL cells leads to a significant increase in spontaneous apoptosis in both CD38(+) (aggressive) and CD38(-) (indolent) cases. Moreover, E2A knockdown synergizes with the immunomodulatory drug lenalidomide to reduce CLL viability. E2A is known to restrain the proliferation of primary B and T lymphocytes at multiple stages of maturation and we report that targeted E2A disruption increases the frequency of Ki-67(+) CLL cells in the absence of effects on de novo proliferation. At the molecular level, E2A siRNA-treated CLL cells display reduced expression of key genes associated with survival and cell cycling including p27, p21 and mcl-1, of which the former two are known E2A target genes. Thus, E2A, a key transcription factor associated with the B-cell activation profile, regulates apoptosis in CLL and may contribute to disease pathology.

  3. E2A is a transcriptional regulator of CD38 expression in chronic lymphocytic leukemia.

    PubMed

    Saborit-Villarroya, I; Vaisitti, T; Rossi, D; D'Arena, G; Gaidano, G; Malavasi, F; Deaglio, S

    2011-03-01

    CD38, a nucleotide-metabolizing ectoenzyme and a receptor, is a negative prognostic marker for chronic lymphocytic leukemia (CLL) patients. CD38 has a genetic polymorphism, with a C → G variation in a putative E-box located in a regulatory region. E2A, the predominant E-box factor in B lymphocytes, was found to be highly expressed by CD38(+) CLL patients. The highest CD38 levels scored by E2A(+)/G carrier patients suggested that E2A is (i) directly associated with CD38 expression, and that (ii) the binding of the transcription factor is influenced by the CD38 genotype. Chromatin immunoprecipitation indicated that E2A directly interacts with the CD38 regulatory region. Furthermore, E2A binding was stronger in the presence of the G allele. Experiments of E2A silencing led to a significant reduction of surface levels of CD38, confirming the working hypothesis. A direct functional interplay between E2A and CD38 was shown by exposing CLL cells to interleukin-2 and TLR-9 ligands, both inducers of CD38 expression. Under these conditions, CD38 upregulation was primarily conditioned by the presence of E2A and then by the G allele. The results of this study link E2A and CD38 expression within a common pathway, in which E-protein activity is required for the efficient induction of CD38 transcription.

  4. Chronic lymphocytic leukemia: a paradigm of innate immune cross-tolerance.

    PubMed

    Jurado-Camino, Teresa; Córdoba, Raúl; Esteban-Burgos, Laura; Hernández-Jiménez, Enrique; Toledano, Victor; Hernandez-Rivas, Jose-Angel; Ruiz-Sainz, Elena; Cobo, Teresa; Siliceo, María; Perez de Diego, Rebeca; Belda, Cristobal; Cubillos-Zapata, Carolina; López-Collazo, Eduardo

    2015-01-15

    Infections are a significant cause of morbidity and mortality in patients with chronic lymphocytic leukemia (CLL). The pathogenesis of infections is multifactorial and includes hypogammaglobulinemia, conventional therapy with alkylating drugs, and recently, purine analogs and mAb-associated T cells. Patients without these risk factors also suffer from infections, although the mechanism remains unknown. In a cohort of 70 patients with CLL, we demonstrated that their monocytes were locked into a refractory state and were unable to mount a classic inflammatory response to pathogens. In addition, they exhibited the primary features of endotoxin tolerance, including low cytokine production, high phagocytic activity, and impaired Ag presentation. The involvement of miR-146a in this phenomenon was suspected. We found miR-146a target genes, such as IRAK1 and TRAF6, were manifestly downregulated. Our study provides a new explanation for infections in patients with CLL and describes a cross-tolerance between endotoxins and tumors.

  5. Ibrutinib Improves Survival in Patients with Previously Treated Chronic Lymphocytic Leukemia

    Cancer.gov

    A summary of results from an international phase III trial that compared ibrutinib (Imbruvica®) and ofatumumab (Arzerra®) for the treatment of relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

  6. Prognosis of Binet stage A chronic lymphocytic leukemia patients: the strength of routine parameters.

    PubMed

    Letestu, Rémi; Lévy, Vincent; Eclache, Virginie; Baran-Marszak, Fanny; Vaur, Dominique; Naguib, Dina; Schischmanoff, Olivier; Katsahian, Sandrine; Nguyen-Khac, Florence; Davi, Frédéric; Merle-Béral, Hélène; Troussard, Xavier; Ajchenbaum-Cymbalista, Florence

    2010-11-25

    Recent developments in the management of chronic lymphocytic leukemia (CLL) patients have made necessary the availability of dependable prognostic factors. We have developed a prognostic index derived from the multivariate analysis of 339 stage A patients at diagnosis, exhaustively studied for classical and recent predictive markers. Only 4 biologic parameters were found to be independent predictors of progression-free survival (PFS): serum thymidine kinase (sTK), lymphocytosis, β2-microglobulin, and CD38 expression. Two groups were distinguishable: cases with no or 1 risk factor (among whom 85% did not progress after 7 years), and cases with 2 or more factors showing a median PFS of 20 months. Finally, we propose an easy, fast, cost-effective strategy for a trustworthy prognostication in stage A patients, who currently represent more than 80% of the CLL population, allowing physicians to adapt follow-up individually.

  7. Recurrent Malignant Melanoma Presenting as Isolated Pleural Metastases in a Patient with Chronic Lymphocytic Leukemia

    PubMed Central

    Anand, Kartik; Cingam, Shashank; Peddi, Prakash

    2017-01-01

    Isolated pleural metastasis with pleural effusion is a rare occurrence in malignant melanoma. We report an unusual case of a patient with chronic lymphocytic leukemia (CLL) and recurrent pleural effusions. The pleural fluid cytology and immunohistochemistry profile were consistent with the diagnosis of CLL. However, chemotherapy with pentostatin, cyclophosphamide, and rituximab did not result in any meaningful clinical response. A video-assisted thoracoscopic surgery and biopsy of the affected nodular parietal layer of the pleura were consistent with malignant melanoma. Our case underlines the importance of having a suspicion for secondary causes of effusion in patients with CLL. We briefly discuss the mechanisms of an increased incidence of secondary cancers in CLL and the diagnosis of isolated pleural metastases in malignant melanoma. PMID:28203169

  8. Celiac crisis in a patient with chronic lymphocytic leukemia and hypogammaglobulinemia.

    PubMed

    Krishna, K; Krishna, S G; Coviello-malle, J M; Yacoub, A; Hutchins, L F

    2011-01-01

    Celiac crisis is an acute, fulminant form of celiac disease manifesting with severe diarrhea, metabolic and electrolyte abnormalities, and weight loss. It is mostly seen in children, and there are very few reports in adults. We present a 67-year-old patient with chronic lymphocytic leukemia (CLL) who presented with weight loss of 40 pounds, severe diarrhea, hypoalbuminemia and hypokalemia. The patient was immunosuppressed with hypogammaglobulinemia, which is common in CLL. Thus, the patient had negative serological studies for celiac disease. An endoscopic evaluation and HLA typing supported the diagnosis of celiac disease. Although the differential diagnosis was broad, exclusion of other etiologies for diarrhea, prompt diagnosis of celiac disease and initiation of gluten-free diet resolved the crisis. This is the first such report of a patient presenting with celiac crisis on a background of hypogammaglobulinemia.

  9. Obinutuzumab: A FDA approved monoclonal antibody in the treatment of untreated chronic lymphocytic leukemia.

    PubMed

    Sachdeva, Mamta; Dhingra, Sameer

    2015-01-01

    Chronic lymphocytic leukemia (CLL) is an adult lymphoid malignancy with a variable clinical course. There is considerable interest in the identification of new treatments, as most current approaches are not curative. While most patients respond to initial chemotherapy, relapsed disease is often resistant to the drugs commonly used in CLL and patients are left with limited therapeutic options. Obinutuzumab is recently approved in combination with chlorambucil for people with previously untreated CLL and is additionally being investigated in a large clinical program, including multiple head-to-head phase III studies compared with Rituxan in indolent non-Hodgkin's lymphoma and diffuse large B-cell lymphoma. In this article, author has made an attempt to review the therapeutic profile of this newly approved monoclonal antibody in the treatment of CLL.

  10. Three hematologic malignancies in the same patient: chronic lymphocytic leukemia, followed by chronic myeloid leukemia and acute myeloid leukemia.

    PubMed

    Fattizzo, Bruno; Radice, Tommaso; Cattaneo, Daniele; Pomati, Mauro; Barcellini, Wilma; Iurlo, Alessandra

    2014-01-01

    The co-existence of both chronic myeloid leukemia (CML) and chronic lymphocytic leukemia (CLL) have been described in a few cases, either simultaneously or subsequently presenting. We report an unusual case of three he-matological malignancies in the same patient: CLL, CML, and acute myeloid leukemia (AML). None of the three malignancies shared the same origin, since the marrow sample was negative for BCR-ABL1 transcript at the time of CLL diagnosis, CLL was in remission at CML diagnosis, and CML was in complete cytogenetic response at AML onset, indicating that this was not a blast crisis. Background: Chronic lymphocytic leukemia (CLL) and chronic myeloid leukemia (CML) are the most common proliferative disorders in Western countries, with an incidence of 4.2/100,000/year and 1-1.5/100,000/year, respectively. The co-existence of both CML and CLL is an extremely rare event, even if it has been described in a few cases, either simultaneously or subsequently presenting. Above all, the presence of more than two different hematologic neoplasms has not been described in literature so far. In the present study we report a particular case of a CLL patient, who first developed CML and then acute myeloid leukemia (AML).

  11. Prevalence and characteristics of central nervous system involvement by chronic lymphocytic leukemia.

    PubMed

    Strati, Paolo; Uhm, Joon H; Kaufmann, Timothy J; Nabhan, Chadi; Parikh, Sameer A; Hanson, Curtis A; Chaffee, Kari G; Call, Timothy G; Shanafelt, Tait D

    2016-04-01

    Abroad array of conditions can lead to neurological symptoms in chronic lymphocytic leukemia patients and distinguishing between clinically significant involvement of the central nervous system by chronic lymphocytic leukemia and symptoms due to other etiologies can be challenging. Between January 1999 and November 2014, 172 (4%) of the 4174 patients with chronic lymphocytic leukemia followed at our center had a magnetic resonance imaging of the central nervous system and/or a lumbar puncture to evaluate neurological symptoms. After comprehensive evaluation, the etiology of neurological symptoms was: central nervous system chronic lymphocytic leukemia in 18 patients (10% evaluated by imaging and/or lumbar puncture, 0.4% overall cohort); central nervous system Richter Syndrome in 15 (9% evaluated, 0.3% overall); infection in 40 (23% evaluated, 1% overall); autoimmune/inflammatory conditions in 28 (16% evaluated, 0.7% overall); other cancer in 8 (5% evaluated, 0.2% overall); and another etiology in 63 (37% evaluated, 1.5% overall). Although the sensitivity of cerebrospinal fluid analysis to detect central nervous system disease was 89%, the specificity was only 42% due to the frequent presence of leukemic cells in the cerebrospinal fluid in other conditions. No parameter on cerebrospinal fluid analysis (e.g. total nucleated cells, total lymphocyte count, chronic lymphocytic leukemia cell percentage) were able to offer a reliable discrimination between patients whose neurological symptoms were due to clinically significant central nervous system involvement by chronic lymphocytic leukemia and another etiology. Median overall survival among patients with clinically significant central nervous system chronic lymphocytic leukemia and Richter syndrome was 12 and 11 months, respectively. In conclusion, clinically significant central nervous system involvement by chronic lymphocytic leukemia is a rare condition, and neurological symptoms in patients with chronic lymphocytic

  12. Prevalence and characteristics of central nervous system involvement by chronic lymphocytic leukemia

    PubMed Central

    Strati, Paolo; Uhm, Joon H.; Kaufmann, Timothy J.; Nabhan, Chadi; Parikh, Sameer A.; Hanson, Curtis A.; Chaffee, Kari G.; Call, Timothy G.; Shanafelt, Tait D.

    2016-01-01

    Abroad array of conditions can lead to neurological symptoms in chronic lymphocytic leukemia patients and distinguishing between clinically significant involvement of the central nervous system by chronic lymphocytic leukemia and symptoms due to other etiologies can be challenging. Between January 1999 and November 2014, 172 (4%) of the 4174 patients with chronic lymphocytic leukemia followed at our center had a magnetic resonance imaging of the central nervous system and/or a lumbar puncture to evaluate neurological symptoms. After comprehensive evaluation, the etiology of neurological symptoms was: central nervous system chronic lymphocytic leukemia in 18 patients (10% evaluated by imaging and/or lumbar puncture, 0.4% overall cohort); central nervous system Richter Syndrome in 15 (9% evaluated, 0.3% overall); infection in 40 (23% evaluated, 1% overall); autoimmune/inflammatory conditions in 28 (16% evaluated, 0.7% overall); other cancer in 8 (5% evaluated, 0.2% overall); and another etiology in 63 (37% evaluated, 1.5% overall). Although the sensitivity of cerebrospinal fluid analysis to detect central nervous system disease was 89%, the specificity was only 42% due to the frequent presence of leukemic cells in the cerebrospinal fluid in other conditions. No parameter on cerebrospinal fluid analysis (e.g. total nucleated cells, total lymphocyte count, chronic lymphocytic leukemia cell percentage) were able to offer a reliable discrimination between patients whose neurological symptoms were due to clinically significant central nervous system involvement by chronic lymphocytic leukemia and another etiology. Median overall survival among patients with clinically significant central nervous system chronic lymphocytic leukemia and Richter syndrome was 12 and 11 months, respectively. In conclusion, clinically significant central nervous system involvement by chronic lymphocytic leukemia is a rare condition, and neurological symptoms in patients with chronic lymphocytic

  13. Radiation-Induced Tumor Lysis Syndrome in Chronic Lymphocytic Leukemia

    PubMed Central

    Alkan, Ali; Kütük, Tuğçe; Karcı, Ebru; Yaşar, Arzu; Hiçsönmez, Ayşe; Utkan, Güngör

    2016-01-01

    Tumor lysis syndrome (TLS) is an important oncological emergency that is usually observed with hematological malignancies and rarely with solid tumors. It can be induced either by therapy or spontaneously. Radiotherapy-induced TLS has been rarely reported in the literature. Here we present a patient with a diagnosis of metastatic prostate cancer and chronic lymphocytic leukemia complicated with TLS during palliative radiotherapy. PMID:27093891

  14. New strategies in chronic lymphocytic leukemia: shifting treatment paradigms.

    PubMed

    Awan, Farrukh T; Byrd, John C

    2014-12-01

    Over the past two decades, slow but deliberate progress has been made in understanding the genetics of chronic lymphocytic leukemia (CLL) and how the surrounding microenvironment influences leukemia cell survival. The complexity of CLL with respect to different chromosomal aberrations, lack of a common aberrant signaling pathway activation, and associated immune suppression of the disease has been seen a major stumbling block for developing a single targeted therapy similar to imatinib used in chronic myeloid leukemia. The upcoming therapeutic era we are entering with the B-cell receptor (BCR) tyrosine kinase inhibitors ibrutinib and idelalisib appears to be overcoming this obstacle. Indeed, for the large majority of patients, it appears that application of BCR kinase inhibitors can promote durable remissions without the need for chemotherapy. Where other very active targeted agents such as ABT-199, therapeutic antibodies, and chimeric antigen receptor-modified T-cells will be used in CLL also represents a major question that future clinical trials will answer.

  15. Chronic lymphocytic leukemia antibodies with a common stereotypic rearrangement recognize nonmuscle myosin heavy chain IIA

    PubMed Central

    Catera, Rosa; Hatzi, Katerina; Yan, Xiao-Jie; Zhang, Lu; Wang, Xiao Bo; Fales, Henry M.; Allen, Steven L.; Kolitz, Jonathan E.; Rai, Kanti R.; Chiorazzi, Nicholas

    2008-01-01

    Leukemic B lymphocytes of a large group of unrelated chronic lymphocytic leukemia (CLL) patients express an unmutated heavy chain immunoglobulin variable (V) region encoded by IGHV1-69, IGHD3-16, and IGHJ3 with nearly identical heavy and light chain complementarity-determining region 3 sequences. The likelihood that these patients developed CLL clones with identical antibody V regions randomly is highly improbable and suggests selection by a common antigen. Monoclonal antibodies (mAbs) from this stereotypic subset strongly bind cytoplasmic structures in HEp-2 cells. Therefore, HEp-2 cell extracts were immunoprecipitated with recombinant stereotypic subset-specific CLL mAbs, revealing a major protein band at approximately 225 kDa that was identified by mass spectrometry as nonmuscle myosin heavy chain IIA (MYHIIA). Reactivity of the stereotypic mAbs with MYHIIA was confirmed by Western blot and immunofluorescence colocalization with anti-MYHIIA antibody. Treatments that alter MYHIIA amounts and cytoplasmic localization resulted in a corresponding change in binding to these mAbs. The appearance of MYHIIA on the surface of cells undergoing stress or apoptosis suggests that CLL mAb may generally bind molecules exposed as a consequence of these events. Binding of CLL mAb to MYHIIA could promote the development, survival, and expansion of these leukemic cells. PMID:18812466

  16. GS-1101: a delta-specific PI3K inhibitor in chronic lymphocytic leukemia.

    PubMed

    Macias-Perez, Ines M; Flinn, Ian W

    2013-03-01

    Chronic lymphocytic leukemia (CLL) remains an incurable B-cell malignancy with many unanswered questions. While the cell of origin and etiology are still unknown, significant scientific progress has revealed numerous molecular targets for novel therapeutic interventions. Phosphatidylinositol 3-kinases (PI3K) regulate key cellular functions, including growth, survival and migration, by integrating and transmitting signals from diverse surface molecules including the B-cell receptor (BCR). In lymphocytes, the PI3Kδ isoform plays a critical role in B-cell homeostasis and function. In CLL, the PI3K pathway is constitutively active and dependent on PI3Kδ. GS-1101 is a highly selective PI3Kδ inhibitor that in CLL patients causes a rapid and sustained reduction in lymphadenopathy, accompanied by transient lymphocytosis. This article will review new insights into the pathophysiology of CLL, the preclinical rationale of a PI3Kδ inhibitor in CLL, and the clinical evidence supporting this first-in-class therapeutic target for CLL patients.

  17. The spectrum of use of rituximab in chronic lymphocytic leukemia

    PubMed Central

    Tedeschi, Alessandra; Vismara, Eleonora; Ricci, Francesca; Morra, Enrica; Montillo, Marco

    2010-01-01

    The monoclonal chimeric anti-CD20 antibody, rituximab, has considerably improved therapeutic outcome in B-cell chronic lymphocytic leukemia. Rituximab has limited clinical activity when used as a single agent. The combination of the monoclonal antibody with fludarabine-based regimens clearly demonstrated, in Phase II and randomized trials, an increase in clinical efficacy in previously untreated and pretreated patients. Furthermore the addition of rituximab enabled the eradication of minimal residual disease, which is correlated with the prognosis in a high proportion of patients. Although the combination of rituximab with fludarabine-based regimens increased myelosuppression and immunosuppression, incidence of infections did not increase. The benefit of adding rituximab to other purine analogs or other chemotherapeutic combination regimens has also been explored. Moreover there could be a role for achieving better quality of responses with the combination of different monoclonal antibodies, considering that they target different antigens and exert different mechanism of action. Although the role of rituximab as maintenance therapy in low grade non-Hodgkin’s lymphomas has been determined, the benefit and optimal schedule in chronic lymphocytic leukemia are still under investigation. This review brings together knowledge of the pharmacokinetics, mechanism of action and clinical use of rituximab in chronic lymphocytic leukemia. PMID:21289858

  18. The function of a novel immunophenotype candidate molecule PD-1 in chronic lymphocytic leukemia.

    PubMed

    Grzywnowicz, Maciej; Karabon, Lidia; Karczmarczyk, Agnieszka; Zajac, Malgorzata; Skorka, Katarzyna; Zaleska, Joanna; Wlasiuk, Paulina; Chocholska, Sylwia; Tomczak, Waldemar; Bojarska-Junak, Agnieszka; Dmoszynska, Anna; Frydecka, Irena; Giannopoulos, Krzysztof

    2015-01-01

    Programmed death-1 (PD-1) is a negative receptor expressed on lymphocytes including malignant B cells in chronic lymphocytic leukemia (CLL). In this work, we found that patients with CLL had a higher expression of PD-1 transcript (PDCD1) than healthy volunteers (p < 0.0001). PDCD1 expression was comparable between CLL cells from accumulation (peripheral blood) and proliferation (bone marrow) disease compartments. In blood samples of patients with mutated IGHV genes PDCD1 expression was higher than with unmutated IGHV (p = 0.0299). We demonstrated that phosphorylation of SYK and LYN, key B-cell receptor signaling kinases, was independent of PD-1 expression in patients with CLL, while ZAP-70 phosphorylation in negative tyrosine residue 292 showed strong inverse correlation (r = - 0.8, p = 0.0019). No associations between five single nucleotide polymorphisms of PDCD1, their expressions and susceptibility to CLL were found. In conclusion, PD-1 might be an independent, universal marker of CLL cells and a part of their activated phenotype, and subsequently might modulate the function of ZAP-70.

  19. Transcriptome characterization by RNA sequencing identifies a major molecular and clinical subdivision in chronic lymphocytic leukemia

    PubMed Central

    Ferreira, Pedro G.; Jares, Pedro; Rico, Daniel; Gómez-López, Gonzalo; Martínez-Trillos, Alejandra; Villamor, Neus; Ecker, Simone; González-Pérez, Abel; Knowles, David G.; Monlong, Jean; Johnson, Rory; Quesada, Victor; Djebali, Sarah; Papasaikas, Panagiotis; López-Guerra, Mónica; Colomer, Dolors; Royo, Cristina; Cazorla, Maite; Pinyol, Magda; Clot, Guillem; Aymerich, Marta; Rozman, Maria; Kulis, Marta; Tamborero, David; Gouin, Anaïs; Blanc, Julie; Gut, Marta; Gut, Ivo; Puente, Xose S.; Pisano, David G.; Martin-Subero, José Ignacio; López-Bigas, Nuria; López-Guillermo, Armando; Valencia, Alfonso; López-Otín, Carlos; Campo, Elías; Guigó, Roderic

    2014-01-01

    Chronic lymphocytic leukemia (CLL) has heterogeneous clinical and biological behavior. Whole-genome and -exome sequencing has contributed to the characterization of the mutational spectrum of the disease, but the underlying transcriptional profile is still poorly understood. We have performed deep RNA sequencing in different subpopulations of normal B-lymphocytes and CLL cells from a cohort of 98 patients, and characterized the CLL transcriptional landscape with unprecedented resolution. We detected thousands of transcriptional elements differentially expressed between the CLL and normal B cells, including protein-coding genes, noncoding RNAs, and pseudogenes. Transposable elements are globally derepressed in CLL cells. In addition, two thousand genes—most of which are not differentially expressed—exhibit CLL-specific splicing patterns. Genes involved in metabolic pathways showed higher expression in CLL, while genes related to spliceosome, proteasome, and ribosome were among the most down-regulated in CLL. Clustering of the CLL samples according to RNA-seq derived gene expression levels unveiled two robust molecular subgroups, C1 and C2. C1/C2 subgroups and the mutational status of the immunoglobulin heavy variable (IGHV) region were the only independent variables in predicting time to treatment in a multivariate analysis with main clinico-biological features. This subdivision was validated in an independent cohort of patients monitored through DNA microarrays. Further analysis shows that B-cell receptor (BCR) activation in the microenvironment of the lymph node may be at the origin of the C1/C2 differences. PMID:24265505

  20. NCCN Guidelines Insights: Chronic Lymphocytic Leukemia/Small Lymphocytic Leukemia, Version 1.2017.

    PubMed

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

    2017-03-01

    Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are different manifestations of the same disease and managed in much the same way. The advent of novel CD20 monoclonal antibodies led to the development of effective chemoimmunotherapy regimens. More recently, small molecule inhibitors targeting kinases involved in a number of critical signaling pathways and a small molecule inhibitor of the BCL-2 family of proteins have demonstrated activity for the treatment of patients with CLL/SLL. These NCCN Guidelines Insights highlight important updates to the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for CLL/SLL for the treatment of patients with newly diagnosed or relapsed/refractory CLL/SLL.

  1. Clonally related Histiocytic/dendritic cell sarcoma and chronic lymphocytic leukemia/small lymphocytic lymphoma: A study of 7 cases

    PubMed Central

    Shao, Haipeng; Xi, Liqiang; Raffeld, Mark; Feldman, Andrew L.; Ketterling, Rhett P.; Knudson, Ryan; Rodriguez-Canales, Jaime; Hanson, Jeffrey; Pittaluga, Stefania; Jaffe, Elaine S

    2011-01-01

    Histiocytic and interdigitating dendritic cell sarcomas are rare tumors originating from bone marrow derived myeloid stem cells. Recent studies have shown evidence of cross-lineage transdifferentiation of B-cells in follicular lymphoma to histiocytic and dendritic cell sarcomas. In this study, we report the morphologic, molecular and cytogenetic analysis of 7 cases of chronic lymphocytic leukemia/small lymphocytic lymphoma associated with histiocytic and dendritic cell sarcomas. All seven patients were elderly males (median age, 71 years). The B-cell neoplasms preceded the development of the histiocytic and dendritic cell sarcomas in 6 of 7 patients, and one patient had both tumors diagnosed at the same time. The tumors included 4 interdigitating dendritic cell sarcomas; 1 Langerhans cell sarcoma, 1 histiocytic sarcoma, and 1 immature neoplasm with evidence of histiocytic origin. Laser-capture microdissection and PCR analysis showed identical clonal immunoglobulin gene rearrangements in the two phenotypically distinct components in all cases. There was a preferential usage of IGHV4-39 by the V-D-J gene rearrangement. By FISH analysis two cases showed deletion 17p in both components, while 4 cases had normal cytogenetic findings by FISH in the CLL/SLL cells, but acquired cytogenetic abnormalities in the corresponding histiocytic and dendritic tumors. Chromosome 17p abnormalities were the most common cytogenetic abnormality detected in the sarcomas, seen in 5 of 6 cases studied. Compared with the CLL/SLL cells, the histiocytic/dendritic cells were largely negative for PAX5, but showed strong expression of PU.1 and variable and weak expression of CEBPβ. Our study provides evidence for transdifferentiation of CLL/SLL B-cells to tumors of dendritic and less often histiocytic lineage, and suggests that secondary genetic events may play a role in this phenomenon. PMID:21666687

  2. Successful treatment of refractory Guillain-Barré syndrome with alemtuzumab in a patient with chronic lymphocytic leukemia.

    PubMed

    Tzachanis, Dimitrios; Hamdan, Ayad; Uhlmann, Erik J; Joyce, Robin M

    2014-01-01

    This is the case of a 79-year-old man with chronic lymphocytic leukemia who presented with Guillain-Barré syndrome with features overlapping with the Miller Fisher syndrome and Bickerstaff brainstem encephalitis and positive antiganglioside GQ1b antibody about 6 months after treatment with bendamustine and rituximab. His clinical and neurologic condition continued to deteriorate despite sequential treatment with corticosteroids, intravenous immunoglobulin and plasmapheresis, but in the end, he had a complete and durable response to treatment with alemtuzumab.

  3. Chronic Lymphocytic Leukemia Prognostic Index: A New Integrated Scoring System to Predict the Time to First Treatment in Chinese Patients with Chronic Lymphocytic Leukemia

    PubMed Central

    Li, Heng; Yi, Shu-Hua; Xiong, Wen-Jie; Liu, Hui-Min; Lyu, Rui; Wang, Ting-Yu; Liu, Wei; Zhong, Shi-Zhen; Yu, Zhen; Zou, De-Hui; Xu, Yan; An, Gang; Li, Zeng-Jun; Qiu, Lu-Gui

    2017-01-01

    Background: The established clinical staging systems (Rai/Binet) of chronic lymphocytic leukemia (CLL) cannot accurately predict the appropriate treatment of patients in the earlier stages. In the past two decades, several prognostic factors have been identified to predict the outcome of patients with CLL, but only a few studies investigated more markers together. To predict the time to first treatment (TTFT) in patients of early stages, we evaluated the prognostic role of conventional markers as well as cytogenetic abnormalities and combined them together in a new prognostic scoring system, the CLL prognostic index (CLL-PI). Methods: Taking advantage of a population of 406 untreated Chinese patients with CLL at early and advanced stage of disease, we identified the strongest prognostic markers of TTFT and, subsequently, in a cohort of 173 patients who had complete data for all 3 variables, we integrated the data of traditional staging system, cytogenetic aberrations, and mutational status of immunoglobulin heavy chain variable region (IGHV) in CLL-PI. The median follow-up time was 45 months and the end point was TTFT. Results: The median TTFT was 38 months and the 5-year overall survival was 80%. According to univariate analysis, patients of advanced Rai stages (P < 0.001) or with 11q- (P = 0.002), 17p- (P < 0.001), unmutated IGHV (P < 0.001), negative 13q- (P = 0.007) and elevated lactate dehydrogenase levels (P = 0.001) tended to have a significantly shorter TTFT. And subsequently, based on multivariate Cox regression analysis, three independent factors for TTFT were identified: advanced clinical stage (P = 0.002), 17p- (P = 0.050) and unmutated IGHV (P = 0.049). Applying weighted grading of these independent factors, a CLL-PI was constructed based on regression parameters, which could categorize four different risk groups (low risk [score 0], intermediate low [score 1], intermediate high [score 2] and high risk [score 3–6]) with significantly different TTFT

  4. Arresting the Inflammatory Drive of Chronic Lymphocytic Leukemia with Ibrutinib

    PubMed Central

    Bachireddy, Pavan; Wu, Catherine J.

    2016-01-01

    Summary The clinical success of agents targeting the B cell receptor (BCR) signaling pathway in chronic lymphocytic leukemia (CLL) may also derive from disrupting the CLL microenvironment. Investigation of the immunomodulatory effects of these agents illuminates the unique immunobiology of CLL and highlights potential targets for dismantling the chronic inflammatory drive. PMID:26847060

  5. Metformin Hydrochloride and Ritonavir in Treating Patients With Relapsed or Refractory Multiple Myeloma or Chronic Lymphocytic Leukemia

    ClinicalTrials.gov

    2017-03-22

    Anemia; Fatigue; Fever; Lymphadenopathy; Lymphocytosis; Night Sweats; Recurrent Chronic Lymphocytic Leukemia; Recurrent Plasma Cell Myeloma; Refractory Chronic Lymphocytic Leukemia; Refractory Plasma Cell Myeloma; Splenomegaly; Thrombocytopenia; Weight Loss

  6. Disseminated Cryptococcal Disease in a Patient with Chronic Lymphocytic Leukemia on Ibrutinib

    PubMed Central

    Proia, Laurie A.; Demarais, Patricia L.

    2016-01-01

    Cryptococcus is a unique environmental fungus that can cause disease most often in immunocompromised individuals with defective cell-mediated immunity. Chronic lymphocytic leukemia (CLL) is not known to be a risk factor for cryptococcal disease although cases have been described mainly in patients treated with agents that suppress cell-mediated immunity. Ibrutinib is a new biologic agent used for treatment of CLL, mantle cell lymphoma, and Waldenstrom's macroglobulinemia. It acts by inhibiting Bruton's tyrosine kinase, a kinase downstream of the B-cell receptor critical for B-cell survival and proliferation. Ibrutinib use has not been associated previously with cryptococcal disease. However, recent evidence suggested that treatments aimed at blocking the function of Bruton's tyrosine kinase could pose a higher risk for cryptococcal infection in a mice model. Here, we report the first case of disseminated cryptococcal disease in a patient with CLL treated with ibrutinib. When evaluating possible infection in CLL patients receiving ibrutinib, cryptococcal disease, which could be life threatening if overlooked, could be considered. PMID:27703818

  7. A unique proteomic profile on surface IgM ligation in unmutated chronic lymphocytic leukemia

    PubMed Central

    Perrot, Aurore; Pionneau, Cédric; Nadaud, Sophie; Davi, Frédéric; Leblond, Véronique; Jacob, Frédéric; Merle-Béral, Hélène; Herbrecht, Raoul; Béné, Marie-Christine; Gribben, John G.; Vallat, Laurent

    2011-01-01

    Chronic lymphocytic leukemia (CLL) is characterized by a highly variable clinical course with 2 extreme subsets: indolent, ZAP70− and mutated immunoglobulin heavy chain gene (M-CLL); and aggressive, ZAP70+ and unmutated immunoglobulin heavy chain (UM-CLL). Given the long-term suspicion of antigenic stimulation as a primum movens in the disease, the role of the B-cell receptor has been extensively studied in various experimental settings; albeit scarcely in a comparative dynamic proteomic approach. Here we use a quantitative 2-dimensional fluorescence difference gel electrophoresis technology to compare 48 proteomic profiles of the 2 CLL subsets before and after anti-IgM ligation. Differentially expressed proteins were subsequently identified by mass spectrometry. We show that unstimulated M- and UM-CLL cells display distinct proteomic profiles. Furthermore, anti-IgM stimulation induces a specific proteomic response, more pronounced in the more aggressive CLL. Statistical analyses demonstrate several significant protein variations according to stimulation conditions. Finally, we identify an intermediate form of M-CLL cells, with an indolent profile (ZAP70−) but sharing aggressive proteomic profiles alike UM-CLL cells. Collectively, this first quantitative and dynamic proteome analysis of CLL further dissects the complex molecular pathway after B-cell receptor stimulation and depicts distinct proteomic profiles, which could lead to novel molecular stratification of the disease. PMID:21602524

  8. Epigenetic changes during disease progression in a murine model of human chronic lymphocytic leukemia

    PubMed Central

    Chen, Shih-Shih; Raval, Aparna; Johnson, Amy J.; Hertlein, Erin; Liu, Te-Hui; Jin, Victor X.; Sherman, Mara H.; Liu, Shu-Jun; Dawson, David W.; Williams, Katie E.; Lanasa, Mark; Liyanarachchi, Sandya; Lin, Thomas S.; Marcucci, Guido; Pekarsky, Yuri; Davuluri, Ramana; Croce, Carlo M.; Guttridge, Denis C.; Teitell, Michael A.; Byrd, John C.; Plass, Christoph

    2009-01-01

    Epigenetic alterations, including gain or loss of DNA methylation, are a hallmark of nearly every malignancy. Changes in DNA methylation can impact expression of cancer-related genes including apoptosis regulators and tumor suppressors. Because such epigenetic changes are reversible, they are being aggressively investigated as potential therapeutic targets. Here we use the Eμ-TCL1 transgenic mouse model of chronic lymphocytic leukemia (CLL) to determine the timing and patterns of aberrant DNA methylation, and to investigate the mechanisms that lead to aberrant DNA methylation. We show that CLL cells from Eμ-TCL1 mice at various stages recapitulate epigenetic alterations seen in human CLL. Aberrant methylation of promoter sequences is observed as early as 3 months of age in these animals, well before disease onset. Abnormally methylated promoter regions include binding sites for the transcription factor FOXD3. We show that loss of Foxd3 expression due to an NF-κB p50/p50:HDAC1 repressor complex occurs in TCL1-positive B cells before methylation. Therefore, specific transcriptional repression is an early event leading to epigenetic silencing of target genes in murine and human CLL. These results provide strong rationale for the development of strategies to target NF-κB components in CLL and potentially other B-cell malignancies. PMID:19666576

  9. Epigenetic changes during disease progression in a murine model of human chronic lymphocytic leukemia.

    PubMed

    Chen, Shih-Shih; Raval, Aparna; Johnson, Amy J; Hertlein, Erin; Liu, Te-Hui; Jin, Victor X; Sherman, Mara H; Liu, Shu-Jun; Dawson, David W; Williams, Katie E; Lanasa, Mark; Liyanarachchi, Sandya; Lin, Thomas S; Marcucci, Guido; Pekarsky, Yuri; Davuluri, Ramana; Croce, Carlo M; Guttridge, Denis C; Teitell, Michael A; Byrd, John C; Plass, Christoph

    2009-08-11

    Epigenetic alterations, including gain or loss of DNA methylation, are a hallmark of nearly every malignancy. Changes in DNA methylation can impact expression of cancer-related genes including apoptosis regulators and tumor suppressors. Because such epigenetic changes are reversible, they are being aggressively investigated as potential therapeutic targets. Here we use the Emu-TCL1 transgenic mouse model of chronic lymphocytic leukemia (CLL) to determine the timing and patterns of aberrant DNA methylation, and to investigate the mechanisms that lead to aberrant DNA methylation. We show that CLL cells from Emu-TCL1 mice at various stages recapitulate epigenetic alterations seen in human CLL. Aberrant methylation of promoter sequences is observed as early as 3 months of age in these animals, well before disease onset. Abnormally methylated promoter regions include binding sites for the transcription factor FOXD3. We show that loss of Foxd3 expression due to an NF-kappaB p50/p50:HDAC1 repressor complex occurs in TCL1-positive B cells before methylation. Therefore, specific transcriptional repression is an early event leading to epigenetic silencing of target genes in murine and human CLL. These results provide strong rationale for the development of strategies to target NF-kappaB components in CLL and potentially other B-cell malignancies.

  10. Splenic irradiation in chronic lymphocytic leukemia. A 10-year experience at a single institution

    SciTech Connect

    Roncadin, M.; Arcicasa, M.; Trovo, M.G.; Franchin, G.; de Paoli, A.; Volpe, R.; Carbone, A.; Tirelli, U.; Grigoletto, E.

    1987-12-01

    A group of 38 patients with a median age of 70 years and chronic lymphocytic leukemia (CLL) were treated using a cobalt 60 U or a 6-MeV linear accelerator. A direct field or two opposite fields covered the palpable spleen area in most patients. 100 cGy were administered weekly for a total dose of 10 Gy, given over 10 weeks. The stage arrangement (according to Rai) for the 32 evaluable patients was as follows: Stage I: 11 patients, Stage II: nine patients, Stage III: three patients, and Stage IV: nine patients. Patients in Stages I and II were treated when symptomatic. Twenty-five patients (78%) achieved hematologic response (HR), defined as normalization of the differential leukocyte count, of the total blood cell count, and of bone marrow infiltration. However, no complete response according to the standard criteria of response has been obtained. The median response time of HR was 7 months (range, 1.5 months to greater than 120 months). The overall median survival time from the start of splenic irradiation (SI) was 40 months. More than 50% splenomegaly reduction was obtained in 63% of patients, whereas no benefit was verified in the lymphadenopathy. The incidence of second tumor was 29%. Fourteen patients benefited from a further 21 SI cycles. SI does not result in a complete remission and therefore cannot modify the course of CLL. This treatment is most advisable for elderly patients with predominant bone marrow lymphocytosis, for patients with previous extensive chemotherapy or radiotherapy, and for patients with poor marrow reserve. Moreover, because of the absence of toxicity subsequent treatment is not compromised.

  11. Mantle cell lymphoma displays a homogenous methylation profile: a comparative analysis with chronic lymphocytic leukemia.

    PubMed

    Halldórsdóttir, Anna Margrét; Kanduri, Meena; Marincevic, Millaray; Mansouri, Larry; Isaksson, Anders; Göransson, Hanna; Axelsson, Tomas; Agarwal, Prasoon; Jernberg-Wiklund, Helena; Stamatopoulos, Kostas; Sander, Birgitta; Ehrencrona, Hans; Rosenquist, Richard

    2012-04-01

    Mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) are mature CD5(+) B-cell malignancies with different biological/clinical characteristics. We recently reported an association between different prognostic subgroups of CLL (i.e., IGHV mutated and unmutated) and genomic methylation pattern. However, the relationship between DNA methylation and prognostic markers, such as the proliferation gene expression signature, has not been investigated in MCL. We applied high-resolution methylation microarrays (27,578 CpG sites) to assess the global DNA methylation profiles in 20 MCL (10 each with high/low proliferation signature) and 30 CLL (15 poor-prognostic IGHV unmutated subset #1 and 15 good-prognostic IGHV mutated subset #4) samples. Notably, MCL and each CLL subset displayed distinct genomic methylation profiles. After unsupervised hierarchical clustering, 17/20 MCL cases formed a cluster separate from CLL, while CLL subsets #1 and #4 formed subclusters. Surprisingly, few differentially methylated genes (n = 6) were identified between high vs. low proliferation MCL. In contrast, distinct methylation profiles were demonstrated for MCL and CLL. Importantly, certain functional classes of genes were preferentially methylated in either disease. For instance, developmental genes, in particular homeobox transcription factor genes (e.g., HLXB9, HOXA13), were more highly methylated in MCL, whereas apoptosis-related genes were enriched among targets methylated in CLL (e.g., CYFIP2, NR4A1). Results were validated using pyrosequencing, RQ-PCR and reexpression of specific genes. In summary, the methylation profile of MCL was homogeneous and no correlation with the proliferation signature was observed. Compared to CLL, however, marked differences were discovered such as the preferential methylation of homeobox genes in MCL.

  12. Infrequent normal B lymphocytes express features of B-chronic lymphocytic leukemia

    PubMed Central

    1982-01-01

    An infrequent (2-3%) B lymphocyte subpopulation was found in the normal human tonsil and lymph nodes that shows the phenotypic characteristics of B-chronic lymphocytic leukemia (B-CLL) (rosette formation with mouse erythrocytes, weak expression of membrane Ig, staining for HLA-DR, and OKT1 or Leu-1 detecting a T cell-associated p65 antigen). Preliminary evidence suggests that at least a subpopulation of these cells is found, in small proportions, within the germinal centers. These cells were not observed in the human bone marrow. B-CLL may involve this peripheral B lymphocyte subset. PMID:6977012

  13. Prognostic markers and stratification of chronic lymphocytic leukemia.

    PubMed

    Furman, Richard R

    2010-01-01

    Chronic lymphocytic leukemia (CLL) is one of the most common lymphoid malignancies and is characterized by a tremendously variable clinical course. Additionally, whereas the median age at diagnosis is 72 years, CLL is diagnosed with increasing frequency in younger patients. Given the toxicities associated with currently available therapies, being able to predict which patients will need treatment could play a significant role in preserving bone marrow function and reducing morbidity and mortality. While a great many prognostic markers have been identified that predict outcomes for patients with CLL. Learning how to use these prognostic markers to provide patient care is more difficult.

  14. Electrophoretic abnormalities in chronic lymphocytic leukemia and cancer sera.

    PubMed

    Werthamer, S; Amaral, L

    1976-01-01

    It was previously shown (Am J Clin Pathol 55: 65-67, 1971) that sera from patients with chronic lymphocytic leukemia (CLL) produce a characteristic pattern on disk-acrylamide gels. Other observations indicating the presence of immunosuppressive proteins in the sera of patients with cancer suggested the search for characteristic protein patterns employing the same technic. Utilizing sera from patients with various types of malignancies and appropriate controls, the results appear to indicate that there is a consistent and distinctive pattern to the gels. The nature of the (different) protein(s) remains to be elucidated.

  15. Chronic lymphocytic leukemia: molecular genetics and animal models.

    PubMed

    Pekarsky, Y; Calin, G A; Aqeilan, R

    2005-01-01

    Chronic lymphocytic leukemia accounts for almost 30% of all adult leukemia cases in the United States and Western Europe. Although several common genomic abnormalities in CLL have been identified, mutational and functional analysis of corresponding genes so far have not proved their involvement in CLL. Our latest studies demonstrated functional involvement of Tcl1 oncoprotein and microRNA genes in the pathogenesis of CLL. Deregulated expression of Tcl1 in transgenic mice resulted in CLL. These CLL tumors showed abnormalities in expression of murine microRNA genes mmu-mir-15a and mmu-mir-16-1. Interestingly, human homologs of these genes, mir-15a and mir-16-1, located at the chromosome 13q14 are also deleted in human CLL samples. In this review we summarize and discuss these new developments. These recently emerged insights into the molecular mechanisms of CLL will allow for the development of new approaches to treat this disease.

  16. Vaccine- and immune-based therapy in chronic lymphocytic leukemia.

    PubMed

    Le Dieu, Rifca; Gribben, John

    2006-04-01

    B-cell chronic lymphocytic leukemia (CLL) would appear to be an ideal target of T-cell-mediated responses against the cancer cell. The cancer arises in cells that can act as antigen-presenting cells (APCs), CLL cells express tumor antigens, and the cells can be a target of the allogeneic T cells in a graft-versus-leukemia effect. Despite these potential benefits, immune responses against CLL cells have been difficult to elicit. CLL induces immune defects in the host, the tumor cells are inefficient APCs, and therapies given to patients with CLL are themselves immunosuppressive. Successful vaccination approaches in this disease will require steps to overcome these difficulties, including steps to improve the immune defects in this disease, identification of the targets of the immune response to monitor immunologic responses, and improved presentation of antigen.

  17. The potential of venetoclax (ABT-199) in chronic lymphocytic leukemia.

    PubMed

    Itchaki, Gilad; Brown, Jennifer R

    2016-10-01

    Venetoclax (VEN, ABT-199/GDC-0199) is an orally bioavailable BH3-mimetic that specifically inhibits the anti-apoptotic B-cell lymphoma/leukemia 2 (BCL2) protein. Although BCL2 overexpression is not genetically driven in chronic lymphocytic leukemia (CLL), it is nearly universal and represents a highly important and prevalent mechanism of apoptosis evasion, making it an attractive therapeutic target. This review summarizes the role of BCL2 in CLL pathogenesis, the development path targeting its inhibition prior to VEN, and the preclinical and clinical data regarding the effectiveness and safety of VEN. We further strive to contextualize VEN in the current CLL treatment landscape and discuss potential mechanisms of resistance.

  18. The potential of venetoclax (ABT-199) in chronic lymphocytic leukemia

    PubMed Central

    Itchaki, Gilad; Brown, Jennifer R.

    2016-01-01

    Venetoclax (VEN, ABT-199/GDC-0199) is an orally bioavailable BH3-mimetic that specifically inhibits the anti-apoptotic B-cell lymphoma/leukemia 2 (BCL2) protein. Although BCL2 overexpression is not genetically driven in chronic lymphocytic leukemia (CLL), it is nearly universal and represents a highly important and prevalent mechanism of apoptosis evasion, making it an attractive therapeutic target. This review summarizes the role of BCL2 in CLL pathogenesis, the development path targeting its inhibition prior to VEN, and the preclinical and clinical data regarding the effectiveness and safety of VEN. We further strive to contextualize VEN in the current CLL treatment landscape and discuss potential mechanisms of resistance. PMID:27695617

  19. A phase 1 clinical trial of flavopiridol consolidation in chronic lymphocytic leukemia patients following chemoimmunotherapy

    PubMed Central

    Awan, Farrukh T.; Jones, Jeffrey A.; Maddocks, Kami; Poi, Ming; Grever, Michael R.; Johnson, Amy; Byrd, John C.; Andritsos, Leslie A.

    2016-01-01

    Patients with chronic lymphocytic leukemia (CLL) who receive chemoimmunotherapy and do not achieve complete remission experience significantly shortened progression-free interval (PFS). Additionally, the majority of patients treated for relapsed disease demonstrate evidence of measurable disease. Eradication of minimal residual disease (MRD) results in improved PFS and overall survival. Maintenance therapy might result in eradication of MRD and improve response duration but might be associated with an increase in incidence of infectious complications. Flavopiridol is a broad cyclin-dependent kinase (CDK) inhibitor with established safety and efficacy in patients with relapsed CLL, particularly patients with high-risk cytogenetic features. A pharmacologically derived schedule was utilized as consolidation therapy in this phase I study to assess the safety and feasibility of outpatient therapy with flavopiridol in patients with low tumor burden. Flavopiridol was administered as a 30-min loading dose of 30 mg/m2 followed by a 4-h infusion of 30 mg/ m2 once weekly for 3 weeks every 5 weeks (1 cycle) for planned 2 cycles in ten patients. Therapy was extremely well tolerated and no patient developed acute tumor lysis syndrome. The most common toxicities were gastrointestinal. Of the patients, 22 % improved their response from a PR to CR. Eighty-eight percent experienced a reduction in tumor burden as measured by extent of bone marrow involvement including patients with del17p and complex karyotype. The study establishes the safety and efficacy of flavopiridol as consolidation therapy after chemoimmunotherapy for patients with CLL. Further evaluation is required in larger trials for the utility of CDK inhibitors as consolidation or maintenance strategies. Registration number at ClinicalTrials.gov: NCT00377104. PMID:27118540

  20. A phase 1 clinical trial of flavopiridol consolidation in chronic lymphocytic leukemia patients following chemoimmunotherapy.

    PubMed

    Awan, Farrukh T; Jones, Jeffrey A; Maddocks, Kami; Poi, Ming; Grever, Michael R; Johnson, Amy; Byrd, John C; Andritsos, Leslie A

    2016-06-01

    Patients with chronic lymphocytic leukemia (CLL) who receive chemoimmunotherapy and do not achieve complete remission experience significantly shortened progression-free interval (PFS). Additionally, the majority of patients treated for relapsed disease demonstrate evidence of measurable disease. Eradication of minimal residual disease (MRD) results in improved PFS and overall survival. Maintenance therapy might result in eradication of MRD and improve response duration but might be associated with an increase in incidence of infectious complications. Flavopiridol is a broad cyclin-dependent kinase (CDK) inhibitor with established safety and efficacy in patients with relapsed CLL, particularly patients with high-risk cytogenetic features. A pharmacologically derived schedule was utilized as consolidation therapy in this phase I study to assess the safety and feasibility of outpatient therapy with flavopiridol in patients with low tumor burden. Flavopiridol was administered as a 30-min loading dose of 30 mg/m(2) followed by a 4-h infusion of 30 mg/m(2) once weekly for 3 weeks every 5 weeks (1 cycle) for planned 2 cycles in ten patients. Therapy was extremely well tolerated and no patient developed acute tumor lysis syndrome. The most common toxicities were gastrointestinal. Of the patients, 22 % improved their response from a PR to CR. Eighty-eight percent experienced a reduction in tumor burden as measured by extent of bone marrow involvement including patients with del17p and complex karyotype. The study establishes the safety and efficacy of flavopiridol as consolidation therapy after chemoimmunotherapy for patients with CLL. Further evaluation is required in larger trials for the utility of CDK inhibitors as consolidation or maintenance strategies.Registration number at ClinicalTrials.gov: NCT00377104.

  1. A Novel Natural Product, KL-21, Inhibits Proliferation and Induces Apoptosis in Chronic Lymphocytic Leukemia Cells

    PubMed Central

    Adan Gökbulut, Aysun; Yaşar, Mustafa; Baran, Yusuf

    2015-01-01

    Objective: The aims of this study were to examine the cytotoxic and apoptotic effects of KL-21, a novel plant product (produced by Naturin Natural Products, İzmir, Turkey), on 232B4 chronic lymphocytic leukemia (CLL) cells and to determine the cytotoxic effects on healthy BEAS-2B human bronchial epithelial cells. Materials and Methods: The cytotoxic effect of KL-21 was determined by MTT cell proliferation assay. Changes in caspase-3 enzyme activity were measured using the caspase-3 colorimetric assay. Changes in mitochondrial membrane potential were determined using the JC-1 dye-based method. Annexin V-FITC/PI double staining was performed to measure the apoptotic cell population. Effects of KL-21 on cell cycle profiles of CLL cells were investigated by flow cytometry. Results: We detected time- and concentration-dependent increases in the cytotoxic effect of KL-21 on 232B4 CLL cells. However, we also showed that, especially at higher concentrations, KL-21 was less cytotoxic towards BEAS-2B healthy cells than towards CLL cells. Annexin-V/PI double staining results showed that the apoptotic cell population increased in 232B4 cells. Increasing concentrations of KL-21 increased caspase-3 enzyme activity and induced loss of mitochondrial membrane potential. KL-21 administration resulted in small increases in the percentage of the cells in the G0/G1 phase while it decreased the S phase cell population up to 1 mg/mL. At the highest concentration, most of the cells accumulated in the G0/G1 phase. Conclusion: KL-21 has a growth-inhibitory effect on 232B4 CLL cells. KL-21 causes apoptosis and cell cycle arrest at G0/G1. PMID:26316479

  2. Chronic lymphocytic leukemia in the elderly: clinico-biological features, outcomes, and proposal of a prognostic model.

    PubMed

    Baumann, Tycho; Delgado, Julio; Santacruz, Rodrigo; Martínez-Trillos, Alejandra; Royo, Cristina; Navarro, Alba; Pinyol, Magda; Rozman, María; Pereira, Arturo; Villamor, Neus; Aymerich, Marta; López, Cristina; Carrió, Anna; Montserrat, Emili

    2014-10-01

    We investigated the clinico-biological features, outcomes, and prognosis of 949 patients with chronic lymphocytic leukemia according to age. No biological differences (cytogenetics by fluorescent in situ hybridization, IGHV, ZAP-70, CD38, NOTCH1, SF3B1) were found across age groups. Elderly patients (>70 years; n=367) presented more frequently with advanced disease (Binet C/Rai III-IV: 10/12% versus 5/5%; P<0.001), were treated less frequently (23.8% versus 41.9% at 3 years; P<0.001) and in most cases did not receive highly effective regimens and thus had a lower overall response rate (49% with 14% having complete responses versus 69% with 31% having complete responses; P<0.001). The elderly patients also had a shorter overall survival (6.6 versus 13.3 years; P<0.001) and higher disease-unrelated mortality (34.9% versus 6.9% at 10 years; P<0.001). However, disease-attributable mortality was not significantly different between younger and older patients. A combination of Binet stage, ZAP-70 level, β2-microglobulin concentration and comorbidity identified two risk groups (low-risk: 0-1 parameters; high-risk: 2-4 parameters) with different overall survivals (median: 6.8 versus 11.4 years, P<0.001). In patients requiring treatment, comorbidity at treatment (Cumulative Illness Rating Scale-T>4; hazard ratio 2.2, P<0.001) and response (treatment failure versus response: hazard ratio 1.60, P<0.04) were the most important prognostic factors for overall survival. In conclusion, in our series, elderly patients with chronic lymphocytic leukemia did not present with any biological features distinct from those of younger patients, but did have a poorer clinical outcome. This study highlights the importance of comprehensive medical care, achieving response to therapy, and specific management strategies for elderly patients with chronic lymphocytic leukemia.

  3. Detection of chromothripsis‐like patterns with a custom array platform for chronic lymphocytic leukemia

    PubMed Central

    Salaverria, Itziar; Martín‐Garcia, David; López, Cristina; Clot, Guillem; García‐Aragonés, Manel; Navarro, Alba; Delgado, Julio; Baumann, Tycho; Pinyol, Magda; Martin‐Guerrero, Idoia; Carrió, Ana; Costa, Dolors; Queirós, Ana C.; Jayne, Sandrine; Aymerich, Marta; Villamor, Neus; Colomer, Dolors; González, Marcos; López‐Guillermo, Armando; Campo, Elías; Dyer, Martin J. S.; Siebert, Reiner; Armengol, Lluís

    2015-01-01

    Chronic lymphocytic leukemia (CLL) is a common disease with highly variable clinical course. Several recurrent chromosomal alterations are associated with prognosis and may guide risk‐adapted therapy. We have developed a targeted genome‐wide array to provide a robust tool for ascertaining abnormalities in CLL and to overcome limitations of the 4‐marker fluorescence in situ hybridization (FISH). DNA from 180 CLL patients were hybridized to the qChip®Hemo array with a high density of probes covering commonly altered loci in CLL (11q22‐q23, 13q14, and 17p13), nine focal regions (2p15‐p16.1, 2p24.3, 2q13, 2q36.3‐q37.1, 3p21.31, 8q24.21, 9p21.3, 10q24.32, and 18q21.32‐q21.33) and two larger regions (6q14.1‐q22.31 and 7q31.33‐q33). Overall, 86% of the cases presented copy number alterations (CNA) by array. There was a high concordance of array findings with FISH (84% sensitivity, 100% specificity); all discrepancies corresponded to subclonal alterations detected only by FISH. A chromothripsis‐like pattern was detected in eight cases. Three showed concomitant shattered 5p with gain of TERT along with isochromosome 17q. Presence of 11q loss was associated with shorter time to first treatment (P = 0.003), whereas 17p loss, increased genomic complexity, and chromothripsis were associated with shorter overall survival (P < 0.001, P = 0.001, and P = 0.02, respectively). In conclusion, we have validated a targeted array for the diagnosis of CLL that accurately detects, in a single experiment, all relevant CNAs, genomic complexity, chromothripsis, copy number neutral loss of heterozygosity, and CNAs not covered by the FISH panel. This test may be used as a practical tool to stratify CLL patients for routine diagnostics or clinical trials. © 2015 The Authors. Genes, Chromosomes & Cancer Published by Wiley Periodicals, Inc. PMID:26305789

  4. Targeting chronic lymphocytic leukemia using CIGB-300, a clinical-stage CK2-specifc cell-permeable peptide inhibitor

    PubMed Central

    Martins, Leila R.; Perera, Yasser; Lúcio, Paulo; Silva, Maria G.; Perea, Silvio E.; Barata, João T.

    2014-01-01

    Chronic lymphocytic leukemia (CLL) remains an incurable malignancy, urging for the identifcation of new molecular targets for therapeutic intervention. CLL cells rely on overexpression and hyperactivation of the ubiquitous serine/threonine protein kinase CK2 for their viability in vitro. CIGB-300 is a cell-permeable selective CK2 inhibitor peptide undergoing clinical trials for several cancers. Here, we show that CIGB-300 promotes activation of the tumor suppressor PTEN and abrogates PI3K-mediated downstream signaling in CLL cells. In accordance, CIGB-300 decreases the viability and proliferation of CLL cell lines, promotes apoptosis of primary leukemia cells and displays antitumor efcacy in a xenograft mouse model of human CLL. Our studies provide pre-clinical support for the testing and possible inclusion of CK2 inhibitors in the clinical arsenal against CLL. PMID:24473900

  5. A Case of Complete and Durable Molecular Remission of Chronic Lymphocytic Leukemia Following Treatment with Epigallocatechin-3-gallate, an Extract of Green Tea

    PubMed Central

    Block, Keith I; Kressel, Bruce R; Sukhatme, Vikas P; White, Jeffrey D

    2015-01-01

    We report the case of a 48-year-old man who achieved a complete molecular remission 20 years after a diagnosis of chronic lymphocytic leukemia while using epigallicatechin-3-gallate, an extract of green tea. The patient presented at age 28 with lymphocytosis, mild anemia, mild thrombocytopenia, and massive splenomegaly, for which a splenectomy was performed. He was then followed expectantly. Over the next two decades, he suffered two symptomatic chronic lymphocytic leukemia-related events. The first occurred twelve years after diagnosis (at age 40) when the patient developed fevers, night sweats, and moderate anemia. He was diagnosed with autoimmune hemolytic anemia secondary to chronic lymphocytic leukemia. The patient declined conventional therapy in favor of a diet, exercise, and supplement regimen, and recovered from the autoimmune hemolytic anemia though the underlying chronic lymphocytic leukemia remained evident. This is the first published case report of "spontaneous" recovery from secondary autoimmune hemolytic anemia in an adult.  Over the second decade following chronic lymphocytic leukemia diagnosis, serial bone marrow biopsies demonstrated increasing lymphocytosis, with minimal peripheral lymphocytosis. However, twenty years after diagnosis, peripheral lymphocytosis accelerated, with white blood cell counts rising to 55,000/µL. Because the patient continued to refuse conventional therapy, he was treated instead with a supplement regimen that included high doses of epigallocatechin-3-gallate, a green tea extract. Peripheral lymphocytosis resolved. More remarkably, a bone marrow examination, including flow cytometry, showed no evidence of a malignant clone. Two years later (at age 51), the peripheral blood and bone marrow were without molecular evidence of chronic lymphocytic leukemia or any malignancy. The patient remains well at age 52.  PMID:26858922

  6. Docosahexaenoic Acid Induces Apoptosis in Primary Chronic Lymphocytic Leukemia Cells

    PubMed Central

    Gyan, Emmanuel; Tournilhac, Olivier; Halty, Christelle; Veyrat-Masson, Richard; Akil, Saïda; Berger, Marc; Hérault, Olivier; Callanan, Mary; Bay, Jacques-Olivier

    2015-01-01

    Chronic lymphocytic leukemia is an indolent disorder with an increased infectious risk remaining one of the main causes of death. Development of therapies with higher safety profile is thus a challenging issue. Docosahexaenoic acid (DHA, 22:6) is an omega-3 fatty acid, a natural compound of normal cells, and has been shown to display antitumor potency in cancer. We evaluated the potential in vitro effect of DHA in primary CLL cells. DHA induces high level of in vitro apoptosis compared to oleic acid in a dose-dependent and time-dependent manner. Estimation of IC50 was only of 4.813 µM, which appears lower than those reported in solid cancers. DHA is highly active on CLL cells in vitro. This observation provides a rationale for further studies aiming to understand its mechanisms of action and its potent in vivo activity. PMID:26734128

  7. Frequency of monoclonal B-cell lymphocytosis in relatives of patients with chronic lymphocytic leukemia

    PubMed Central

    Franco Alzate, Catalina; Rendón Henao, Javier; Torres Hernández, José Domingo; Jaramillo Arbelaez, Patricia Elena

    2016-01-01

    Introduction: Monoclonal B-cell lymphocytosis is a symptom free condition characterized by the circulation of small clonal population of B lymphocytes in peripheral blood (less than 5x109/L) expressing an immunophenotype similar to chronic lymphocytic leukemia. Different studies based on big hospital series have manifested a higher risk in subjects with monoclonal B-cell lymphocytosis to progress to a chronic lymphocytic leukemia. The behavior of this hematologic entity is unknown therefore its frequency in sporadic chronic lymphocytic leukemia patient relatives was determined. Methods: Transversal descriptive study, 8 color flow cytometry was performed using two of the tubes of the Euro Flow recommended panel, with modifications, for the diagnose of chronic lymphoproliferative disorders of B lymphocytes; besides, a fluorescence in situ hybridization was performed. univariate and bivariate analyses of the information were performed. Results: Monoclonal B-cell lymphocytosis frequency found in 51 analyzed relatives was 2%, it was a female participant, 59 years old, with a total leukocyte count of 7.7x109/L and a B lymphocyte count of 0.124x109/L; from these, 0.04x109/L were clonal cells with restrictions of the kappa light chain. Rearrangements of the IGH gene (14q32) were found. Conclusion: Monoclonal B-cell lymphocytosis was detected in one relative of a patient with sporadic chronic lymphocytic leukemia in a frequency similar to the one reported in general population. PMID:27546929

  8. Cutaneous presentation of chronic lymphocytic leukemia as unique extramedullar involvement in a patient with normal peripheral blood lymphocyte count (monoclonal B-cell lymphocytosis).

    PubMed

    Tapia, Gustavo; Mate, José-Luis; Fuente, María-José; Navarro, José-Tomás; Fernández-Figueras, Maria-Teresa; Juncà, Jordi; Ferrándiz, Carlos; Ariza, Aurelio

    2013-08-01

    Skin infiltration by chronic lymphocytic leukemia (CLL) is very rare and almost all reported cases occur in advanced stage. We report a patient with no relevant past medical history who presented with cutaneous erythematous plaques. A punch biopsy showed typical CLL morphologic and immunophenotypic features. Subsequent studies revealed a normal lymphocyte count in peripheral blood, and there was no evidence of lymphadenopathy or organomegaly. Flow cytometry demonstrated a clonal B-cell population both in the bone marrow and peripheral blood (1.60 × 10(9)/l) with a CLL phenotype, but it did not fulfill required criteria for CLL diagnosis. Without cutaneous involvement, this case should be classified as monoclonal B-cell lymphocytosis.

  9. Treatment of younger patients with chronic lymphocytic leukemia.

    PubMed

    Ferrajoli, Alessandra

    2010-01-01

    Younger patients (defined as patients younger than 50-55 years of age) represent a small group of newly diagnosed patients with chronic lymphocytic leukemia, accounting only for 10% to 20% of newly diagnosed cases. However, once these patients become symptomatic and require treatment, their life expectancy is significantly reduced. Therapeutic approaches for younger patients should be directed at improving survival by achieving a complete remission and, where possible, eradicating minimal residual disease. Chemoimmunotherapy combinations carry the highest response rates and are commonly offered to younger patients. Additional strategies that should be considered for younger patients include early referral for stem-cell transplantation and clinical trials of consolidation therapy to eliminate minimal residual disease.

  10. Practical approach to management of chronic lymphocytic leukemia

    PubMed Central

    Šimkovič, Martin

    2015-01-01

    Revolutionary progress has recently changed the landscape of chronic lymphocytic leukemia (CLL). Powerful prognostic factors, especially p53 mutation and/or deletion and IGHV mutation status, have refined individual patient prognosis. Purine analogs and monoclonal antibodies paved the way from palliative treatment to chemoimmunotherapy capable of eradication of minimal residual disease and prolongation of survival. Obinutuzumab (GA-101) and ofatumumab have been recently approved for the treatment of comorbid patients. Bendamustine is available for first-line treatment of patients ineligible for fludarabine, cyclophosphamide, and rituximab (FCR). High-dose glucocorticoids combined with rituximab represent a promising option for refractory CLL; ofatumumab is approved for fludarabine- and alemtuzumab-refractory patients. Allogeneic stem cell transplantation is the only curative option but is feasible in a highly selected group of patients only. The novel small molecule inhibitors ibrutinib and idelalisib have been recently approved for relapsed/refractory CLL. This review provides practical advice for diagnosis, prognostication and treatment of CLL. PMID:27186193

  11. Chronic Lymphocytic Leukemia: An Update on Current Treatment Approaches.

    PubMed

    Rozman, C; Montserrat, E

    1997-01-01

    During the last two decades, important progress has been made in the understanding of the biology, natural history, and prognosis of chronic lymphocytic leukemia (CLL). In addition, new and more effective treatment modalities are changing the objectives of treatment in patients with CLL. In this regard, the purine analogues offer great promise and fludarabine is already considered the treatment of choice for patients failing standard therapies. The role of purine analogues either alone or combined with other agents as front-line therapy is being actively investigated. Certain situations (e.g, autoimmune cytopenias, hypersplenism) require special treatment approaches (e.g., corticosteroids, splenectomy). Transplants of hemopoietic progenitor cells are also increasingly performed. As a result of these advances, treatment of subjects with CLL can be decided on the basis of the individual risk of each patient and the possibility of curing some of them may become a realistic objective.

  12. Chronic Lymphocytic Leukemia: Exploiting Vulnerabilities with Targeted Agents

    PubMed Central

    Maly, Joseph

    2016-01-01

    The field of oncology has been transformed over the course of the last 20 years in large part due to the enhanced understanding of cellular biology and cellular signaling. The indolent natural history of chronic lymphocytic leukemia (CLL) has permitted extensive study of cancer biology and can in some ways be thought of a model for understanding and translating concepts to other diseases. By systematically probing the biology of CLL cells and working out in stepwise fashion the transduction of signals from the surface immunoglobulin to nuclear transcription factors, investigators have paved the way for rational targeting of therapies at natural vulnerabilities that mimic oncogene addiction. These key targets include Bruton’s tyrosine kinase (BTK), phosphatidylinositol 3-kinase (PI3K), Src, Bcl2, and cyclin-dependent kinases (CDKs). In this review, we will consider these proteins and describe the current and future molecules designed to target them in CLL. PMID:26893063

  13. Natural History Study of Monoclonal B Cell Lymphocytosis (MBL), Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL), Lymphoplasmacytic Lymphoma (LPL)/Waldenstrom Macroglobulinemia (WM), and Splenic Marginal Zone Lymphoma (SMZL)

    ClinicalTrials.gov

    2017-03-10

    B-Cell Chronic Lymphocytic Leukemia; Monoclonal B-Cell Lymphocytosis; Lymhoma, Small Lymphocytic; Chronic Lymphocytic Leukemia; Lymphoplasmacytic Lymphoma; Waldenstrom Macroglobulinemia; Splenic Marginal Zone Lymphoma

  14. Generation of leukemia-reactive cytotoxic T lymphocytes from HLA-identical donors of patients with chronic myeloid leukemia using modifications of a limiting dilution assay.

    PubMed

    Smit, W M; Rijnbeek, M; van Bergen, C A; Willemze, R; Falkenburg, J H

    1998-03-01

    Donor leukocyte transfusions (DLT) have an anti-leukemic effect in most patients with a relapse of chronic myeloid leukemia (CML) after allogeneic stem cell transplantation. However, DLT are often complicated by graft-versus-host disease. Selection of donor lymphocytes with a relative specificity for leukemic cells is desirable. The generation of leukemia-reactive cytotoxic T lymphocyte (CTL) responses between HLA-identical donors and patients in bulk cultures showed major variations, and false negative results were observed. In a modification of a limiting dilution analysis (LDA) two-fold serial dilutions of HLA-identical donor mononuclear cells (MNC) were cultured in the presence of CML cells. The anti-leukemic CTL precursor frequencies in these donors varied between <1 and 9 per 106 MNC. HLA-restricted CD4+ or CD8+ lymphocytes as well as MHC non-restricted gammadelta T cells were responsible for the anti-leukemic responses. A positive correlation between cytotoxicity in the various wells after 3, 4 and 5 weeks of culture could be found. The LDA may be superior to bulk cultures in selecting stable immune responses and in separating multiple different anti-leukemic T cell responses in each donor-patient combination.

  15. Enhancement of fludarabine sensitivity by all-trans-retinoic acid in chronic lymphocytic leukemia cells

    PubMed Central

    Fernández-Calotti, Paula X.; Lopez-Guerra, Mónica; Colomer, Dolors; Pastor-Anglada, Marçal

    2012-01-01

    Background A subset of patients with fludarabine-resistant chronic lymphocytic leukemia has previously been shown to express elevated intracellular levels of the concentrative high-affinity fludarabine transporter hCNT3, without any detectable related activity. We have recently shown that all-trans-retinoic acid is capable of inducing hCNT3 trafficking to plasma membrane in the MEC1 cell line. We, therefore, evaluated the effect of all-trans-retinoic acid on hCNT3 in primary chronic lymphocytic leukemia cells as a suitable mechanism to improve fludarabine-based therapy of chronic lymphocytic leukemia. Design and Methods Cells from 23 chronic lymphocytic leukemia patients wild-type for P53 were analyzed for ex vivo sensitivity to fludarabine. hCNT3 activity in chronic lymphocytic leukemia cell samples was evaluated by measuring the uptake of [8-3H]-fludarabine. The amounts of transforming growth factor-β1 and hCNT3 messenger RNA were analyzed by real-time polymerase chain reaction. The effect of all-trans-retinoic acid on hCNT3 subcellular localization was analyzed by confocal microscopy and its effect on fludarabine-induced apoptosis was evaluated by flow cytometry analysis using annexin V staining. Results Chronic lymphocytic leukemia cases showing higher ex vivo basal sensitivity to fludarabine also had a greater basal hCNT3-associated fludarabine uptake capacity compared to the subset of patients showing ex vivo resistance to the drug. hCNT3 transporter activity in chronic lymphocytic leukemia cells from the latter patients was either negligible or absent. Treatment of the fludarabine-resistant subset of chronic lymphocytic leukemia cells with all-trans-retinoic acid induced increased fludarabine transport via hCNT3 which was associated with a significant increase in fludarabine sensitivity. Conclusions Improvement of ex vivo fludarabine sensitivity in chronic lymphocytic leukemia cells is associated with increased hCNT3 activity after all-trans-retinoic acid

  16. Obinutuzumab treatment in the elderly patient with chronic lymphocytic leukemia.

    PubMed

    Seiter, Karen; Mamorska-Dyga, Aleksandra

    2015-01-01

    Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults in Western countries. Fludarabine-based regimens demonstrate higher response rates in younger patients but have a significant risk of infection and are thus poorly tolerated by older, frail patients. Anti-CD20 monoclonal antibodies have added to the efficacy of chemotherapy in CLL. Obinutuzumab is a potent Type II anti-CD20 monoclonal antibody with enhanced antibody-dependent cellular toxicity and direct cell death compared with rituximab. In Phase I studies, infusion reactions and neutropenia were the predominant toxicities. Phase II studies demonstrated efficacy both as a single agent and in combination with chemotherapy in patients with CLL. The CLL11 trial was a Phase III randomized trial of chlorambucil alone or with either obinutuzumab or rituximab in elderly, unfit patients. Progression-free survival (the primary end point) was 26.7 months for patients receiving obinutuzumab plus chlorambucil versus 16.3 months for those receiving rituximab plus chlorambucil and 11.1 months for those receiving chlorambucil alone (P<0.001). Overall survival was improved for patients receiving obinutuzumab plus chlorambucil versus chlorambucil alone (P=0.002). This trial led to the US Food and Drug Administration (FDA) approval of obinutuzumab in this patient population.

  17. The clinical application of monoclonal antibodies in chronic lymphocytic leukemia

    PubMed Central

    Jaglowski, Samantha M.; Alinari, Lapo; Lapalombella, Rosa; Muthusamy, Natarajan

    2010-01-01

    Chronic lymphocytic leukemia (CLL) represents the most prevalent adult leukemia. Treatment with chemotherapy over the past 3 decades has been palliative. The introduction of therapeutic antibodies has increased the number of treatment options for this disease. Despite this increase, our true understanding of the mechanism of action of antibody therapy in CLL remains limited. Rituximab, a CD20 antibody, is currently widely used in combination-based strategies for both previously untreated symptomatic CLL and as salvage therapy. Recent data suggest that the addition of rituximab to fludarabine with or without cyclophosphamide prolongs survival in younger patients with CLL. Other improved CD20 antibodies with promising clinical activity, including ofatumumab and GA-101, are coming forward. Alemtuzumab, a CD52 antibody, likewise has demonstrated benefit in both symptomatic, previously untreated CLL and in patients with relapsed disease but has less selectivity. Development of other therapeutic antibodies targeting alternative B-cell–specific antigens in CLL has been less successful, although many promising candidate antibodies and/or small modular immune pharmaceuticals (SMIPs) are coming forward. In addition, recent efforts to combine currently applied therapeutic antibodies with other biologic and targeted therapies with efficacy in CLL offers the potential to move toward alternative non–chemotherapy-based treatment approaches. PMID:20610811

  18. Chronic lymphocytic leukemia cells diversify and differentiate in vivo via a nonclassical Th1-dependent, Bcl-6-deficient process.

    PubMed

    Patten, Piers E M; Ferrer, Gerardo; Chen, Shih-Shih; Simone, Rita; Marsilio, Sonia; Yan, Xiao-Jie; Gitto, Zachary; Yuan, Chaohui; Kolitz, Jonathan E; Barrientos, Jacqueline; Allen, Steven L; Rai, Kanti R; MacCarthy, Thomas; Chu, Charles C; Chiorazzi, Nicholas

    2016-04-07

    Xenografting primary tumor cells allows modeling of the heterogeneous natures of malignant diseases and the influences of the tissue microenvironment. Here, we demonstrate that xenografting primary chronic lymphocytic leukemia (CLL) B lymphocytes with activated autologous T cells into alymphoid mice results in considerable CLL B cell division and sizable T cell expansion. Nevertheless, most/all CD5(+)CD19(+) cells are eventually lost, due in part to differentiation into antibody-secreting plasmablasts/plasma cells. CLL B cell differentiation is associated with isotype class switching and development of new IGHV-D-J mutations and occurs via an activation-induced deaminase-dependent pathway that upregulates IRF4 and Blimp-1 without appreciable levels of the expected Bcl-6. These processes were induced in IGHV-unmutated and IGHV-mutated clones by Th1-polarized T-bet(+) T cells, not classical T follicular helper (Tfh) cells. Thus, the block in B cell maturation, defects in T cell action, and absence of antigen-receptor diversification, which are often cardinal characteristics of CLL, are not inherent but imposed by external signals and the microenvironment. Although these activities are not dominant features in human CLL, each occurs in tissue proliferation centers where the mechanisms responsible for clonal evolution operate. Thus, in this setting, CLL B cell diversification and differentiation develop by a nonclassical germinal center-like reaction that might reflect the cell of origin of this leukemia.

  19. Novel agents for the treatment of chronic lymphocytic leukemia.

    PubMed

    Abou-Nassar, Karim; Brown, Jennifer R

    2010-12-01

    Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world. Currently, the most effective treatment for CLL consists of a combination of fludarabine, cyclophosphamide, and rituximab. Although this approach has encouraging results, patients with CLL eventually relapse and require additional therapies. Many of the current therapeutic regimens for CLL are myelotoxic, immunosuppressive, and associated with infectious complications. Targeted therapies can often minimize these complications. The US Food and Drug Administration has recently approved 2 agents, bendamustine and ofatumumab, for the treatment of CLL. Emerging therapies ranging from new monoclonal antibodies to small molecules that interfere with vital pathways in signal transduction and cell cycle regulation are currently being developed. This article will focus on novel agents in earlier development phases for CLL, including the immunomodulator lenalidomide; monoclonal antibodies, such as lumiliximab, GA-101, and small molecule immunopharmaceuticals; BCL-2 inhibitors, such as oblimersen, obatoclax, and ABT-263; and protein kinase inhibitors, such as flavopiridol, spleen tyrosine kinase inhibitors, and phosphatidylinositol 3-kinase inhibitors.

  20. Targeted therapy in chronic lymphocytic leukemia: past, present and future

    PubMed Central

    Danilov, Alexey V

    2013-01-01

    Background Chronic lymphocytic leukemia (CLL) is the most prevalent leukemia in the western world. Recent advances in understanding the biology of B-cell malignancies resulted in the development of novel agents targeting key pro-survival pathways in the neoplastic B-cell. Objective The goal of this article was to summarize current literature on the emerging therapeutic approaches in CLL and B-cell malignancies. Methods A literature review was performed, identifying pathways and key clinical trials involving novel therapies in CLL with special emphasis on B-cell receptor targeting agents. Results Understanding the biology of B-cell receptor signaling pathway led to identification of novel molecular targets. Most notably, inhibitors of Bruton tyrosine kinase and phosphatidylinositide 3-kinase-δ have entered clinical trials and demonstrated high response rates in CLL, including high-risk disease. Cyclin-dependent kinase inhibitors may evolve into an alternative therapeutic approach in CLL. New drugs which target molecules within and outside of the B-cell receptor signaling pathway show promise in pre-clinical studies. Conclusions Both pre-clinical and early clinical trial results involving novel targeted therapies suggest that the standard treatment paradigm in CLL and B-cell malignancies will soon change. Particular attention should be paid to the BCR-targeting agents, whose favorable side effect profile may improve lives of the elderly patients with CLL. PMID:24054703

  1. Venetoclax in patients with previously treated chronic lymphocytic leukemia.

    PubMed

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

    2017-01-18

    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 pharmacological 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 1 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 2 trial demonstrating a 79% response rate and an estimated 1 year progression-free survival of 72% with 400mg/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.

  2. Richter Transformation of Chronic Lymphocytic Leukemia: A Review of Fluorodeoxyglucose Positron Emission Tomography–Computed Tomography and Molecular Diagnostics

    PubMed Central

    Janjua, Amna; Van Gestel, Frederick; Ahmad, Adeel

    2017-01-01

    Chronic lymphocytic leukemia (CLL) is a low-grade B-cell proliferative disease with a generally indolent course. In a few cases, it undergoes transformation and becomes a more aggressive malignancy, such as diffuse large B-cell lymphoma (DLBCL). This process, which is called Richter transformation (RT), is often detected too late and is associated with a poor prognosis. There are multiple molecular diagnostic approaches to detect RT in preexisting CLL. Metabolic imaging using 18-fluorine fluorodeoxyglucose positron emission tomography–computed tomography (18F-FDG PET/CT) can be a very useful tool for early detection of RT and which can hence allow for timely intervention, thereby improving the patient’s chances of survival. PMID:28191372

  3. Decitabine and Valproic Acid in Treating Patients With Refractory or Relapsed Acute Myeloid Leukemia or Previously Treated Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

    ClinicalTrials.gov

    2013-09-27

    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); Recurrent Adult Acute Myeloid Leukemia; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Untreated Adult Acute Myeloid Leukemia

  4. A Canadian perspective on the use of immunoglobulin therapy to reduce infectious complications in chronic lymphocytic leukemia

    PubMed Central

    Lachance, S.; Christofides, A.L.; Lee, J.K.; Sehn, L.H.; Ritchie, B.C.; Shustik, C.; Stewart, D.A.; Toze, C.L.; Haddad, E.; Vinh, D.C.

    2016-01-01

    Infections are a major cause of morbidity and mortality in patients with chronic lymphocytic leukemia (cll), who typically have increased susceptibility because of hypogammaglobulinemia (hgg) related to their disease and its treatment. Immunoglobulin replacement therapy (igrt) has been shown to reduce the frequency of bacterial infections and associated hospitalizations in patients with hgg or a history of infection, or both. However, use of igrt in cll is contentious. Studies examining such treatment were conducted largely before the use of newer chemoimmunotherapies, which can extend lifespan, but do not correct the hgg inherent to the disease. Thus, the utility of igrt has to be re-evaluated in the current setting. Here, we discuss the evidence for the use of igrt in cll and provide a practical approach to its use in the prevention and management of infections. PMID:26966403

  5. Survival of young patients with chronic lymphocytic leukemia failing fludarabine therapy: a basis for the use of myeloablative therapies.

    PubMed

    Seymour, J F; Robertson, L E; O'Brien, S; Lerner, S; Keating, M J

    1995-08-01

    We examined the survival of 91 young patients (< or = 55 years) with chronic lymphocytic leukemia from the time of failure of fludarabine therapy, in an attempt to identify those with a poor outcome who may benefit from investigative dose-intensive therapies. The median survival of patients unresponsive to fludarabine (n = 42) was 48 weeks, and only 11% responded to subsequent therapies. The median survival of patients relapsing following a fludarabine-induced remission (n = 49) was 87 weeks, and 83% of those who had received fludarabine as their first therapy (n = 14) responded to further fludarabine-containing therapies, with 60% alive at four years. Only 7% of those relapsing patients who had received fludarabine as salvage therapy (n = 35) responded to subsequent therapies (median survival 72 weeks). The poor outlook for these patients justifies the consideration of innovative dose-intensive therapies, such as bone marrow transplantation, with their attendant risk of toxicity.

  6. Obinutuzumab for the treatment of chronic lymphocytic leukemia.

    PubMed

    Rogers, K A; Jones, J A

    2014-06-01

    Obinutuzumab is a novel therapeutic anti-CD20 monoclonal antibody recently approved by the United States Food and Drug Administration (FDA) for use in combination with chlorambucil as first-line treatment of chronic lymphocytic leukemia (CLL). It is distinguished from other anti-B-lymphocyte antigen CD20 (anti-CD20) therapeutic antibodies in current clinical use by its type II properties and glycoengineered Fc region. In vitro these unique properties translate into higher rates of antibody-dependent cytotoxicity and direct cell death compared to rituximab, and obinutuzumab demonstrates improved efficacy in human lymphoma xenograft models and whole blood lymphocyte depletion assays. FDA approval was based upon results from a randomized phase III trial comparing treatment with single-agent chlorambucil to the combination of chlorambucil and either rituximab or obinutuzu-mab. The obinutuzumab arm resulted in higher rates of complete remission and significant improvements in progression-free survival versus either comparator regimen. The majority of patients in the obinutuzumab and chlorambucil arm finished all six planned treatment cycles, and therapy was well tolerated. Toxicities of obinutuzumab are similar to those of other anti-CD20 antibodies, although infusion-related reactions and neutropenia appear to be more common. This trial establishes chemoimmunotherapy with obinutuzumab and chlorambucil as an attractive treatment option for CLL patients, particularly those with comorbid medical illnesses or advanced age. Obinutuzumab remains under study in combination with both chemotherapy and novel agents for CLL and non-Hodgkin's lymphoma, where it is expected to find additional clinical applications.

  7. From a 2DE-Gel Spot to Protein Function: Lesson Learned From HS1 in Chronic Lymphocytic Leukemia

    PubMed Central

    Apollonio, Benedetta; Bertilaccio, Maria Teresa Sabrina; Restuccia, Umberto; Ranghetti, Pamela; Barbaglio, Federica; Ghia, Paolo; Caligaris-Cappio, Federico; Scielzo, Cristina

    2014-01-01

    The identification of molecules involved in tumor initiation and progression is fundamental for understanding disease’s biology and, as a consequence, for the clinical management of patients. In the present work we will describe an optimized proteomic approach for the identification of molecules involved in the progression of Chronic Lymphocytic Leukemia (CLL). In detail, leukemic cell lysates are resolved by 2-dimensional Electrophoresis (2DE) and visualized as “spots” on the 2DE gels. Comparative analysis of proteomic maps allows the identification of differentially expressed proteins (in terms of abundance and post-translational modifications) that are picked, isolated and identified by Mass Spectrometry (MS). The biological function of the identified candidates can be tested by different assays (i.e. migration, adhesion and F-actin polymerization), that we have optimized for primary leukemic cells. PMID:25350848

  8. National trends in incidence and survival of chronic lymphocytic leukemia in Norway for 1953-2012: a systematic analysis of population-based data.

    PubMed

    Lenartova, Andrea; Johannesen, Tom Børge; Tjønnfjord, Geir Erland

    2016-12-01

    Chronic lymphocytic leukemia is a disease of the elderly, and despite major advances in treatment, remains incurable. The Cancer Registry of Norway has registered data on patients with chronic lymphocytic leukemia since 1953. We aimed to analyze trends in incidence and survival of chronic lymphocytic leukemia in Norway. We identified 7664 patients reported with chronic lymphocytic leukemia to the registry between 1953 and 2012. We gathered information on sex, age at diagnosis, date of death and basis for diagnosis. The age-standardized incidence increased from 0.6/100.000 person-years in 1953 to 3.1/100,000 person-years in 2012. We found a significant decrease in median age between 1993-2002 and 2003-2012 (75 vs. 72 years, 95%CI: 2.52-3.98, P < 0.001). Men were diagnosed at a significantly younger age than women. Immunophenotyping has become the most important diagnostic method after 2002. Median observed survival increased from 3 years in 1952-1963 to 8.5 years in 2003-2012. Five- and 10-year age-standardized net survival increased throughout the whole period across age groups and reached 79% and 57%, respectively. Median observed survival was significantly shorter in men than in women in 1993-2002 (4.9 vs. 6.1 years, P < 0.001). The gap between survival rates for men and women was diminishing in 2003-2012 in patients younger than 60 years while it remained considerable in older patients. Despite an aging Norwegian population, chronic lymphocytic leukemia (CLL) patients become younger at diagnosis. A fourfold increase in incidence, a prolonged survival, and major changes in diagnostic methods in Norway were observed.

  9. Merkel cell polyomavirus (MCPyV) in chronic lymphocytic leukemia/small lymphocytic lymphoma.

    PubMed

    Teman, Carolin J; Tripp, Sheryl R; Perkins, Sherrie L; Duncavage, Eric J

    2011-05-01

    Merkel cell polyomavirus (MCPyV) is a novel polyomavirus that shows a strong association with Merkel cell carcinoma (MCC). Recent studies have demonstrated MCPyV in some cases of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), a malignancy with a similar demographic as MCC. We tested for the presence of MCPyV by PCR and immunohistochemistry in 18 cases of CLL/SLL. Very low-level MCPyV DNA was detected in 33% of CLL/SLL cases by real-time PCR, but only one case demonstrated immunohistochemical positivity for MCPyV. MCPyV was not identified in 17 cases of follicular lymphoma, suggesting either that MCPyV is involved in CLL/SLL pathogenesis or that the immunodeficiency state of CLL/SLL induces low-level MCPyV reactivation.

  10. Therapeutic CD94/NKG2A blockade improves natural killer cell dysfunction in chronic lymphocytic leukemia.

    PubMed

    McWilliams, Emily M; Mele, Jennifer M; Cheney, Carolyn; Timmerman, Elizabeth A; Fiazuddin, Faraz; Strattan, Ethan J; Mo, Xiaokui; Byrd, John C; Muthusamy, Natarajan; Awan, Farrukh T

    2016-01-01

    Natural killer (NK)-cell count is predictive of chronic lymphoid leukemia (CLL) disease progression and their dysfunction is well documented, but the etiology of this is currently lacking. CLL cells have been shown to over-express HLA-E, the natural ligand for NKG2A expressed on NK-cells that generates a distinct negative signal relative to direct NK-cell cytotoxicity in other disease models. Utilizing a novel anti-NKG2A monoclonal blocking antibody (mAb), monalizumab, we explored the in vitro preclinical activity of targeting the NKG2A receptor, and the NKG2A/HLA-E interaction as a mechanism of tumor evasion in CLL patients. Our work confirmed overexpression of HLA-E on CLL B-cells and demonstrated NKG2A expression on CD56+/16+ NK-cells from CLL patients. We also demonstrate that blocking NKG2A on CLL NK-cells was sufficient to restore direct cytotoxicity ability of NK-cells against HLA-E-expressing targets without impacting NK-cell mediated antibody-dependent cellular cytotoxicity. Additionally, we proved the specificity of monalizumab in blocking NKG2A through Fc-blocking mechanisms. This paper provides justification for the potential clinical utility of monalizumab in the treatment of patients with CLL.

  11. A high proportion of cells carrying trisomy 12 is associated with a worse outcome in patients with chronic lymphocytic leukemia.

    PubMed

    González-Gascón Y Marín, Isabel; Hernández-Sánchez, María; Rodríguez-Vicente, Ana-Eugenia; Sanzo, Carmen; Aventín, Anna; Puiggros, Anna; Collado, Rosa; Heras, Cecilia; Muñoz, Carolina; Delgado, Julio; Ortega, Margarita; González, María-Teresa; Marugán, Isabel; de la Fuente, Ignacio; Recio, Isabel; Bosch, Francesc; Espinet, Blanca; González, Marcos; Hernández-Rivas, Jesús-María; Hernández, José-Ángel

    2016-06-01

    The prognosis of chronic lymphocytic leukemia (CLL) patients displaying trisomy 12 (+12) remains unclear. In this study, we analyzed the influence of the proportion of cells with +12, and other clinical and biologic factors, in time to first therapy (TTFT) and overall survival (OS), in 289 patients diagnosed with CLL carrying +12. Median OS was 129 months. One hundred seventy-four patients (60.2%) presented +12 in <60% of cells. TTFT and OS for this subgroup were longer than for the subgroup with +12 in ≥60% of cells, with a median TTFT of 49 months (CI95%, 39-58) vs 30 months (CI95%, 22-38) (P = 0.001); and a median OS of 159 months (CI95%, 119-182), vs 96 months (CI95%, 58-134) (P = 0.015). Other factors associated with a shorter TTFT were: Binet stage, B symptoms, lymphadenopathy, splenomegaly, high lymphocyte count, 11q-, high β2 microglobulin, and high LDH. In the multivariate analysis, clinical stage, +12 in ≥60% of cells, high lymphocyte count, B symptoms, and 11q- in addition, resulted of significance in predicting shorter TTFT. Significant variables for OS were: Binet stage, lymphadenopathy, splenomegaly, high LDH, high β2 microglobulin, 11q-, and CD38. In the multivariate analysis, only Binet stage, 11q-, and high β2microglobulin significantly predicted shorter OS. CLL with +12 entails a heterogeneous group with intermediate prognosis. However, a high proportion of cells carrying +12 separates a subgroup of patients with poor outcome. Copyright © 2015 John Wiley & Sons, Ltd.

  12. Reverse-engineering the genetic circuitry of a cancer cell with predicted intervention in chronic lymphocytic leukemia.

    PubMed

    Vallat, Laurent; Kemper, Corey A; Jung, Nicolas; Maumy-Bertrand, Myriam; Bertrand, Frédéric; Meyer, Nicolas; Pocheville, Arnaud; Fisher, John W; Gribben, John G; Bahram, Seiamak

    2013-01-08

    Cellular behavior is sustained by genetic programs that are progressively disrupted in pathological conditions--notably, cancer. High-throughput gene expression profiling has been used to infer statistical models describing these cellular programs, and development is now needed to guide orientated modulation of these systems. Here we develop a regression-based model to reverse-engineer a temporal genetic program, based on relevant patterns of gene expression after cell stimulation. This method integrates the temporal dimension of biological rewiring of genetic programs and enables the prediction of the effect of targeted gene disruption at the system level. We tested the performance accuracy of this model on synthetic data before reverse-engineering the response of primary cancer cells to a proliferative (protumorigenic) stimulation in a multistate leukemia biological model (i.e., chronic lymphocytic leukemia). To validate the ability of our method to predict the effects of gene modulation on the global program, we performed an intervention experiment on a targeted gene. Comparison of the predicted and observed gene expression changes demonstrates the possibility of predicting the effects of a perturbation in a gene regulatory network, a first step toward an orientated intervention in a cancer cell genetic program.

  13. Reverse-engineering the genetic circuitry of a cancer cell with predicted intervention in chronic lymphocytic leukemia

    PubMed Central

    Vallat, Laurent; Kemper, Corey A.; Jung, Nicolas; Maumy-Bertrand, Myriam; Bertrand, Frédéric; Meyer, Nicolas; Pocheville, Arnaud; Fisher, John W.; Gribben, John G.; Bahram, Seiamak

    2013-01-01

    Cellular behavior is sustained by genetic programs that are progressively disrupted in pathological conditions—notably, cancer. High-throughput gene expression profiling has been used to infer statistical models describing these cellular programs, and development is now needed to guide orientated modulation of these systems. Here we develop a regression-based model to reverse-engineer a temporal genetic program, based on relevant patterns of gene expression after cell stimulation. This method integrates the temporal dimension of biological rewiring of genetic programs and enables the prediction of the effect of targeted gene disruption at the system level. We tested the performance accuracy of this model on synthetic data before reverse-engineering the response of primary cancer cells to a proliferative (protumorigenic) stimulation in a multistate leukemia biological model (i.e., chronic lymphocytic leukemia). To validate the ability of our method to predict the effects of gene modulation on the global program, we performed an intervention experiment on a targeted gene. Comparison of the predicted and observed gene expression changes demonstrates the possibility of predicting the effects of a perturbation in a gene regulatory network, a first step toward an orientated intervention in a cancer cell genetic program. PMID:23267079

  14. Nurture versus nature: the microenvironment in chronic lymphocytic leukemia.

    PubMed

    Burger, Jan A

    2011-01-01

    Intrinsic factors such as genetic lesions, anti-apoptotic proteins, and aberrant signaling networks within leukemia cells have long been the main focus of chronic lymphocytic leukemia (CLL) research. However, over the past decade, it became increasingly clear that external signals from the leukemia microenvironment make pivotal contributions to disease progression in CLL and other B-cell malignancies. Consequently, increasing emphasis is now placed on exploring and targeting the CLL microenvironment. This review highlights critical cellular and molecular pathways of CLL-microenvironment cross-talk. In vitro and in vivo models for studying the CLL microenvironment are discussed, along with their use in searching for therapeutic targets and in drug testing. Clinically, CXCR4 antagonists and small-molecule antagonists of B cell receptor (BCR)-associated kinases (spleen tyrosine kinase [Syk], Bruton's tyrosine kinase [Btk], and PI3Kδ) are the most advanced drugs for targeting specific interactions between CLL cells and the miocroenvironment. Preclinical and first clinical evidence suggests that high-risk CLL patients can particularly benefit from these alternative agents. These findings indicate that interplay between leukemia-inherent and environmental factors, nature and nurture determines disease progression in CLL.

  15. Role of allogeneic transplantation in patients with chronic lymphocytic leukemia in the era of novel therapies: a review

    PubMed Central

    Nathan, Sunita

    2014-01-01

    Chronic lymphocytic leukemia (CLL) is the most common form of adult leukemia and is characterized by a highly variable clinical course. In the past decade, several prognostic risk factors have been identified facilitating the classification of CLL into various risk groups. Patients with poor risk disease, such as poor cytogenetics or relapsing after purine-based analogues, had limited therapeutic options, with allogeneic hematopoietic cell transplantation (allo-SCT) the only known therapy with curative potential. More recently, the introduction of novel agents inhibiting the B-cell receptor pathway, and the early success with chimeric antigen receptor T cells offers an effective and relatively safe option for this poor prognostic group which holds promise in the future. Alternatively, the use of reduced intensity conditioning regimens in the allo-SCT setting has led to a significant decrease in nonrelapse mortality to 16–23%, making it an attractive therapeutic option. No recent guidelines have been developed since these novel therapies became available regarding the optimal time to allo-SCT in this patient population. The advent of these novel and highly active therapeutic agents, therefore, warrants a reappraisal of the role and timing of allo-SCT in patients with CLL. In this article, we summarize the literature regarding the novel therapeutic agents available today as well as focus on the efficacy and safety of allo-SCT. PMID:25324955

  16. How Is Chronic Lymphocytic Leukemia Diagnosed?

    MedlinePlus

    ... bone marrow has a certain number of blood-forming cells and fat cells. Marrow with too many blood-forming cells is said to be hypercellular . This is ... immunoglobulin heavy chain variable region (IGHV or IgV H ) has changed (mutated) can help your doctor know ...

  17. Targeting chronic lymphocytic leukemia cells in the tumor microenviroment: A review of the in vitro and clinical trials to date

    PubMed Central

    Crassini, Kyle; Mulligan, Stephen P; Best, O Giles

    2015-01-01

    Chronic lymphocytic leukemia (CLL) is the most common leukemia in the western world. Despite significant advances in therapy over the last decade CLL remains incurable. Current front-line therapy often consists of chemoimmunotherapy-based regimens, most commonly the fludarabine, cyclophosphamide plus rituximab combination, but rates of relapse and refractory disease are high among these patients. Several key signaling pathways are now known to mediate the survival and proliferation of CLL cells in vivo, the most notable of which are the pathways mediated by the B-cell receptor (BCR) and cytokine receptors. A better understanding of the pathogenesis of the disease, the underlying biology of the CLL-cell and the roles of the tumour microenvironment has provided the rationale for trials of a range of novel, more targeted therapeutic agents. In particular, clinical trials of ibrutinib and idelalisib, which target the Brutons tyrosine kinase and the delta isoform of phosphoinositol-3 kinase components of the BCR signaling pathway respectively, have shown extremely promising results. Here we review the current literature on the key signaling pathways and interactions of CLL cells that mediate the survival and proliferation of the leukemic cells. For each we describe the results of the recent clinical trials and in vitro studies of novel therapeutic agents. PMID:26301230

  18. Laboratory Treated T Cells in Treating Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia, Non-Hodgkin Lymphoma, or Acute Lymphoblastic Leukemia

    ClinicalTrials.gov

    2016-12-08

    CD19-Positive Neoplastic Cells Present; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Chronic Lymphocytic Leukemia; Recurrent Diffuse Large B-Cell Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Non-Hodgkin Lymphoma; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Diffuse Large B-Cell Lymphoma; Refractory Mantle Cell Lymphoma; Refractory Non-Hodgkin Lymphoma; Refractory Small Lymphocytic Lymphoma

  19. Genetic lesions associated with chronic lymphocytic leukemia chemo-refractoriness

    PubMed Central

    Messina, Monica; Del Giudice, Ilaria; Khiabanian, Hossein; Rossi, Davide; Chiaretti, Sabina; Rasi, Silvia; Spina, Valeria; Holmes, Antony B.; Marinelli, Marilisa; Fabbri, Giulia; Piciocchi, Alfonso; Mauro, Francesca R.; Guarini, Anna; Gaidano, Gianluca; Dalla-Favera, Riccardo; Pasqualucci, Laura; Rabadan, Raul; Foà, Robin

    2014-01-01

    Fludarabine refractoriness (FR) represents an unsolved clinical problem of chronic lymphocytic leukemia (CLL) management. Although next-generation sequencing studies have led to the identification of a number of genes frequently mutated in FR-CLL, a comprehensive evaluation of the FR-CLL genome has not been reported. Toward this end, we studied 10 FR-CLLs by combining whole-exome sequencing and copy number aberration (CNA) analysis, which showed an average of 16.3 somatic mutations and 4 CNAs per sample. Screening of recurrently mutated genes in 48 additional FR-CLLs revealed that ∼70% of FR-CLLs carry ≥1 mutation in genes previously associated with CLL clinical course, including TP53 (27.5%), NOTCH1 (24.1%), SF3B1 (18.9%), and BIRC3 (15.5%). In addition, this analysis showed that 10.3% of FR-CLL cases display mutations of the FAT1 gene, which encodes for a cadherin-like protein that negatively regulates Wnt signaling, consistent with a tumor suppressor role. The frequency of FAT1-mutated cases was significantly higher in FR-CLL than in unselected CLLs at diagnosis (10.3% vs 1.1%, P = .004), suggesting a role in the development of a high-risk phenotype. These findings have general implications for the mechanisms leading to FR and point to Wnt signaling as a potential therapeutic target in FR-CLL. PMID:24550227

  20. The splicing modulator sudemycin induces a specific antitumor response and cooperates with ibrutinib in chronic lymphocytic leukemia

    PubMed Central

    Rosich, Laia; Montraveta, Arnau; Roldán, Jocabed; Rodríguez, Vanina; Villamor, Neus; Aymerich, Marta; Lagisetti, Chandraiah; Webb, Thomas R.; López-Otín, Carlos; Campo, Elias; Colomer, Dolors

    2015-01-01

    Mutations or deregulated expression of the components of the spliceosome can influence the splicing pattern of several genes and contribute to the development of tumors. In this context, we report that the spliceosome modulator sudemycin induces selective cytotoxicity in primary chronic lymphocytic leukemia (CLL) cells when compared with healthy lymphocytes and tumor cells from other B-lymphoid malignancies, with a slight bias for CLL cases with mutations in spliceosome-RNA processing machinery. Consistently, sudemycin exhibits considerable antitumor activity in NOD/SCID/IL2Rγ−/− (NSG) mice engrafted with primary cells from CLL patients. The antileukemic effect of sudemycin involves the splicing modulation of several target genes important for tumor survival, both in SF3B1-mutated and -unmutated cases. Thus, the apoptosis induced by this compound is related to the alternative splicing switch of MCL1 toward its proapoptotic isoform. Sudemycin also functionally disturbs NF-κB pathway in parallel with the induction of a spliced RELA variant that loses its DNA binding domain. Importantly, we show an enhanced antitumor effect of sudemycin in combination with ibrutinib that might be related to the modulation of the alternative splicing of the inhibitor of Btk (IBTK). In conclusion, we provide first evidence that the spliceosome is a relevant therapeutic target in CLL, supporting the use of splicing modulators alone or in combination with ibrutinib as a promising approach for the treatment of CLL patients. PMID:26068951

  1. OSU-T315: a novel targeted therapeutic that antagonizes AKT membrane localization and activation of chronic lymphocytic leukemia cells

    PubMed Central

    Liu, Ta-Ming; Ling, Yonghua; Woyach, Jennifer A.; Beckwith, Kyle; Yeh, Yuh-Ying; Hertlein, Erin; Zhang, Xiaoli; Lehman, Amy; Awan, Farrukh; Jones, Jeffrey A.; Andritsos, Leslie A.; Maddocks, Kami; MacMurray, Jessica; Salunke, Santosh B.; Chen, Ching-Shih; Phelps, Mitch A.; Byrd, John C.

    2015-01-01

    Aberrant regulation of endogenous survival pathways plays a major role in progression of chronic lymphocytic leukemia (CLL). Signaling via conjugation of surface receptors within the tumor environmental niche activates survival and proliferation pathways in CLL. Of these, the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway appears to be pivotal to support CLL pathogenesis, and pharmacologic inhibitors targeting this axis have shown clinical activity. Here we investigate OSU-T315, a compound that disrupts the PI3K/AKT pathway in a novel manner. Dose-dependent selective cytotoxicity by OSU-T315 is noted in both CLL-derived cell lines and primary CLL cells relative to normal lymphocytes. In contrast to the highly successful Bruton's tyrosine kinase and PI3K inhibitors that inhibit B-cell receptor (BCR) signaling pathway at proximal kinases, OSU-T315 directly abrogates AKT activation by preventing translocation of AKT into lipid rafts without altering the activation of receptor-associated kinases. Through this mechanism, the agent triggers caspase-dependent apoptosis in CLL by suppressing BCR, CD49d, CD40, and Toll-like receptor 9-mediated AKT activation in an integrin-linked kinase-independent manner. In vivo, OSU-T315 attains pharmacologically active drug levels and significantly prolongs survival in the TCL1 mouse model. Together, our findings indicate a novel mechanism of action of OSU-T315 with potential therapeutic application in CLL. PMID:25293770

  2. OSU-T315: a novel targeted therapeutic that antagonizes AKT membrane localization and activation of chronic lymphocytic leukemia cells.

    PubMed

    Liu, Ta-Ming; Ling, Yonghua; Woyach, Jennifer A; Beckwith, Kyle; Yeh, Yuh-Ying; Hertlein, Erin; Zhang, Xiaoli; Lehman, Amy; Awan, Farrukh; Jones, Jeffrey A; Andritsos, Leslie A; Maddocks, Kami; MacMurray, Jessica; Salunke, Santosh B; Chen, Ching-Shih; Phelps, Mitch A; Byrd, John C; Johnson, Amy J

    2015-01-08

    Aberrant regulation of endogenous survival pathways plays a major role in progression of chronic lymphocytic leukemia (CLL). Signaling via conjugation of surface receptors within the tumor environmental niche activates survival and proliferation pathways in CLL. Of these, the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway appears to be pivotal to support CLL pathogenesis, and pharmacologic inhibitors targeting this axis have shown clinical activity. Here we investigate OSU-T315, a compound that disrupts the PI3K/AKT pathway in a novel manner. Dose-dependent selective cytotoxicity by OSU-T315 is noted in both CLL-derived cell lines and primary CLL cells relative to normal lymphocytes. In contrast to the highly successful Bruton's tyrosine kinase and PI3K inhibitors that inhibit B-cell receptor (BCR) signaling pathway at proximal kinases, OSU-T315 directly abrogates AKT activation by preventing translocation of AKT into lipid rafts without altering the activation of receptor-associated kinases. Through this mechanism, the agent triggers caspase-dependent apoptosis in CLL by suppressing BCR, CD49d, CD40, and Toll-like receptor 9-mediated AKT activation in an integrin-linked kinase-independent manner. In vivo, OSU-T315 attains pharmacologically active drug levels and significantly prolongs survival in the TCL1 mouse model. Together, our findings indicate a novel mechanism of action of OSU-T315 with potential therapeutic application in CLL.

  3. Chronic lymphocytic leukemia: treatment options for patients with refractory disease.

    PubMed

    Motta, Marina; Wierda, William G; Ferrajoli, Alessandra

    2009-09-01

    Patients with purine analogue-refractory chronic lymphocytic leukemia (CLL) have short survival and limited treatment options. Defining the best salvage strategies for this population is challenging, because limited data are available from clinical trials, and because studies have enrolled mixed populations (patients with recurrent and refractory disease or patients with refractory disease and Richter transformation). Moreover, patients with refractory CLL have a high incidence of unfavorable molecular and clinical features, such as high-risk genomic profiles, unmutated immunoglobulin heavy-chain genes, expression of zeta-chain-associated protein kinase 70, and bulky lymphadenopathies. These patients are also severely immunosuppressed because of the underlying disease and the treatments received, and experience a high rate of infectious complications that pose an additional difficulty in selecting treatment. Despite these challenges, in parallel with better characterizations of the biologic features of refractory CLL, the number of available treatment modalities for this population has increased. Several chemoimmunotherapy combinations have been developed, and novel agents with a different mechanism of action are being investigated in clinical trials. Furthermore, allogeneic stem cell transplantation with nonmyeloablative conditioning regimens is a therapeutic strategy that is increasingly offered to patients with refractory CLL.

  4. Prevalence, characteristics and management of occult hepatitis B virus infection in patients with chronic lymphocytic leukemia: a single center experience.

    PubMed

    Laurenti, Luca; Autore, Francesco; Innocenti, Idanna; Vannata, Barbara; Piccirillo, Nicola; Sorà, Federica; Speziale, Domenico; Pompili, Maurizio; Efremov, Dimitar; Sica, Simona

    2015-01-01

    Several reports have emphasized the risk of hepatitis B virus (HBV) reactivation in patients with lymphoproliferative disorders undergoing cytotoxic treatment. To determine the prevalence of occult B infection (OBI) in a population with chronic lymphocytic leukemia (CLL) and management with universal prophylaxis (UP) in all patients undergoing chemoimmunotherapy or targeted prophylaxis (TP) in patients experiencing seroreversion during therapy, we analyzed 397 patients with CLL from our database. The prevalence of OBI in our patients with CLL was 8.6% (34 patients). When comparing patients with OBI/CLL with those with CLL, we did not find any statistical difference among clinical-biological parameters and time dependent endpoints except for a lower peripheral blood lymphocyte count in the OBI/CLL group (p = 0.036). From 2000 to 2010 careful follow-up and TP were adopted; two out of 10 patients (20%) showed seroreversion. From June 2010 we adopted UP during and 12 months after immunosuppressive treatment in all patients with CLL with OBI; no evidence of seroreversion was detected.

  5. The genomic landscape of chronic lymphocytic leukemia: clinical implications

    PubMed Central

    2013-01-01

    A precise understanding of the genomic and epigenomic features of chronic lymphocytic leukemia (CLL) may benefit the study of the disease’s staging and treatment. While recent reports have shed some light on these aspects, several challenges need to be addressed before translating this research into clinical practice. Thus, even the best candidate driver genes display low mutational rates compared to other tumors. This means that a large percentage of cases do not display clear tumor-driving point mutations, or show candidate driving point mutations with no obvious biochemical relationship to the more frequently mutated genes. This genomic landscape probably reflects either an unknown underlying biochemical mechanism playing a key role in CLL or multiple biochemical pathways independently driving the development of this tumor. The elucidation of either scenario will have important consequences on the clinical management of CLL. Herein, we review the recent advances in the definition of the genomic landscape of CLL and the ongoing research to characterize the underlying biochemical events that drive this disease. PMID:23656622

  6. Outcomes of patients with chronic lymphocytic leukemia after discontinuing ibrutinib.

    PubMed

    Jain, Preetesh; Keating, Michael; Wierda, William; Estrov, Zeev; Ferrajoli, Alessandra; Jain, Nitin; George, Binsah; James, Danelle; Kantarjian, Hagop; Burger, Jan; O'Brien, Susan

    2015-03-26

    Ibrutinib is a Bruton tyrosine kinase inhibitor approved for the treatment of patients with relapsed refractory chronic lymphocytic leukemia (RR-CLL). We describe the characteristics, causes of discontinuation, and outcomes in patients who discontinued treatment with ibrutinib. One hundred twenty-seven patients were enrolled in various clinical trials of ibrutinib, with or without rituximab, at our center. Thirty-three (26%) patients have discontinued ibrutinib to date. The majority of those patients had high-risk features: 94% with unmutated immunoglobulin heavy chain variable gene rearrangement, 58% with del(17p) by fluorescence in situ hybridization, and 54% with a complex karyotype. Causes of discontinuation were disease transformation (7), progressive CLL (7), stem cell transplantation (3), adverse events (11), serious adverse events/deaths (3), and miscellaneous reasons (2). Twenty five patients (76%) died after discontinuing ibrutinib; the median overall survival was 3.1 months after discontinuation. Most patients with RR-CLL who discontinued ibrutinib early were difficult to treat and had poor outcomes.

  7. Outcomes of patients with chronic lymphocytic leukemia after discontinuing ibrutinib

    PubMed Central

    Jain, Preetesh; Keating, Michael; Wierda, William; Estrov, Zeev; Ferrajoli, Alessandra; Jain, Nitin; George, Binsah; James, Danelle; Kantarjian, Hagop; Burger, Jan

    2015-01-01

    Ibrutinib is a Bruton tyrosine kinase inhibitor approved for the treatment of patients with relapsed refractory chronic lymphocytic leukemia (RR-CLL). We describe the characteristics, causes of discontinuation, and outcomes in patients who discontinued treatment with ibrutinib. One hundred twenty-seven patients were enrolled in various clinical trials of ibrutinib, with or without rituximab, at our center. Thirty-three (26%) patients have discontinued ibrutinib to date. The majority of those patients had high-risk features: 94% with unmutated immunoglobulin heavy chain variable gene rearrangement, 58% with del(17p) by fluorescence in situ hybridization, and 54% with a complex karyotype. Causes of discontinuation were disease transformation (7), progressive CLL (7), stem cell transplantation (3), adverse events (11), serious adverse events/deaths (3), and miscellaneous reasons (2). Twenty five patients (76%) died after discontinuing ibrutinib; the median overall survival was 3.1 months after discontinuation. Most patients with RR-CLL who discontinued ibrutinib early were difficult to treat and had poor outcomes. PMID:25573991

  8. [Chronic lymphocytic leukemia. Treatment and genetic risk profile].

    PubMed

    Stilgenbauer, S; Hallek, M

    2013-02-01

    Chronic lymphocytic leukemia (CLL) is characterized by a highly variable clinical course. Among the biological features underlying this heterogeneity, genetic lesions and the mutational status of the immunoglobulin heavy chain variable genes (IGHV) are of importance. Therapeutic options in CLL have been considerably expanded during recent years. The combination of fludarabine, cyclophosphamide and rituximab (FCR) has become gold standard in the first-line treatment of physically fit patients. Bendamustine plus rituximab (BR) is currently being compared to FCR in studies and chlorambucil is still of relevance for elderly patients with comorbidities. Alemtuzumab is an alternative for high-risk patients (refractory CLL, 17p deletion, TP53 mutation). Allogeneic stem cell transplantation (allo-SCT) offers the only chance of cure but not without substantial mortality. Innovative approaches focus on individualized, targeted therapies. A number of novel agents are in clinical trials and show marked efficacy combined with good tolerability. This review provides an overview of the current therapeutic options and of promising novel approaches.

  9. Telomere status in chronic lymphocytic leukemia with TP53 disruption.

    PubMed

    Guièze, Romain; Pages, Mélanie; Véronèse, Lauren; Combes, Patricia; Lemal, Richard; Gay-Bellile, Mathilde; Chauvet, Martine; Callanan, Mary; Kwiatkowski, Fabrice; Pereira, Bruno; Vago, Philippe; Bay, Jacques-Olivier; Tournilhac, Olivier; Tchirkov, Andreï

    2016-08-30

    In chronic lymphocytic leukemia (CLL), telomere dysfunction is associated with poor outcomes. TP53 is involved in cellular responses to dysfunctional telomeres, and its inactivation is the strongest adverse prognostic factor for CLL. Given the biological relationship between TP53 and telomeres, and their prognostic value, it is important to improve our understanding of the impact of TP53 alterations on telomeres. We performed a comprehensive study of the deletions and mutations of the TP53 gene and telomere parameters, including hTERT and the shelterin complex, in 115 CLL patients. We found that any type of TP53 alteration was associated with very short telomeres and high hTERT expression, independently of other biological CLL features. Patients with disrupted TP53 showed telomere deletions and chromosomal end-to-end fusions in cells with complex karyotypes. TP53 disruption was characterized by downregulation of shelterin genes. Interestingly, low expression of POT1, TPP1 and TIN2 was also found in some patients with wild-type TP53 and had an adverse impact on progression-free survival after standard genotoxic therapy. In conclusion, we have demonstrated that patients with disrupted TP53 have severe telomere dysfunction and high genomic instability. Thus, the telomeric profile could be tested as a biomarker in CLL patients treated with new therapeutic agents.

  10. Telomere status in chronic lymphocytic leukemia with TP53 disruption

    PubMed Central

    Guièze, Romain; Pages, Mélanie; Véronèse, Lauren; Combes, Patricia; Lemal, Richard; Gay-bellile, Mathilde; Chauvet, Martine; Callanan, Mary; Kwiatkowski, Fabrice; Pereira, Bruno; Vago, Philippe; Bay, Jacques-Olivier; Tournilhac, Olivier; Tchirkov, Andreï

    2016-01-01

    In chronic lymphocytic leukemia (CLL), telomere dysfunction is associated with poor outcomes. TP53 is involved in cellular responses to dysfunctional telomeres, and its inactivation is the strongest adverse prognostic factor for CLL. Given the biological relationship between TP53 and telomeres, and their prognostic value, it is important to improve our understanding of the impact of TP53 alterations on telomeres. We performed a comprehensive study of the deletions and mutations of the TP53 gene and telomere parameters, including hTERT and the shelterin complex, in 115 CLL patients. We found that any type of TP53 alteration was associated with very short telomeres and high hTERT expression, independently of other biological CLL features. Patients with disrupted TP53 showed telomere deletions and chromosomal end-to-end fusions in cells with complex karyotypes. TP53 disruption was characterized by downregulation of shelterin genes. Interestingly, low expression of POT1, TPP1 and TIN2 was also found in some patients with wild-type TP53 and had an adverse impact on progression-free survival after standard genotoxic therapy. In conclusion, we have demonstrated that patients with disrupted TP53 have severe telomere dysfunction and high genomic instability. Thus, the telomeric profile could be tested as a biomarker in CLL patients treated with new therapeutic agents. PMID:27486974

  11. New emerging therapies in the management of chronic lymphocytic leukemia

    PubMed Central

    Li, Xiao-Lin; Zhang, Ci-Xian

    2016-01-01

    Chronic lymphocytic leukemia (CLL) is considered incurable despite advances in management strategies. New drugs targeting cell pathways are currently being developed for the efficient management of CLL. Various strategies involving different targets have been developed, or are currently in the developing stage. A search was conducted in the electronic database PubMed, for pre-clinical as well as clinically controlled trials reporting various strategies against CLL currently under investigation. Novel strategies included use of antibodies, small cell inhibitors, such as spleen tyrosine kinase, LYN, cyclin-dependent kinase, and histone deacetylase inhibitors. The present review examined these new and emerging strategies for the efficient management of CLL. The review involves a discussion of novel strategies being examined worldwide against CLL, including anti-CD20, anti-CD37, anti-CD23, anti-CD40, SYK/LYN inhibitors, BTK inhibitors, p13k inhibitors and recent developments such as the use of cyclin-dependent kinase inhibitors/histone deacetylase inhibitors. PMID:27899962

  12. Lenalidomide in the Treatment of Chronic Lymphocytic Leukemia

    PubMed Central

    Cortelezzi, Agostino; Sciumè, Mariarita; Reda, Gianluigi

    2012-01-01

    The application of nucleoside analogue-based chemotherapy and immunotherapy with rituximab or alemtuzumab has increased both response rate and survival in patients with Chronic Lymphocytic Leukemia (CLL). However, because none of these therapies is curative, sequential therapeutic regimens are required. The majority of patients with relapsed or refractory CLL carry poor prognostic factors and show shorter overall survival and resistance to standard treatment. Numerous drugs have recently been approved for CLL therapy and many novel agents are under clinical investigation. The role of the tumor microenvironment and of immune dysfunction in CLL have allowed to enlarge the therapeutic armamentarium for CLL patients. This article will provide a comprehensive summary regarding mechanism of action, efficacy and safety of lenalidomide in CLL patients. Relevant clinical trials using lenalidomide alone or in combinations are discussed. Lenalidomide shows good activity also in relapsed/refractory or treatment-naive CLL patients. Definitive data from ongoing studies are needed to validate overall and progression-free survival. The toxicity profile might limit lenalidomide use because it can result in serious side effects, but largely controlled by gradual dose escalation. Further understanding of the exact mechanism of action in CLL will allow more efficacious use of lenalidomide alone or in combination regimens. PMID:22851972

  13. Study of splenic irradiation in chronic lymphocytic leukemia

    SciTech Connect

    Guiney, M.J.; Liew, K.H.; Quong, G.G.; Cooper, I.A.

    1989-01-01

    A retrospective study was performed to assess the effect of splenic irradiation (SI) on splenomegaly, splenic pain, anemia, and thrombocytopenia in patients with chronic lymphocytic leukemia. Twenty-two patients received 32 courses of SI. Of 31 courses of SI given for splenomegaly there were 19 responders (61%). Ten courses of SI were given for splenic pain resulting in partial relief of pain in 4 courses and complete relief in 4 courses. Only 4 of 16 courses given for anemia resulted in elevations of hemoglobin of 2 g/dL or more. Of the 14 courses of SI given for thrombocytopenia there were only 2 responses with platelet counts decreasing further in another 9 courses. The median duration of response was 14 months (range: 3-116 months). There was no dose-response relationship detected for SI in CLL. Treatment related toxicity was hematologic and secondary to leucopenia and thrombocytopenia. We recommend the use of small fraction sizes of 25 cGy to 50 cGy and close monitoring of hematological parameters. Splenic irradiation effectively palliates splenomegaly and reduces spleen size in CLL. It was of limited value in correcting anemia and thrombocytopenia in this patient population.

  14. Sepsis due to Erysipelothrix rhusiopathiae in a patient with chronic lymphocytic leukemia associated with bronchopneumonia due to Pseudomonas aeruginosa and Escherichia coli: A case report

    PubMed Central

    Bîrlutiu, Victoria

    2015-01-01

    INTRODUCTION: The present report describes a case of sepsis due to Erysipelothrix rhusiopathiae in a patient with B-cell chronic lymphocytic leukemia with no animal exposure, associated with concomitant bronchopneumonia due to Pseudomonas aeruginosa and Escherichia coli. CASE PRESENTATION: A 54-year-old Caucasian man presented to an emergency room with a three-day history of chest pain, fever, cough with purulent sputum, chills and dyspnea. The patient had associated erythematous papules on the chest and enlarged axillary, submandibular, pectoral and supraclavicular lymph nodes, which regressed under treatment with penicillin. The patient was found to have sepsis without endocarditis caused by E rhusiopathiae, associated with bronchopneumonia that was induced by a double Gram-negative infection. CONCLUSIONS: The underlying-B cell chronic lymphocytic leukemia may have favoured the development of bacteremia due to E rhusiopathiae, which occurred subsequent to glossitis in an immunocompromised host being treated with methylprednisolone and cladribine. PMID:26015797

  15. Beetroot-Carrot Juice Intake either Alone or in Combination with Antileukemic Drug 'Chlorambucil' As A Potential Treatment for Chronic Lymphocytic Leukemia.

    PubMed

    Shakib, Marie-Christine R; Gabrial, Shreef G N; Gabrial, Gamal N

    2015-06-15

    Chronic lymphocytic leukemia (CLL) is one of the chronic lymphoproliferative disorders (lymphoid neoplasms). It is characterized by a progressive accumulation of functionally incompetent lymphocytes. Patients with leukemia often seek unconventional treatments not prescribed by hematologist in order to improve their cancer treatment outcome or to manage symptoms. In the present report, a 76-year-old patient was diagnosed with B-cell chronic lymphocytic leukemia (B-CLL). Beetroot-carrot juice is used as a complementary and or/alternative therapy used in conjunction with conventional leukemic treatment (chlorambucil) that has been a standard first-line chemotherapeutic agent for patients with CLL and known to have serious and undesirable side-effects. After one month and 15 days of administration of beetroot-carrot juice therapy, the patient had improved appetite, a sense of general well-being and increased vigor daily activities. Furthermore, beetroot-carrot juice was used as an adjuvant to chlorambucil resulted in a substantial reduction in leukocytes and lymphocytes count in peripheral blood and improvement in the relevant biochemical parameters. Beetroot-carrot juice can be used as an effective treatment for CLL alone or in combination with chlorambucil when taken orally with regular diet on daily basis.

  16. Beetroot-Carrot Juice Intake either Alone or in Combination with Antileukemic Drug ‘Chlorambucil’ As A Potential Treatment for Chronic Lymphocytic Leukemia

    PubMed Central

    Shakib, Marie-Christine R.; Gabrial, Shreef G. N.; Gabrial, Gamal N.

    2015-01-01

    Chronic lymphocytic leukemia (CLL) is one of the chronic lymphoproliferative disorders (lymphoid neoplasms). It is characterized by a progressive accumulation of functionally incompetent lymphocytes. Patients with leukemia often seek unconventional treatments not prescribed by hematologist in order to improve their cancer treatment outcome or to manage symptoms. In the present report, a 76-year-old patient was diagnosed with B-cell chronic lymphocytic leukemia (B-CLL). Beetroot-carrot juice is used as a complementary and or/alternative therapy used in conjunction with conventional leukemic treatment (chlorambucil) that has been a standard first-line chemotherapeutic agent for patients with CLL and known to have serious and undesirable side-effects. After one month and 15 days of administration of beetroot-carrot juice therapy, the patient had improved appetite, a sense of general well-being and increased vigor daily activities. Furthermore, beetroot-carrot juice was used as an adjuvant to chlorambucil resulted in a substantial reduction in leukocytes and lymphocytes count in peripheral blood and improvement in the relevant biochemical parameters. Beetroot-carrot juice can be used as an effective treatment for CLL alone or in combination with chlorambucil when taken orally with regular diet on daily basis. PMID:27275246

  17. [Successful treatment for cryptococcal meningoencephalitis complicated by cerebral salt-wasting syndrome in a patient with chronic lymphocytic leukemia: A clinical case].

    PubMed

    Potapenko, V G; Konovalenko, I B; Oksema, E V; Filippova, L N; Dulaeva, E N; Derevyannykh, N A; Krasnoruzhsky, A I; Klimovich, A V; Klimko, N N; Medvedeva, N V

    2015-01-01

    Cryptococcus neoformans is a common agent of fungal meningoencephalitis in immunocompromised patients. Cerebral salt-wasting syndrome is one of the rare causes of severe hyponatremia in patients with CNS diseases. The paper describes the first clinical case of a patient, whose onset of chronic lymphocytic leukemia was complicated by cryptococcal meningoencephalitis presenting with mental disorders and severe electrolytic imbalance. Antifungal treatment with amphotericin B and fluconazole could alleviate an infectious process and metabolic disturbances.

  18. Selective toxicity of persian gulf sea cucumber holothuria parva on human chronic lymphocytic leukemia b lymphocytes by direct mitochondrial targeting.

    PubMed

    Salimi, Ahmad; Motallebi, Abbasali; Ayatollahi, Maryam; Seydi, Enayatollah; Mohseni, Ali Reza; Nazemi, Melika; Pourahmad, Jalal

    2017-04-01

    Natural products isolated from marine environment are well known for their pharmacodynamic potential in diversity of disease treatments such as cancer or inflammatory conditions. Sea cucumbers are one of the marine animals of the phylum Echinoderm. Many studies have shown that the sea cucumber contains antioxidants and anti-cancer compounds. Chronic lymphocytic leukemia (CLL) is a disease characterized by the relentless accumulation of CD5(+) B lymphocytes. CLL is the most common leukemia in adults, about 25-30% of all leukemias. In this study B lymphocytes and their mitochondria (cancerous and non-cancerous) were obtained from peripheral blood of human subjects and B lymphocyte cytotoxicity assay, and caspase 3 activation along with mitochondrial upstream events of apoptosis signaling including reactive oxygen species (ROS) production, collapse of mitochondrial membrane potential (MMP) and mitochondrial swelling were determined following the addition of Holothuria parva extract to both cancerous and non-cancerous B lymphocytes and their mitochondria. Our in vitro finding showed that mitochondrial ROS formation, MMP collapse, and mitochondrial swelling and cytochrome c release were significantly (P < 0.05) increased after addition of different concentrations of H. parva only in cancerous BUT NOT normal non-cancerous mitochondria. Consistently, different concentrations of H. parva significantly (P < 0.05) increased cytotoxicity and caspase 3 activation only in cancerous BUT NOT normal non-cancerous B lymphocytes. These results showed that H. parva methanolic extract has a selective mitochondria mediated apoptotic effect on chronic lymphocytic leukemia B lymphocytes hence may be promising in the future anticancer drug development for treatment of CLL. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1158-1169, 2017.

  19. Acalabrutinib (ACP-196) in Relapsed Chronic Lymphocytic Leukemia

    PubMed Central

    Byrd, John C; Harrington, Bonnie; O’Brien, Susan; Jones, Jeffrey A; Schuh, Anna; Devereux, Steve; Chaves, Jorge; Wierda, William G; Awan, Farrukh T; Brown, Jennifer R; Hillmen, Peter; Stephens, Deborah M; Ghia, Paolo; Barrientos, Jacqueline C; Pagel, John M; Woyach, Jennifer; Johnson, Dave; Huang, Jane; Wang, Xiaolin; Lannutti, Brian J; Covey, Todd; Fardis, Maria; McGreivy, Jesse; Hamdy, Ahmed; Rothbaum, Wayne; Izumi, Raquel; Diacovo, Thomas G; Johnson, Amy J; Furman, Richard R

    2016-01-01

    Background Irreversible inhibition of Bruton tyrosine kinase (Btk) by ibrutinib represents a significant therapeutic advance for chronic lymphocytic leukemia (CLL). However, ibrutinib also irreversibly inhibits alternative kinase targets, which potentially compromise its therapeutic index. Acalabrutinib (ACP-196) is a more selective irreversible Btk inhibitor specifically designed to improve upon the safety and efficacy of first generation Btk inhibitors. Methods Sixty-one patients with relapsed CLL were treated in a phase 1–2 multicenter study designed to assess the safety, efficacy, pharmacokinetics and pharmacodynamics of oral acalabrutinib. Patients were continuously treated with acalabrutinib 100 to 400 mg once daily in the dose-escalation portion of the study, and 100 mg twice daily in the expansion portion. Results Patient demographics include a median age of 62 years; median of 3 prior therapies; 31% del(17)(p13.1) and 75% unmutated immunoglobulin heavy chain variable genes. No dose-limiting toxicities occurred. The most common adverse events observed were headache (43%), diarrhea (39%) and increased weight (26%). Most adverse events were Grade 1–2. At a median follow-up of 14.3 months, the best overall response rate was 95%, including 85% partial response, 10% partial response with lymphocytosis and 5% stable disease. In patients with del(17)(p13.1), the best overall response was 100%. No cases of Richter’s transformation and only 1 CLL progression have occurred. Conclusions Acalabrutinib is a highly selective Btk inhibitor that provides effective and well tolerated treatment for patients with relapsed CLL, including those with del(17)(p13.1). PMID:26641137

  20. A combination of an anti-SLAMF6 antibody and ibrutinib efficiently abrogates expansion of chronic lymphocytic leukemia cells

    PubMed Central

    Yigit, Burcu; Halibozek, Peter J.; Chen, Shih-Shih; O'Keeffe, Michael S.; Arnason, Jon; Avigan, David; Gattei, Valter; Bhan, Atul; Cen, Osman; Longnecker, Richard; Chiorazzi, Nicholas; Wang, Ninghai; Engel, Pablo; Terhorst, Cox

    2016-01-01

    The signaling lymphocyte activation molecule family [SLAMF] of cell surface receptors partakes in both the development of several immunocyte lineages and innate and adaptive immune responses in humans and mice. For instance, the homophilic molecule SLAMF6 (CD352) is in part involved in natural killer T cell development, but also modulates T follicular helper cell and germinal B cell interactions. Here we report that upon transplantation of a well-defined aggressive murine B220+CD5+ Chronic Lymphocytic Leukemia (CLL) cell clone, TCL1-192, into SCID mice one injection of a monoclonal antibody directed against SLAMF6 (αSlamf6) abrogates tumor progression in the spleen, bone marrow and blood. Similarly, progression of a murine B cell lymphoma, LMP2A/λMyc, was also eliminated by αSlamf6. But, surprisingly, αSLAMF6 neither eliminated TCL1-192 nor LMP2A/λMyc cells, which resided in the peritoneal cavity or omentum. This appeared to be dependent upon the tumor environment, which affected the frequency of sub-populations of the TCL1-192 clone or the inability of peritoneal macrophages to induce Antibody Dependent Cellular Cytotoxicity (ADCC). However, co-administering αSlamf6 with the Bruton tyrosine kinase (Btk) inhibitor, ibrutinib, synergized to efficiently eliminate the tumor cells in the spleen, bone marrow, liver and the peritoneal cavity. Because an anti-human SLAMF6 mAb efficiently killed human CLL cells in vitro and in vivo, we propose that a combination of αSlamf6 with ibrutinib should be considered as a novel therapeutic approach for CLL and other B cell tumors. PMID:27029059

  1. p53 mutations in human lymphoid malignancies: Association with Burkitt lymphoma and chronic lymphocytic leukemia

    SciTech Connect

    Gaidano, G.; Ballerini, P.; Gong, J.Z.; Inghirami, G.; Knowles, D.M.; Dalla-Favera, R. ); Neri, A, Centro Malattie del Sangue G. Marcora, Milan ); Newcomb, E.W. ); Magrath, I.T. )

    1991-06-15

    The authors have investigated the frequency of p53 mutations in B- and T-cell human lymphoid malignancies, including acute lymphoblastic leukemia, the major subtypes of non-Hodgkin lymphoma, and chronic lymphocytic leukemia. p53 exons 5-9 were studied by using genomic DNA from 197 primary tumors and 27 cell lines by single-strand conformation polymorphism analysis and by direst sequencing of PCR-amplified fragments. Mutations were found associated with (i) Burkitt lymphoma (9/27 biopsoes; 17/27 cell lines) and its leukemic counterpart L{sub 3}-type B-cell acute lymphoblastic leukemia (5/9), both of which also carry activated c-myc oncogenes, and (ii) B-cell chronic lymphocytic leukemia (6/40) and, in particular, its stage of progression known as Richter's transformation (3/7). Mutations were not found at any significant frequency in other types of non-Hodgkin lymphoma or acute lymphoblastic leukemia. In many cases, only the mutated allele was detectable, implying loss of the normal allele. These results suggest that (1) significant differences in the frequency of p53 mutations are present among subtypes of neoplasms derived from the same tissue; (2) p53 may play a role in tumor progression in B-cell chronic lymphocytic leukemia; (3) the presence of both p53 loss/inactivation and c-myc oncogene activation may be important in the pathogenesis of Burkitt lymphoma and its leukemia form L{sub 3}-type B-cell acute lymphoblastic leukemia.

  2. Idelalisib and Rituximab in Relapsed Chronic Lymphocytic Leukemia

    PubMed Central

    Cheson, Bruce D.; Pagel, John M.; Hillmen, Peter; Barrientos, Jacqueline C.; Zelenetz, Andrew D.; Kipps, Thomas J.; Flinn, Ian; Ghia, Paolo; Eradat, Herbert; Ervin, Thomas; Lamanna, Nicole; Coiffier, Bertrand; Pettitt, Andrew R.; Ma, Shuo; Stilgenbauer, Stephan; Cramer, Paula; Aiello, Maria; Johnson, Dave M.; Miller, Langdon L.; Li, Daniel; Jahn, Thomas M.; Dansey, Roger D.; Hallek, Michael; O’Brien, Susan M.

    2014-01-01

    BACKGROUND Patients with relapsed chronic lymphocytic leukemia (CLL) who have clinically significant coexisting medical conditions are less able to undergo standard chemo-therapy. Effective therapies with acceptable side-effect profiles are needed for this patient population. METHODS In this multicenter, randomized, double-blind, placebo-controlled, phase 3 study, we assessed the efficacy and safety of idelalisib, an oral inhibitor of the delta iso-form of phosphatidylinositol 3-kinase, in combination with rituximab versus rituximab plus placebo. We randomly assigned 220 patients with decreased renal function, previous therapy-induced myelosuppression, or major coexisting illnesses to receive rituximab and either idelalisib (at a dose of 150 mg) or placebo twice daily. The primary end point was progression-free survival. At the first prespecified interim analysis, the study was stopped early on the recommendation of the data and safety monitoring board owing to overwhelming efficacy. RESULTS The median progression-free survival was 5.5 months in the placebo group and was not reached in the idelalisib group (hazard ratio for progression or death in the idelalisib group, 0.15; P<0.001). Patients receiving idelalisib versus those receiving placebo had improved rates of overall response (81% vs. 13%; odds ratio, 29.92; P<0.001) and overall survival at 12 months (92% vs. 80%; hazard ratio for death, 0.28; P = 0.02). Serious adverse events occurred in 40% of the patients receiving idelalisib and rituximab and in 35% of those receiving placebo and rituximab. CONCLUSIONS The combination of idelalisib and rituximab, as compared with placebo and rituximab, significantly improved progression-free survival, response rate, and overall survival among patients with relapsed CLL who were less able to undergo chemo-therapy. (Funded by Gilead; ClinicalTrials.gov number, NCT01539512.) PMID:24450857

  3. Characterization of a new chronic lymphocytic leukemia cell line for mechanistic in vitro and in vivo studies relevant to disease.

    PubMed

    Hertlein, Erin; Beckwith, Kyle A; Lozanski, Gerard; Chen, Timothy L; Towns, William H; Johnson, Amy J; Lehman, Amy; Ruppert, Amy S; Bolon, Brad; Andritsos, Leslie; Lozanski, Arletta; Rassenti, Laura; Zhao, Weiqiang; Jarvinen, Tiina M; Senter, Leigha; Croce, Carlo M; Symer, David E; de la Chapelle, Albert; Heerema, Nyla A; Byrd, John C

    2013-01-01

    Studies of chronic lymphocytic leukemia (CLL) have yielded substantial progress, however a lack of immortalized cell lines representative of the primary disease has hampered a full understanding of disease pathogenesis and development of new treatments. Here we describe a novel CLL cell line (OSU-CLL) generated by EBV transformation, which displays a similar cytogenetic and immunophenotype observed in the patient's CLL (CD5 positive with trisomy 12 and 19). A companion cell line was also generated from the same patient (OSU-NB). This cell line lacked typical CLL characteristics, and is likely derived from the patient's normal B cells. In vitro migration assays demonstrated that OSU-CLL exhibits migratory properties similar to primary CLL cells whereas OSU-NB has significantly reduced ability to migrate spontaneously or towards chemokine. Microarray analysis demonstrated distinct gene expression patterns in the two cell lines, including genes on chromosomes 12 and 19, which is consistent with the cytogenetic profile in this cell line. Finally, OSU-CLL was readily transplantable into NOG mice, producing uniform engraftment by three weeks with leukemic cells detectable in the peripheral blood spleen and bone marrow. These studies describe a new CLL cell line that extends currently available models to study gene function in this disease.

  4. Characterization of a New Chronic Lymphocytic Leukemia Cell Line for Mechanistic In Vitro and In Vivo Studies Relevant to Disease

    PubMed Central

    Hertlein, Erin; Beckwith, Kyle A.; Lozanski, Gerard; Chen, Timothy L.; Towns, William H.; Johnson, Amy J.; Lehman, Amy; Ruppert, Amy S.; Bolon, Brad; Andritsos, Leslie; Lozanski, Arletta; Rassenti, Laura; Zhao, Weiqiang; Jarvinen, Tiina M.; Senter, Leigha; Croce, Carlo M.; Symer, David E.; de la Chapelle, Albert; Heerema, Nyla A.; Byrd, John C.

    2013-01-01

    Studies of chronic lymphocytic leukemia (CLL) have yielded substantial progress, however a lack of immortalized cell lines representative of the primary disease has hampered a full understanding of disease pathogenesis and development of new treatments. Here we describe a novel CLL cell line (OSU-CLL) generated by EBV transformation, which displays a similar cytogenetic and immunophenotype observed in the patient’s CLL (CD5 positive with trisomy 12 and 19). A companion cell line was also generated from the same patient (OSU-NB). This cell line lacked typical CLL characteristics, and is likely derived from the patient’s normal B cells. In vitro migration assays demonstrated that OSU-CLL exhibits migratory properties similar to primary CLL cells whereas OSU-NB has significantly reduced ability to migrate spontaneously or towards chemokine. Microarray analysis demonstrated distinct gene expression patterns in the two cell lines, including genes on chromosomes 12 and 19, which is consistent with the cytogenetic profile in this cell line. Finally, OSU-CLL was readily transplantable into NOG mice, producing uniform engraftment by three weeks with leukemic cells detectable in the peripheral blood spleen and bone marrow. These studies describe a new CLL cell line that extends currently available models to study gene function in this disease. PMID:24130782

  5. A randomized phase II trial comparing chemoimmunotherapy with or without bevacizumab in previously untreated patients with chronic lymphocytic leukemia

    PubMed Central

    Kay, Neil E.; Strati, Paolo; LaPlant, Betsy R.; Leis, Jose F.; Nikcevich, Daniel; Call, Timothy G.; Pettinger, Adam M.; Lesnick, Connie E.; Hanson, Curtis A.; Shanafelt, Tait D.

    2016-01-01

    Bevacizumab is a monoclonal antibody targeting vascular endothelial growth factor (VEGF) with in vitro pro-apoptotic and antiangiogenic effects on chronic lymphocytic leukemia (CLL) cells. As monotherapy in patients with CLL, it has no clinical activity. Here we report the results of an open-label, randomized phase II trial comparing the combination of pentostatin, cyclophosphamide and rituximab (PCR) either without or with bevacizumab (PCR-B) in previously untreated CLL patients. A total of 65 evaluable patients were enrolled, 32 receiving PCR and 33 PCR-B. A higher rate of grade 3-4 cardiovascular toxicity was observed with PCR-B (33% vs. 3%, p < 0.003). Patients treated with PCR-B had a trend for a higher complete remission (CR) rate (54.5% vs 31.3%; p = 0.08), longer progression-free survival (PFS)(p = 0.06) and treatment-free survival (TFS)(p = 0.09). No differences in PFS and TFS by IGHV mutational status were observed with the addition of bevacizumab. A significant post-treatment increase in VEGF levels was observed in the PCR-B arm (29.77 to 57.05 pg/mL); in the PCR-B arm, lower baseline CCL-3 levels were significantly associated with achievement of CR (p = 0.01). In conclusion, the addition of bevacizumab to chemoimmunotherapy in CLL is generally well-tolerated and appears to prolong PFS and TFS. PMID:27861157

  6. An entity evolving into a community: defining the common ancestor and evolutionary trajectory of chronic lymphocytic leukemia stereotyped subset #4.

    PubMed

    Sutton, Lesley-Ann; Papadopoulos, Giorgos; Hadzidimitriou, Anastasia; Papadopoulos, Stavros; Kostareli, Efterpi; Rosenquist, Richard; Tzovaras, Dimitrios; Stamatopoulos, Kostas

    2015-04-02

    Patients with chronic lymphocytic leukemia (CLL) assigned to stereotyped subset #4 express highly homologous B-cell receptor immunoglobulin (BcR IG) sequences with intense intraclonal diversification (ID) in the context of ongoing somatic hypermutation (SHM). Their remarkable biological and clinical similarities strongly support derivation from a common ancestor. We here revisited ID in subset #4 CLL to reconstruct their evolutionary history as a community of related clones. To this end, using specialized bioinformatics tools we assessed both IGHV-IGHD-IGHJ rearrangements (n = 511) and IGKV-IGKJ rearrangements (n = 397) derived from eight subset #4 cases. Due to high sequence relatedness, a number of subclonal clusters from different cases lay very close to one another, forming a core from which clusters exhibiting greater variation stemmed. Minor subclones from individual cases were mutated to such an extent that they now resembled the sequences of another patient. Viewing the entire subset #4 data set as a single entity branching through diversification enabled inference of a common sequence representing the putative ancestral BcR IG expressed by their still elusive common progenitor. These results have implications for improved understanding of the ontogeny of CLL subset #4, as well as the design of studies concerning the antigenic specificity of the clonotypic BcR IGs.

  7. Severe viral hepatitis in a patient with chronic lymphocytic leukemia (CLL) complicated with autoimmune hemolytic anemia (AIHA), treated with steroids.

    PubMed

    Orvain, Corentin; Ducancelle, Alexandra; Eymerit-Morin, Caroline; Rousselet, Marie-Christine; Oberti, Frederic; Hunault-Berger, Mathilde; Tanguy-Schmidt, Aline

    2015-01-01

    Infectious complications are a major cause of morbidity and mortality in patients with chronic lymphocytic leukemia (CLL) due to impaired immunity secondary to the disease itself and to the immunosuppressive therapies administered to these patients. We report a 78-year-old woman with CLL who was treated with steroids for autoimmune hemolytic anemia (AIHA). A few weeks later, she was admitted for severe acute hepatitis with disseminated intravascular coagulation (DIC). Despite the symptomatic treatment of DIC, standard reanimation and probabilistic antibiotics, the patient died within 24h with severe hepatic failure. Autopsy was in favor of a disseminated viral infection with esophageal, hepatic and pulmonary cytopathologic lesions with acidophilic intranuclear inclusions suggestive of herpes virus, even though HSV 1 and 2, CMV and HHV6 PCRs were negative. This case of severe viral hepatitis with esophagitis occurring three weeks after the introduction of high-dose steroid treatment for AIHA in a CLL patient calls for anti-herpetic prophylaxis in such patients, immunodepressed by their diseases and the treatment they receive.

  8. NOTCH1 mutations identify a genetic subgroup of chronic lymphocytic leukemia patients with high risk of transformation and poor outcome.

    PubMed

    Villamor, N; Conde, L; Martínez-Trillos, A; Cazorla, M; Navarro, A; Beà, S; López, C; Colomer, D; Pinyol, M; Aymerich, M; Rozman, M; Abrisqueta, P; Baumann, T; Delgado, J; Giné, E; González-Díaz, M; Hernández, J M; Colado, E; Payer, A R; Rayon, C; Navarro, B; José Terol, M; Bosch, F; Quesada, V; Puente, X S; López-Otín, C; Jares, P; Pereira, A; Campo, E; López-Guillermo, A

    2013-04-01

    NOTCH1 has been found recurrently mutated in a subset of patients with chronic lymphocytic leukemia (CLL). To analyze biological features and clinical impact of NOTCH1 mutations in CLL, we sequenced this gene in 565 patients. NOTCH1 mutations, found in 63 patients (11%), were associated with unmutated IGHV, high expression of CD38 and ZAP-70, trisomy 12, advanced stage and elevated lactate dehydrogenase. Sequential analysis in 200 patients demonstrated acquisition of mutation in one case (0.5%) and disappearance after treatment in two. Binet A and B patients with NOTCH1-mutated had a shorter time to treatment. NOTCH1-mutated patients were more frequently refractory to therapy and showed shorter progression-free and overall survival after complete remission. Overall survival was shorter in NOTCH1-mutated patients, although not independently from IGHV. NOTCH1 mutation increased the risk of transformation to diffuse large B-cell lymphoma independently from IGHV, with this being validated in resampling tests of replicability. In summary, NOTCH1 mutational status, that was rarely acquired during the course of the disease, identify a genetic subgroup with high risk of transformation and poor outcome. This recently identified genetic subgroup of CLL patients deserves prospective studies to define their best management.

  9. Gain of chromosome 2p in chronic lymphocytic leukemia: significant heterogeneity and a new recurrent dicentric rearrangement.

    PubMed

    Jarosova, Marie; Urbankova, Helena; Plachy, Radek; Papajik, Tomas; Holzerova, Milena; Balcarkova, Jana; Pikalova, Zuzana; Divoky, Vladimir; Indrak, Karel

    2010-02-01

    Array-based comparative genomic hybridization (arrayCGH) studies in chronic lymphocytic leukemia (CLL) have revealed novel recurrent chromosomal imbalances, such as a gain of chromosome 2p. However, a detailed cytogenetic analysis of the 2p gain region has not been elucidated. Here, we present cytogenetic and molecular cytogenetic analysis of 16 such cases selected from a group of 200 patients with CLL based on CGH and/or arrayCGH data. We revealed significant heterogeneity of the region of gain on 2p in CLL, including a new recurrent aberration: the dicentric chromosome, dic(2;18). In our cases, the region of gain involved three genes (MYCN, REL, and ALK) and was associated with an unmutated IgVH status in 14 out of 16 cases. We consider this aberration clinically important in CLL and suggest that an examination of the gene(s) located in region of gain should be included in the routine fluorescence in situ hybridization screening method used for patients with CLL.

  10. Impaired expression of p66Shc, a novel regulator of B-cell survival, in chronic lymphocytic leukemia.

    PubMed

    Capitani, Nagaja; Lucherini, Orso Maria; Sozzi, Elisa; Ferro, Micol; Giommoni, Nico; Finetti, Francesca; De Falco, Giulia; Cencini, Emanuele; Raspadori, Donatella; Pelicci, Pier Giuseppe; Lauria, Francesco; Forconi, Francesco; Baldari, Cosima T

    2010-05-06

    Intrinsic apoptosis defects underlie to a large extent the extended survival of malignant B cells in chronic lymphocytic leukemia (CLL). Here, we show that the Shc family adapter p66Shc uncouples the B-cell receptor (BCR) from the Erk- and Akt-dependent survival pathways, thereby enhancing B-cell apoptosis. p66Shc expression was found to be profoundly impaired in CLL B cells compared with normal peripheral B cells. Moreover, significant differences in p66Shc expression were observed in patients with favorable or unfavorable prognosis, based on the mutational status of IGHV genes, with the lowest expression in the unfavorable prognosis group. Analysis of the expression of genes implicated in apoptosis defects of CLL showed an alteration in the balance of proapoptotic and antiapoptotic members of the Bcl-2 family in patients with CLL. Reconstitution experiments in CLL B cells, together with data obtained on B cells from p66Shc(-/-) mice, showed that p66Shc expression correlates with a bias in the Bcl-2 family toward proapoptotic members. The data identify p66Shc as a novel regulator of B-cell apoptosis which attenuates BCR-dependent survival signals and modulates Bcl-2 family expression. They moreover provide evidence that the p66Shc expression defect in CLL B cells may be causal to the imbalance toward the antiapoptotic Bcl-2 family members in these cells.

  11. The antileukemia activity of a human anti-CD40 antagonist antibody, HCD122, on human chronic lymphocytic leukemia cells

    PubMed Central

    Klabunde, Sha; Lin, Karen; Georgakis, Georgios V.; Cherukuri, Anu; Holash, Jocelyn; Goldbeck, Cheryl; Xu, Xiaomei; Kadel, Edward E.; Lee, Sang Hoon; Aukerman, Sharon Lea; Jallal, Bahija; Aziz, Natasha; Weng, Wen-Kai; Wierda, William; O'Brien, Susan; Younes, Anas

    2008-01-01

    B-cell chronic lymphocytic leukemia (B-CLL) is a lymphoproliferative disorder characterized by the surface expression of CD20, CD5 antigens, as well as the receptor CD40. Activation of CD40 by its ligand (CD40L) induces proliferation and rescues the cells from spontaneous and chemotherapy-induced apoptosis. CD40 activation also induces secretion of cytokines, such as IL-6, IL-10, TNF-α, IL-8, and GM-CSF, which are involved in tumor cell survival, migration, and interaction with cells in the tumor microenvironment. Here we demonstrate that in primary B-CLL tumor cells, the novel antagonist anti-CD40 monoclonal antibody, HCD122, inhibits CD40L-induced activation of signaling pathways, proliferation and survival, and secretion of cytokines. Furthermore, HCD122 is also a potent mediator of antibody-dependent cellular cytotoxicity (ADCC), lysing B-CLL cells more efficiently than rituximab in vitro, despite a significantly higher number of cell surface CD20 binding sites compared with CD40. Unlike rituximab, however, HCD122 (formerly CHIR-12.12) does not internalize upon binding to the cells. Our data suggest that HCD122 may inhibit B-CLL growth by blocking CD40 signaling and by ADCC-mediated cell lysis. PMID:18497318

  12. The antileukemia activity of a human anti-CD40 antagonist antibody, HCD122, on human chronic lymphocytic leukemia cells.

    PubMed

    Luqman, Mohammad; Klabunde, Sha; Lin, Karen; Georgakis, Georgios V; Cherukuri, Anu; Holash, Jocelyn; Goldbeck, Cheryl; Xu, Xiaomei; Kadel, Edward E; Lee, Sang Hoon; Aukerman, Sharon Lea; Jallal, Bahija; Aziz, Natasha; Weng, Wen-Kai; Wierda, William; O'Brien, Susan; Younes, Anas

    2008-08-01

    B-cell chronic lymphocytic leukemia (B-CLL) is a lymphoproliferative disorder characterized by the surface expression of CD20, CD5 antigens, as well as the receptor CD40. Activation of CD40 by its ligand (CD40L) induces proliferation and rescues the cells from spontaneous and chemotherapy-induced apoptosis. CD40 activation also induces secretion of cytokines, such as IL-6, IL-10, TNF-alpha, IL-8, and GM-CSF, which are involved in tumor cell survival, migration, and interaction with cells in the tumor microenvironment. Here we demonstrate that in primary B-CLL tumor cells, the novel antagonist anti-CD40 monoclonal antibody, HCD122, inhibits CD40L-induced activation of signaling pathways, proliferation and survival, and secretion of cytokines. Furthermore, HCD122 is also a potent mediator of antibody-dependent cellular cytotoxicity (ADCC), lysing B-CLL cells more efficiently than rituximab in vitro, despite a significantly higher number of cell surface CD20 binding sites compared with CD40. Unlike rituximab, however, HCD122 (formerly CHIR-12.12) does not internalize upon binding to the cells. Our data suggest that HCD122 may inhibit B-CLL growth by blocking CD40 signaling and by ADCC-mediated cell lysis.

  13. DNA methylation dynamics during B cell maturation underlie a continuum of disease phenotypes in chronic lymphocytic leukemia

    PubMed Central

    Oakes, Christopher C; Seifert, Marc; Assenov, Yassen; Gu, Lei; Przekopowitz, Martina; Ruppert, Amy S; Wang, Qi; Imbusch, Charles D; Serva, Andrius; Koser, Sandra D; Brocks, David; Lipka, Daniel B; Bogatyrova, Olga; Weichenhan, Dieter; Brors, Benedikt; Rassenti, Laura; Kipps, Thomas J; Mertens, Daniel; Zapatka, Marc; Lichter, Peter; Döhner, Hartmut; Küppers, Ralf; Zenz, Thorsten; Stilgenbauer, Stephan; Byrd, John C; Plass, Christoph

    2016-01-01

    Charting differences between tumors and normal tissue is a mainstay of cancer research. However, clonal tumor expansion from complex normal tissue architectures potentially obscures cancer-specific events, including divergent epigenetic patterns. Using whole-genome bisulfite sequencing of normal B cell subsets, we observed broad epigenetic programming of selective transcription factor binding sites coincident with the degree of B cell maturation. By comparing normal B cells to malignant B cells from 268 patients with chronic lymphocytic leukemia (CLL), we showed that tumors derive largely from a continuum of maturation states reflected in normal developmental stages. Epigenetic maturation in CLL was associated with an indolent gene expression pattern and increasingly favorable clinical outcomes. We further uncovered that most previously reported tumor-specific methylation events are normally present in non-malignant B cells. Instead, we identified a potential pathogenic role for transcription factor dysregulation in CLL, where excess programming by EGR and NFAT with reduced EBF and AP-1 programming imbalances the normal B cell epigenetic program. PMID:26780610

  14. Mutations in TLR/MYD88 pathway identify a subset of young chronic lymphocytic leukemia patients with favorable outcome.

    PubMed

    Martínez-Trillos, Alejandra; Pinyol, Magda; Navarro, Alba; Aymerich, Marta; Jares, Pedro; Juan, Manel; Rozman, María; Colomer, Dolors; Delgado, Julio; Giné, Eva; González-Díaz, Marcos; Hernández-Rivas, Jesús M; Colado, Enrique; Rayón, Consolación; Payer, Angel R; Terol, Maria José; Navarro, Blanca; Quesada, Victor; Puente, Xosé S; Rozman, Ciril; López-Otín, Carlos; Campo, Elías; López-Guillermo, Armando; Villamor, Neus

    2014-06-12

    Mutations in Toll-like receptor (TLR) and myeloid differentiation primary response 88 (MYD88) genes have been found in chronic lymphocytic leukemia (CLL) at low frequency. We analyzed the incidence, clinicobiological characteristics, and outcome of patients with TLR/MYD88 mutations in 587 CLL patients. Twenty-three patients (3.9%) had mutations, 19 in MYD88 (one with concurrent IRAK1 mutation), 2 TLR2 (one with concomitant TLR6 mutation), 1 IRAK1, and 1 TLR5. No mutations were found in IRAK2 and IRAK4. TLR/MYD88-mutated CLL overexpressed genes of the nuclear factor κB pathway. Patients with TLR/MYD88 mutations were significantly younger (83% age ≤50 years) than those with no mutations. TLR/MYD88 mutations were the most frequent in young patients. Patients with mutated TLR/MYD88 CLL had a higher frequency of mutated IGHV and low expression of CD38 and ZAP-70. Overall survival (OS) was better in TLR/MYD88-mutated than unmutated patients in the whole series (10-year OS, 100% vs 62%; P = .002), and in the subset of patients age ≤50 years (100% vs 70%; P = .02). In addition, relative OS of TLR/MYD88-mutated patients was similar to that in the age- and gender-matched population. In summary, TLR/MYD88 mutations identify a population of young CLL patients with favorable outcome.

  15. Ibrutinib: A New Frontier in the Treatment of Chronic Lymphocytic Leukemia by Bruton’s Tyrosine Kinase Inhibition

    PubMed Central

    Dias, Ajoy Lawrence; Jain, Dharamvir

    2013-01-01

    Chronic lymphocytic leukemia (CLL) is characterized by progressive accumulation of nonfunctional mature B cells in blood, bone marrow and lymphoid tissues. In the last decade, our understanding of CLL and consequently our diagnostic and therapeutic approaches have changed dramatically. Conventional fludarabine based chemotherapy has led to improved disease response and longer survival in young patients with CLL. However its application in elderly patients has been restricted by substantial myelosuppression and infection. Treatment of CLL is now moving towards targeted therapy. The success of new class of agents such as monoclonal antibodies, proteasome inhibitors and immunomodulatory derivatives has sparked further search for treatment agents with novel targets to inhibit. The B cell receptor activating pathway involving the Bruton’s tyrosine kinase (BTK) is crucial in B cell production and maintenance and is an attractive therapeutic target. Ibrutinib is an oral covalent inhibitor of the BTK pathway that induces apoptosis of B cells. Early phase studies with Ibrutinib either as a single agent or in combination regimens have shown promising results with an excellent safety profile in patients with high-risk, refractory or relapsed CLL and elderly treatment-naïve patients. This review summarizes the current knowledge of Ibrutinib in the treatment of CLL. PMID:24433470

  16. Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL)

    MedlinePlus

    ... over time, it can progress to a more aggressive type of lymphoma. Common signs of disease include ... older or frail are typically treated with less aggressive regimens than those who are younger and healthier. ...

  17. Purple patches in an immunocompromised patient: a report of secondary disseminated cutaneous mucormycosis in a man with chronic lymphocytic leukemia.

    PubMed

    Iyengar, Sanjana; Chambers, Cindy J; Millsop, Jillian W; Fung, Maxwell A; Sharon, Victoria R

    2017-03-15

    A 60-year-old man with chronic lymphocytic leukemiadeveloped a deeply violaceous annular patchwith a halo of erythema on the right thigh duringhospitalization for neutropenic fever. Associatedsymptoms included chronic cough and fatigue.Bilateral lung opacities with hilar lymphadenopathywere noted on chest computed tomographyscan. Punch biopsy and tissue culture confirmeda diagnosis of secondary disseminated cutaneousmucormycosis. Although rare, physicians shouldinclude mucormycosis in the differential diagnosisof purpuric patches in immunosuppressed patients.Prompt skin biopsy and tissue culture may optimizethe success of treatment.

  18. Granulomatous interstitial nephritis secondary to chronic lymphocytic leukemia/small lymphocytic lymphoma.

    PubMed

    Nasr, Samih H; Shanafelt, Tait D; Hanson, Curtis A; Fidler, Mary E; Cornell, Lynn D; Sethi, Sanjeev; Chaffee, Kari G; Morris, Joseph; Leung, Nelson

    2015-06-01

    Granulomatous interstitial nephritis (GIN) is an uncommon pathologic lesion encountered in 0.5% to 5.9% of renal biopsies. Drugs, sarcoidosis, and infections are responsible for most cases of GIN. Malignancy is not an established cause of GIN. Here, we report a series of 5 patients with GIN secondary to chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Patients were mostly elderly white males with an established history of CLL/SLL who presented with severe renal impairment (median peak serum creatinine, 7.3 mg/dL), leukocyturia, and mild proteinuria. One had nephromegaly. In 2 patients, the development and relapse of renal insufficiency closely paralleled the level of lymphocytosis. Kidney biopsy in all patients showed GIN concomitant with CLL/SLL leukemic interstitial infiltration. Granulomas were nonnecrotizing and epithelioid and were associated with giant cells. One biopsy showed granulomatous arteritis. One patient had a granulomatous reaction in lymph nodes and skin. Steroids with/without CLL/SLL-directed chemotherapy led to partial improvement of kidney function in all patients except 1 who had advanced cortical scarring on biopsy. In conclusion, we report an association between CLL/SLL and GIN. Patients typically present with severe renal failure due to both GIN and leukemic interstitial infiltration, which tends to respond to steroids with/without CLL/SLL-directed chemotherapy. The pathogenesis of GIN in this clinical setting is unknown but may represent a local hypersensitivity reaction to the CLL/SLL tumor cells.

  19. New Strategies in Chronic Lymphocytic Leukemia: Shifting Treatment Paradigms

    PubMed Central

    Awan, Farrukh T.; Byrd, John C.

    2014-01-01

    Over the past two decades, slow but deliberate progress has been made in understanding the genetics of CLL and how the surrounding microenvironment influences leukemia cell survival. The complexity of CLL with respect to different chromosomal aberrations, lack of a common aberrant signaling pathway activation, and associated immune suppression of the disease has been seen a major stumbling block for developing a single targeted therapy similar to imatinib used in chronic myeloid leukemia (CML). The upcoming therapeutic era we are entering with the B-cell receptor (BCR) tyrosine kinase inhibitors ibrutinib and idelalisib, appear to be overcoming this obstacle. Indeed, for the large majority of patients it appears that application of BCR kinase inhibitors can promote durable remissions without the need for chemotherapy. Where other very active targeted agents such as ABT-199, therapeutic antibodies, and chimeric antigen receptor-modified T-cells will be used in CLL also represents a major question that future clinical trials will answer. PMID:25294898

  20. A Systemic Capillary Leak Syndrome (Clarkson Syndrome) in a Patient with Chronic Lymphocytic Leukemia: A Case Report in an Out-of-Hospital Setting

    PubMed Central

    Durand Bechu, Manon; Rouget, Antoine; Recher, Christian; Azoulay, Elie; Bounes, Vincent

    2016-01-01

    Systemic Capillary Leak Syndrome (SCLS) is a rare disease with poor prognosis, characterized by the occurrence of mucocutaneous and visceral edema with hypotension, hemoconcentration, and unexpected hypoalbuminemia. The disease can be idiopathic (Clarkson syndrome) or secondary to other diseases and treatments. We describe this syndrome in a prehospitalized, 63-year-old patient with chronic lymphocytic leukemia and an idiopathic form of SCLS manifesting as hypovolemic shock. Initial care is hospitalization in intensive care. In addition to etiological treatment if fluid replacement is necessary, treatment must be closely monitored for secondary overload complications. Catecholamine rather than arrhythmogenic support may be associated. PMID:27069700

  1. CD39 Expression on T Lymphocytes Correlates With Severity of Disease in Patients With Chronic Lymphocytic Leukemia

    PubMed Central

    Pulte, Dianne; Furman, Richard R.; Broekman, M. Johan; Drosopoulos, Joan H. F.; Ballard, Harold S.; Olson, Kim E.; Kizer, Jorge R.; Marcus, Aaron J.

    2012-01-01

    Introduction Chronic lymphocytic leukemia (CLL) is a B-cell disorder, but it is also associated with abnormalities in T-lymphocyte function. In this study we examine changes in T-lymphocyte CD39 and CD73 expression in patients with CLL. Methods Blood samples were drawn from 34 patients with CLL and 31 controls. The cells were stained for CD3, CD4, CD8, CD19, CD39, and CD73 and analyzed by flow cytometry. Results Overall, patients with CLL had a higher percentage of CD39+ T lymphocytes than did controls. The percentage of cells expressing CD39 was higher in both CD4+ cells and CD8+ cells. Higher CD3/CD39 expression was associated with a later disease stage. No correlations between T-lymphocyte CD39 levels and CD38 or Zap-70 expression were observed. In contrast, the percentage of T lymphocytes and B lymphocytes that expressed CD73 was decreased in patients with CLL. Average B-lymphocyte CD73 expression was decreased in CLL because the majority of CLL clones were CD73. However a minority of CLL clones were CD73+, and patients with CD73+ clones tended to have earlier stage disease. Conclusion T-lymphocyte CD39 and CD73 expression may be useful prognostic markers in patients with CLL. Expression of CD73 on the malignant cell population in CLL may be a marker of better prognosis. PMID:21816376

  2. Accelerated development of chronic lymphocytic leukemia in New Zealand Black mice expressing a low level of interferon regulatory factor 4.

    PubMed

    Ma, Shibin; Shukla, Vipul; Fang, Leilei; Gould, Karen A; Joshi, Shantaram S; Lu, Runqing

    2013-09-13

    A recent genome-wide SNP association study identified IRF4 as a major susceptibility gene for chronic lymphocytic leukemia (CLL). Moreover, the SNPs located in the 3' UTR of the IRF4 gene have been linked to a down-regulation of IRF4. However, whether a low level of IRF4 is critical for CLL development remains unclear. New Zealand Black (NZB) mice are a naturally occurring, late-onset mouse model of CLL. To examine the role of a reduced level of IRF4 in CLL development, we generated, through breeding, IRF4 heterozygous mutant mice in the NZB background (NZB IRF4(+/-)). Our results show that CLL development is accelerated dramatically in the NZB IRF4(+/-) mice. The average onset of CLL in NZB mice is 12 months, but CLL cells can be detected in NZB IRF4(+/-) mice at 3 months of age. By 5 months of age, 80% of NZB IRF4(+/-) mice developed CLL. CLL cells are derived from B1 cells in mice. Interestingly, NZB IRF4(+/-) B1 cells exhibit prolonged survival, accelerated self-renewal, and defects in differentiation. Although NZB IRF4(+/-) CLL cells are resistant to apoptosis, high levels of IRF4 inhibit their survival. High levels of IRF4 also reduce the survival of MEC-1 human CLL cells. Our analysis further reveals that high levels of IRF4 suppress Akt activity and can do so without the IRF4 DNA binding domain. Thus, our findings reveal a causal relationship between a low level of IRF4 and the development of CLL and establish IRF4 as a novel regulator in the pathogenesis of CLL.

  3. Analytic errors in Sysmex-generated hematology results in blood from a dog with chronic lymphocytic leukemia.

    PubMed

    Novacco, Marilisa; Martini, Valeria; Grande, Carmen; Comazzi, Stefano

    2015-09-01

    A blood sample from a 14-year-old dog was submitted to the veterinary diagnostic laboratory of the University of Milan for marked leukocytosis with atypical cells. A diagnosis of chronic T-cell lymphocytic leukemia (CLL) was made based on blood smear evaluation and flow cytometric phenotyping. A CBC by Sysmex XT-2000iV revealed a moderate normocytic normochromic anemia. Red blood cells counted by optic flow cytometry (RBC-O) resulted in a higher value than using electrical impedance (RBC-I). The relative reticulocyte count based on RNA content and size was 35.3%, while the manual reticulocyte count was < 1%. The WBC count of 1,562,680 cells/μL was accompanied by a flag. Manual counts for RBC and WBC using the Bürker chamber confirmed the Sysmex impedance results. Finally the manual PCV was lower than HCT by Sysmex. While Sysmex XT can differentiate between RBC and WBC by impedance, even in the face of extreme lymphocytosis due to CLL, RBC-O can be affected by bias, resulting in falsely increased RBC and reticulocyte numbers. Overestimation of RBC-O may be due to incorrect Sysmex classification of leukemic cells or their fragments as reticulocytes. This phenomenon is known as pseudoreticulocytosis and can lead to misinterpretation of regenerative anemia. On the other side PCV can be affected by bias in CLL due to the trapping of RBC in the buffy coat, resulting in a pink hue in the separation area. As HGB concentration is not affected by flow cytometric or other cell-related artifacts it may represent the most reliable variable to assess the degree of anemia in cases of CLL.

  4. Regulatory B lymphocyte functions should be considered in chronic lymphocytic leukemia

    PubMed Central

    Mohr, Audrey; Renaudineau, Yves; Bagacean, Cristina; Pers, Jacques-Olivier; Jamin, Christophe; Bordron, Anne

    2016-01-01

    ABSTRACT Chronic lymphocytic leukemia (CLL) is characterized by an abnormal expansion of mature B cells in the bone marrow and their accumulation in blood and secondary lymphoid organs. Tumor CLL cells share expression of various surface molecules with many subsets of B cells and have several common characteristics with regulatory B cells (B regs). However, the identification of B regs and their role in CLL remain elusive. The aim of this review is to summarize recent works regarding the regulatory and phenotypic characteristic of B regs and their associated effects on the immune system. It is also meant to highlight their potential importance with regards to the immunotherapeutic response. PMID:27467951

  5. Regulatory B lymphocyte functions should be considered in chronic lymphocytic leukemia.

    PubMed

    Mohr, Audrey; Renaudineau, Yves; Bagacean, Cristina; Pers, Jacques-Olivier; Jamin, Christophe; Bordron, Anne

    2016-05-01

    Chronic lymphocytic leukemia (CLL) is characterized by an abnormal expansion of mature B cells in the bone marrow and their accumulation in blood and secondary lymphoid organs. Tumor CLL cells share expression of various surface molecules with many subsets of B cells and have several common characteristics with regulatory B cells (B regs). However, the identification of B regs and their role in CLL remain elusive. The aim of this review is to summarize recent works regarding the regulatory and phenotypic characteristic of B regs and their associated effects on the immune system. It is also meant to highlight their potential importance with regards to the immunotherapeutic response.

  6. Targeted treatment for chronic lymphocytic leukemia: clinical potential of obinutuzumab

    PubMed Central

    Smolej, Lukáš

    2015-01-01

    Introduction of targeted agents revolutionized the treatment of chronic lymphocytic leukemia (CLL) in the past decade. Addition of chimeric monoclonal anti-CD20 antibody rituximab to chemotherapy significantly improved efficacy including overall survival (OS) in untreated fit patients; humanized anti-CD52 antibody alemtuzumab and fully human anti-CD20 antibody ofatumumab lead to improvement in refractory disease. Novel small molecule inhibitors such as ibrutinib and idelalisib demonstrated excellent activity and were very recently licensed in relapsed/refractory CLL. Obinutuzumab (GA101) is the newest monoclonal antibody approved for the treatment of CLL. This novel, glycoengineered, type II humanized anti-CD20 antibody is characterized by enhanced antibody-dependent cellular cytotoxicity and direct induction of cell death compared to type I antibodies. Combination of obinutuzumab and chlorambucil yielded significantly better OS in comparison to chlorambucil monotherapy in untreated comorbid patients. These results led to approval of obinuzutumab for the treatment of CLL. Numerous clinical trials combining obinutuzumab with other cytotoxic drugs and novel small molecules are currently under way. This review focuses on the role of obinutuzumab in the treatment of CLL. PMID:25691812

  7. Targeted treatment for chronic lymphocytic leukemia: clinical potential of obinutuzumab.

    PubMed

    Smolej, Lukáš

    2015-01-01

    Introduction of targeted agents revolutionized the treatment of chronic lymphocytic leukemia (CLL) in the past decade. Addition of chimeric monoclonal anti-CD20 antibody rituximab to chemotherapy significantly improved efficacy including overall survival (OS) in untreated fit patients; humanized anti-CD52 antibody alemtuzumab and fully human anti-CD20 antibody ofatumumab lead to improvement in refractory disease. Novel small molecule inhibitors such as ibrutinib and idelalisib demonstrated excellent activity and were very recently licensed in relapsed/refractory CLL. Obinutuzumab (GA101) is the newest monoclonal antibody approved for the treatment of CLL. This novel, glycoengineered, type II humanized anti-CD20 antibody is characterized by enhanced antibody-dependent cellular cytotoxicity and direct induction of cell death compared to type I antibodies. Combination of obinutuzumab and chlorambucil yielded significantly better OS in comparison to chlorambucil monotherapy in untreated comorbid patients. These results led to approval of obinuzutumab for the treatment of CLL. Numerous clinical trials combining obinutuzumab with other cytotoxic drugs and novel small molecules are currently under way. This review focuses on the role of obinutuzumab in the treatment of CLL.

  8. Imatinib sensitizes T-cell lymphocytes from chronic myeloid leukemia patients to FasL-induced cell death: a brief communication.

    PubMed

    Legros, Laurence; Ebran, Nathalie; Stebe, Emmanuelle; Rousselot, Philippe; Rea, Delphine; Cassuto, Jill Patrice; Mahon, Francois-Xavier; Hueber, Anne-Odile

    2012-01-01

    There is now substantial evidence that imatinib may affect immune responses, especially those mediated by T lymphocytes. Fas (CD95/Apo-1), a cell death receptor, is a key regulator of the immune system. We have explored the consequences of treatment on the Fas system in chronic myeloid leukemia patients treated with imatinib. In comparison with healthy controls, we found not only a mild blood lymphopenia but also impairment of phytohemagglutinin activation in CD4Fas and CD8Fas lymphocytes of imatinib-treated patients. Moreover, these lymphocyte populations were more sensitive to FasL-induced cell death in relation to an increase in Fas expression at the cell surface. Taken together, these results reveal the role of Fas receptor in the lymphopenia observed in patients treated with imatinib, with potential deleterious consequences on antileukemic responses against this immunogenic hematological malignancy.

  9. Targeting B-cell receptor signaling kinases in chronic lymphocytic leukemia: the promise of entospletinib

    PubMed Central

    Sharman, Jeff; Di Paolo, Julie

    2016-01-01

    The B-cell receptor signaling pathway has emerged as an important therapeutic target in chronic lymphocytic leukemia and other B-cell malignancies. Novel agents have been developed targeting the signaling enzymes spleen tyrosine kinase (SYK), Bruton’s tyrosine kinase, and phosphoinositide 3-kinase delta. This review discusses the rationale for targeting these enzymes, as well as the preclinical and clinical evidence supporting their role as therapeutic targets, with a particular focus on SYK inhibition with entospletinib. PMID:27247756

  10. A Novel Case of Penile Gangrene in a Patient Treated with Ibrutinib for Chronic Lymphocytic Leukemia

    PubMed Central

    Skelton IV, William Paul; Akhavan, Neeka N.; Taylor, Zachary A.; Nguyen, Thu-Cuc; Hassan, Hassan; Townsend, Tabitha N.; Trikha, Gaurav; Dang, Nam H.

    2016-01-01

    Introduction. Ibrutinib is commonly used for the treatment of patients with CLL in either first-line or relapsed/refractory settings. Case Presentation. We present the case of a 74-year-old Caucasian man with CLL who presented with penile gangrene upon initiation of ibrutinib treatment. Our case is the first showing the complication of penile gangrene associated with ibrutinib use. The gangrene was self-limited upon discontinuing ibrutinib. Conclusion. Our finding describes a very rare yet important adverse event associated with ibrutinib use. PMID:27999696

  11. Simultaneous occurrence of B-cell chronic lymphocytic leukemia and chronic myeloid leukemia with further evolution to lymphoid blast crisis.

    PubMed

    Esteve, J; Cervantes, F; Rives, S; Rozman, M; Zarco, M A; Montserrat, E

    1997-01-01

    The coexistence of chronic myeloid leukemia (CML) and B-cell chronic lymphocytic leukemia (CLL) in the same patient is rare. A 71-year-old woman developed a B-lineage lymphoid blast crisis at 18 months after diagnosis of Ph-positive CML. At this time, a lymphoid cell population with morphologic and immunophenotypic features of CLL was demonstrated. The retrospective review of the tests performed at diagnosis and thereafter disclosed the presence of lymphoid nodules in the initial bone marrow biopsy in the absence of lymphocytosis. Subsequently, there was an appearance of moderate lymphocytosis in the following months. Therefore, diagnosis of CML and coexistent CLL was established. Although a transient remission of blast crisis was achieved, blast cells reappeared two months later and the patient died shortly afterwards. Molecular studies of the immunoglobulin heavy chain gene (IH) rearrangement pattern point to the origin of the diseases in two different cell clones. In addition, previously published cases of simultaneous CLL and CML are reviewed.

  12. Spotlight on ibrutinib and its potential in frontline treatment of chronic lymphocytic leukemia

    PubMed Central

    Khan, Maliha; Gibbons, Jamie L; Ferrajoli, Alessandra

    2017-01-01

    Chronic lymphocytic leukemia (CLL) is the most prevalent leukemia in the adult population. Current efforts are focused on better understanding the intricate pathophysiology of the disease to develop successful targeted therapies. Ibrutinib is emerging as an important agent in this new age of targeted treatment for CLL. As a Bruton’s tyrosine kinase inhibitor, it blocks the signaling pathway that malignant B-lymphocytes need for growth and maturation. Ibrutinib’s role in therapy was further expanded recently when the US Food and Drug Administration approved its use in both frontline and salvage treatment for patients with CLL. This review assesses the effectiveness of ibrutinib in the frontline setting, its efficacy in various types of patients with CLL, and its safety and tolerability.

  13. Immunoglobulin gene translocations in chronic lymphocytic leukemia: A report of 35 patients and review of the literature

    PubMed Central

    DE BRAEKELEER, MARC; TOUS, CORINE; GUÉGANIC, NADIA; LE BRIS, MARIE-JOSÉE; BASINKO, AUDREY; MOREL, FRÉDÉRIC; DOUET-GUILBERT, NATHALIE

    2016-01-01

    Chronic lymphocytic leukemia (CLL) represents the most common hematological malignancy in Western countries, with a highly heterogeneous clinical course and prognosis. Translocations involving the immunoglobulin (IG) genes are regularly identified. From 2000 to 2014, we identified an IG gene translocation in 18 of the 396 patients investigated at diagnosis (4.6%) and in 17 of the 275 analyzed during follow-up (6.2%). A total of 4 patients in whom the IG translocation was identified at follow-up did not carry the translocation at diagnosis. The IG heavy locus (IGH) was involved in 27 translocations (77.1%), the IG κ locus (IGK) in 1 (2.9%) and the IG λ locus (IGL) in 7 (20.0%). The chromosome band partners of the IG translocations were 18q21 in 16 cases (45.7%), 11q13 and 19q13 in 4 cases each (11.4% each), 8q24 in 3 cases (8.6%), 7q21 in 2 cases (5.7%), whereas 6 other bands were involved once (2.9% each). At present, 35 partner chromosomal bands have been described, but the partner gene has solely been identified in 10 translocations. CLL associated with IG gene translocations is characterized by atypical cell morphology, including plasmacytoid characteristics, and the propensity of being enriched in prolymphocytes. The IG heavy chain variable region (IGHV) mutational status varies between translocations, those with unmutated IGHV presumably involving cells at an earlier stage of B-cell lineage. All the partner genes thus far identified are involved in the control of cell proliferation and/or apoptosis. The translocated partner gene becomes transcriptionally deregulated as a consequence of its transposition into the IG locus. With the exception of t(14;18)(q32;q21) and its variants, prognosis appears to be poor for the other translocations. Therefore, searching for translocations involving not only IGH, but also IGL and IGK, by banding and molecular cytogenetics is required. Furthermore, it is important to identify the partner gene to ensure the patients receive

  14. Efficacy of lenalidomide in relapsed/refractory chronic lymphocytic leukemia patient: a systematic review and meta-analysis.

    PubMed

    Liang, Liang; Zhao, Ming; Zhu, Yuan-Chao; Hu, Xin; Yang, Li-Ping; Liu, Hui

    2016-09-01

    Therapeutic results of relapsed/refractory chronic lymphocytic leukemia (CLL) are very disappointing at present. Lenalidomide has been proved to be effective for relapsed/refractory CLL as a single agent or in combination with various chemo-immunotherapeutic regimens. However, current clinical experience in its usage is still limited. Because of existing considerable variability in different studies, a systematic review and meta-analysis was conducted to describe overall response rate (ORR) of lenalidomide in patients with relapsed/refractory CLL. Pooled estimate of cumulative prevalence of total ORR was 42.23 % (95 % confidence interval [CI], 32.49-52.61 %), while pooled ORR in regimen with lenalidomide plus anti-CD20 monoclonal antibody (mAbs) and lenalidomide mono-therapy were 60.01 % (95 % CI, 53.86-65.86 %) and 24.38 % (95 % CI, 16.15-35.06 %), respectively. There was no significant difference between L + R (lenalidomide plus rituximab) group and L + O (lenalidomide plus ofatumumab) group, with pooled ORR of 66.38 % (95 % CI, 57.96-73.87 %) and 57.40 % (95 % CI, 46.46-67.65 %), respectively. When co-administrated with anti-CD20 mAbs, dosage of lenalidomide was not the key factor of ORR in combination therapy. Pooled ORR of patient with high-risk cytogenetic in L + anti-CD20 mAbs group was 56.74 % (95 % CI, 45.53-67.30 %). In comparison with patients without high-risk cytogenetic receiving the same treatment regimen, no significant difference was observed, with relative risk (RR) of 0.87 (95 % CI 0.68-1.11). Our finding demonstrated that lenalidomide plus anti-CD20 mAbs could be an efficient therapy regimen for relapsed/refractory CLL patients, especially for those with high-risk cytogenetic factor.

  15. Subcutaneous injections of low doses of humanized anti-CD20 veltuzumab: a phase I study in chronic lymphocytic leukemia.

    PubMed

    Kalaycio, Matt E; George Negrea, O; Allen, Steven L; Rai, Kanti R; Abbasi, Rashid M; Horne, Heather; Wegener, William A; Goldenberg, David M

    2016-01-01

    To evaluate the potential of subcutaneous (SC) injections with anti-CD20 antibody veltuzumab in chronic lymphocytic leukemia (CLL), 21 patients received 80, 160, or 320 mg injections every 2 weeks × 4 doses (n = 11) or 160 or 320 mg twice-weekly × 16 doses (n = 10). Treatment was well tolerated with only occasional, mild-moderate, transient injection reactions. Lymphocytosis decreased in all patients (maximum decrease, 5-91%), with 12 patients obtaining >50% decreases. Of 14 patients with lymphadenopathy on CT imaging, 5 (36%) achieved 14-61% reductions (sum of perpendicular diameters). By NCI-WG criteria, two patients achieved partial responses (10%). SC veltuzumab appeared active in all dose groups, with no obvious exposure-response relationship, despite cumulative doses ranging from 320-5120 mg. Overall median progression-free survival was 7.7 months; three patients remained progression-free >1 year (2 ongoing at 2-year study completion). These data suggest further studies of SC veltuzumab in CLL are warranted.

  16. The role of B-cell receptor inhibitors in the treatment of patients with chronic lymphocytic leukemia.

    PubMed

    Wiestner, Adrian

    2015-12-01

    Chronic lymphocytic leukemia is a malignancy of mature auto-reactive B cells. Genetic and functional studies implicate B-cell receptor signaling as a pivotal pathway in its pathogenesis. Full B-cell receptor activation requires tumor-microenvironment interactions in lymphoid tissues. Spleen tyrosine kinase, Bruton's tyrosine kinase, and the phosphatidylinositol 3-kinase (PI3K) δ isoform are essential for B-cell receptor signal transduction but also mediate the effect of other pathways engaged in chronic lymphocytic leukemia cells in the tissue-microenvironment. Orally bioavailable inhibitors of spleen tyrosine kinase, Bruton's tyrosine kinase, or PI3Kδ, induce high rates of durable responses. Ibrutinib, a covalent inhibitor of Bruton's tyrosine kinase, and idelalisib, a selective inhibitor of PI3Kδ, have obtained regulatory approval in chronic lymphocytic leukemia. Ibrutinib and idelalisib are active in patients with high-risk features, achieving superior disease control in difficult-to-treat patients than prior best therapy, making them the preferred agents for chronic lymphocytic leukemia with TP53 aberrations and for patients resistant to chemoimmunotherapy. In randomized trials, both ibrutinib, versus ofatumumab, and idelalisib in combination with rituximab, versus placebo with rituximab improved survival in relapsed/refractory chronic lymphocytic leukemia. Responses to B-cell receptor inhibitors are mostly partial, and within clinical trials treatment is continued until progression or occurrence of intolerable side effects. Ibrutinib and idelalisib are, overall, well tolerated; notable adverse events include increased bruising and incidence of atrial fibrillation on ibrutinib and colitis, pneumonitis and transaminase elevations on idelalisib. Randomized trials investigate the role of B-cell receptor inhibitors in first-line therapy and the benefit of combinations. This review discusses the biological basis for targeted therapy of chronic lymphocytic

  17. The role of B-cell receptor inhibitors in the treatment of patients with chronic lymphocytic leukemia

    PubMed Central

    Wiestner, Adrian

    2015-01-01

    Chronic lymphocytic leukemia is a malignancy of mature auto-reactive B cells. Genetic and functional studies implicate B-cell receptor signaling as a pivotal pathway in its pathogenesis. Full B-cell receptor activation requires tumor-microenvironment interactions in lymphoid tissues. Spleen tyrosine kinase, Bruton’s tyrosine kinase, and the phosphatidylinositol 3-kinase (PI3K) δ isoform are essential for B-cell receptor signal transduction but also mediate the effect of other pathways engaged in chronic lymphocytic leukemia cells in the tissue-microenvironment. Orally bioavailable inhibitors of spleen tyrosine kinase, Bruton’s tyrosine kinase, or PI3Kδ, induce high rates of durable responses. Ibrutinib, a covalent inhibitor of Bruton’s tyrosine kinase, and idelalisib, a selective inhibitor of PI3Kδ, have obtained regulatory approval in chronic lymphocytic leukemia. Ibrutinib and idelalisib are active in patients with high-risk features, achieving superior disease control in difficult-to-treat patients than prior best therapy, making them the preferred agents for chronic lymphocytic leukemia with TP53 aberrations and for patients resistant to chemoimmunotherapy. In randomized trials, both ibrutinib, versus ofatumumab, and idelalisib in combination with rituximab, versus placebo with rituximab improved survival in relapsed/refractory chronic lymphocytic leukemia. Responses to B-cell receptor inhibitors are mostly partial, and within clinical trials treatment is continued until progression or occurrence of intolerable side effects. Ibrutinib and idelalisib are, overall, well tolerated; notable adverse events include increased bruising and incidence of atrial fibrillation on ibrutinib and colitis, pneumonitis and transaminase elevations on idelalisib. Randomized trials investigate the role of B-cell receptor inhibitors in first-line therapy and the benefit of combinations. This review discusses the biological basis for targeted therapy of chronic lymphocytic

  18. Rapidly progressive renal failure due to chronic lymphocytic leukemia - Response to chlorambucil

    PubMed Central

    Junglee, N. A.; Shrikanth, S.; Seale, J. R.

    2012-01-01

    Chronic lymphocytic leukemia tends to follow an indolent course and despite infiltration of leukemic cells in numerous organs, resultant target organ damage is uncommon. We present a case of an 83-year-old Caucasian lady who presented with rapidly worsening renal impairment over a several month period with a serum creatinine peak of 2.82 mg/dl. Despite numerous investigations an immediate cause was not apparent. A renal biopsy was therefore conducted which revealed dense infiltration of the interstitium with small lymphocytic lymphoma. Given her age and frailty she was treated with single alkylating agent chemotherapy (chlorambucil). This resulted in a marked decrease in lymphocyte count and resolution of renal impairment close to her previous baseline level. To our knowledge, this is the first case in the literature to demonstrate a marked resolution in renal impairment with chlorambucil alone. We also highlight the value of renal biopsy in identifying a rare cause of renal impairment. PMID:23087560

  19. Loss of a chromosomal region with synteny to human 13q14 occurs in mouse chronic lymphocytic leukemia that originates from early-generated B1 B cells

    PubMed Central

    Hayakawa, Kyoko; Formica, Anthony M.; Colombo, Matthew J.; Shinton, Susan A.; Brill-Dashoff, Joni; Morse, Herbert C.; Li, Yue-Sheng; Hardy, Richard R.

    2016-01-01

    A common feature of B cell chronic lymphocytic leukemia (CLL) is chromosomal loss of 13q14, containing the miR15a/16-1 locus controlling B cell proliferation. However, CLL etiology remains unclear. CLL is an adult leukemia with an incidence that increases with advancing age. A unique feature of CLL is biased B cell antigen receptor (BCR) usage, autoreactivity with polyreactivity, and CD5 expression, all suggest a role for the BCR in driving CLL pathogenesis. Among human CLLs, BCRs autoreactive with non-muscle myosin IIA (AMyIIA) are recurrent. Here we identify an unmutated AMyIIA BCR in mouse, with distinctive CDR3 segments capable of promoting leukemogenesis. B cells with this AMyIIA BCR are generated by BCR-dependent signaling during B-1 fetal/neonatal development with CD5 induction, but not in adults. These early-generated AMyIIA B1 B cells self-renew, increase during aging, and can progress to become monoclonal B cell lymphocytosis, followed by aggressive CLL in aged mice, often with loss of a chromosomal region containing the miR15a/16-1 locus of varying length, as in human CLL. Thus, the ability to generate this defined autoreactive BCR by B1 B cells is a key predisposing step in mice, promoting progression to chronic leukemia. PMID:27055869

  20. Limited clinical relevance of imaging techniques in the follow-up of patients with advanced chronic lymphocytic leukemia: results of a meta-analysis.

    PubMed

    Eichhorst, Barbara F; Fischer, Kirsten; Fink, Anna-Maria; Elter, Thomas; Wendtner, Clemens M; Goede, Valentin; Bergmann, Manuela; Stilgenbauer, Stephan; Hopfinger, Georg; Ritgen, Matthias; Bahlo, Jasmin; Busch, Raymonde; Hallek, Michael

    2011-02-10

    The clinical value of imaging is well established for the follow-up of many lymphoid malignancies but not for chronic lymphocytic leukemia (CLL). A meta-analysis was performed with the dataset of 3 German CLL Study Group phase 3 trials (CLL4, CLL5, and CLL8) that included 1372 patients receiving first-line therapy for CLL. Response as well as progression during follow-up was reassessed according to the National Cancer Institute Working Group1996 criteria. A total of 481 events were counted as progressive disease during treatment or follow-up. Of these, 372 progressions (77%) were detected by clinical symptoms or blood counts. Computed tomography (CT) scans or ultrasound were relevant in 44 and 29 cases (9% and 6%), respectively. The decision for relapse treatment was determined by CT scan or ultrasound results in only 2 of 176 patients (1%). CT scan results had an impact on the prognosis of patients in complete remission only after the administration of conventional chemotherapy but not after chemoimmunotherapy. In conclusion, physical examination and blood count remain the methods of choice for staging and clinical follow-up of patients with CLL as recommended by the International Workshop on Chronic Lymphocytic Leukemia 2008 guidelines. These trials are registered at http://www.isrctn.org as ISRCTN 75653261 and ISRCTN 36294212 and at http://www.clinicaltrials.gov as NCT00281918.

  1. The role of idelalisib in the treatment of relapsed and refractory chronic lymphocytic leukemia

    PubMed Central

    Nair, Kruti Sheth; Cheson, Bruce

    2016-01-01

    Idelalisib is a first in class, delta isoform specific, PI3-kinase inhibitor. Based on its high level of efficacy and acceptable safety profile, this oral drug has been approved by the US Food and Drug Administration as a single agent for the treatment of relapsed or refractory small lymphocytic lymphoma, and follicular non-Hodgkin lymphoma, and in combination with rituximab for patients with chronic lymphocytic leukemia. Adverse effects of particular concern include diarrhea, pneumonitis, and transient elevations of hepatic transaminase levels. Efforts to improve on the activity of this drug have included combinations with standard chemotherapy agents, such as bendamustine, and other targeted therapies, including checkpoint inhibitors. However, other combinations have been associated with life-threatening and fatal toxicities. Thus, the development of such regimens should be conducted carefully in the context of a clinical research study. Idelalisib has a vital role as second-line therapy for chronic lymphocytic leukemia, especially for patients with high-risk disease and multiple comorbidities, and studies are exploring the use of this agent as front-line therapy to improve the outcome of patients with indolent B-cell malignancies. PMID:27054023

  2. Concurrent classical Hodgkin lymphoma and plasmablastic lymphoma in a patient with chronic lymphocytic leukemia/small lymphocytic lymphoma treated with fludarabine: a dimorphic presentation of iatrogenic immunodeficiency-associated lymphoproliferative disorder with evidence suggestive of multiclonal transformability of B cells by Epstein-Barr virus.

    PubMed

    Foo, Wen-Chi; Huang, Qin; Sebastian, Siby; Hutchinson, Charles B; Burchette, Jim; Wang, Endi

    2010-12-01

    A small fraction of patients with chronic lymphocytic leukemia/small lymphocytic lymphoma develop Epstein-Barr virus-positive B-cell lymphoproliferative disorders. These Epstein-Barr virus-B-cell lymphoproliferative disorders are thought to be related to immune suppression induced by fludarabine/other chemotherapeutic regimens. As in other immunodeficiency-associated lymphoproliferative disorders, these disorders demonstrate a heterogeneous histological spectrum that ranges from polymorphic to monomorphic to classical Hodgkin lymphoma-like lesions. We report a case of concurrent classical Hodgkin lymphoma and plasmablastic lymphoma in a patient with chronic lymphocytic leukemia/small lymphocytic lymphoma treated with fludarabine. Both classical Hodgkin lymphoma and plasmablastic lymphoma were positive for Epstein-Barr virus-encoded RNA, whereas classical Hodgkin lymphoma was also positive for Epstein-Barr virus- latent membrane protein 1, suggesting a different viral latency. Immunoglobulin gene rearrangement studies demonstrated distinct clones in the plasmablastic lymphoma and chronic lymphocytic leukemia/small lymphocytic lymphoma. These findings suggest biclonal secondary lymphomas associated with iatrogenic immunodeficiency. Epstein-Barr virus-B-cell lymphoproliferative disorders in the setting of chronic lymphocytic leukemia/small lymphocytic lymphoma, in particular those arising after chemotherapy, should be separated from true Richter's transformation, and be categorized as (iatrogenic) immunodeficiency-associated lymphoproliferative disorder.

  3. The sesquiterpene lactone parthenolide induces selective apoptosis of B-chronic lymphocytic leukemia cells in vitro.

    PubMed

    Steele, A J; Jones, D T; Ganeshaguru, K; Duke, V M; Yogashangary, B C; North, J M; Lowdell, M W; Kottaridis, P D; Mehta, A B; Prentice, A G; Hoffbrand, A V; Wickremasinghe, R G

    2006-06-01

    We have studied the in vitro actions of the sesquiterpene lactone parthenolide (PTL) on cells isolated from patients with chronic lymphocytic leukemia (CLL). Dye reduction viability assays showed that the median LD(50) for PTL was 6.2 muM (n=78). Fifteen of these isolates were relatively resistant to the conventional agent chlorambucil but retained sensitivity to PTL. Brief exposures to PTL (1-3 h) were sufficient to induce caspase activation and commitment to cell death. Chronic lymphocytic leukemia cells were more sensitive towards PTL than were normal T lymphocytes or CD34(+) haematopoietic progenitor cells. The mechanism of cell killing was via PTL-induced generation of reactive oxygen species, resulting in turn in a proapoptotic Bax conformational change, release of mitochondrial cytochrome c and caspase activation. Parthenolide also decreased nuclear levels of the antiapoptotic transcription factor nuclear factor-kappa B and diminished phosphorylation of its negative regulator IkappaB. Killing of CLL cells by PTL was apparently independent of p53 induction. This is the first report showing the relative selectivity of PTL towards CLL cells. The data here warrant further investigation of this class of natural product as potential therapeutic agents for CLL.

  4. Simultaneous presentation of kappa-restricted chronic lymphocytic leukemia and lambda light chain AL amyloidosis.

    PubMed

    von Keudell, Gottfried; Sanchorawala, Vaishali; O'Hara, Carl; C Seldin, David; Sloan, J Mark

    2014-06-01

    We report on a 58-year-old man who presented with simultaneous kappa-restricted chronic lymphocytic leukemia (CLL) and a lambda-restricted plasma cell dyscrasia causing AL amyloidosis involving the kidney and GI tract. While monoclonal immunoglobulins occasionally produced by CLL has previously been implicated in AL amyloidosis, this is the first case of AL amyloidosis resulting from a distinct plasma cell dyscrasia that is not clonally related to the concurrent CLL. Appropriate treatment depended on detailed pathologic diagnosis of both disease processes.

  5. Pilot experience with continuous infusion alemtuzumab in patients with fludarabine-refractory chronic lymphocytic leukemia.

    PubMed

    Ferrajoli, Alessandra; Wierda, William G; LaPushin, Ruth; O'Brien, Susan M; Faderl, Stefan; Browning, Mary L; Keating, Michael J

    2008-04-01

    We evaluated the activity and tolerability of alemtuzumab given as a continuous infusion for 7 d followed by subcutaneous administration for 11 wk as salvage therapy for 10 patients with fludarabine-refractory chronic lymphocytic leukemia. The continuous infusion of alemtuzumab was well tolerated. The typical infusion reaction seen with intravenous alemtuzumab was abolished. Two patients achieved a partial response with an overall response rate of 20%. Alemtuzumab levels were measured in four patients and detectable levels were obtained in three. Clinical activity needs to be confirmed in a larger patient population.

  6. Chronic Lymphocytic Leukemia as an Unusual Cause of Rapid Airway Compromise

    PubMed Central

    Ezzell, Erin E.; Renshaw, John S.

    2017-01-01

    Chronic Lymphocytic Leukemia (CLL) is the most prevalent form of non-Hodgkin's lymphoma (NHL) in Western countries predominantly affecting adults over the age of 65. CLL is commonly indolent in nature but can present locally and aggressively at extranodal sites. Although CLL may commonly present with cervical lymphadenopathy, manifestation in nonlymphoid regions of the head and neck is not well described. CLL causing upper airway obstruction is even more uncommon. We describe a case of a patient with known history of CLL and stable lymphocytosis that developed an enlarging lymphoid base of tongue (BOT) mass resulting in rapid airway compromise.

  7. Interesting coincidence of atypical TSH-secreting pituitary adenoma and chronic lymphocytic leukemia.

    PubMed

    Bolanowski, Marek; Zieliński, Grzegorz; Jawiarczyk-Przybyłowska, Aleksandra; Maksymowicz, Maria; Potoczek, Stanisław; Syrycka, Joanna; Podgórski, Jan K

    2014-01-01

    Thyrotropin-secreting adenomas (TSH-oma) are very rare pituitary tumours. They are macroadenomas usually presenting with signs and symptoms of hyperthyroidism, and mass effects. They can co-secrete other hormones such as growth hormone or prolactin. Different malignancies, including haematological ones, are reported in patients with pituitary diseases. Chronic lymphocytic leukemia (CLL) occurs mostly in older patients, more often in males. CLL is associated with increased risk of second malignancies such as other blood neoplasms, skin and solid tumours. We present a successful neurosurgical outcome in a patient with an interesting coincidence of atypical TSH-oma and asymptomatic CLL.

  8. The planar cell polarity pathway drives pathogenesis of chronic lymphocytic leukemia by the regulation of B-lymphocyte migration.

    PubMed

    Kaucká, Markéta; Plevová, Karla; Pavlová, Sárka; Janovská, Pavlína; Mishra, Archana; Verner, Jan; Procházková, Jirina; Krejcí, Pavel; Kotasková, Jana; Ovesná, Petra; Tichy, Boris; Brychtová, Yvona; Doubek, Michael; Kozubík, Alois; Mayer, Jirí; Pospísilová, Sárka; Bryja, Vítezslav

    2013-03-01

    The planar cell polarity (PCP) pathway is a conserved pathway that regulates cell migration and polarity in various contexts. Here we show that key PCP pathway components such as Vangl2, Celsr1, Prickle1, FZD3, FZD7, Dvl2, Dvl3, and casein kinase 1 (CK1)-ε are upregulated in B lymphocytes of patients with chronic lymphocytic leukemia (CLL). Elevated levels of PCP proteins accumulate in advanced stages of the disease. Here, we show that PCP pathway is required for the migration and transendothelial invasion of CLL cells and that patients with high expression of PCP genes, FZD3, FZD7, and PRICKLE1, have a less favorable clinical prognosis. Our findings establish that the PCP pathway acts as an important regulator of CLL cell migration and invasion. PCP proteins represent an important class of molecules regulating pathogenic interaction of CLL cells with their microenvironment.

  9. TCL1 transgenic mouse model as a tool for the study of therapeutic targets and microenvironment in human B-cell chronic lymphocytic leukemia

    PubMed Central

    Bresin, A; D'Abundo, L; Narducci, M G; Fiorenza, M T; Croce, C M; Negrini, M; Russo, G

    2016-01-01

    Chronic lymphocytic leukemia (CLL) is a B-cell malignancy with a mature phenotype. In spite of its relatively indolent nature, no radical cure is as yet available. CLL is not associated with either a unique cytogenetic or a molecular defect, which might have been a potential therapeutic target. Instead, several factors are involved in disease development, such as environmental signals which interact with genetic abnormalities to promote survival, proliferation and an immune surveillance escape. Among these, PI3-Kinase signal pathway alterations are nowadays considered to be clearly important. The TCL1 gene, an AKT co-activator, is the cause of a mature T-cell leukemia, as well as being highly expressed in all B-CLL. A TCL1 transgenic mouse which reproduces leukemia with a distinct immunophenotype and similar to the course of the human B-CLL was developed several years ago and is widely used by many groups. This is a review of the CLL biology arising from work of many independent investigators who have used TCL1 transgenic mouse model focusing on pathogenetic, microenviroment and therapeutic targets. PMID:26821067

  10. TCL1 transgenic mouse model as a tool for the study of therapeutic targets and microenvironment in human B-cell chronic lymphocytic leukemia.

    PubMed

    Bresin, A; D'Abundo, L; Narducci, M G; Fiorenza, M T; Croce, C M; Negrini, M; Russo, G

    2016-01-28

    Chronic lymphocytic leukemia (CLL) is a B-cell malignancy with a mature phenotype. In spite of its relatively indolent nature, no radical cure is as yet available. CLL is not associated with either a unique cytogenetic or a molecular defect, which might have been a potential therapeutic target. Instead, several factors are involved in disease development, such as environmental signals which interact with genetic abnormalities to promote survival, proliferation and an immune surveillance escape. Among these, PI3-Kinase signal pathway alterations are nowadays considered to be clearly important. The TCL1 gene, an AKT co-activator, is the cause of a mature T-cell leukemia, as well as being highly expressed in all B-CLL. A TCL1 transgenic mouse which reproduces leukemia with a distinct immunophenotype and similar to the course of the human B-CLL was developed several years ago and is widely used by many groups. This is a review of the CLL biology arising from work of many independent investigators who have used TCL1 transgenic mouse model focusing on pathogenetic, microenviroment and therapeutic targets.

  11. t(14;18)(q32;q21) in chronic lymphocytic leukemia patients: Report of two cases and a literature review

    PubMed Central

    Chen, Weifeng; Miao, Yi; Wang, Rong; Wu, Yujie; Qiu, Hairong; Xu, Wei; Li, Jianyong; Fan, Lei; Xu, Xin

    2016-01-01

    The chromosomal abnormality t(14;18)(q32;q21) is most commonly associated with germinal center-derived B-cell lymphomas, particularly follicular lymphoma (FL). Generally, it is considered a hallmark of FL. The t(14;18)(q32;q21) translocation is rare in chronic lymphocytic leukemia (CLL) and its prognostic significance remains unclear. In the present study, two cases of CLL with t(14;18)(q32;q21) were diagnosed using conventional cytogenetic analysis and fluorescence in situ hybridization. Both patients presented with leukemia and the morphological features and immunophenotypes were typical of CLL. Case 2 underwent a further lymph node biopsy, which established a diagnosis of CD5– CLL/small lymphocyte lymphoma. In addition to t(14;18)(q32;q21), trisomy 12 was identified in the same clone in Case 2. Both cases exhibited immunoglobulin heavy chain variable mutations, and heavy-chain variable region gene (VH) 4–39 and VH3-62 were used in Case 1 and Case 2, respectively. In addition, direct Sanger sequencing of exons 4–9 revealed that Case 2 harbored the tumor protein p53 mutation, c.829T>G. Both cases had indications for therapy. Case 1 responded well to chlorambucil treatment, and was still alive at the last follow-up. Conversely, Case 2 exhibited aggressive disease that appeared refractory to treatment, and eventually succumbed to the disease. PMID:28105149

  12. Idelalisib therapy of indolent B-cell malignancies: chronic lymphocytic leukemia and small lymphocytic or follicular lymphomas

    PubMed Central

    Madanat, Yazan F; Smith, Mitchell R; Almasan, Alexandru; Hill, Brian T

    2016-01-01

    Chronic lymphocytic leukemia, small lymphocytic lymphoma, and follicular lymphoma are indolent B-cell lymphoproliferative disorders that mainly affect an older population. Although the majority of patients in need of treatment derive significant benefit from conventional chemotherapeutic agents as well as monoclonal antibodies, less toxic and more effective treatments are needed. Novel agents that inhibit the B-cell receptor signaling pathway have shown promising outcomes in these disorders. Idelalisib is a potent selective oral inhibitor of phosphatidylinositol 3-kinase delta and has shown significant clinical activity in B-cell malignancies. In this review, we summarize the clinical trial data using idelalisib as monotherapy or in combination with rituximab for the treatment of relapsed/refractory disease. The adverse effect profile includes autoimmune disorders such as transaminitis, colitis, and pneumonitis. Given the efficacy and manageable toxicity profile of idelalisib, it is being increasingly incorporated into the management of indolent B-cell malignancies. PMID:27375364

  13. [Successful treatment with rituximab for autoimmune hemolytic anemia associated with chronic lymphocytic leukemia].

    PubMed

    Tanaka, Yuko; Ito, Yoshikazu; Yoshizawa, Sei-ichiro; Fujimoto, Hiroaki; Gotoh, Moritaka; Tauchi, Tetsuzo; Kimura, Yukihiko; Ohyashiki, Kazuma

    2013-02-01

    A 68-year-old man was diagnosed with chronic lymphocytic leukemia (CLL) 3 years ago. His course was progressive, and he was complicated with autoimmune hemolytic anemia (AIHA). After the lack of efficacy of prednisone and cyclo-phosphamide, rituximab (375mg/m(2)) was administered based on the presence of CD20 positive leukemic cells by flow cytometric analysis of bone marrow. During 4 courses of rituximab administration, both anemia and hemolysis improved dramatically. Furthermore, the percentage of CLL cells in his peripheral blood was reduced. Rituximab may be one of the effective treatments for CLL associated AIHA in Japan as well as in foreign countries.

  14. Contribution of MLPA to routine diagnostic testing of recurrent genomic aberrations in chronic lymphocytic leukemia.

    PubMed

    Véronèse, Lauren; Tournilhac, Olivier; Combes, Patricia; Prie, Nolwen; Pierre-Eymard, Eléonore; Guièze, Romain; Veyrat-Masson, Richard; Bay, Jacques-Olivier; Vago, Philippe; Tchirkov, Andreï

    2013-01-01

    To better define the place of multiplex ligation-dependent probe amplification (MLPA) in routine cytogenetic diagnosis in chronic lymphocytic leukemia (CLL), we compared MLPA and fluorescence in situ hybridization (iFISH) data obtained in 77 CLL patients. Although MLPA detected most recurrent copy number genomic aberrations (90.9%), false-negative results were found in cases with small-size abnormal clones and false-positive MLPA findings resulting from point mutations (TP53) or an apparent lack of probe specificity (chromosome 19) were observed. Thus, MLPA may be a useful complementary but not alternative approach for iFISH testing of genomic aberration in CLL.

  15. Chronic lymphocytic leukemia cells diversify and differentiate in vivo via a nonclassical Th1-dependent, Bcl-6–deficient process

    PubMed Central

    Patten, Piers E.M.; Ferrer, Gerardo; Chen, Shih-Shih; Simone, Rita; Marsilio, Sonia; Yan, Xiao-Jie; Gitto, Zachary; Yuan, Chaohui; Kolitz, Jonathan E.; Barrientos, Jacqueline; Allen, Steven L.; Rai, Kanti R.; MacCarthy, Thomas; Chu, Charles C.

    2016-01-01

    Xenografting primary tumor cells allows modeling of the heterogeneous natures of malignant diseases and the influences of the tissue microenvironment. Here, we demonstrate that xenografting primary chronic lymphocytic leukemia (CLL) B lymphocytes with activated autologous T cells into alymphoid mice results in considerable CLL B cell division and sizable T cell expansion. Nevertheless, most/all CD5+CD19+ cells are eventually lost, due in part to differentiation into antibody-secreting plasmablasts/plasma cells. CLL B cell differentiation is associated with isotype class switching and development of new IGHV-D-J mutations and occurs via an activation-induced deaminase-dependent pathway that upregulates IRF4 and Blimp-1 without appreciable levels of the expected Bcl-6. These processes were induced in IGHV-unmutated and IGHV-mutated clones by Th1-polarized T-bet+ T cells, not classical T follicular helper (Tfh) cells. Thus, the block in B cell maturation, defects in T cell action, and absence of antigen-receptor diversification, which are often cardinal characteristics of CLL, are not inherent but imposed by external signals and the microenvironment. Although these activities are not dominant features in human CLL, each occurs in tissue proliferation centers where the mechanisms responsible for clonal evolution operate. Thus, in this setting, CLL B cell diversification and differentiation develop by a nonclassical germinal center–like reaction that might reflect the cell of origin of this leukemia. PMID:27158669

  16. Concurrent nephrotic syndrome and acute renal failure caused by chronic lymphocytic leukemia (CLL): a case report and literature review.

    PubMed

    Dou, Xianrui; Hu, Haitang; Ju, Yongle; Liu, Yongdong; Kang, Kaifu; Zhou, Shufeng; Chen, Wenfang

    2011-10-13

    Kidney injury associated with lymphocytic leukemia (CLL) is typically caused by direct tumor infiltration which occasionally results in acute renal failure. Glomerular involvement presenting as proteinuria or even nephrotic syndrome is exceptionally rare. Here we report a case of 54-year-old male CLL patient with nephrotic syndrome and renal failure. The lymph node biopsy confirmed that the patients had CLL with remarkable immunoglobulin light chain amyloid deposition. The renal biopsy demonstrated the concurrence of AL amyloidosis and neoplastic infiltration. Combined treatment of fludarabine, cyclophosphamide and rituximab resulted in remission of CLL, as well as the renal disfunction and nephrotic syndrome, without recurrence during a 12-month follow-up. To our knowledge, this is the first case of CLL patient showing the nephrotic syndrome and acute renal failure caused by AL amyloidosis and neoplastic infiltration. Though AL amyloidosis caused by plasma cell dyscrasia usually responses poorly to chemotherapy, this patient exhibited a satisfactory clinical outcome due to successful inhibition of the production of amylodogenic light chains by combined chemotherapy.

  17. JAK2 V617F detected in two B-cell chronic lymphocytic leukemia patients without coexisting Philadelphia chromosome-negative myeloproliferative neoplasms: A report of two cases

    PubMed Central

    YANG, YI-NING; QIN, YOU-WEN; WANG, CHUN

    2014-01-01

    The JAK2 V617F mutation has been observed in patients with Philadelphia chromosome-negative myeloproliferative neoplasms (Ph-MPNs), including polycythemia vera, essential thrombocythemia and idiopathic myelofibrosis. This mutation has also been observed in a small number of other myeloid malignancies, such as acute myeloid leukemia, chronic myeloid leukemia and myelodysplastic syndrome. The JAK2 V617F allele has rarely been evaluated in lymphoproliferative disorders. In total, 28 JAK2 V617F-positive B-cell lymphocytic leukemia (B-CLL) patients have previously been reported and all presented with Ph-MPN concomitantly. However, following investigation of the JAK2 V617F mutation in 63 B-CLL patients at the Shanghai First People’s Hospital (Shanghai, China) between January 2008 and December 2012 via allele-specific polymerase chain reaction, two B-CLL patients without a history of Ph-MPN were identified to carry the JAK2 V617F allele. PMID:25013507

  18. Immunoglobulin heavy chain variable gene usage and (super)-antigen drive in chronic lymphocytic leukemia.

    PubMed

    Bühler, Andreas; Zenz, Thorsten; Stilgenbauer, Stephan

    2010-01-15

    Increasing evidence supports the prognostic relevance of specific immunoglobulin heavy chain variable (IGHV) genes or stereotyped B-cell receptors (BCR) in chronic lymphocytic leukemia (CLL). The clonotypic BCRs differ in their specificity and affinity toward classical antigens and/or superantigens. The BCR-triggered mechanisms are distinct but could explain in part the different clinical behavior among CLL subgroups.

  19. Computational identification of CDR3 sequence archetypes among immunoglobulin sequences in chronic lymphocytic leukemia.

    PubMed

    Messmer, Bradley T; Raphael, Benjamin J; Aerni, Sarah J; Widhopf, George F; Rassenti, Laura Z; Gribben, John G; Kay, Neil E; Kipps, Thomas J

    2009-03-01

    The leukemia cells of unrelated patients with chronic lymphocytic leukemia (CLL) display a restricted repertoire of immunoglobulin (Ig) gene rearrangements with preferential usage of certain Ig gene segments. We developed a computational method to rigorously quantify biases in Ig sequence similarity in large patient databases and to identify groups of patients with unusual levels of sequence similarity. We applied our method to sequences from 1577 CLL patients through the CLL Research Consortium (CRC), and identified 67 similarity groups into which roughly 20% of all patients could be assigned. Immunoglobulin light chain class was highly correlated within all groups and light chain gene usage was similar within sets. Surprisingly, over 40% of the identified groups were composed of somatically mutated genes. This study significantly expands the evidence that antigen selection shapes the Ig repertoire in CLL.

  20. Clinical significance of LAIR1 (CD305) as assessed by flow cytometry in a prospective series of patients with chronic lymphocytic leukemia

    PubMed Central

    Perbellini, Omar; Falisi, Erika; Giaretta, Ilaria; Boscaro, Elisa; Novella, Elisabetta; Facco, Monica; Fortuna, Stefania; Finotto, Silvia; Amati, Eliana; Maniscalco, Francesco; Montaldi, Anna; Alghisi, Alberta; Aprili, Fiorenza; Bonaldi, Laura; Paolini, Rossella; Scupoli, Maria Teresa; Trentin, Livio; Ambrosetti, Achille; Semenzato, Gianpietro; Pizzolo, Giovanni; Rodeghiero, Francesco; Visco, Carlo

    2014-01-01

    Most patients affected by chronic lymphocytic leukemia are diagnosed by flow cytometry. Several immunophenotypic markers have been identified as significant and independent prognostic variables, especially from retrospective cohorts. However, while attractive because their detection is inexpensive and feasible in most laboratories, only few have been validated by independent series. The expression of leukocyte-associated immunoglobulin-like receptor-1 (also known as LAIR1, LAIR-1 or CD305), an inhibitor of B-cell receptor-mediated signaling, has been reported to be lacking in high-risk chronic lymphocytic leukemia. However, its correlation with biological variables and its prognostic significance remain unknown. We investigated 311 consecutive patients, prospectively enrolled since 2007. Methods for studying patients were standardized and included clinical assessment, immunophenotype, fluorescence in situ hybridization, and status of immunoglobulin heavy chain variable region genes. Overall, 22.1% of patients had Binet stage B or C disease, 38.5% had unmutated immunoglobulin genes, 15.1% had high-risk cytogenetic abnormalities, 23.4% were CD38+, 37.8% CD49d+, and 59.8% LAIR1+. Expression of LAIR1 was inversely related to that of CD38 (P=0.0005), but was not associated with CD49d expression (P=0.96). A significantly lower expression of LAIR1 was observed in patients with Binet stage B or C disease (P=0.023), and in the presence of high-risk cytogenetic abnormalities (P=0.048) or unmutated immunoglobulin heavy chain variable region genes (P<0.0001). At univariate analysis LAIR1+ was significantly associated with longer time to first treatment (P=0.0002). This favorable effect of LAIR1+ was confirmed by multivariate analysis (hazard ratio=2.1, P=0.03 for LAIR1). Our results indicate that LAIR1 expression is a reliable and inexpensive marker capable of independently predicting time to first treatment in newly diagnosed unselected patients with chronic lymphocytic

  1. Role of microRNA in chronic lymphocytic leukemia onset and progression.

    PubMed

    Balatti, Veronica; Pekarky, Yuri; Croce, Carlo M

    2015-02-20

    B-cell chronic lymphocytic leukemia (CLL) is the most common human leukemia occurring as indolent or aggressive form. CLL clinical features and genetic abnormalities are well documented, but molecular details are still under investigation. MicroRNAs are small non-coding RNAs involved in several cellular processes and expressed in a tissue-specific manner. MicroRNAs regulate gene expression, and their deregulation can alter expression levels of genes involved in development/progression of tumors. In CLL, microRNAs can function as oncogenes or tumor suppressors and can also serve as markers for CLL onset/progression. Here, we discuss the most recent findings about the role of microRNAs in CLL and how this knowledge can be used to identify new biomarkers and treatment approaches.

  2. Perspectives on the use of new diagnostic tools in the treatment of chronic lymphocytic leukemia.

    PubMed

    Binet, Jacques-Louis; Caligaris-Cappio, Federico; Catovsky, Daniel; Cheson, Bruce; Davis, Tom; Dighiero, Guillaume; Döhner, Hartmut; Hallek, Michael; Hillmen, Peter; Keating, Michael; Montserrat, Emili; Kipps, Thomas J; Rai, Kanti

    2006-02-01

    Recently, considerable progress has been made in the identification of molecular and cellular markers that may predict the tendency for disease progression in patients with chronic lymphocytic leukemia (CLL) or detect minimal residual disease after therapy. These developments have created uncertainty for clinicians who hope to incorporate the use of these markers and new disease-assessment tools into standard clinical practice. However, clinical trials are required to determine whether poor-prognosis leukemia-cell markers, such as expression of unmutated immunoglobulin genes or the zeta-associated protein of 70 kDa (ZAP-70), can be used as the basis for determining the time or type of therapy. Pending the outcome of such trials, treatment decisions outside the context of a clinical trial still should be based on guidelines established by the most recent National Cancer Institute-sponsored Working Group.

  3. Diagnosis of Large Granular Lymphocytic Leukemia in a Patient Previously Treated for Acute Myeloblastic Leukemia

    PubMed Central

    Bozdag, Sinem Civriz; Namdaroglu, Sinem; Kayikci, Omur; Kaygusuz, Gülsah; Demiriz, Itir; Cinarsoy, Murat; Tekgunduz, Emre; Altuntas, Fevzi

    2013-01-01

    Large granular lymphocytic (LGL) leukemia is a lymphoproliferative disease characterized by the clonal expansion of cytotoxic T or natural killer cells. We report on a patient diagnosed with T-cell LGL leukemia two years after the achievement of hematologic remission for acute myeloblastic leukemia. PMID:24416499

  4. Clinical role of obinutuzumab in the treatment of naive patients with chronic lymphocytic leukemia.

    PubMed

    Cerquozzi, Sonia; Owen, Carolyn

    2015-01-01

    The introduction of targeted therapy against CD20(+) with the monoclonal antibody rituximab has dramatically improved the survival of B-cell non-Hodgkin lymphoma including chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma. Unfortunately, CLL remains incurable with chemoimmunotherapy, with many patients having refractory or relapsing disease after rituximab-containing therapy. Obinutuzumab (GA101) is a novel humanized Type II anti-CD20 monoclonal antibody that has been investigated and compared to rituximab. Here, we provide an overview of obinutuzumab, including its mechanisms of action, preclinical data, and Phase I to III clinical studies. Preclinical data illustrate obinutuzumab's higher potency compared to rituximab through antibody-dependent cellular cytotoxicity and direct cell death. Recently, the CLL11 study presented a significant benefit from obinutuzumab chemoimmunotherapy and supports its use for treatment-naive unfit CLL patients. Herein, we review that obinutuzumab is both a safe and effective alternative to rituximab.

  5. Improving Therapy of Chronic Lymphocytic Leukemia (CLL) with Chimeric Antigen Receptor (CAR) T Cells

    PubMed Central

    Fraietta, Joseph A.; Schwab, Robert D.; Maus, Marcela V.

    2016-01-01

    Adoptive cell immunotherapy for the treatment of chronic lymphocytic leukemia (CLL) has heralded a new era of synthetic biology. The infusion of genetically-engineered, autologous chimeric antigen receptor (CAR) T cells directed against CD19 expressed by normal and malignant B cells represents a novel approach to cancer therapy. The results of recent clinical trials of CAR T cells in relapsed and refractory CLL have demonstrated long-term disease-free remissions, underscoring the power of harnessing and re-directing the immune system against cancer. This review will briefly summarize T cell therapies in development for CLL disease. We discuss the role of T cell function and phenotype, T cell culture optimization, CAR design, and approaches to potentiate the survival and anti-tumor effects of infused lymphocytes. Future efforts will focus on improving the efficacy of CAR T cells for the treatment of CLL and incorporating adoptive cell immunotherapy into standard medical management of CLL. PMID:27040708

  6. The histone deacetylase inhibitor suberoylanilide hydroxamic acid induces apoptosis, down-regulates the CXCR4 chemokine receptor and impairs migration of chronic lymphocytic leukemia cells

    PubMed Central

    Stamatopoulos, Basile; Meuleman, Nathalie; De Bruyn, Cécile; Delforge, Alain; Bron, Dominique; Lagneaux, Laurence

    2010-01-01

    Background Chronic lymphocytic leukemia is a neoplastic disorder that arises largely as a result of defective apoptosis leading to chemoresistance. Stromal cell-derived factor-1 and its receptor, CXCR4, have been shown to play an important role in chronic lymphocytic leukemia cell trafficking and survival. Design and Methods Since histone acetylation is involved in the modulation of gene expression, we evaluated the effects of suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, on chronic lymphocytic leukemia cells and in particular on cell survival, CXCR4 expression, migration, and drug sensitization. Results Here, we showed that treatment with suberoylanilide hydroxamic acid (20 μM) for 48 hours induced a decrease in chronic lymphocytic leukemia cell viability via apoptosis (n=20, P=0.0032). Using specific caspase inhibitors, we demonstrated the participation of caspases-3, -6 and -8, suggesting an activation of the extrinsic pathway. Additionally, suberoylanilide hydroxamic acid significantly decreased CXCR4 mRNA (n=10, P=0.0010) and protein expression (n=40, P<0.0001). As a result, chronic lymphocytic leukemia cell migration in response to stromal cell-derived factor-1 (n=23, P<0.0001) or through bone marrow stromal cells was dramatically impaired. Consequently, suberoylanilide hydroxamic acid reduced the protective effect of the microenvironment and thus sensitized chronic lymphocytic leukemia cells to chemotherapy such as fludarabine. Conclusions In conclusion, suberoylanilide hydroxamic acid induces apoptosis in chronic lymphocytic leukemia cells via the extrinsic pathway and down-regulates CXCR4 expression leading to decreased cell migration. Suberoylanilide hydroxamic acid in combination with other drugs represents a promising therapeutic approach to inhibiting migration, chronic lymphocytic leukemia cell survival and potentially overcoming drug resistance. PMID:20145270

  7. Characterization and prognostic relevance of circulating microvesicles in chronic lymphocytic leukemia.

    PubMed

    De Luca, Luciana; D'Arena, Giovanni; Simeon, Vittorio; Trino, Stefania; Laurenzana, Ilaria; Caivano, Antonella; La Rocca, Francesco; Villani, Oreste; Mansueto, Giovanna; Deaglio, Silvia; Innocenti, Idanna; Laurenti, Luca; Molica, Stefano; Pietrantuono, Giuseppe; De Stradis, Angelo; Del Vecchio, Luigi; Musto, Pellegrino

    2017-06-01

    Microvescicles (MV) are shedding particles released by normal and neoplastic cells, whose levels in biological fluids highlight their potential role as disease biomarkers and therapeutic targets. By analyzing 131 newly diagnosed chronic lymphocytic leukemia (CLL), we found that the absolute number of serum CLL MV was significantly higher than in controls, in particular in advanced stages of disease. In addition, CD19 + and CD37+, B-cell derived MV, significantly correlated with high tumor burden. Absolute MV number cutoff selected by ROC analysis distinguished Rai stage 0 patients with shorter time to treatment (TTT) from those with more stable disease. Likewise, in the entire cohort, two groups of patients with different overall survival (OS) and different TTT were identified. At multivariate analysis, serum MV independently predicted for OS (along with Rai stage) and TTT (along with Rai stage, lymphocytes and CD38). In conclusion, circulating MV represent a new potential prognostic biomarker in CLL.

  8. CD40 ligand, Bcl-2 and apoptosis in B-chronic lymphocytic leukemia.

    PubMed

    Hussein, Ola A; Omran, Alaa A; Elnaggar, Amina M; Fathy, Ayman

    2009-01-01

    Chronic lymphocytic leukemia (CLL) is a haematopoetic neoplasm caused primarily by defects in apoptosis mechanisms and complicated by progressive marrow failure, immunosupression and increased resistance to chemotherapy. The CD40-CD40 ligand (CD40L) interaction has been shown to significantly increase antigen presentation in normal and malignant B-cells and it is a powerful regulator of cell survival. Bcl-2 expression is common in CLL and is associated with decreased overall survival. Our objective was to asses CD40 ligand (CD154) and Bcl-2 expressions and their correlation with clinical and laboratory features in CLL patients. This study was conducted on 40 subjects, including 10 healthy volunteers as the control group and 30 patients presented with de novo chronic lymphocytic leukemia (CLL), all of them were subjected to thorough history taking, full clinical examinations, routine laboratory investigations and flowcytometric assessment of CD40L and Bcl-2 on lymphocytes. There was a highly significant increase in TLC, absolute lymphocytic count, serum LDH, B2-microglobulin and Bcl-2 expression (P<0.001); there was a significant increase in CD40L expression (P<0.05); whereas there was a highly significant decrease in hemoglobin concentration and platelets count between the study group (P<0.001). There was no significant difference as regard direct Coombs' test between both groups. There was no significant relation between CD154 expression and clinical findings, Rai staging system and other laboratory parameters. CD40L expression is increased with staging of Modified Rai staging system but not reaching the significant level. There was no significant correlation between CD154 expression and some of clinical and laboratory parameters, whereas there was only significantly negative correlation between Bcl-2 expression and both haemoglobin concentration and platelets count (P<0.001). Combination of Bcl-2 antisense oligonucleotide with conventional chemotherapeutic drugs

  9. Acute Lymphocytic Leukemia

    MedlinePlus

    ... hard for blood to do its work. In acute lymphocytic leukemia (ALL), also called acute lymphoblastic leukemia, there are too ... of white blood cells called lymphocytes or lymphoblasts. ALL is the most common type of cancer in ...

  10. Obinutuzumab for chronic lymphocytic leukemia: promise of the first treatment approved with breakthrough therapy designation.

    PubMed

    Kakkar, Ashish Kumar; Balakrishnan, Sadasivam

    2015-10-01

    Obinutuzumab (also known as GA101, afutuzumab, Gazyva) is a humanized, glycoengineered type II monoclonal antibody targeted against CD20. The US Food and Drug Administration has approved obinutuzumab for use with chlorambucil in patients with previously untreated chronic lymphocytic leukemia. The drug is the first treatment to receive approval under the agency's breakthrough therapy designation, a program intended to facilitate and expedite the review and development of therapies for serious and life-threatening conditions. In preclinical studies, obinutuzumab has showed superior efficacy, as compared with rituximab, by inducing direct cell death and increased antibody-dependent cellular cytotoxicity activity with less complement-dependent cytotoxicity. Regulatory approval of obinutuzumab is based on a phase III (CLL11) study that demonstrated improved outcomes with a combination of obinutuzumab with chlorambucil in previously untreated patients with chronic lymphocytic leukemia and comorbidities. Obinutuzumab plus chlorambucil induced deeper and longer remissions than rituximab plus chlorambucil combination as evidenced by prolongation of progression-free survival and higher complete response and molecular response rates. Marketing applications for obinutuzumab have also been submitted to other regulatory authorities including the European Medicines Agency.

  11. Clinical utility and patient considerations in the use of ofatumumab in chronic lymphocytic leukemia

    PubMed Central

    Frustaci, Anna Maria; Tedeschi, Alessandra; Picardi, Paola; Cairoli, Roberto; Montillo, Marco

    2015-01-01

    Treatment aim for chronic lymphocytic leukemia has been radically changed over the past years from providing only a palliative approach to reaching disease eradication and improving survival. Ofatumumab is a monoclonal humanized antibody with peculiar in vitro and in vivo properties, at present approved for double fludarabine and alemtuzumab refractory chronic lymphocytic leukemia. Its efficacy in this subset of patients, who typically have an unfavorable prognosis, facilitated its use in different Phase II and III trials. Ofatumumab as single agent or combined with chemotherapeutic or biologic agents, led to sundry results in the setting of both previously treated or untreated patients. Its role in maintenance therapy is also under investigation. Further advances concerning ofatumumab administration as first line therapy in combination with chlorambucil, came recently from the COMPLEMENT 1 study. Results from this trial will open the door to new perspectives of its use in treatment-naïve patients. Ofatumumab was well tolerated in almost all the studies, with the main adverse events relating mostly to infusion reaction. Hematologic toxicity, especially neutropenia, was also common. A significant improvement in patients’ quality of life was reported following ofatumumab treatment and this was mainly due to its effect on constitutional symptoms. Nevertheless, some concerns remain regarding the long-term efficacy of the drug in terms of response duration and survival. The real strength of this drug needs to be confirmed by further studies and direct comparative trials. PMID:26425075

  12. A phase 1 study evaluating the safety and tolerability of otlertuzumab, an anti-CD37 mono-specific ADAPTIR therapeutic protein in chronic lymphocytic leukemia

    PubMed Central

    Pagel, John M.; Awan, Farrukh T.; Forero, Andres; Flinn, Ian W.; Deauna-Limayo, Delva P.; Spurgeon, Stephen E.; Andritsos, Leslie A.; Gopal, Ajay K.; Leonard, John P.; Eisenfeld, Amy J.; Bannink, Jeannette E.; Stromatt, Scott C.; Furman, Richard R.

    2014-01-01

    Otlertuzumab is a novel humanized anti-CD37 protein therapeutic. This study evaluated the safety of otlertuzumab administered intravenously to patients with chronic lymphocytic leukemia (CLL). Otlertuzumab was administered weekly for up to 8 weeks followed by 1 dose per month for 4 months ranging from 0.03 to 20 mg/kg in the dose-escalation phase and 10 to 30 mg/kg in the dose-expansion phase. Responses were determined by using the 1996 National Cancer Institute (NCI-96) and 2008 International Workshop on Chronic Lymphocytic Leukaemia (IWCLL) criteria. Fifty-seven patients were treated in the dose-escalation phase and 26 in the dose-expansion phase. A maximum-tolerated dose was not identified. Response occurred in 19 (23%) of 83 treated patients by NCI-96 criteria. All responses were partial and occurred more commonly in patients with symptomatic untreated CLL (6/7) or 1 to 2 prior therapies (12/28) vs 3 or more therapies (1/48). Twenty percent (12/61) with serial computed tomography scan assessment had a response per IWCLL criteria. The most frequent adverse events were infusion reactions, fatigue, nausea, and diarrhea and were not dose related. Otlertuzumab was well tolerated, and modest clinical activity was observed. Otlertuzumab warrants further evaluation in combination with other agents for the treatment of CLL. This trial was registered at www.clinicaltrials.gov as #NCT00614042. PMID:24381226

  13. Nuclear overexpression of lymphoid-enhancer-binding factor 1 identifies chronic lymphocytic leukemia/small lymphocytic lymphoma in small B-cell lymphomas.

    PubMed

    Tandon, Bevan; Peterson, Loann; Gao, Juehua; Nelson, Beverly; Ma, Shuo; Rosen, Steven; Chen, Yi-Hua

    2011-11-01

    Lymphoid-enhancer-binding factor 1 (LEF1), coupling with β-catenin, functions as a key nuclear mediator of WNT/β-catenin signaling, which regulates cell proliferation and survival. LEF1 has an important role in lymphopoiesis, and is normally expressed in T and pro-B cells but not mature B cells. However, gene expression profiling demonstrates overexpression of LEF1 in chronic lymphocytic leukemia, and knockdown of LEF1 decreases the survival of the leukemic cells. So far, the data on LEF1 expression in B-cell lymphomas are limited. This study represents the first attempt to assess LEF1 by immunohistochemistry in a large series (290 cases) of B-cell lymphomas. Strong nuclear staining of LEF1 was observed in virtually all neoplastic cells in 92 of 92 (100%) chronic lymphocytic leukemia/small lymphocytic lymphomas including two CD5- cases, with strongest staining in cells with Richter's transformation. LEF1 also highlighted the morphologically inconspicuous small lymphocytic lymphoma component in three composite lymphomas. All 53 mantle cell lymphomas, 31 low-grade follicular lymphomas and 31 marginal zone lymphomas, including 3 CD5+ cases, were negative. In 12 grade 3 follicular lymphomas, LEF1 was positive in a small subset (5-15%) of cells. Diffuse large B-cell lymphoma, however, demonstrated significant variability in LEF1 expression with overall positivity in 27 of 71 (38%) cases. Our results demonstrate that nuclear overexpression of LEF1 is highly associated with chronic lymphocytic leukemia/small lymphocytic lymphoma, and may serve as a convenient marker for differential diagnosis of small B-cell lymphomas. The expression of β-catenin, the coactivator of LEF1 in WNT signaling, was examined in 50 chronic lymphocytic leukemia/small lymphocytic lymphomas, of which 44 (88%) showed negative nuclear staining. The findings of universal nuclear overexpression of LEF1 but lack of nuclear β-catenin in the majority of chronic lymphocytic leukemia/small lymphocytic

  14. B-cell chronic lymphocytic leukemia: recent progress in biology, diagnosis, and therapy.

    PubMed

    Montserrat, E; Bosch, F; Rozman, C

    1997-01-01

    B-cell chronic lymphocytic leukemia (CLL) is a highly common form of leukemia characterized by the accumulation of long-lived, functionally inactive, mature appearing neoplastic B lymphocytes. In addition, immune disturbances such as hypogammaglobulinemia and autoimmune phenomena (particularly, autoimmune hemolytic anemia) are frequently found in CLL patients [1-2]. The etiology of CLL is unknown. In contrast with other leukemias, there is no relationship between CLL and exposure to radiation or other cytotoxic agents. A genetic basis is highly likely since there are differences in the incidence of CLL in different countries (e.g., CLL accounts for 30%-40% of all the leukemias in Western countries as compared to 5%-10% in Asian countries) and the risk of contracting CLL is higher among persons with first-degree relatives with the disease [3]. Because the incidence of CLL increases with age and the longer life expectancy of the general population, the age of patients at diagnosis is increasing. The median age at diagnosis is now about 70 years, with only one-third of the patients being less than 60 years of age. In the majority of the series, males predominate over females in a proportion of 1.5/1. The prognosis of patients with CLL is variable. However, clinical stages and other prognostic factors allow the individual risk of each patient to be assessed very accurately, which is useful for making treatment decisions. In the past two decades, significant progress has been made in CLL [4-10]. This review summarizes recent advances in the biology, diagnosis, and therapy of CLL.

  15. miR-181b as a therapeutic agent for chronic lymphocytic leukemia in the Eµ-TCL1 mouse model.

    PubMed

    Bresin, Antonella; Callegari, Elisa; D'Abundo, Lucilla; Cattani, Caterina; Bassi, Cristian; Zagatti, Barbara; Narducci, M Grazia; Caprini, Elisabetta; Pekarsky, Yuri; Croce, Carlo M; Sabbioni, Silvia; Russo, Giandomenico; Negrini, Massimo

    2015-08-14

    The involvement of microRNAs (miRNAs) in chronic lymphocytic leukemia (CLL) pathogenesis suggests the possibility of anti-CLL therapeutic approaches based on miRNAs. Here, we used the Eµ-TCL1 transgenic mouse model, which reproduces leukemia with a similar course and distinct immunophenotype as human B-CLL, to test miR-181b as a therapeutic agent.In vitro enforced expression of miR-181b mimics induced significant apoptotic effects in human B-cell lines (RAJI, EHEB), as well as in mouse Eµ-TCL1 leukemic splenocytes. Molecular analyses revealed that miR-181b not only affected the expression of TCL1, Bcl2 and Mcl1 anti-apoptotic proteins, but also reduced the levels of Akt and phospho-Erk1/2. Notably, a siRNA anti-TCL1 could similarly down-modulate TCL1, but exhibited a reduced or absent activity in other relevant proteins, as well as a reduced effect on cell apoptosis and viability. In vivo studies demonstrated the capability of miR-181b to reduce leukemic cell expansion and to increase survival of treated mice.These data indicate that miR-181b exerts a broad range of actions, affecting proliferative, survival and apoptotic pathways, both in mice and human cells, and can potentially be used to reduce expansion of B-CLL leukemic cells.

  16. Outcomes of first line chemotherapy in patients with chronic lymphocytic leukemia

    PubMed Central

    Nazir, Adil; Fawad; Ali, Sheeraz; Badar, Farhana; Siddique, Neelam; Hameed, Abdul

    2016-01-01

    Objective: Chronic lymphocytic leukemia (CLL) is a heterogeneous disease in terms of survival with and without treatment. Many chemo and immunotherapeutic agents are available to treat this indolent disease. Aim of this study was to determine the outcomes of patients with chronic lymphocytic leukemia treated with different available chemotherapeutic regimens. Methods: All patients with diagnosis of CLL from 2008 to 2013 were included. Data were collected from hospital information system. Objective response rate (ORR) in terms of complete or partial response (CR, PR), stable or progressive disease (SD, PD), overall survival (OS), and progression free survival (PFS) were calculated. Results: Fifty seven patients were included; 42 (74%) male and 15 (26%) were female. Patients with Binet stage A 10 (18%); B 20 (35%) and C were 27(47%). Median age was 50.9 years. Forty six (80%) were treated and 11(20%) remained on watch and wait. Treatment indications were B symptoms 14 (30%), symptomatic nodal disease 18(39%), thrombocytopenia 4(9%), anemia 7(15%) and doubling of lymphocyte count 3 (7%). Chemotherapy regimens used were FC in 38 (83%), FCR 5(11%), chlorambucil 2(4%) and CVP in 1(2%) patient. Twenty two (56%) patients had CR, 13(33%) PR, 3(7.6 %) SD, and 1(2.5%) had PD. ORR was 89%. Median PFS was 23.1 months and median 3 years OS was 55%. Conclusion: Majority of patients was in a relatively younger age group and presented with advanced stage disease requiring treatment. Small number of patients received rituximab due to cost. PFS and OS are comparable with published literature. PMID:27882024

  17. Investigating the Targets of MIR-15a and MIR-16-1 in Patients with Chronic Lymphocytic Leukemia (CLL)

    PubMed Central

    Hanlon, Katy; Rudin, Claudius E.; Harries, Lorna W.

    2009-01-01

    Background MicroRNAs (miRNAs) are short, noncoding RNAs that regulate the expression of multiple target genes. Deregulation of miRNAs is common in human tumorigenesis. The miRNAs, MIR-15a/16-1, at chromosome band 13q14 are down-regulated in the majority of patients with chronic lymphocytic leukaemia (CLL). Methodology/Principal Findings We have measured the expression of MIR-15a/16-1, and 92 computationally-predicted MIR-15a/16-1 target genes in CLL patients and in normal controls. We identified 35 genes that are deregulated in CLL patients, 5 of which appear to be specific targets of the MIR-15a/16-1 cluster. These targets included 2 genes (BAZ2A and RNF41) that were significantly up-regulated (p<0.05) and 3 genes (RASSF5, MKK3 and LRIG1) that were significantly down-regulated (p<0.05) in CLL patients with down-regulated MIR-15a/16-1 expression. Significance The genes identified here as being subject to MIR-15a/16-1 regulation could represent direct or indirect targets of these miRNAs. Many of these are good biological candidates for involvement in tumorigenesis and as such, may be important in the aetiology of CLL. PMID:19779621

  18. A Two-Gene Signature, SKI and SLAMF1, Predicts Time-to-Treatment in Previously Untreated Patients with Chronic Lymphocytic Leukemia

    PubMed Central

    Schweighofer, Carmen D.; Coombes, Kevin R.; Barron, Lynn L.; Diao, Lixia; Newman, Rachel J.; Ferrajoli, Alessandra; O'Brien, Susan; Wierda, William G.; Luthra, Rajyalakshmi; Medeiros, L. Jeffrey; Keating, Michael J.; Abruzzo, Lynne V.

    2011-01-01

    We developed and validated a two-gene signature that predicts prognosis in previously-untreated chronic lymphocytic leukemia (CLL) patients. Using a 65 sample training set, from a cohort of 131 patients, we identified the best clinical models to predict time-to-treatment (TTT) and overall survival (OS). To identify individual genes or combinations in the training set with expression related to prognosis, we cross-validated univariate and multivariate models to predict TTT. We identified four gene sets (5, 6, 12, or 13 genes) to construct multivariate prognostic models. By optimizing each gene set on the training set, we constructed 11 models to predict the time from diagnosis to treatment. Each model also predicted OS and added value to the best clinical models. To determine which contributed the most value when added to clinical variables, we applied the Akaike Information Criterion. Two genes were consistently retained in the models with clinical variables: SKI (v-SKI avian sarcoma viral oncogene homolog) and SLAMF1 (signaling lymphocytic activation molecule family member 1; CD150). We optimized a two-gene model and validated it on an independent test set of 66 samples. This two-gene model predicted prognosis better on the test set than any of the known predictors, including ZAP70 and serum β2-microglobulin. PMID:22194822

  19. Inhibiting B-cell receptor signaling pathways in chronic lymphocytic leukemia.

    PubMed

    Burger, Jan A

    2012-03-01

    B-cell receptor (BCR) signaling is a central pathologic mechanism in B-cell malignancies, including chronic lymphocytic leukemia (CLL), in which it promotes leukemia cell survival and proliferation, and modulates CLL cell migration and tissue homing. BCR signaling now can be targeted with new, small molecule inhibitors of the spleen tyrosine kinase (Syk), Bruton's tyrosine kinase (Btk), or phosphoinositide 3'-kinase (PI3K) isoform p110δ (PI3Kδ), which have recently entered the clinical stage and show promising results in patients with CLL. During the first weeks of therapy, these agents characteristically induce rapid resolution of lymphadenopathy and organomegaly, accompanied by a transient surge in lymphocyte counts due to "mobilization" of tissue-resident CLL cells into the blood. Then, often after months of continuous therapy, a major proportion of patients achieve remissions. This article reviews key biologic aspects of BCR-associated kinases in CLL and other B cell neoplasias, and develops perspectives for future development of this exciting new class of kinase inhibitors.

  20. Ibrutinib, obinutuzumab, idelalisib, and beyond: review of novel and evolving therapies for chronic lymphocytic leukemia.

    PubMed

    Chung, Clement; Lee, Rosetta

    2014-12-01

    Chronic lymphocytic leukemia (CLL) is a neoplasm resulting from the progressive accumulation of functionally incompetent monoclonal B lymphocytes in the blood, bone marrow, lymph nodes, and spleen. It is the most common leukemia in Western countries and typically occurs in elderly patients. Initial treatment of CLL often includes a first-generation anti-CD20 antibody (rituximab) with chemotherapy and is the current standard of treatment for "younger" old adults (< 70 yrs of age) or older, clinically fit patients. However, because disease progression and drug resistance are inevitable, patients typically die from their disease or treatment-related complications. Improved understanding of the B-cell receptor signaling pathway, which is essential for normal B-cell growth and tumorigenesis, has led to the development of targeted therapies, with improved short-term clinical outcomes. Ibrutinib, obinutuzumab, and idelalisib, three novel agents recently approved by the U.S. Food and Administration for CLL, all have the potential to change the treatment paradigm. In this article, we describe the pathogenesis of CLL and some of its prognostic factors. Emphasis is on the pharmacology, dosing, clinical efficacy, safety, and place of therapy of ibrutinib, obinutuzumab, and idelalisib. Investigational agents that target different parts of the CLL pathogenic pathway are also described.

  1. 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

  2. Idelalisib and bendamustine combination is synergistic and increases DNA damage response in chronic lymphocytic leukemia cells.

    PubMed

    Modi, Prexy; Balakrishnan, Kumudha; Yang, Qingshan; Wierda, William G; Keating, Michael J; Gandhi, Varsha

    2017-02-07

    Idelalisib is a targeted agent that potently inhibits PI3Kδ which is exclusively expressed in hematological cells. Bendamustine is a well-tolerated cytotoxic alkylating agent which has been extensively used for treatment of chronic lymphocytic leukemia (CLL). Both these agents are FDA-approved for CLL. To increase the potency of idelalisib and bendamustine, we tested their combination in primary CLL lymphocytes. While each compound alone produced a moderate response, combination at several concentrations resulted in synergistic cytotoxicity. Idelalisib enhanced the bendamustine-mediated DNA damage/repair response, indicated by the phosphorylation of ATM, Chk2, and p53. Each drug alone activated γH2AX but combination treatment further increased the expression of this DNA damage marker. Compared with the control, idelalisib treatment decreased global RNA synthesis, resulting in a decline of early-response and short-lived MCL1 transcripts. In concert, there was a decline in total Mcl-1 protein in CLL lymphocytes. Isogenic mouse embryonic fibroblasts lacking MCL1 had higher sensitivity to bendamustine alone or in combination compared to MCL1 proficient cells. Collectively, these data indicate that bendamustine and idelalisib combination therapy should be investigated for treating patients with CLL.

  3. The composite lymphoma: chronic lymphocytic leukemia--classic Hodgkin's lymphoma.

    PubMed

    Badea, M; Dobrea, Camelia; Badea, Daniela; Genunche-Dumitrescu, Amelia; Mitruţ, P; Duţă, Doriana

    2010-01-01

    The composite lymphoma (CL) is defined by the presence in the same tissue or organ of two distinct histological aspects of non-Hodgkin's lymphoma (NHL), or NHL and Hodgkin's lymphoma (HL). The definition of the CL has evolved, requesting the identification of the immunophenotypic pattern and clonal distinct aspects for the two-lymphoproliferative lesions. We present a case of a 73-year-old farmer who presented with B-symptoms and multiple adenomegaly. The biopsy of a left cervical lymph node reveal a CL: a histological and immunophenotypic aspect of HL-mixed cellularity (CD15+, CD30+, CD20-) and a diffuse small cell infiltrate which meet the criteria for B-CLL (CD20+, CD23+, and CD5+). The lymphocytes in peripheral blood over 15 000/mm(3) and marrow infiltrate with small lymphocytes also sustain the B-CLL diagnosis. The relationship between the two lymphoproliferations is discussed reported to the case above, but also considering the literature data. In most of the cases the two proliferative processes are clonal related which means they have a commune lymphoid progenitor, pre-GC or early-GC with individual detachment and transit through GC (also, the afferent related processes). It is also possible that the two proliferations, which form the composite lesion to have different cellular origins, possibility sustained by the analysis of the IgH rearrangements and of the somatic mutations identified in the two clones. The EBV-role in HL-pathogeny is related to the way of salvage or/and initiation of a clonal process in a GC-cell which has major deletions in the variable part of IgH.

  4. Role of mir-15a/16-1 in early B cell development in a mouse model of chronic lymphocytic leukemia

    PubMed Central

    Underbayev, Chingiz; Kasar, Siddha; Ruezinsky, William; Degheidy, Heba; Schneider, Joel Solomon; Marti, Gerald; Bauer, Steven R.; Fraidenraich, Diego; Lightfoote, Marilyn M.; Parashar, Vijay; Raveche, Elizabeth; Batish, Mona

    2016-01-01

    In both human chronic lymphocytic leukemia (CLL) and the New Zealand Black (NZB) murine model of CLL, decreased levels of microRNAs miR-15a/16 play an important role in the disease. Here we investigate the effects of this microRNA on early steps of B cell development and the capacity of miR-15a-deficient hematopoietic stem cells (HSC) and B1 progenitor cells (B1P) to reproduce CLL-like phenotype both in vitro and in vivo. Our results demonstrate that both miR-15a deficient HSC and B1P cells are capable of repopulating irradiated recipients and produce higher numbers of B1 cells than sources with normal miR-15a/16 levels. Furthermore, induced pluripotent stem (iPS) cells derived for the first time from NZB mice, provided insights into the B cell differentiation roadblock inherent in this strain. In addition, exogenously delivered miR-15a into the NZB derived B cell line provided valuable clues into novel targets such as Mmp10 and Mt2. Our data supports the hypothesis that miR-15a/16 deficient stem cells and B1Ps experience a maturation blockage, which contributes to B1 cells bias in development. This work will help understand the role of miR-15a in early events of CLL and points to B1P cells as potential cells of origin for this incurable disease. PMID:27533467

  5. Oligonucleotide IMT504 induces an immunogenic phenotype and apoptosis in chronic lymphocytic leukemia cells.

    PubMed

    Rodriguez, Juan M; Elias, Fernanda; Montaner, Alejandro; Flo, Juan; Lopez, Ricardo A; Zorzopulos, Jorge; Franco, Raul J; Lenial, Silvina P; Lopez Salón, Mariella; Pirpignani, Maria L; Solimano, Jorge; Garay, Guy; Riveros, Dardo; Fernandez, Jose; Cacchione, Roberto; Dupont, Juan

    2006-01-01

    Oligonucleotides (ODNs) of the PyNTTTTGT class directly stimulate B lymphocytes and plasmacytoid dendritic cells of the immune system of primates. Here we investigated the ability of the PyNTTTTGT ODN prototype IMT504 to regulate the expression of surface molecules and apoptosis in human B-chronic lymphocytic leukemia (CLL) cells. The surface molecules CD25, CD40, CD80 and CD86 were up-regulated upon incubation of the B-CLL cells with IMT504. Co-stimulation with IL-2 resulted in further up-regulation. IMT504-activated B-CLL cells were also good stimulators of T cells in allogeneic mixed lymphocyte reactions and co-stimulation with IL-2 improved this stimulation capacity. Apoptosis of the B-CLL cells in vitro was also stimulated by incubation with IMT504. In this case, co-stimulation with IL-2 was not significant. Furthermore, B-CLL cells of all the patients studied developed an immunogenic phenotype and entered stimulated apoptosis upon in vitro incubation with IMT504 independently of the mutational status of their IgV(H) genes, becoming a good marker for tumor progression.

  6. Vorinostat and Decitabine in Treating Patients With Advanced Solid Tumors or Relapsed or Refractory Non-Hodgkin's Lymphoma, Acute Myeloid Leukemia, Acute Lymphocytic Leukemia, or Chronic Myelogenous Leukemia

    ClinicalTrials.gov

    2014-08-26

    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); Blastic Phase Chronic Myelogenous Leukemia; 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 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; Recurrent Small Lymphocytic Lymphoma; Secondary Acute Myeloid Leukemia; Splenic Marginal Zone Lymphoma; 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 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 Large Cell Lymphoma; Stage IV Adult Diffuse Mixed Cell 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

  7. MiR-181b: new perspective to evaluate disease progression in chronic lymphocytic leukemia.

    PubMed

    Visone, Rosa; Veronese, Angelo; Balatti, Veronica; Croce, Carlo M

    2012-02-01

    Over the past decades numerous markers of the tumor burden have been discovered in chronic lymphocytic leukemia (CLL). Among these, the microRNAs seem to have a promising role. The development and validation of miRNAs as biomarkers should have significant impact in improving early cancer detection and diagnosis, enhancing therapeutic success, and increasing the life expectancy of patients. We identified miR-181b as a biomarker for the progression of this disease from indolent to aggressive. For this study we used sequential samples from patients with either progressive or stable course of the illness. Here, we discuss more extensively this issue by adding novel findings and introducing a novel approach for monitoring CLL patients.

  8. Single nucleotide polymorphisms and inherited risk of chronic lymphocytic leukemia among African Americans

    PubMed Central

    Coombs, Catherine C.; Rassenti, Laura Z.; Falchi, Lorenzo; Slager, Susan L.; Strom, Sara S.; Ferrajoli, Alessandra; Weinberg, J. Brice; Kipps, Thomas J.

    2012-01-01

    The incidence of chronic lymphocytic leukemia (CLL) is significantly lower in African Americans than whites, but overall survival is inferior. The biologic basis for these observations remains unexplored. We hypothesized that germline genetic predispositions differ between African Americans and whites with CLL and yield inferior clinical outcomes among African Americans. We examined a discovery cohort of 42 African American CLL patients ascertained at Duke University and found that the risk allele frequency of most single nucleotide polymorphisms known to confer risk of development for CLL is significantly lower among African Americans than whites. We then confirmed our results in a distinct cohort of 68 African American patients ascertained by the CLL Research Consortium. These results provide the first evidence supporting differential genetic risk for CLL between African Americans compared with whites. A fuller understanding of differential genetic risk may improve prognostication and therapeutic decision making for all CLL patients. PMID:22745306

  9. Lenalidomide induces long-lasting responses in elderly patients with chronic lymphocytic leukemia.

    PubMed

    Strati, Paolo; Keating, Michael J; Wierda, William G; Badoux, Xavier C; Calin, Steliana; Reuben, James M; O'Brien, Susan; Kornblau, Steven M; Kantarjian, Hagop M; Gao, Hui; Ferrajoli, Alessandra

    2013-08-01

    We evaluated long-term outcomes of 60 patients with chronic lymphocytic leukemia treated with an initial therapy of lenalidomide. At a median follow-up of 4 years, time-to-treatment failure has not been reached and overall survival is 82%. Thirty-five (58%) patients had a response lasting >36 months (long-term responders [LTRs]). Best LTR responses consisted of 25 (71%) complete remissions and 10 (29%) partial remissions. In addition to clinical responses, an increase in IgA, IgG, and IgM levels of >50% from baseline was reported in 61%, 45%, and 42% of LTRs. Normalization in the percentage of CD4+ and CD8+ cells and T-cell numbers was observed in 48%, 71% and 99% of LTRs. Compared with other patients in the study, LTRs had lower baseline plasma levels of β-2-microglobulin, were more likely to have trisomy 12, and less likely to have deletion 17p.

  10. Targeting neddylation effectively antagonizes nuclear factor-κB in chronic lymphocytic leukemia B-cells.

    PubMed

    Godbersen, J Claire; Paiva, Cody; Danilova, Olga V; Berger, Allison; Brown, Jennifer R; Danilov, Alexey V

    2015-05-01

    Chronic lymphocytic leukemia (CLL) B-cells demonstrate both constitutive and stroma-mediated activation of nuclear factor-κB (NF-κB). NEDD8, a ubiquitin-like protein, regulates activity of Cullin-RING ubiquitin ligases (CRLs) and thus indirectly controls NF-κB activity. Inhibition of CRLs with MLN4924, an investigational agent that targets the NEDD8-activating enzyme, induces accumulation of CRL substrates, including inhibitor of NF-κB (IκB), a negative pathway modulator. We demonstrate that both continuous and pulse treatments with MLN4924 abrogate NF-κB activity in CLL B-cells ex vivo in a CD40L-expressing stromal co-culture system and identify pathways potentially responsible for resistance to MLN4924. To achieve long-lasting therapeutic effects in CLL, combination strategies are likely necessary.

  11. Fludarabine nucleoside modulates nuclear "survival and death" proteins in resistant chronic lymphocytic leukemia cells.

    PubMed

    Henrich, Silke; Mactier, Swetlana; Best, Giles; Mulligan, Stephen P; Crossett, Ben; Christopherson, Richard Ian

    2011-12-01

    The nuclear mechanisms by which fludarabine nucleoside (F-ara-A) induces apoptosis have been investigated in human MEC1 cells derived from B-cell chronic lymphocytic leukemia. Upon treatment of cells with F-ara-A (100 μM, 72 hours), 15 nuclear proteins changed in abundance by more than 2-fold. Nuclear proteins up-regulated included calmodulin (4.3-fold), prohibitin (3.9-fold), β-actin variant (3.7-fold), and structure-specific recognition protein 1 (3.7-fold); those down-regulated included 60S ribosomal protein P2B (0.12-fold), fumarate hydratase (0.19-fold), splicing factor arginine/serine-rich 3 (0.35-fold), and replication protein A2 (0.42-fold). These changes in the levels of specific proteins promote survival or apoptosis; because the end result is apoptosis of MEC1 cells, apoptotic effects predominate.

  12. Locally disordered methylation forms the basis of intra-tumor methylome variation in chronic lymphocytic leukemia

    PubMed Central

    Landau, Dan A.; Clement, Kendell; Ziller, Michael J.; Boyle, Patrick; Fan, Jean; Gu, Hongcang; Stevenson, Kristen; Sougnez, Carrie; Wang, Lili; Li, Shuqiang; Kotliar, Dylan; Zhang, Wandi; Ghandi, Mahmoud; Garraway, Levi; Fernandes, Stacey M.; Livak, Kenneth J.; Gabriel, Stacey; Gnirke, Andreas; Lander, Eric S.; Brown, Jennifer R.; Neuberg, Donna; Kharchenko, Peter V.; Hacohen, Nir; Getz, Gad; Meissner, Alexander; Wu, Catherine J.

    2014-01-01

    SUMMARY Intra-tumoral heterogeneity plays a critical role in tumor evolution. To define the contribution of DNA methylation to heterogeneity within tumors, we performed genome-scale bisulfite sequencing of 104 primary chronic lymphocytic leukemias (CLL). Compared to 26 normal B cell samples, CLLs consistently displayed higher intra-sample variability of DNA methylation patterns across the genome, which appears to arise from stochastically disordered methylation in malignant cells. Transcriptome analysis of bulk and single CLL cells revealed that methylation disorder was linked to low-level expression. Disordered methylation was further associated with adverse clinical outcome. We therefore propose that disordered methylation plays a similar role to genetic instability, enhancing the ability of cancer cells to search for superior evolutionary trajectories. PMID:25490447

  13. Venetoclax: Bcl-2 inhibition for the treatment of chronic lymphocytic leukemia.

    PubMed

    Del Poeta, G; Postorino, M; Pupo, L; Del Principe, M I; Dal Bo, M; Bittolo, T; Buccisano, F; Mariotti, B; Iannella, E; Maurillo, L; Venditti, A; Gattei, V; de Fabritiis, P; Cantonetti, M; Amadori, S

    2016-04-01

    Venetoclax (ABT-199) is a small-molecule selective oral inhibitor of the antiapoptotic protein Bcl-2 that promotes programmed cell death of chronic lymphocytic leukemia (CLL) cells regulating the release of proapoptotic factors, such as Smac/Diablo, apoptosis-inducing factor (AIF) and cytochrome c. In April 2016, the U.S. Food and Drug Administration (FDA) granted accelerated approval to venetoclax for patients diagnosed with CLL with 17p deletion, as detected by an FDA-approved test, who have received at least one prior therapy. This review will focus on the mechanism of action, preclinical studies and clinical development of venetoclax both as a monotherapy and in combination with other drugs for CLL in the current milieu of therapy dominated by novel tyrosine kinase inhibitors such as ibrutinib and idelalisib.

  14. Transcriptomic Characterization of SF3B1 Mutation Reveals Its Pleiotropic Effects in Chronic Lymphocytic Leukemia.

    PubMed

    Wang, Lili; Brooks, Angela N; Fan, Jean; Wan, Youzhong; Gambe, Rutendo; Li, Shuqiang; Hergert, Sarah; Yin, Shanye; Freeman, Samuel S; Levin, Joshua Z; Fan, Lin; Seiler, Michael; Buonamici, Silvia; Smith, Peter G; Chau, Kevin F; Cibulskis, Carrie L; Zhang, Wandi; Rassenti, Laura Z; Ghia, Emanuela M; Kipps, Thomas J; Fernandes, Stacey; Bloch, Donald B; Kotliar, Dylan; Landau, Dan A; Shukla, Sachet A; Aster, Jon C; Reed, Robin; DeLuca, David S; Brown, Jennifer R; Neuberg, Donna; Getz, Gad; Livak, Kenneth J; Meyerson, Matthew M; Kharchenko, Peter V; Wu, Catherine J

    2016-11-14

    Mutations in SF3B1, which encodes a spliceosome component, are associated with poor outcome in chronic lymphocytic leukemia (CLL), but how these contribute to CLL progression remains poorly understood. We undertook a transcriptomic characterization of primary human CLL cells to identify transcripts and pathways affected by SF3B1 mutation. Splicing alterations, identified in the analysis of bulk cells, were confirmed in single SF3B1-mutated CLL cells and also found in cell lines ectopically expressing mutant SF3B1. SF3B1 mutation was found to dysregulate multiple cellular functions including DNA damage response, telomere maintenance, and Notch signaling (mediated through KLF8 upregulation, increased TERC and TERT expression, or altered splicing of DVL2 transcript, respectively). SF3B1 mutation leads to diverse changes in CLL-related pathways.

  15. State-of-the-Art Management of Patients Suffering from Chronic Lymphocytic Leukemia

    PubMed Central

    Clifford, Ruth; Schuh, Anna

    2012-01-01

    The management of chronic lymphocytic leukemia (CLL) has evolved dramatically in the last decade. For the first time, clinical intervention has been shown to alter the natural history of the disease. Considerable efforts are focussing on better patient selection and response prediction, and it is expected that the publication of the first 200 CLL genomes will spark new insights into risk stratification of CLL patients. Besides, many new agents are being evaluated on their own and in combination therapy in early and late Phase clinical studies. Here, we provide a general clinical introduction into CLL including diagnosis and prognostic markers followed by a summary of the current state-of-the-art treatment. We point to areas of continued clinical research in particular for patients with co-morbidities and highlight the challenges in managing refractory disease. PMID:22474408

  16. Trisomy 12 and t(14;18) in B-cell chronic lymphocytic leukemia.

    PubMed

    Kojima, K; Taniwaki, M; Yoshino, T; Katayama, Y; Sunami, K; Fukuda, S; Omoto, E; Harada, M; Sezaki, T

    1998-02-01

    We report a case of B-cell chronic lymphocytic leukemia (B-CLL) in which trisomy 12 and t(14;18)(q32;q21) were simultaneously detected in the same leukemic clone. Southern blot analysis showed that the BCL2/IgJH rearrangement occurred at the major breakpoint region in the hot spot of the BCL2 gene. Double color fluorescence in situ hybridization analysis using multiple probes indicated that clonal B-cell with t(14;18) represented a subpopulation of the total leukemic cells and that trisomy 12 followed t(14;18) as the cytogenetic aberration in the development of B-CLL. Our findings suggests that both the t(14;18) and the trisomy are secondary chromosomal changes in the leukemogenesis of B-CLL.

  17. The role of ATM mutations and 11q deletions in disease progression in chronic lymphocytic leukemia.

    PubMed

    Stankovic, Tatjana; Skowronska, Anna

    2014-06-01

    Abstract ATM gene alteration is a frequent event in pathogenesis of chronic lymphocytic leukemia (CLL) and occurs as monoallelic loss in the form of 11q23 deletion, with and without mutation in the remaining ATM allele. ATM is a principal DNA damage response gene and biallelic ATM alterations lead to ATM functional loss and chemoresistance. The introduction of new therapies, such as intensive chemoimmunotherapy and inhibition of B-cell receptor (BCR) signaling, has changed clinical responses for the majority of CLL tumors including those with 11q deletion, but it remains to be determined whether these strategies can prevent clonal evolution of tumors with biallelic ATM alterations. In this review we discuss ATM function and the consequences of its loss during CLL pathogenesis, differences in clinical behavior of tumors with monoallelic and biallelic ATM alterations, and we outline possible approaches for targeting the ATM null CLL phenotype.

  18. A study for proposal of use of regulatory T cells as a prognostic marker and establishing an optimal threshold level for their expression in chronic lymphocytic leukemia.

    PubMed

    Dasgupta, Alakananda; Mahapatra, Manoranjan; Saxena, Renu

    2015-06-01

    Although regulatory T cells (Tregs) have been extensively studied in chronic lymphocytic leukemia, there is no uniform guideline or consensus regarding their use as a prognostic marker. This study describes the methodology used to develop an optimal threshold level for Tregs in these patients. Treg levels were assessed in the peripheral blood of 130 patients and 150 controls. Treg frequencies were linked to established prognostic markers as well as overall survival and time to first treatment. The cut-offs for Treg positivity were assessed by receiver operating characteristic (ROC) analysis. A cut-off of 5.7% for Treg cell percentage and of 35 cells/μL for absolute Treg cell count were determined as optimal in patients with CLL along with a median Treg percentage of 15.5% used to separate patients with low- and high-risk disease. The experiments presented here will possibly aid in the use of Treg frequencies as a potential prognostic marker in CLL.

  19. Potentiation of luteolin cytotoxicity by flavonols fisetin and quercetin in human chronic lymphocytic leukemia cell lines.

    PubMed

    Sak, Katrin; Kasemaa, Kristi; Everaus, Hele

    2016-09-14

    Despite numerous studies chronic lymphocytic leukemia (CLL) still remains an incurable disease. Therefore, all new compounds and novel strategies which are able to eradicate CLL cells should be considered as valuable clues for a potential future remedy against this malignancy. In the present study, the cytotoxic profiles of natural flavonoids were described in two human CLL cell lines, HG-3 and EHEB, indicating the flavone luteolin as the most potent flavonoid with half-maximal inhibitory constants (IC50) of 37 μM and 26 μM, respectively. Luteolin significantly increased the apoptotic cell population in both cell lines by increasing the activities of caspases-3 and -9 and triggering the intrinsic apoptotic pathway. Two flavonols, fisetin and quercetin, were somewhat less efficient in suppressing cellular viability, whereas baicalein, chrysin, (+)-catechin and hesperetin exerted only a small or no response at doses as high as 100 μM. Both fisetin and quercetin were able to augment the cytotoxic activity of luteolin in both cell lines by reducing the IC50 values up to four fold. As a result of this, luteolin displayed cytotoxicity activity already at low micromolar concentrations that could potentially be physiologically achievable through oral ingestion. No other tested flavonoids were capable of sensitizing CLL cells to luteolin pointing to a specific binding of fisetin and quercetin to the cellular targets which interfere with the signaling pathways induced by luteolin. Although further molecular studies to unravel this potentiating mechanism are certainly needed, this phenomenon could contribute to future remedies for prevention and treatment of chronic lymphocytic leukemia.

  20. Outcomes of first-line treatment for chronic lymphocytic leukemia with 17p deletion.

    PubMed

    Strati, Paolo; Keating, Michael J; O'Brien, Susan M; Ferrajoli, Alessandra; Burger, Jan; Faderl, Stefan; Tambaro, Francesco Paolo; Jain, Nitin; Wierda, William G

    2014-08-01

    Although uncommon in treatment-naive patients with chronic lymphocytic leukemia, deletion 17p is a high-risk disease characteristic. We analyzed and reported outcomes for 63 patients with deletion 17p chronic lymphocytic leukemia who received first-line therapy at our institution; at time of first treatment, 81% had unmutated immunoglobulin heavy chain variable gene and 58% had complex karyotype. Forty-nine patients (76%) received first-line fludarabine, cyclophosphamide, rituximab-based therapy, 6 (11%) received rituximab-based and 8 (13%) received lenalidomide-based treatment. Overall, the complete plus nodular partial remission rate was 33%; on multivariable model, higher complete plus nodular partial remission rate was observed in patients with less than 50% cells positive for deletion 17p, and a higher probability of achieving at least a partial remission was observed with fludarabine, cyclophosphamide, rituximab-based treatment. After a median follow up of 33 months (range 1-89 months), the estimated median progression-free survival was 14 months (95% confidence interval 10-18) and estimated median overall survival was 63 months (95% confidence interval 43-83). In multivariable analysis, factors independently associated with longer progression-free survival were response to treatment and absence of complex karyotype. Achievement of complete plus nodular partial remission rate and mutated immunoglobulin heavy chain variable gene were independently associated with longer overall survival in multivariable model. Complex karyotype was associated with increased risk for Richter's transformation. New first-line strategies and agents must aim at both improving response and maintaining remission in patients with deletion 17p, particularly in the presence of complex karyotype.

  1. Outcomes of first-line treatment for chronic lymphocytic leukemia with 17p deletion

    PubMed Central

    Strati, Paolo; Keating, Michael J.; O’Brien, Susan M.; Ferrajoli, Alessandra; Burger, Jan; Faderl, Stefan; Tambaro, Francesco Paolo; Jain, Nitin; Wierda, William G.

    2014-01-01

    Although uncommon in treatment-naive patients with chronic lymphocytic leukemia, deletion 17p is a high-risk disease characteristic. We analyzed and reported outcomes for 63 patients with deletion 17p chronic lymphocytic leukemia who received first-line therapy at our institution; at time of first treatment, 81% had unmutated immunoglobulin heavy chain variable gene and 58% had complex karyotype. Forty-nine patients (76%) received first-line fludarabine, cyclophosphamide, rituximab-based therapy, 6 (11%) received rituximab-based and 8 (13%) received lenalidomide-based treatment. Overall, the complete plus nodular partial remission rate was 33%; on multivariable model, higher complete plus nodular partial remission rate was observed in patients with less than 50% cells positive for deletion 17p, and a higher probability of achieving at least a partial remission was observed with fludarabine, cyclophosphamide, rituximab-based treatment. After a median follow up of 33 months (range 1–89 months), the estimated median progression-free survival was 14 months (95% confidence interval 10–18) and estimated median overall survival was 63 months (95% confidence interval 43–83). In multivariable analysis, factors independently associated with longer progression-free survival were response to treatment and absence of complex karyotype. Achievement of complete plus nodular partial remission rate and mutated immunoglobulin heavy chain variable gene were independently associated with longer overall survival in multivariable model. Complex karyotype was associated with increased risk for Richter’s transformation. New first-line strategies and agents must aim at both improving response and maintaining remission in patients with deletion 17p, particularly in the presence of complex karyotype. PMID:24859876

  2. A potential therapeutic strategy for chronic lymphocytic leukemia by combining Idelalisib and GS-9973, a novel spleen tyrosine kinase (Syk) inhibitor.

    PubMed

    Burke, Russell T; Meadows, Sarah; Loriaux, Marc M; Currie, Kevin S; Mitchell, Scott A; Maciejewski, Patricia; Clarke, Astrid S; Dipaolo, Julie A; Druker, Brian J; Lannutti, Brian J; Spurgeon, Stephen E

    2014-02-28

    Agents that target B-cell receptor (BCR) signaling in lymphoid malignancies including idelalisib (GS-1101) and fostamatinib which inhibit the delta isoform of PI3 kinase (PI3Kd) and spleen tyrosine kinase (Syk) respectively have shown significant clinical activity. By disrupting B-cell signaling pathways, idelalisib treatment has been associated with a dramatic lymph node response, but eradication of disease and relapse in high risk disease remain challenges. Targeting the BCR signaling pathway with simultaneous inhibition of PI3Kd and Syk has not yet been reported. We evaluated the pre-clinical activity of idelalisib combined with the novel and selective Syk inhibitor GS-9973 in primary peripheral blood and bone marrow Chronic Lymphocytic Leukemia (CLL) samples. Both PI3Kd and Syk inhibition reduced CLL survival and in combination induced synergistic growth inhibition and further disrupted chemokine signaling at nanomolar concentrations including in bone marrow derived and poor risk samples. Simultaneous targeting of these kinases may significantly increase clinical activity.

  3. A potential therapeutic strategy for chronic lymphocytic leukemia by combining Idelalisib and GS-9973, a novel spleen tyrosine kinase (Syk) inhibitor

    PubMed Central

    Burke, Russell T; Meadows, Sarah; Loriaux, Marc M; Currie, Kevin S.; Mitchell, Scott A.; Maciejewski, Patricia; Clarke, Astrid S.; Dipaolo, Julie A.; Druker, Brian J.; Lannutti, Brian J.; Spurgeon, Stephen E.

    2014-01-01

    Agents that target B-cell receptor (BCR) signaling in lymphoid malignancies including idelalisib (GS-1101) and fostamatinib which inhibit the delta isoform of PI3 kinase (PI3Kd) and spleen tyrosine kinase (Syk) respectively have shown significant clinical activity. By disrupting B-cell signaling pathways, idelalisib treatment has been associated with a dramatic lymph node response, but eradication of disease and relapse in high risk disease remain challenges. Targeting the BCR signaling pathway with simultaneous inhibition of PI3Kd and Syk has not yet been reported. We evaluated the pre-clinical activity of idelalisib combined with the novel and selective Syk inhibitor GS-9973 in primary peripheral blood and bone marrow Chronic Lymphocytic Leukemia (CLL) samples. Both PI3Kd and Syk inhibition reduced CLL survival and in combination induced synergistic growth inhibition and further disrupted chemokine signaling at nanomolar concentrations including in bone marrow derived and poor risk samples. Simultaneous targeting of these kinases may significantly increase clinical activity. PMID:24659719

  4. Autologous stem cell transplantation as a first-line treatment strategy for chronic lymphocytic leukemia: a multicenter, randomized, controlled trial from the SFGM-TC and GFLLC.

    PubMed

    Sutton, Laurent; Chevret, Sylvie; Tournilhac, Olivier; Diviné, Marine; Leblond, Véronique; Corront, Bernadette; Leprêtre, Stéphane; Eghbali, Houchingue; Van Den Neste, Eric; Michallet, Mauricette; Maloisel, Frédéric; Bouabdallah, Krimo; Decaudin, Didier; Berthou, Christian; Brice, Pauline; Gonzalez, Hugo; Chapiro, Elise; Radford-Weiss, Isabelle; Leporrier, Nathalie; Maloum, Karim; Nguyen-Khac, Florence; Davi, Frédéric; Lejeune, Julie; Merle-Béral, Hélène; Leporrier, Michel

    2011-06-09

    Long-term responses have been reported after autologous stem cell transplantation (ASCT) for chronic lymphocytic leukemia (CLL). We conducted a prospective, randomized trial of ASCT in previously untreated CLL patients. We enrolled 241 patients < 66 years of age with Binet stage B or C CLL. They received 3 courses of mini-CHOP (cyclophosphamide, hydroxydaunorubicin, oncovin, and prednisone/prednisolone) and then 3 courses of fludarabine. Patients in complete response (CR) were then randomized to ASCT or observation, whereas the other patients were randomized to dexamethasone, high-dose aracytin, cisplatin (DHAP) salvage followed by either ASCT or 3 courses of fludarabine plus cyclophosphamide (FC). The primary end point was event-free survival (EFS). After up-front treatment, 105 patients entered CR and were randomized between ASCT (n = 52) and observation (n = 53); their respective 3-year EFS rates were 79.8% and 35.5%; the adjusted hazard ratio was 0.3 (95% CI: 0.1-0.7; P = .003). Ninety-four patients who did not enter CR were randomized between ASCT (n = 46) and FC (n = 48); their respective 3-year EFS rates were 48.9% and 44.4%, respectively; the adjusted hazard ratio was 1.7 (95% CI: 0.9-3.2; P = .13). No difference in overall survival was found between the 2 response subgroups. In young CLL patients in CR, ASCT consolidation markedly delayed disease progression. No difference was observed between ASCT and FC in patients requiring DHAP salvage.

  5. The role of combined fludarabine, cyclophosphamide and rituximab chemoimmunotherapy in chronic lymphocytic leukemia: current evidence and controversies

    PubMed Central

    Skarbnik, Alan P.; Faderl, Stefan

    2016-01-01

    Chemoimmunotherapy (CIT) has become a cornerstone in the treatment of patients with chronic lymphocytic leukemia (CLL). The combination of fludarabine, cyclophosphamide and rituximab (FCR) has emerged as the standard of care for therapy of previously untreated patients with CLL who are younger than 65 years and have no significant comorbidities. In this article, we review the role of FCR in the current treatment paradigm for CLL. PMID:28246553

  6. Leukemia cell proliferation and death in chronic lymphocytic leukemia patients on therapy with the BTK inhibitor ibrutinib.

    PubMed

    Burger, Jan A; Li, Kelvin W; Keating, Michael J; Sivina, Mariela; Amer, Ahmed M; Garg, Naveen; Ferrajoli, Alessandra; Huang, Xuelin; Kantarjian, Hagop; Wierda, William G; O'Brien, Susan; Hellerstein, Marc K; Turner, Scott M; Emson, Claire L; Chen, Shih-Shih; Yan, Xiao-Jie; Wodarz, Dominik; Chiorazzi, Nicholas

    2017-01-26

    BACKGROUND. Ibrutinib is an effective targeted therapy for patients with chronic lymphocytic leukemia (CLL) that inhibits Bruton's tyrosine kinase (BTK), a kinase involved in B cell receptor signaling. METHODS. We used stable isotopic labeling with deuterated water ((2)H2O) to measure directly the effects of ibrutinib on leukemia cell proliferation and death in 30 patients with CLL. RESULTS. The measured average CLL cell proliferation ("birth") rate before ibrutinib therapy was 0.39% of the clone per day (range 0.17%-1.04%); this decreased to 0.05% per day (range 0%-0.36%) with treatment. Death rates of blood CLL cells increased from 0.18% per day (average, range 0%-0.7%) prior to treatment to 1.5% per day (range 0%-3.0%) during ibrutinib therapy, and they were even higher in tissue compartments. CONCLUSIONS. This study provides the first direct in vivo measurements to our knowledge of ibrutinib's antileukemia actions, demonstrating profound and immediate inhibition of CLL cell proliferation and promotion of high rates of CLL cell death. TRIAL REGISTRATION. This trial was registered at clinicaltrials.gov (NCT01752426). FUNDING. This study was supported by a Cancer Center Support Grant (National Cancer Institute grant P30 CA016672), an NIH grant (CA081554) from the National Cancer Institute, MD Anderson's Moon Shots Program in CLL, and Pharmacyclics, an AbbVie company.

  7. Leukemia cell proliferation and death in chronic lymphocytic leukemia patients on therapy with the BTK inhibitor ibrutinib

    PubMed Central

    Li, Kelvin W.; Keating, Michael J.; Sivina, Mariela; Ferrajoli, Alessandra; Kantarjian, Hagop; Wierda, William G.; O’Brien, Susan; Hellerstein, Marc K.; Turner, Scott M.; Emson, Claire L.; Wodarz, Dominik; Chiorazzi, Nicholas

    2017-01-01

    BACKGROUND. Ibrutinib is an effective targeted therapy for patients with chronic lymphocytic leukemia (CLL) that inhibits Bruton’s tyrosine kinase (BTK), a kinase involved in B cell receptor signaling. METHODS. We used stable isotopic labeling with deuterated water (2H2O) to measure directly the effects of ibrutinib on leukemia cell proliferation and death in 30 patients with CLL. RESULTS. The measured average CLL cell proliferation (“birth”) rate before ibrutinib therapy was 0.39% of the clone per day (range 0.17%–1.04%); this decreased to 0.05% per day (range 0%–0.36%) with treatment. Death rates of blood CLL cells increased from 0.18% per day (average, range 0%–0.7%) prior to treatment to 1.5% per day (range 0%–3.0%) during ibrutinib therapy, and they were even higher in tissue compartments. CONCLUSIONS. This study provides the first direct in vivo measurements to our knowledge of ibrutinib’s antileukemia actions, demonstrating profound and immediate inhibition of CLL cell proliferation and promotion of high rates of CLL cell death. TRIAL REGISTRATION. This trial was registered at clinicaltrials.gov (NCT01752426). FUNDING. This study was supported by a Cancer Center Support Grant (National Cancer Institute grant P30 CA016672), an NIH grant (CA081554) from the National Cancer Institute, MD Anderson’s Moon Shots Program in CLL, and Pharmacyclics, an AbbVie company. PMID:28138560

  8. Final Results of EFC6663: A Multicenter, International, Phase 2 Study of Alvocidib for Patients with Fludarabine-Refractory Chronic Lymphocytic Leukemia

    PubMed Central

    Lanasa, Mark C.; Andritsos, Leslie; Brown, Jennifer R.; Gabrilove, Janice; Caligaris, Federico -Cappio; Ghia, Paolo; Larson, Richard A.; Kipps, Thomas J.; Leblond, Veronique; Milligan, Donald W.; Janssens, Ann; Johnson, Amy J.; Heerema, Nyla A.; Bühler, Andreas; Stilgenbauer, Stephan; Devin, Jeanne; Hallek, Michael; Byrd, John C.; Grever, Michael R.

    2015-01-01

    Purpose Chronic lymphocytic leukemia (CLL) patients refractory to fludarabine based therapies have poor outcomes with currently available therapies. Early phase studies of alvocidib showed activity in relapsed CLL including patients with high risk genomic features and those refractory to fludarabine. A multi-center, international, phase II study of alvocidib in fludarabine refractory CLL was undertaken to validate these early results. Patients and Methods Patients with fludarabine refractory CLL or prolymphocytic leukemia arising from CLL were treated with single agent alvocidib. The primary outcome measure was overall response rate, with secondary outcomes including survival, toxicity, and response duration. Results One hundred and sixty five patients were enrolled at 34 centers, and 159 patients were treated. The median age was 61 years, the median number of prior therapies was 4, and 96% of patients were fludarabine refractory. The investigator-assessed overall response rate was 25%; the majority of responses were partial. Response rates were lower among patients with del(17p) (14%), but equivalent in patients with del(11q) or bulky lymphadenopathy. Median progression free and overall survival were 7.6 and 14.6 months respectively. Tumor lysis occurred in 39 patients (25%), and 13 received hemodialysis. Diarrhea, fatigue, and hematologic toxicities were common. Conclusion Alvocidib has clinical activity in patients with advanced, fludarabine refractory CLL. Clinical responses were observed in patients with high risk clinical and genomic features. With careful monitoring, alvocidib has a manageable safety profile. Future studies should focus on discovery of biomarkers of clinical response and tumor lysis, and enhanced supportive care measures. PMID:25804339

  9. A complementary role of multiparameter flow cytometry and high-throughput sequencing for minimal residual disease detection in chronic lymphocytic leukemia: an European Research Initiative on CLL study

    PubMed Central

    Rawstron, A C; Fazi, C; Agathangelidis, A; Villamor, N; Letestu, R; Nomdedeu, J; Palacio, C; Stehlikova, O; Kreuzer, K-A; Liptrot, S; O'Brien, D; de Tute, R M; Marinov, I; Hauwel, M; Spacek, M; Dobber, J; Kater, A P; Gambell, P; Soosapilla, A; Lozanski, G; Brachtl, G; Lin, K; Boysen, J; Hanson, C; Jorgensen, J L; Stetler-Stevenson, M; Yuan, C; Broome, H E; Rassenti, L; Craig, F; Delgado, J; Moreno, C; Bosch, F; Egle, A; Doubek, M; Pospisilova, S; Mulligan, S; Westerman, D; Sanders, C M; Emerson, R; Robins, H S; Kirsch, I; Shanafelt, T; Pettitt, A; Kipps, T J; Wierda, W G; Cymbalista, F; Hallek, M; Hillmen, P; Montserrat, E; Ghia, P

    2016-01-01

    In chronic lymphocytic leukemia (CLL) the level of minimal residual disease (MRD) after therapy is an independent predictor of outcome. Given the increasing number of new agents being explored for CLL therapy, using MRD as a surrogate could greatly reduce the time necessary to assess their efficacy. In this European Research Initiative on CLL (ERIC) project we have identified and validated a flow-cytometric approach to reliably quantitate CLL cells to the level of 0.0010% (10−5). The assay comprises a core panel of six markers (i.e. CD19, CD20, CD5, CD43, CD79b and CD81) with a component specification independent of instrument and reagents, which can be locally re-validated using normal peripheral blood. This method is directly comparable to previous ERIC-designed assays and also provides a backbone for investigation of new markers. A parallel analysis of high-throughput sequencing using the ClonoSEQ assay showed good concordance with flow cytometry results at the 0.010% (10−4) level, the MRD threshold defined in the 2008 International Workshop on CLL guidelines, but it also provides good linearity to a detection limit of 1 in a million (10−6). The combination of both technologies would permit a highly sensitive approach to MRD detection while providing a reproducible and broadly accessible method to quantify residual disease and optimize treatment in CLL. PMID:26639181

  10. Barriers to the Access and Use of Rituximab in Patients with Non-Hodgkin's Lymphoma and Chronic Lymphocytic Leukemia: A Physician Survey.

    PubMed

    Baer Ii, William H; Maini, Archana; Jacobs, Ira

    2014-05-07

    Biologics such as rituximab are an important component of oncology treatment strategies, although access to such therapies is challenging in countries with limited resources. This study examined access to rituximab and identified potential barriers to its use in the United States, Mexico, Turkey, Russia, and Brazil. The study also examined whether availability of a biosimilar to rituximab would improve access to, and use of, rituximab. Overall, 450 hematologists and oncologists completed a survey examining their use of rituximab in patients with non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Less than 40% of physicians considered rituximab as easy to access from a cost perspective. Furthermore, many physicians chose not to treat, were unable to treat, or had to modify treatment with rituximab despite guidelines recommending its use in NHL and CLL patients. Insurance coverage, reimbursement, and cost to patient were commonly reported as barriers to the use of rituximab. Across all markets, over half of physicians reported that they would increase use of rituximab if a biosimilar was available. We conclude that rituximab use would increase across all therapy types and markets if a biosimilar was available, although a biosimilar would have the greatest impact in Brazil, Mexico, and Russia.

  11. Global histone deacetylase enzymatic activity is an independent prognostic marker associated with a shorter overall survival in chronic lymphocytic leukemia patients.

    PubMed

    Van Damme, Michaël; Crompot, Emerence; Meuleman, Nathalie; Mineur, Philippe; Dessars, Barbara; El Housni, Hakim; Bron, Dominique; Lagneaux, Laurence; Stamatopoulos, Basile

    2014-10-01

    Histone deacetylases (HDAC) play a crucial role in transcriptional regulation and are often deregulated in many cancers. However, global HDAC enzymatic activity has never been investigated in Chronic Lymphocytic Leukemia (CLL). We measured HDAC activity in protein extracts from CD19+ B-cells purified from 114 CLL patients with a median follow-up of 91 months (range: 11-376). HDAC activity was equivalent in CLL and normal B-cells but higher in patients who died during the study than in living patients (152.1 vs. 65.04 pmol; P = 0.0060). Furthermore, HDAC activity correlated with treatment-free survival (TFS; P = 0.0156) and overall survival (OS; P < 0.0001): patients with low HDAC activity (n = 75) had a median TFS and OS of 101 and > 376 months, respectively, whereas patients with high HDAC activity (n = 39) had a median TFS and OS of 47 and 137 months, respectively. Multivariate analyses indicated that HDAC activity is an independent predictor of OS (hazard ratio = 7.68; P = 0.0017). Finally, HDAC activity increased after B-cell receptor stimulation using IgM, suggesting a role for microenvironment stimuli (n = 10; P = 0.0371). In conclusion, high HDAC activity in CLL B-cells is associated with shorter TFS and OS and is an independent marker of OS, refining the use of other prognostic factors. This work provides a biological base for the use of HDAC inhibitors in CLL treatment.

  12. Long-term survival in a patient with progressive multifocal leukoencephalopathy after therapy with rituximab, fludarabine and cyclophosphamide for chronic lymphocytic leukemia.

    PubMed

    Garrote, Heidys; de la Fuente, Adolfo; Oña, Raquel; Rodríguez, Inmaculada; Echevarría, Juan E; Sepúlveda, Juan M; García, Juan F

    2015-01-01

    A 50-year-old male with chronic lymphocytic leukemia (CLL) was treated with fludarabine, cyclophosphamide and rituximab, which produced a complete remission. Eight months after the last dose of rituximab he had visual disturbance, diminished muscular strength in the right arm and vesicular-papular lesions in the left ophthalmic branch region of the V cranial nerve. These were initially interpreted as herpes virus encephalopathy (HVE), but brain magnetic resonance imaging (MRI) showed evidence of demyelination consistent with progressive multifocal leukoencephalopathy (PML). Cerebrospinal fluid (CSF) analysis was negative for varicella zoster virus (VZV) and John Cunningham virus (JCV) DNA. The clinical suggestion of PML prompted us to perform a brain biopsy and to start treatment with mefloquine. In the brain biopsy, histopathological features of demyelination were described and the polymerase chain reaction (PCR) identified JCV, confirming the diagnosis of PML. Treatment with mefloquine (250 mg/week) and dexamethasone (4 mg/day) was started and maintained for 6 months. A year later there was an almost complete resolution of the MRI lesions and the patient achieved a stable clinical state with persisting motor impairment and severe epilepsy. The patient is alive 38 months after diagnosis of PML, which is the longest known survival to date.

  13. Ofatumumab plus chlorambucil as a first-line therapy in less fit patients with chronic lymphocytic leukemia: analysis of COMPLEMENT1 and other monoclonal antibodies association data

    PubMed Central

    Frustaci, Anna Maria; Tedeschi, Alessandra; Picardi, Paola; Mazzucchelli, Maddalena; Cairoli, Roberto; Montillo, Marco

    2016-01-01

    The management of patients with chronic lymphocytic leukemia (CLL) has radically improved over the last few years with the addition of anti-CD20 monoclonal antibodies (MoAbs) to chemotherapy. Chlorambucil has been considered for decades as a suitable therapeutic option for frail patients. Taking into account the advantage offered by the addition of MoAbs to chemotherapy, different studies up to now have explored the feasibility of chlorambucil-based chemoimmunotherapies in treatment-naïve CLL. COMPLEMENT1 is a prospective, randomized, open-label trial evaluating the efficacy and safety of ofatumumab added to chlorambucil, compared with chlorambucil in monotherapy, in the setting of untreated patients with CLL considered unsuitable for a fludarabine-based approach. Progression-free survival was significantly longer in the chemoimmunotherapy arm when compared with the single-agent chlorambucil (22.4 months versus 13.1 months). Response rate and quality were also improved in the combination arm. Furthermore, the addition of ofatumumab did not lead to an unmanageable toxicity. While the employment of anti-CD20 antibodies represents an advantage in the treatment of the CLL symptomatic population, at present different patient selection and treatment schedules do not allow a reliable comparison between chlorambucil-based regimens. The addition of ofatumumab to chlorambucil represents a further therapeutic gain in CLL. Longer follow up and direct comparison with other MoAbs are warranted to establish the preferred first-line treatment in elderly and unfit patients. PMID:27493712

  14. The down-regulation of miR-125b in chronic lymphocytic leukemias leads to metabolic adaptation of cells to a transformed state.

    PubMed

    Tili, Esmerina; Michaille, Jean-Jacques; Luo, Zhenghua; Volinia, Stefano; Rassenti, Laura Z; Kipps, Thomas J; Croce, Carlo M

    2012-09-27

    MiR-125b-1 maps at 11q24, a chromosomal region close to the epicenter of 11q23 deletions in chronic lymphocytic leukemias (CLLs). Our results establish that both aggressive and indolent CLL patients show reduced expression of miR-125b. Overexpression of miR-125b in CLL-derived cell lines resulted in the repression of many transcripts encoding enzymes implicated in cell metabolism. Metabolomics analyses showed that miR-125b overexpression modulated glucose, glutathione, lipid, and glycerolipid metabolism. Changes on the same metabolic pathways also were observed in CLLs. We furthermore analyzed the expression of some of miR-125b-target transcripts that are potentially involved in the aforementioned metabolic pathways and defined a miR-125b-dependent CLL metabolism-related transcript signature. Thus, miR-125b acts as a master regulator for the adaptation of cell metabolism to a transformed state. MiR-125b and miR-125b-dependent metabolites therefore warrant further investigation as possible novel therapeutic approaches for patients with CLL.

  15. PI3K Signaling in Normal B Cells and Chronic Lymphocytic Leukemia (CLL)

    PubMed Central

    Okkenhaug, Klaus; Burger, Jan A.

    2016-01-01

    B cells provide immunity to extracellular pathogens by secreting a diverse repertoire of antibodies with high affinity and specificity for exposed antigens. The B cell receptor (BCR) is a transmembrane antibody, which facilitates the clonal selection of B cells producing secreted antibodies of the same specificity. The diverse antibody repertoire is generated by V(D)J recombination of heavy and light chain genes, whereas affinity maturation is mediated by activation-induced cytidine deaminase (AID)-mediated mutagenesis. These processes, which are essential for the generation of adaptive humoral immunity, also render B cells susceptible to chromosomal rearrangements and point mutations that in some cases lead to cancer. In this chapter, we will review the central role of PI3Ks in mediating signals from the B cell receptor that not only facilitate the development of functional B cell repertoire, but also support the growth and survival of neoplastic B cells, focusing on chronic lymphocytic leukemia (CLL) B cells. Perhaps because of the central role played by PI3K in BCR signaling, B cell leukemia and lymphomas are the first diseases for which a PI3K inhibitor has been approved for clinical use. PMID:26350103

  16. CIP4 controls CCL19-driven cell steering and chemotaxis in chronic lymphocytic leukemia.

    PubMed

    Malet-Engra, Gema; Viaud, Julien; Ysebaert, Loïc; Farcé, Manon; Lafouresse, Fanny; Laurent, Guy; Gaits-Iacovoni, Frédérique; Scita, Giorgio; Dupré, Loïc

    2013-06-01

    Solid tumor dissemination relies on the reprogramming of molecular pathways controlling chemotaxis. Whether the motility of nonsolid tumors such as leukemia depends on the deregulated expression of molecules decoding chemotactic signals remains an open question. We identify here the membrane remodeling F-BAR adapter protein Cdc42-interacting protein 4 (CIP4) as a key regulator of chemotaxis in chronic lymphocytic leukemia (CLL). CIP4 is expressed at abnormally high levels in CLL cells, where it is required for CCL19-induced chemotaxis. Upon CCL19 stimulation of CLL cells, CIP4 associates with GTP-bound Cdc42 and is recruited to the rear of the lamellipodium and along microspikes radiating through the lamellipodium. Consistent with its cellular distribution, CIP4 removal impairs both the assembly of the polarized lamellipodium and directional migration along a diffusible CCL19 gradient. Furthermore, CIP4 depletion results in decreased activation of WASP, but increased activation of PAK1 and p38 mitogen-activated protein kinase (MAPK). Notably, p38 MAPK inhibition results in impaired lamellipodium assembly and loss of directional migration. This suggests that CIP4 modulates both the WASP and p38 MAPK pathways to promote lamellipodium assembly and chemotaxis. Overall, our study reveals a critical role of CIP4 in mediating chemotaxis of CLL cells by controlling the dynamics of microspike-containing protrusions and cell steering.

  17. Systematic identification of personal tumor-specific neoantigens in chronic lymphocytic leukemia.

    PubMed

    Rajasagi, Mohini; Shukla, Sachet A; Fritsch, Edward F; Keskin, Derin B; DeLuca, David; Carmona, Ellese; Zhang, Wandi; Sougnez, Carrie; Cibulskis, Kristian; Sidney, John; Stevenson, Kristen; Ritz, Jerome; Neuberg, Donna; Brusic, Vladimir; Gabriel, Stacey; Lander, Eric S; Getz, Gad; Hacohen, Nir; Wu, Catherine J

    2014-07-17

    Genome sequencing has revealed a large number of shared and personal somatic mutations across human cancers. In principle, any genetic alteration affecting a protein-coding region has the potential to generate mutated peptides that are presented by surface HLA class I proteins that might be recognized by cytotoxic T cells. To test this possibility, we implemented a streamlined approach for the prediction and validation of such neoantigens derived from individual tumors and presented by patient-specific HLA alleles. We applied our computational pipeline to 91 chronic lymphocytic leukemias (CLLs) that underwent whole-exome sequencing (WES). We predicted ∼22 mutated HLA-binding peptides per leukemia (derived from ∼16 missense mutations) and experimentally confirmed HLA binding for ∼55% of such peptides. Two CLL patients that achieved long-term remission following allogeneic hematopoietic stem cell transplantation were monitored for CD8(+) T-cell responses against predicted or confirmed HLA-binding peptides. Long-lived cytotoxic T-cell responses were detected against peptides generated from personal tumor mutations in ALMS1, C6ORF89, and FNDC3B presented on tumor cells. Finally, we applied our computational pipeline to WES data (N = 2488 samples) across 13 different cancer types and estimated dozens to thousands of predicted neoantigens per individual tumor, suggesting that neoantigens are frequent in most tumors.

  18. B-cell antigen receptor signaling enhances chronic lymphocytic leukemia cell migration and survival: specific targeting with a novel spleen tyrosine kinase inhibitor, R406

    PubMed Central

    Quiroga, Maite P.; Balakrishnan, Kumudha; Kurtova, Antonina V.; Sivina, Mariela; Keating, Michael J.; Wierda, William G.; Gandhi, Varsha

    2009-01-01

    Antigenic stimulation through the B-cell antigen receptor (BCR) is considered to promote the expansion of chronic lymphocytic leukemia (CLL) B cells. The spleen tyrosine kinase (Syk), a key component of BCR signaling, can be blocked by R406, a small-molecule Syk inhibitor, that displayed activity in CLL patients in a first clinical trial. In this study, we investigated the effects of BCR stimulation and R406 on CLL cell survival and migration. The prosurvival effects promoted by anti-IgM stimulation and nurselike cells were abrogated by R406. BCR triggering up-regulated adhesion molecules, and increased CLL cell migration toward the chemokines CXCL12 and CXCL13. BCR activation also enhanced CLL cell migration beneath marrow stromal cells. These responses were blocked by R406, which furthermore abrogated BCR-dependent secretion of T-cell chemokines (CCL3 and CCL4) by CLL cells. Finally, R406 inhibited constitutive and BCR-induced activation of Syk, extracellular signal-regulated kinases, and AKT, and blocked BCR-induced calcium mobilization. These findings suggest that BCR activation favors CLL cell homing, retention, and survival in tissue microenvironments. R406 effectively blocks these BCR-dependent responses in CLL cells, providing an explanation for the activity of R406 in patients with CLL. PMID:19491390

  19. B-cell antigen receptor signaling enhances chronic lymphocytic leukemia cell migration and survival: specific targeting with a novel spleen tyrosine kinase inhibitor, R406.

    PubMed

    Quiroga, Maite P; Balakrishnan, Kumudha; Kurtova, Antonina V; Sivina, Mariela; Keating, Michael J; Wierda, William G; Gandhi, Varsha; Burger, Jan A

    2009-07-30

    Antigenic stimulation through the B-cell antigen receptor (BCR) is considered to promote the expansion of chronic lymphocytic leukemia (CLL) B cells. The spleen tyrosine kinase (Syk), a key component of BCR signaling, can be blocked by R406, a small-molecule Syk inhibitor, that displayed activity in CLL patients in a first clinical trial. In this study, we investigated the effects of BCR stimulation and R406 on CLL cell survival and migration. The prosurvival effects promoted by anti-IgM stimulation and nurselike cells were abrogated by R406. BCR triggering up-regulated adhesion molecules, and increased CLL cell migration toward the chemokines CXCL12 and CXCL13. BCR activation also enhanced CLL cell migration beneath marrow stromal cells. These responses were blocked by R406, which furthermore abrogated BCR-dependent secretion of T-cell chemokines (CCL3 and CCL4) by CLL cells. Finally, R406 inhibited constitutive and BCR-induced activation of Syk, extracellular signal-regulated kinases, and AKT, and blocked BCR-induced calcium mobilization. These findings suggest that BCR activation favors CLL cell homing, retention, and survival in tissue microenvironments. R406 effectively blocks these BCR-dependent responses in CLL cells, providing an explanation for the activity of R406 in patients with CLL.

  20. Isoform-selective phosphoinositide 3'-kinase inhibitors inhibit CXCR4 signaling and overcome stromal cell-mediated drug resistance in chronic lymphocytic leukemia: a novel therapeutic approach.

    PubMed

    Niedermeier, Matthias; Hennessy, Bryan T; Knight, Zachary A; Henneberg, Marina; Hu, Jianhua; Kurtova, Antonina V; Wierda, William G; Keating, Michael J; Shokat, Kevan M; Burger, Jan A

    2009-05-28

    Phosphoinositide 3-kinases (PI3Ks) are among the most frequently activated signaling pathways in cancer. In chronic lymphocytic leukemia (CLL), signals from the microenvironment are critical for expansion of the malignant B cells, and cause constitutive activation of PI3Ks. CXCR4 is a key receptor for CLL cell migration and adhesion to marrow stromal cells (MSCs). Because of the importance of CXCR4 and PI3Ks for CLL-microenvironment cross-talk, we investigated the activity of novel, isoform-selective PI3K inhibitors that target different isoforms of the p110-kDa subunit. Inhibition with p110alpha inhibitors (PIK-90 and PI-103) resulted in a significant reduction of chemotaxis and actin polymerization to CXCL12 and reduced migration beneath MSC (pseudoemperipolesis). Western blot and reverse phase protein array analyses consistently demonstrated that PIK-90 and PI-103 inhibited phosphorylation of Akt and S6, whereas p110delta or p110beta/p110delta inhibitors were less effective. In suspension and MSC cocultures, PI-103 and PIK-90 were potent inducers of CLL cell apoptosis. Moreover, these p110alpha inhibitors enhanced the cytotoxicity of fludarabine and reversed the protective effect of MSC on fludarabine-induced apoptosis. Collectively, our data demonstrate that p110alpha inhibitors antagonize stromal cell-derived migration, survival, and drug-resistance signals and therefore provide a rational to explore the therapeutic activity of these promising agents in CLL.

  1. Somatic MED12 mutations are associated with poor prognosis markers in chronic lymphocytic leukemia

    PubMed Central

    Heikkinen, Tuomas; Ruppert, Amy S.; Senter, Leigha; Hoag, Kevin W.; Dufva, Olli; Kontro, Mika; Rassenti, Laura; Hertlein, Erin; Kipps, Thomas J.; Porkka, Kimmo; Byrd, John C.; de la Chapelle, Albert; Vahteristo, Pia

    2015-01-01

    Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults. We performed systematic database search and identified highly specific MED12 mutations in CLL patients. To study this further, we collected three independent sample series comprising over 700 CLL samples and screened MED12 exons 1 and 2 by direct sequencing. Mutations were identified at significant frequency in all three series with a combined mutation frequency of 5.2% (37/709). Positive mutation status was found to be associated with unmutated IGHV and ZAP70 expression, which are well-known poor prognosis markers in CLL. Our results recognize CLL as the first extrauterine cancer type where 5′ terminus of MED12 is mutated at significant frequency. Functional analyses have shown that these mutations lead to dissociation of Cyclin C-CDK8/19 from the core Mediator and to the loss of Mediator-associated CDK kinase activity. Additional studies on the role of MED12 mutation status as a putative prognostic factor as well as mutations' exact tumorigenic mechanism in CLL are warranted. PMID:25595892

  2. Somatic MED12 mutations are associated with poor prognosis markers in chronic lymphocytic leukemia.

    PubMed

    Kämpjärvi, Kati; Järvinen, Tiina M; Heikkinen, Tuomas; Ruppert, Amy S; Senter, Leigha; Hoag, Kevin W; Dufva, Olli; Kontro, Mika; Rassenti, Laura; Hertlein, Erin; Kipps, Thomas J; Porkka, Kimmo; Byrd, John C; de la Chapelle, Albert; Vahteristo, Pia

    2015-01-30

    Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults. We performed systematic database search and identified highly specific MED12 mutations in CLL patients. To study this further, we collected three independent sample series comprising over 700 CLL samples and screened MED12 exons 1 and 2 by direct sequencing. Mutations were identified at significant frequency in all three series with a combined mutation frequency of 5.2% (37/709). Positive mutation status was found to be associated with unmutated IGHV and ZAP70 expression, which are well-known poor prognosis markers in CLL. Our results recognize CLL as the first extrauterine cancer type where 5'terminus of MED12 is mutated at significant frequency. Functional analyses have shown that these mutations lead to dissociation of Cyclin C-CDK8/19 from the core Mediator and to the loss of Mediator-associated CDK kinase activity. Additional studies on the role of MED12 mutation status as a putative prognostic factor as well as mutations' exact tumorigenic mechanism in CLL are warranted.

  3. Ibrutinib Therapy Increases T Cell Repertoire Diversity in Patients with Chronic Lymphocytic Leukemia.

    PubMed

    Yin, Qingsong; Sivina, Mariela; Robins, Harlan; Yusko, Erik; Vignali, Marissa; O'Brien, Susan; Keating, Michael J; Ferrajoli, Alessandra; Estrov, Zeev; Jain, Nitin; Wierda, William G; Burger, Jan A

    2017-02-15

    The Bruton's tyrosine kinase inhibitor ibrutinib is a highly effective, new targeted therapy for chronic lymphocytic leukemia (CLL) that thwarts leukemia cell survival, growth, and tissue homing. The effects of ibrutinib treatment on the T cell compartment, which is clonally expanded and thought to support the growth of malignant B cells in CLL, are not fully characterized. Using next-generation sequencing technology, we characterized the diversity of TCRβ-chains in peripheral blood T cells from 15 CLL patients before and after 1 y of ibrutinib therapy. We noted elevated CD4(+) and CD8(+) T cell numbers and a restricted TCRβ repertoire in all pretreatment samples. After 1 y of ibrutinib therapy, elevated peripheral blood T cell numbers and T cell-related cytokine levels had normalized, and T cell repertoire diversity increased significantly. Dominant TCRβ clones in pretreatment samples declined or became undetectable, and the number of productive unique clones increased significantly during ibrutinib therapy, with the emergence of large numbers of low-frequency TCRβ clones. Importantly, broader TCR repertoire diversity was associated with clinical efficacy and lower rates of infections during ibrutinib therapy. These data demonstrate that ibrutinib therapy increases diversification of the T cell compartment in CLL patients, which contributes to cellular immune reconstitution.

  4. Upregulation of long noncoding RNA MIAT in aggressive form of chronic lymphocytic leukemias

    PubMed Central

    Sattari, Arash; Siddiqui, Hasan; Moshiri, Farzaneh; Ngankeu, Apollinaire; Nakamura, Tatsuya; Kipps, Thomas J.; Croce, Carlo M.

    2016-01-01

    Long noncoding RNAs (lncRNAs) are non-proten-coding transcripts of more than 200 nucleotides generated by RNA polymerase II and their expressions are tightly regulated in cell type specific- and/or cellular differential stage specific- manner. MIAT, originally isolated as a candidate gene for myocardial infarction, encodes lncRNA (termed MIAT). Here, we determined the expression level of MIAT in established leukemia/lymphoma cell lines and found its upregulation in lymphoid but not in myeloid cell lineage with mature B cell phenotype. MIAT expression level was further determined in chronic lymphocytic leukemias (CLL), characterized by expansion of leukemic cells with mature B phenotype, to demonstrate relatively high occurrence of MIAT upregulation in aggressive form of CLL carrying either 17p-deletion, 11q-deletion, or Trisomy 12 over indolent form carrying 13p-deletion. Furthermore, we show that MIAT constitutes a regulatory loop with OCT4 in malignant mature B cell, as was previously reported in mouse pulripotent stem cell, and that both molecules are essential for cell survival. PMID:27527866

  5. Interphase cytogenetics of B-cell chronic lymphocytic leukemia by FISH-technique

    SciTech Connect

    Peddanna, N.; Gogineni, S.K.; Rosenthal, C.J.

    1994-09-01

    Chronic lymphocytic leukemia [CLL] accounts for about 30% of all lymphoproliferative disorders. In over 95% of these cases, the leukemia is caused by B-cells, rarely T-cells. Fifty percent of B-CLL have chromosomal aberrations and of such cases, one-third have trisomy 12. Malignant B-cells have a very low mitotic index and those metaphases that can be analyzed usually represent the normal T-cell population. Retrospectively, we decided to identify the additional chromosome 12 (trisomy 12) directly at interphase by the FISH-technique using centrometric 12 specific alphoid probe (Oncor, Gaithersburg, MD). Preparations were made from 9 patients with B-CLL. All cultures except one failed to produce metaphases for conventional karyotyping. Eighty percent of the cells have two dots (normal cells) over the interphase nuclei while the remaining 20% have three dots (trisomy 12). The clinical implication of trisomy 12 in the pathogenesis of CLL including age, staging and duration of disease, differentials and immunological markers are correlated with interphase cytogenetic data. The loss and/or gain of specific chromosomes in human neoplasia is common and rapid evaluation of such cases should be considered as a routine approach.

  6. What Is Acute Lymphocytic Leukemia (ALL)?

    MedlinePlus

    ... Adults About Acute Lymphocytic Leukemia (ALL) What Is Acute Lymphocytic Leukemia? Cancer starts when cells in the body begin ... Acute Lymphocytic Leukemia Research and Treatment? More In Acute Lymphocytic Leukemia About Acute Lymphocytic Leukemia Causes, Risk Factors, and ...

  7. Targeted Therapy for Acute Lymphocytic Leukemia

    MedlinePlus

    ... Adults Treating Acute Lymphocytic Leukemia Targeted Therapy for Acute Lymphocytic Leukemia In recent years, new drugs that target specific ... Typical Treatment of Acute Lymphocytic Leukemia More In Acute Lymphocytic Leukemia About Acute Lymphocytic Leukemia Causes, Risk Factors, and ...

  8. Tris (dibenzylideneacetone) dipalladium: a small-molecule palladium complex is effective in inducing apoptosis in chronic lymphocytic leukemia B-cells.

    PubMed

    Kay, Neil E; Sassoon, Traci; Secreto, Charla; Sinha, Sutapa; Shanafelt, Tait D; Ghosh, Asish K; Arbiser, Jack L

    2016-10-01

    Here we tested impact of Tris (dibenzylideneacetone) dipalladium (Tris-DBA) on chronic lymphocytic leukemia (CLL) B-cell survival. Indeed, treatment of CLL B-cells with Tris-DBA induced apoptosis in a dose-dependent manner irrespective of IgVH mutational status. Further analyses suggest that Tris-DBA-induced apoptosis involves reduced expression of the anti-apoptotic proteins Bcl-xL, and XIAP with an upregulation of the pro-apoptotic protein BIM in CLL B-cells. Our findings also indicate that Tris-DBA targets the ribosomal protein (rp)-S6, an essential component of the Akt/mTOR signaling axis in CLL B-cells. Of interest, CLL bone marrow stromal cells were unable to protect the leukemic B cells from Tris-DBA-induced apoptosis in an in vitro co-culture system. Finally, co-administration of Tris-DBA and the purine nucleoside analog fludarabine (F-ara-A) augmented CLL B-cell apoptosis levels in vitro showing synergistic effects. In total, Tris-DBA is effective at inducing apoptosis in CLL B-cells even in the presence of stromal cells likely by targeting directly the signal mediator, rpS6.

  9. Stromal endothelial cells establish a bidirectional crosstalk with chronic lymphocytic leukemia cells through the TNF-related factors BAFF, APRIL and CD40L

    PubMed Central

    Cols, Montserrat; Barra, Carolina M.; He, Bing; Puga, Irene; Xu, Weifeng; Chiu, April; Tam, Wayne; Knowles, Daniel M.; Dillon, Stacey R.; Leonard, John P.; Furman, Richard R.; Chen, Kang; Cerutti, Andrea

    2012-01-01

    Chronic lymphocytic leukemia (CLL) is a clonal B cell disorder of unknown origin. Accessory signals from the microenvironment are critical for the survival, expansion and progression of malignant B cells. We found that the CLL stroma included microvascular endothelial cells (MVECs) expressing BAFF and APRIL, two TNF family members related to the T cell-associated B cell-stimulating molecule CD40 ligand (CD40L). Constitutive release of soluble BAFF and APRIL increased upon engagement of CD40 on MVECs by CD40L aberrantly expressed on CLL cells. In addition to enhancing MVEC expression of the CD40 receptor, leukemic CD40L induced cleavases that elicited intracellular processing of pro-BAFF and pro-APRIL proteins in MVECs. The resulting soluble BAFF and APRIL proteins delivered survival, proliferation, Ig gene-remodeling and differentiation signals by activating CLL cells through TACI, BAFF-R and BCMA receptors. BAFF and APRIL further amplified CLL cell survival by up-regulating the expression of leukemic CD40L. Inhibition of TACI, BCMA and BAFF-R expression on CLL cells, abrogation of CD40 expression in MVECs, or suppression of BAFF and APRIL cleavases in MVECs reduced the survival and diversification of malignant B cells. These data indicate that BAFF, APRIL and CD40L form a CLL-enhancing bidirectional signaling network linking neoplastic B cells with the microvascular stroma. PMID:22593611

  10. Immune phenotype and some enzyme patterns in phorbol ester-induced chronic lymphocytic leukemia cells.

    PubMed

    Babusíková, O; Mesárosová, A; Kusenda, J; Koníková, E; Klobusická, M; Hrivnáková, A

    1995-01-01

    Leukemic cells from 10 patients with B-chronic lymphocytic leukemia (B-CLL) were isolated and cultured in the presence of 12-0-tetradecanoylphorbol 13-acetate (TPA) at a concentration of 8 x 10(-7) mol for 72 hours. Cells were analyzed before cultivation and after 72 h of cultivation with and without TPA for changes in surface membrane (Sm) and cytoplasmic (cyt) markers expression, presence of receptor for mouse rosette forming cells (MRFC) and some enzyme profiles. All B-CLL cases studied showed typical B-cell phenotype. TPA treatment induced hairy cell leukemia (HCL) characteristics, given by the membrane CD22 and CD25 expression and TRAP positivity in the majority of the cases tested. Cells had hairy cell-like morphology with more intensive cytoplasmic immunoglobulin (CIg) fluorescence staining, absent receptor for MRFC and increased activity of purine nucleosidephosphorylase. In common these changes indicate that TPA can induce hairy cell characteristics on B-CLL cells in vitro suggesting the more mature differentiation stage of HCL compared with CLL. Furthermore, we originally demonstrated that the CD22, present in the cell membrane after TPA, could be detected in the majority of unaffected B-CLL cells in their cytoplasm. From the technical point of view some intracellular CD markers and Igs of B-CLL cells in viable cells in suspension assayed by flow cytometry are described in this study.

  11. Mechanisms of Idelalisib-Associated Diarrhea in Patients With Relapsed Chronic Lymphocytic Leukemia, Indolent Non-hodgkin Lymphoma, or Small Lymphocytic Lymphoma

    ClinicalTrials.gov

    2016-10-06

    Absence of Signs or Symptoms; B-Cell Non-Hodgkin Lymphoma; Digestive System Signs and Symptoms; Indolent Adult Non-Hodgkin Lymphoma; Recurrent B-Cell Non-Hodgkin Lymphoma; Recurrent Chronic Lymphocytic Leukemia; Recurrent Indolent Adult Non-Hodgkin Lymphoma; Recurrent Small Lymphocytic Lymphoma

  12. Bruton tyrosine kinase represents a promising therapeutic target for treatment of chronic lymphocytic leukemia and is effectively targeted by PCI-32765.

    PubMed

    Herman, Sarah E M; Gordon, Amber L; Hertlein, Erin; Ramanunni, Asha; Zhang, Xiaoli; Jaglowski, Samantha; Flynn, Joseph; Jones, Jeffrey; Blum, Kristie A; Buggy, Joseph J; Hamdy, Ahmed; Johnson, Amy J; Byrd, John C

    2011-06-09

    B-cell receptor (BCR) signaling is aberrantly activated in chronic lymphocytic leukemia (CLL). Bruton tyrosine kinase (BTK) is essential to BCR signaling and in knockout mouse models its mutation has a relatively B cell-specific phenotype. Herein, we demonstrate that BTK protein and mRNA are significantly over expressed in CLL compared with normal B cells. Although BTK is not always constitutively active in CLL cells, BCR or CD40 signaling is accompanied by effective activation of this pathway. Using the irreversible BTK inhibitor PCI-32765, we demonstrate modest apoptosis in CLL cells that is greater than that observed in normal B cells. No influence of PCI-32765 on T-cell survival is observed. Treatment of CD40 or BCR activated CLL cells with PCI-32765 results in inhibition of BTK tyrosine phosphorylation and also effectively abrogates downstream survival pathways activated by this kinase including ERK1/2, PI3K, and NF-κB. In addition, PCI-32765 inhibits activation-induced proliferation of CLL cells in vitro, and effectively blocks survival signals provided externally to CLL cells from the microenvironment including soluble factors (CD40L, BAFF, IL-6, IL-4, and TNF-α), fibronectin engagement, and stromal cell contact. Based on these collective data, future efforts targeting BTK with the irreversible inhibitor PCI-32765 in clinical trials of CLL patients is warranted.

  13. Bruton tyrosine kinase represents a promising therapeutic target for treatment of chronic lymphocytic leukemia and is effectively targeted by PCI-32765

    PubMed Central

    Herman, Sarah E. M.; Gordon, Amber L.; Hertlein, Erin; Ramanunni, Asha; Zhang, Xiaoli; Jaglowski, Samantha; Flynn, Joseph; Jones, Jeffrey; Blum, Kristie A.; Buggy, Joseph J.; Hamdy, Ahmed

    2011-01-01

    B-cell receptor (BCR) signaling is aberrantly activated in chronic lymphocytic leukemia (CLL). Bruton tyrosine kinase (BTK) is essential to BCR signaling and in knockout mouse models its mutation has a relatively B cell–specific phenotype. Herein, we demonstrate that BTK protein and mRNA are significantly over expressed in CLL compared with normal B cells. Although BTK is not always constitutively active in CLL cells, BCR or CD40 signaling is accompanied by effective activation of this pathway. Using the irreversible BTK inhibitor PCI-32765, we demonstrate modest apoptosis in CLL cells that is greater than that observed in normal B cells. No influence of PCI-32765 on T-cell survival is observed. Treatment of CD40 or BCR activated CLL cells with PCI-32765 results in inhibition of BTK tyrosine phosphorylation and also effectively abrogates downstream survival pathways activated by this kinase including ERK1/2, PI3K, and NF-κB. In addition, PCI-32765 inhibits activation-induced proliferation of CLL cells in vitro, and effectively blocks survival signals provided externally to CLL cells from the microenvironment including soluble factors (CD40L, BAFF, IL-6, IL-4, and TNF-α), fibronectin engagement, and stromal cell contact. Based on these collective data, future efforts targeting BTK with the irreversible inhibitor PCI-32765 in clinical trials of CLL patients is warranted. PMID:21422473

  14. Preservation of lower incidence of chronic lymphocytic leukemia in Chinese residents in British Columbia: a 26-year survey from 1983 to 2008.

    PubMed

    Mak, Vivien; Ip, Dennis; Mang, Oscar; Dalal, Chinmay; Huang, Steven; Gerrie, Alina; Gillan, Tanya; Ramadan, Khaled M; Toze, Cynthia; Au, Wing-Yan

    2014-04-01

    The incidence of chronic lymphocytic leukemia (CLL) in the Asian population is up to 10 times lower than that in Caucasians. Studies on CLL in Asian residents in North America may help to determine the relative genetic and environmental causes of such a difference. Computerized records of CLL incidence from the combined British Columbia (BC) databases (n = 2736) and the Hong Kong Cancer Registry (HKCR, n = 572) were traced. Ethnic Chinese cases of CLL in BC were identified (n = 35). The world age standardized rates (WASRs) of CLL (per 100 000) were calculated in BC (1.71), HK (0.28) and BC Chinese (0.4), respectively. Using standard incidence ratios (SIRs), the observed BC Chinese case number was comparable to the figure projected from HK rates (SIR 1.3, p = 0.1) but significantly lower than the figure following BC rates (SIR 0.22, p < 0.0001). The difference was maintained over both genders, in all age groups and through the years. Our data over three decades suggest that genetic factors outplay environmental factors to give lower CLL rates in Chinese.

  15. An open-label phase 2 trial of entospletinib (GS-9973), a selective spleen tyrosine kinase inhibitor, in chronic lymphocytic leukemia.

    PubMed

    Sharman, Jeff; Hawkins, Michael; Kolibaba, Kathryn; Boxer, Michael; Klein, Leonard; Wu, Meihua; Hu, Jing; Abella, Steve; Yasenchak, Chris

    2015-04-09

    Small-molecule inhibitors of kinases involved in B-cell receptor signaling are an important advance in managing lymphoid malignancies. Entospletinib (GS-9973) is an oral, selective inhibitor of spleen tyrosine kinase. This multicenter, phase 2 study enrolled subjects with relapsed or refractory chronic lymphocytic leukemia (CLL; n = 41) or non-Hodgkin lymphoma (n = 145). Participants received 800 mg entospletinib twice daily. We report efficacy outcomes in the CLL cohort (n = 41) and safety outcomes in all cohorts (N = 186). The primary end point was a progression-free survival (PFS) rate at 24 weeks in subjects with CLL. The PFS rate at 24 weeks was 70.1% (95% confidence interval [CI], 51.3%-82.7%); median PFS was 13.8 months (95% CI, 7.7 months to not reached). The objective response rate was 61.0% (95% CI, 44.5%-75.8%), including 3 subjects (7.3%) who achieved nodal response with persistent lymphocytosis. Fifty-four subjects (29.0%) had serious adverse events (SAEs). The most common treatment-emergent SAEs included dyspnea, pneumonia, febrile neutropenia, dehydration, and pyrexia. Common grade 3/4 laboratory abnormalities included neutropenia (14.5%) and reversible alanine aminotransferase/aspartate aminotransferase elevations (13.4%). Entospletinib demonstrates clinical activity in subjects with relapsed or refractory CLL with acceptable toxicity. This trial was registered at www.clinicaltrials.gov as #NCT01799889.

  16. An open-label phase 2 trial of entospletinib (GS-9973), a selective spleen tyrosine kinase inhibitor, in chronic lymphocytic leukemia

    PubMed Central

    Hawkins, Michael; Kolibaba, Kathryn; Boxer, Michael; Klein, Leonard; Wu, Meihua; Hu, Jing; Abella, Steve; Yasenchak, Chris

    2015-01-01

    Small-molecule inhibitors of kinases involved in B-cell receptor signaling are an important advance in managing lymphoid malignancies. Entospletinib (GS-9973) is an oral, selective inhibitor of spleen tyrosine kinase. This multicenter, phase 2 study enrolled subjects with relapsed or refractory chronic lymphocytic leukemia (CLL; n = 41) or non-Hodgkin lymphoma (n = 145). Participants received 800 mg entospletinib twice daily. We report efficacy outcomes in the CLL cohort (n = 41) and safety outcomes in all cohorts (N = 186). The primary end point was a progression-free survival (PFS) rate at 24 weeks in subjects with CLL. The PFS rate at 24 weeks was 70.1% (95% confidence interval [CI], 51.3%-82.7%); median PFS was 13.8 months (95% CI, 7.7 months to not reached). The objective response rate was 61.0% (95% CI, 44.5%-75.8%), including 3 subjects (7.3%) who achieved nodal response with persistent lymphocytosis. Fifty-four subjects (29.0%) had serious adverse events (SAEs). The most common treatment-emergent SAEs included dyspnea, pneumonia, febrile neutropenia, dehydration, and pyrexia. Common grade 3/4 laboratory abnormalities included neutropenia (14.5%) and reversible alanine aminotransferase/aspartate aminotransferase elevations (13.4%). Entospletinib demonstrates clinical activity in subjects with relapsed or refractory CLL with acceptable toxicity. This trial was registered at www.clinicaltrials.gov as #NCT01799889. PMID:25696919

  17. Fludarabine, cyclophosphamide and lenalidomide in patients with relapsed/refractory chronic lymphocytic leukemia. A multicenter phase I-II GIMEMA trial.

    PubMed

    Mauro, Francesca R; Carella, Angelo M; Molica, Stefano; Paoloni, Francesca; Liberati, Anna M; Zaja, Francesco; Belsito, Valeria; Cortellezzi, Agostino; Rizzi, Rita; Tosi, Patrizia; Spriano, Mauro; Ferretti, Antonietta; Nanni, Mauro; Marinelli, Marilisa; De Propris, Maria S; Orlando, Sonia M; Vignetti, Marco; Cuneo, Antonio; Guarini, Anna R; Foà, Robin

    2017-07-01

    The activity and safety of a regimen combining lenalidomide with fludarabine and cyclophosphamide (FC) was investigated in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). Treatment consisted of six monthly courses of the FC regimen combined with 14 days of lenalidomide given at the starting dose of 2.5 mg during course 1. The maximum tolerated dose of lenalidomide was 5 mg. Forty patients were assessed for response, 66% were IGHV unmutated, 45% showed deletion 11q or 17p. The overall response and complete remission rates were 62.5% and 22.5%, respectively, the median progression-free and overall survival (OS) were 19 and 45 months, respectively. Grade 3-4 granulocytopenia was observed in 65% of cases, severe infections in 7.5%, the lenalidomide-related toxicity was mild. In conclusion, the results of this study demonstrate that low-dose lenalidomide associated with the FC schedule is an effective treatment for R/R patients with CLL, associated with an acceptable safety profile.

  18. Identifying High-Risk Chronic Lymphocytic Leukemia: A Pathogenesis-Oriented Appraisal of Prognostic and Predictive Factors in Patients Treated with Chemotherapy with or without Immunotherapy

    PubMed Central

    Martinelli, Sara; Cuneo, Antonio; Formigaro, Luca; Cavallari, Maurizio; Lista, Enrico; Quaglia, Francesca Maria; Ciccone, Maria; Bardi, Antonella; Volta, Eleonora; Tammiso, Elisa; Saccenti, Elena; Sofritti, Olga; Daghia, Giulia; Negrini, Massimo; Dabusti, Melissa; Tomasi, Paolo; Moretti, Sabrina; Cavazzini, Francesco; Rigolin, Gian Matteo

    2016-01-01

    Chronic lymphocytic leukemia (CLL) displays an extremely variable clinical behaviour. Accurate prognostication and prediction of response to treatment are important in an era of effective first-line regimens and novel molecules for high risk patients. Because a plethora of prognostic biomarkers were identified, but few of them were validated by multivariable analysis in comprehensive prospective studies, we applied in this survey stringent criteria to select papers from the literature in order to identify the most reproducible prognostic/predictive markers. Each biomarker was analysed in terms of reproducibility across the different studies with respect to its impact on time to first treatment (TTFT), progression free survival (PFS), overall survival (OS) and response to treatment. We were able to identify the following biomarkers as the most reliable in guiding risk stratification in the daily clinical practice: 17p-/TP53 mutations, IGHV unmutated configuration, short telomeres and 11q-. However, the method for measuring telomere length was not validated yet and 11q- was predictive of inferior OS only in those patients who did not receive FCR-like combinations. Stage and lymphocytosis were predictive of shorter TTFT and age, high serum thymidine kinase levels and poor performance status were predictive of shorter OS. Using our criteria no parameter was found to independently predict for inferior response to treatment. PMID:27872727

  19. Obinutuzumab (GA101) for the treatment of chronic lymphocytic leukemia and other B-cell non-hodgkin's lymphomas: a glycoengineered type II CD20 antibody.

    PubMed

    Goede, Valentin; Klein, Christian; Stilgenbauer, Stephan

    2015-01-01

    Obinutuzumab (GA101) is a humanized, monoclonal type II CD20 antibody modified by glycoengineering. The glycoengineered Fc portion enhances the binding affinity to the FcγRIII receptor on immune effector cells, resulting in increased antibody-dependent cellular cytotoxicity and phagocytosis. In addition, the type II antibody binding characteristics of obinutuzumab to CD20 lead to an efficient induction of direct non-apoptotic cell death. Preclinical data demonstrated more efficient B-cell depletion in whole blood and superior antitumor activity in xenograft models of obinutuzumab as compared to the type I CD20 antibody rituximab. In previously untreated patients with chronic lymphocytic leukemia (CLL) and comorbidities, obinutuzumab plus chlorambucil increased response rates and prolonged progression-free survival compared with rituximab plus chlorambucil. Obinutuzumab had an acceptable and manageable safety profile, with infusion-related reactions during the first infusion as the most common adverse event. Further phase I/II clinical trials have also shown promising activity in other CD20-positive B-cell non-Hodgkin's lymphomas (NHL). Therefore, several clinical studies are planned or ongoing to investigate obinutuzumab with different combination partners in both untreated and relapsed/refractory patients with different B-cell NHL entities, which in addition to CLL include diffuse large B-cell lymphoma and follicular lymphoma. © 2015 S. Karger GmbH, Freiburg.

  20. Improved survival for patients diagnosed with chronic lymphocytic leukemia in the era of chemo-immunotherapy: a Danish population-based study of 10455 patients

    PubMed Central

    da Cunha-Bang, C; Simonsen, J; Rostgaard, K; Geisler, C; Hjalgrim, H; Niemann, C U

    2016-01-01

    The treatment of chronic lymphocytic leukemia (CLL) is in rapid transition, and during recent decades both combination chemotherapy and immunotherapy have been introduced. To evaluate the effects of this development, we identified all CLL patients registered in the nation-wide Danish Cancer Register between 1978 and 2013. We identified 10 455 CLL patients and 508 995 CLL-free control persons from the general population. Compared with the latter, the relative mortality rate between CLL patients and their controls decreased from 3.4 (95% CI 3.2–3.6) to 1.9 (95% CI 1.7–2.1) for patients diagnosed in 1978–1984 and 2006–2013, respectively. The improved survival corresponded to a decreasing risk of death from malignant hematological diseases, whereas the risk of death from infections was stable during the study period. These population-based data substantiate the improved survival for patients treated with chemo-immunotherapy demonstrated in clinical studies. PMID:27834937

  1. High-level ROR1 associates with accelerated disease progression in chronic lymphocytic leukemia

    PubMed Central

    Cui, Bing; Ghia, Emanuela M.; Chen, Liguang; Rassenti, Laura Z.; Widhopf, George F.; Yu, Jian; Wierda, William G.; Brown, Jennifer R.; Jones, Jeffrey A.; Gribben, John G.

    2016-01-01

    ROR1 is an oncoembryonic orphan receptor found on chronic lymphocytic leukemia (CLL) B cells, but not on normal postpartum tissues. ROR1 is a receptor for Wnt5a that may complex with TCL1, a coactivator of AKT that is able to promote development of CLL. We found the CLL cells of a few patients expressed negligible ROR1 (ROR1Neg), but expressed TCL1A at levels comparable to those of samples that expressed ROR1 (ROR1Pos). Transcriptome analyses revealed that ROR1Neg cases generally could be distinguished from those that were ROR1Pos in unsupervised gene-expression clustering analysis. Gene-set enrichment analyses demonstrated that ROR1Neg CLL had lower expression and activation of AKT signaling pathways relative to ROR1Pos CLL, similar to what was noted for leukemia that respectively developed in TCL1 vs ROR1xTCL1 transgenic mice. In contrast to its effect on ROR1Pos CLL, Wnt5a did not enhance the proliferation, chemotaxis, or survival of ROR1Neg CLL. We examined the CLL cells from 1568 patients, which we randomly assigned to a training or validation set of 797 or 771 cases, respectively. Using recursive partitioning, we defined a threshold for ROR1 surface expression that could segregate samples of the training set into ROR1-Hi vs ROR1-Lo subgroups that differed significantly in their median treatment-free survival (TFS). Using this threshold, we found that ROR1-Hi cases had a significantly shorter median TFS and overall survival than ROR1-Lo cases in the validation set. These data demonstrate that expression of ROR1 may promote leukemia-cell activation and survival and enhance disease progression in patients with CLL. PMID:27815263

  2. MiRNA expression profile of chronic lymphocytic leukemia patients with 13q deletion.

    PubMed

    Hernández-Sánchez, María; Rodríguez-Vicente, Ana E; Hernández, José-Ángel; Lumbreras, Eva; Sarasquete, María-Eugenia; Martín, Ana-África; Benito, Rocío; Vicente-Gutiérrez, Carlos; Robledo, Cristina; Heras, Natalia de Las; Rodríguez, Juan-Nicolás; Alcoceba, Miguel; Coca, Alfonso García de; Aguilar, Carlos; González, Marcos; Hernández-Rivas, Jesús-María

    2016-07-01

    Deletion 13q (13q-) is the most common cytogenetic aberration in chronic lymphocytic leukemia (CLL) and is associated with the most favorable prognosis as the sole cytogenetic abnormality. However, it is heterogeneous whereby CLL patients with higher percentages of 13q- cells (13q-H) have a more aggressive clinical course and a distinct gene expression profile. The microRNA (miRNA) expression profile of CLL gives additional biological and prognostic information, but its expression in 13q- CLL has not been examined in detail. The miRNA expression of clonal B cell lymphocytes (CD19+ cells) of 38 CLL patients and normal B cells of six healthy donors was analyzed. CLL patients with higher percentages of 13q- cells (≥80%) showed a different level of miRNA expression from patients with lower percentages (<80%). Interestingly, miR-143 was downregulated and miR-155 was overexpressed in 13q-H. This deregulation affected important validated target genes involved in apoptosis (BCL2, MDM2, TP53INP1) and proliferation (KRAS, PI3K-AKT signaling), that could lead to decreased apoptosis and increased proliferation in 13q-H patients. This study provides new evidence about the heterogeneity of the 13q deletion in CLL patients, showing that miRNA regulation could be involved in several significant pathways deregulated in CLL patients with a high number of losses in 13q.

  3. Salinomycin inhibits Wnt signaling and selectively induces apoptosis in chronic lymphocytic leukemia cells.

    PubMed

    Lu, Desheng; Choi, Michael Y; Yu, Jian; Castro, Januario E; Kipps, Thomas J; Carson, Dennis A

    2011-08-09

    Salinomycin, an antibiotic potassium ionophore, has been reported recently to act as a selective breast cancer stem cell inhibitor, but the biochemical basis for its anticancer effects is not clear. The Wnt/β-catenin signal transduction pathway plays a central role in stem cell development, and its aberrant activation can cause cancer. In this study, we identified salinomycin as a potent inhibitor of the Wnt signaling cascade. In Wnt-transfected HEK293 cells, salinomycin blocked the phosphorylation of the Wnt coreceptor lipoprotein receptor related protein 6 (LRP6) and induced its degradation. Nigericin, another potassium ionophore with activity against cancer stem cells, exerted similar effects. In otherwise unmanipulated chronic lymphocytic leukemia cells with constitutive Wnt activation nanomolar concentrations of salinomycin down-regulated the expression of Wnt target genes such as LEF1, cyclin D1, and fibronectin, depressed LRP6 levels, and limited cell survival. Normal human peripheral blood lymphocytes resisted salinomycin toxicity. These results indicate that ionic changes induced by salinomycin and related drugs inhibit proximal Wnt signaling by interfering with LPR6 phosphorylation, and thus impair the survival of cells that depend on Wnt signaling at the plasma membrane.

  4. Effects of phenylacetate on cells from patients with B-chronic lymphocytic leukemia.

    PubMed

    Call, T G; Stenson, M J; Witzig, T E

    1994-06-01

    Peripheral blood mononuclear cells from 11 patients with untreated B-chronic lymphocytic leukemia (CLL) were exposed to sodium phenylacetate (NaPA) in culture to assess its ability to induce differentiation. We found no evidence of cellular differentiation or induction of tartrate resistant acid phosphatase activity, as seen when B-CLL cells were treated with phorbol ester. We observed a striking decrease in the viability of the B-CLL cells in a time and dose dependent fashion when exposed to NaPA. After six days of culture, control cells from the 11 patients studied had a median viability of 90%, whereas cells exposed to NaPA at 5 and 10 mM concentrations had median viabilities of 39 and 16%, respectively. The cells treated with NaPA developed prominent cytoplasmic vacuoles. NaPA binds and depletes glutamine which is an important amino acid for lymphocyte metabolism. Although the mechanism of the cytocidal effects demonstrated in this study are unknown, they may relate at least partially to glutamine deprivation.

  5. TET2 Overexpression in Chronic Lymphocytic Leukemia Is Unrelated to the Presence of TET2 Variations

    PubMed Central

    Hernández-Sánchez, María; Rodríguez, Ana Eugenia; Kohlmann, Alexander; Benito, Rocío; García, Juan Luis; Risueño, Alberto; Fermiñán, Encarna; De Las Rivas, Javier; González, Marcos; Hernández-Rivas, Jesús-María

    2014-01-01

    TET2 is involved in a variety of hematopoietic malignancies, mainly in myeloid malignancies. Most mutations of TET2 have been identified in myeloid disorders, but some have also recently been described in mature lymphoid neoplasms. In contrast to the large amount of data about mutations of TET2, some data are available for gene expression. Moreover, the role of TET2 in chronic lymphocytic leukemia (CLL) is unknown. This study analyzes both TET2 expression and mutations in 48 CLL patients. TET2 expression was analyzed by exon arrays and quantitative real-time polymerase chain reaction (qRT-PCR). Next-generation sequencing (NGS) technology was applied to investigate the presence of TET2 variations. Overexpression of TET2 was observed in B-cell lymphocytes from CLL patients compared with healthy donors (P = 0.004). In addition, in CLL patients, an overexpression of TET2 was also observed in the clonal B cells compared with the nontumoral cells (P = 0.002). However, no novel mutations were observed. Therefore, overexpression of TET2 in CLL seems to be unrelated to the presence of genomic TET2 variations. PMID:24693539

  6. Three newly approved drugs for chronic lymphocytic leukemia: incorporating ibrutinib, idelalisib, and obinutuzumab into clinical practice.

    PubMed

    Sanford, David S; Wierda, William G; Burger, Jan A; Keating, Michael J; O'Brien, Susan M

    2015-07-01

    Three agents have received Food and Drug Administration (FDA) approval for treatment of chronic lymphocytic leukemia (CLL) within the past year. Ibrutinib and idelalisib block B-cell receptor signaling through inhibition of Bruton tyrosine kinase and phosphatidylinositol 3-kinase δ molecules respectively, interfering with several pathways required for leukemia cell survival. Idelalisib has shown efficacy in the relapsed setting and is currently approved by the FDA for use in combination with rituximab. Ibrutinib has been studied in patients with relapsed CLL and as frontline therapy. In the relapsed setting, these agents produce durable remissions, and might be preferable to re-treatment with chemoimmunotherapy for many patients. Ibrutinib is also effective treatment for patients with deletion 17p and is approved by the FDA as frontline therapy in this patient group, although it does not appear to completely abrogate this adverse prognostic factor. These agents have a unique side effect profile and longer follow-up is required to further understand tolerability and rare adverse effects. Obinutuzumab is a type-2 monoclonal anti-CD20 antibody which results in direct and antibody-dependent cell-mediated cytotoxicity of leukemia cells. It is approved by the FDA for use in combination with chlorambucil, and has shown efficacy in the frontline setting in patients unfit for more intensive chemoimmunotherapy. It produces increased response rates and minimal residual disease negativity compared with chlorambucil/rituximab and is associated with an advantage in progression-free survival but not yet overall survival. These agents underscore our advancement in the understanding of the biology of CLL and will improve outcomes for many patients with CLL.

  7. High Mitochondrial DNA Stability in B-Cell Chronic Lymphocytic Leukemia

    PubMed Central

    Cerezo, María; Bandelt, Hans-Jürgen; Martín-Guerrero, Idoia; Ardanaz, Maite; Vega, Ana; Carracedo, Ángel; García-Orad, África; Salas, Antonio

    2009-01-01

    Background Chronic Lymphocytic Leukemia (CLL) leads to progressive accumulation of lymphocytes in the blood, bone marrow, and lymphatic tissues. Previous findings have suggested that the mtDNA could play an important role in CLL. Methodology/Principal Findings The mitochondrial DNA (mtDNA) control-region was analyzed in lymphocyte cell DNA extracts and compared with their granulocyte counterpart extract of 146 patients suffering from B-Cell CLL; B-CLL (all recruited from the Basque country). Major efforts were undertaken to rule out methodological artefacts that would render a high false positive rate for mtDNA instabilities and thus lead to erroneous interpretation of sequence instabilities. Only twenty instabilities were finally confirmed, most of them affecting the homopolymeric stretch located in the second hypervariable segment (HVS-II) around position 310, which is well known to constitute an extreme mutational hotspot of length polymorphism, as these mutations are frequently observed in the general human population. A critical revision of the findings in previous studies indicates a lack of proper methodological standards, which eventually led to an overinterpretation of the role of the mtDNA in CLL tumorigenesis. Conclusions/Significance Our results suggest that mtDNA instability is not the primary causal factor in B-CLL. A secondary role of mtDNA mutations cannot be fully ruled out under the hypothesis that the progressive accumulation of mtDNA instabilities could finally contribute to the tumoral process. Recommendations are given that would help to minimize erroneous interpretation of sequencing results in mtDNA studies in tumorigenesis. PMID:19924307

  8. Lenalidomide Induces Immunomodulation in Chronic Lymphocytic Leukemia and Enhances Antitumor Immune Responses Mediated by NK and CD4 T Cells

    PubMed Central

    Acebes-Huerta, Andrea; Huergo-Zapico, Leticia; Gonzalez-Rodriguez, Ana Pilar; Fernandez-Guizan, Azahara; Payer, Angel R.; Gonzalez, Segundo

    2014-01-01

    Lenalidomide is an immunomodulatory drug with therapeutic activity in chronic lymphocytic leukemia (CLL). However, it has pleiotropic effects, and the mechanism of action responsible for its therapeutic activity has not been well defined yet. Herein, we show that lenalidomide treatment does not have an effect on the proliferation of leukemia cells, but it increases the proliferation of B cells from healthy donors. Lenalidomide did not exert a direct effect on the apoptosis of leukemia cells obtained from CLL patients, although it indirectly induced their apoptosis through the activation of nonmalignant immune cells. Thus, lenalidomide markedly increased the proliferation of NK and CD4 T cells. The effect of lenalidomide on NK cells was secondary to the induction of IL-2 production by CD4 T cells. Accordingly, depletion of T cells or blockade of IL-2 activity completely abrogated the proliferation of NK cells. Additionally, lenalidomide enhanced NK and NKT-like cell-mediated natural cytotoxicity against leukemia cells from CLL patients. Lenalidomide also upregulated CD20 expression on leukemia cells and, accordingly, it had a synergistic effect with rituximab on promoting antibody-dependent cell-mediated cytotoxicity against primary leukemia cells. Overall, these observations provide a support for combining lenalidomide with rituximab as a treatment in CLL. PMID:25313353

  9. Nucleic acid distribution pattern as a possible biomarker for metabolic activities of neoplastic cells: a digitally-aided fluorescence microscopy study on normal and neoplastic lymphocytes of acute and chronic canine lymphocytic leukemia

    PubMed Central

    Isitor, Godwin N; Campbell, Mervyn; Nayak, Shivananda B

    2009-01-01

    Background Metabolic states of neoplastic cells are increasingly being relied upon for diagnostic and prognostic assessment of neoplastic conditions. The nucleic acid distribution pattern of cells in general, in terms of degree of condensation of the nuclear chromatin and overall spread of the nucleic acid within the nuclear and cytoplasmic compartments, can reflect the metabolic state of the cell. This simple but logical concept appears not be put into consideration to date as numerous attempts are being made towards formulating reliable biomarkers for rapid diagnosis, prognosis and subsequent therapeutic interventions for neoplastic conditions. We comparatively evaluated nucleic acid distribution patterns of normal lymphocytes and neoplastic cells of lymphocytic lineage, employing light and fluorescence microscopy procedures, as well as digital imaging analytical methods. Results The results demonstrate distinctiveness in the pattern of nucleic acid distribution for the normal lymphocytes and three lymphocytic neoplastic cell-types of canine lymphocytic leukemia that are categorized as small, intermediate and large neoplastic lymphocytes. Variably-shaped cytoplasmic processes laden with single-stranded nucleic acids (SSNA) were observed for the small and intermediate-sized neoplastic lymphocytes, compared with large neoplastic lymphocytes and the normal lymphocytes; the latter two categories of cells being virtually devoid of similar processes. Prominent cytoplasmic and nuclear clumps of SSNA, indicative of a higher rate of metabolic activity, were also observed within the neoplastic cells compared with fewer and narrower SSNA of the normal cells. Conclusion The comparative relative increases of SSNA in cytoplasmic processes and other cellular areas of small and intermediate-sized neoplastic lymphocytes is reflective of greater metabolic activity in neoplastic cells in general compared with their normal cellular counterparts. PMID:19432993

  10. Cytochrome P450 allele CYP3A7*1C associates with adverse outcomes in chronic lymphocytic leukemia, breast and lung cancer

    PubMed Central

    Orr, Nick; Broderick, Peter; Catovsky, Daniel; Matakidou, Athena; Eisen, Timothy; Goldsmith, Christy; Dudbridge, Frank; Peto, Julian; dos-Santos-Silva, Isabel; Ashworth, Alan; Ross, Gillian; Houlston, Richard S; Fletcher, Olivia

    2016-01-01

    CYP3A enzymes metabolize endogenous hormones and chemotherapeutic agents used to treat cancer, thereby potentially impacting drug effectiveness. Here we refined the genetic basis underlying the functional effects of a CYP3A haplotype on urinary estrone glucuronide (E1G) levels and tested for an association between CYP3A genotype and outcome in patients with chronic lymphocytic leukemia (CLL), breast, or lung cancers. The most significantly associated single nucleotide polymorphism (SNP) was rs45446698, a SNP that tags the CYP3A7*1C allele; this SNP was associated with a 54% decrease in urinary E1G levels. Genotyping this SNP in 1,008 breast cancer, 1,128 lung cancer, and 347 CLL patients, we found that rs45446698 was associated with breast cancer mortality (hazard ratio [HR]=1.74, P=0.03), all-cause mortality in lung cancer patients (HR=1.43, P=0.009), and CLL progression (HR=1.62, P=0.03). We also found borderline evidence of a statistical interaction between the CYP3A7*1C allele, treatment of patients with a cytotoxic agent that is a CYP3A substrate and clinical outcome (Pinteraction=0.06). The CYP3A7*1C allele, which results in adult expression of the fetal CYP3A7 gene, is likely to be the functional allele influencing levels of circulating endogenous sex hormones and outcome in these various malignancies. Further studies confirming these associations and determining the mechanism by which CYP3A7*1C influences outcome are required. One possibility is that standard chemotherapy regimens that include CYP3A substrates may not be optimal for the approximately 8% of cancer patients who are CYP3A7*1C carriers. PMID:26964624

  11. miR-181a/b significantly enhances drug sensitivity in chronic lymphocytic leukemia cells via targeting multiple anti-apoptosis genes.

    PubMed

    Zhu, Dan-Xia; Zhu, Wei; Fang, Cheng; Fan, Lei; Zou, Zhi-Jian; Wang, Yin-Hua; Liu, Ping; Hong, Min; Miao, Kou-Rong; Liu, Peng; Xu, Wei; Li, Jian-Yong

    2012-07-01

    MicroRNAs (miRNAs) have been shown to play critical roles in regulating the progress of leukemia. We performed miRNA expression profile in six Chinese patients with chronic lymphocytic leukemia (CLL), and in peripheral B cells from pooled 30 healthy donors, using a platform containing 866 human miRNAs. The most frequent changes in miRNAs in CLL cells included downregulation of miR-126, miR-572, miR-494, miR-923, miR-638, miR-130a, miR-181a and miR-181b and up-regulation of miR-29a, miR-660, miR-20a, miR-106b, miR-142-5p, miR-101, miR-30b, miR-34a, miR-let-7f, miR-21 and miR-155. Among the miRNAs down-regulated in CLL cells, we showed that miR-181a/b expression levels were significantly lower in poor prognostic subgroups defined by unmutated immunoglobulin heavy chain variable status and p53 aberrations. Furthermore, under-expression of miR-181a and miR-181b was associated with shorter overall survival and treatment-free survival in CLL patients. We further evaluated fludarabine-induced apoptosis after transfection of primary CLL cells from 40 patients with miR-15a, miR-16-1, miR-34a, miR-181a and miR-181b mimics. Transfection of miR-34a, miR-181a and miR-181b mimics into CLL cells from p53 wild-type patients led to significant increase in apoptosis compared with miRNA control. However, enforced expression of these miRNAs had no effect on B-CLL cells from p53-attenuated patients. We further demonstrated that miR-181a and miR-181b inhibiting BCL-2, MCL-1 and X-linked inhibitor of apoptosis protein by direct binding to 3'UTR. Thus, these results suggest that miR-181a/b may play important roles in the pathogenesis of CLL and may provide a possible therapeutic avenue and a sensitive indicator of the activity of the p53 axis in CLL.

  12. Pharmacokinetics of Venetoclax, a Novel BCL-2 Inhibitor, in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia or Non-Hodgkin Lymphoma.

    PubMed

    Salem, Ahmed Hamed; Agarwal, Suresh K; Dunbar, Martin; Enschede, Sari L Heitner; Humerickhouse, Rod A; Wong, Shekman L

    2017-04-01

    Venetoclax is a selective BCL-2 inhibitor that is approved in the United States for the treatment of patients with chronic lymphocytic leukemia (CLL) with 17p deletion who have received at least 1 prior therapy. The aim of this analysis was to characterize venetoclax pharmacokinetics in the plasma and urine of patients with hematological malignancies and evaluate the effect of dose proportionality, accumulation, weak and moderate CYP3A inhibitors, as well as low- and high-fat meals on venetoclax pharmacokinetics. Patients received a once-daily venetoclax dose of 20 to 1200 mg. Pharmacokinetic parameters were estimated using noncompartmental methods. Venetoclax peak exposures were achieved at 5 to 8 hours under low-fat conditions, and the mean terminal-phase elimination half-life ranged between 14.1 and 18.2 hours at different doses. Venetoclax steady-state exposures showed minimal accumulation and increased proportionally over the dose range of 300 to 900 mg. Low-fat and high-fat meals increased venetoclax exposures by approximately 4-fold relative to the fasting state. Moderate CYP3A inhibitors increased venetoclax exposures by 40% to 60%, whereas weak CYP3A inhibitors had no effect. A negligible amount of venetoclax was excreted in the urine. In summary, venetoclax exhibits a pharmacokinetic profile that is compatible with once-daily dosing with food regardless of fat content. Concomitant use of venetoclax with moderate CYP3A inhibitors should be avoided or venetoclax dose should be reduced during the venetoclax initiation and ramp-up phase in CLL patients. Renal excretion plays a minimal role in the elimination of venetoclax.

  13. Sustained NF-kappaB activity in chronic lymphocytic leukemia is independent of genetic and epigenetic alterations in the TNFAIP3 (A20) locus.

    PubMed

    Frenzel, Lukas P; Claus, Rainer; Plume, Nadine; Schwamb, Janine; Konermann, Carolin; Pallasch, Christian P; Claasen, Julia; Brinker, Reinhild; Wollnik, Bernd; Plass, Christoph; Wendtner, Clemens-Martin

    2011-05-15

    Inappropriate nuclear factor (NF) κB activity is one major hallmark of B-cell malignancies and chronic lymphocytic leukemia (CLL). NFκB-dependent genes are involved in antiapoptosis, cell proliferation and metastasis and are responsible for survival and proliferation of tumors. However, the mechanisms of NFκB activity in CLL still need to be elucidated. Previously, we identified translocations in a region on chromosome 6q that encodes tumor necrosis factor alpha-induced protein 3, which is a key player in negative feedback loop regulation of NFκB. Inactivation of this ubiquitin-editing enzyme is involved in immunopathologies and in tumorigenesis. Frequent mutations in the A20 locus--leading to sustained NFκB activity--could be shown to play a dominant role in development of different B-cell malignancies. To check if A20 is involved in upregulation of NFκB activity in CLL, we sequenced Exons 2-9 of the A20 gene in 55 CLL DNA samples. Furthermore, we determined the methylation status of the promoter region in 63 CLL DNA samples and compared to 10 control DNAs of B cells from healthy donors. Contrary to reports from other B-cell malignancies, the A20 region showed neither mutations nor aberrant DNA methylation. Moreover, its expression could be confirmed by immunoblotting and showing comparable results to healthy B cells. These results indicate that malignant development in CLL differs from most of other B-cell malignancies, which show frequent inactivation of A20.

  14. Cellular Immunotherapy Following Chemotherapy in Treating Patients With Recurrent Non-Hodgkin Lymphomas, Chronic Lymphocytic Leukemia or B-Cell Prolymphocytic Leukemia

    ClinicalTrials.gov

    2016-07-29

    Post-transplant Lymphoproliferative Disorder; B-Cell Prolymphocytic Leukemia; Recurrent Adult Burkitt 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; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; B-Cell Lymphoma, Unclassifiable, With Features Intermediate Between Diffuse Large B-Cell Lymphoma and Burkitt Lymphoma; B-Cell Lymphoma, Unclassifiable, With Features Intermediate Between Diffuse Large B-Cell Lymphoma and Classical Hodgkin Lymphoma; Recurrent Lymphoplasmacytic Lymphoma

  15. Sequential cis-platinum and fludarabine with or without arabinosyl cytosine in patients failing prior fludarabine therapy for chronic lymphocytic leukemia: a phase II study.

    PubMed

    Giles, F J; O'Brien, S M; Santini, V; Gandhi, V; Plunkett, W; Seymour, J F; Robertson, L E; Kantarjian, H M; Keating, M J

    1999-12-01

    Patients with chronic lymphocytic leukemia (CLL) who fail fludarabine (Fluda) therapy have a poor response to subsequent salvage regimens and a poor prognosis. This study was undertaken to determine the efficacy and toxicity of a cis-platinum, (cis-p)fluda and arabinosyl cytosine (ara-C) combination in patients who were refractory to fluda or had relapsed following prior fluda therapy for CLL. Forty-one patients who had progressive CLL were treated on study. Eleven patients (27%) were sensitive to fluda and thirty (73%) refractory prior to study entry. Therapy consisted of cis-p 100 mg/m2 continuous intravenous (i.v.) infusion over 4 days, fluda 30 mg/m2 i.v. over 15 minutes on Days 3 and 4 either given alone (PF) or with ara-C 500 mg/m2 i.v. over 1 hour on Day 4 (PFA). The median number of PF or PFA courses received was two. No patient achieved a complete response. Eight patients (19%) achieved a partial response (PR), 28 were taken off study with progressive or refractory disease and 5 had induction deaths. The overall median survival was 6 months, 15 months in responding patients, and 4 months in non-responding patients. Rai stage I-II patients had a median survival of 7 months and stage III-IV patients had a median survival of 3 months. Major toxicities (myelosuppression, sepsis, renal failure and tumor lysis syndrome) were frequent. In conclusion, it can be said that the PF and PFA regimens have equivalent modest activity in patients with progressive CLL following prior fluda therapy, predominantly among patients whose disease was sensitive to fluda at last prior exposure. Ara-C did not add to the activity of the cis-p/fluda combination in this study group.

  16. Characterization of treatment and outcomes in a population-based cohort of patients with chronic lymphocytic leukemia referred for cytogenetic testing in British Columbia, Canada.

    PubMed

    Huang, Steven J; Lee, Lauren J; Gerrie, Alina S; Gillan, Tanya L; Bruyere, Helene; Hrynchak, Monica; Smith, Adam C; Karsan, Aly; Ramadan, Khaled M; Jayasundara, Kavisha S; Toze, Cynthia L

    2017-04-01

    This study evaluates outcomes in chronic lymphocytic leukemia (CLL) based on first-line therapy in a large consecutive population-based cohort of 669 patients with fluorescence in-situ hybridization (FISH) data in British Columbia, Canada during the period when chemoimmunotherapy was standard first-line treatment. When analyzed as a time-dependent variable, patients who required treatment (n=336) had a 4.7 times higher hazard of death than patients who did not (95% confidence interval 2.8-7.9, P<0.001). The majority of patients received fludarabine-rituximab (FR) in front-line. On multivariate Cox regression analysis, fludarabine-based first-line therapy predicted longer time-to-next-treatment (TTNT) (HR 0.53, 95% confidence interval 0.33-0.87, P=0.012) but no difference in overall survival (OS) compared to alkylator-based therapy. Deletion 17p was an independent predictor of worse TTNT and OS. The most common second-line treatments were cyclophosphamide-vincristine-prednisone-rituximab and FR. There was no difference in OS between patients retreated in second-line with the same first-line regimen (n=33) versus different regimen (n=113). In conclusion, front-line treatment with fludarabine leads to a longer time until need for next treatment than alkylator-based therapy; however, fludarabine or alkylator therapy produces no difference in OS. This study provides a historical baseline for the comparison of novel agents with standard treatments in CLL on a population-level.

  17. 5-Year Survival in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia in a Randomized, Phase III Trial of Fludarabine Plus Cyclophosphamide With or Without Oblimersen

    PubMed Central

    O'Brien, Susan; Moore, Joseph O.; Boyd, Thomas E.; Larratt, Loree M.; Skotnicki, Aleksander B.; Koziner, Benjamin; Chanan-Khan, Asher A.; Seymour, John F.; Gribben, John; Itri, Loretta M.; Rai, Kanti R.

    2009-01-01

    Purpose A randomized trial of oblimersen plus fludarabine/cyclophosphamide (OBL-FC; n = 120) versus FC (n = 121) was conducted in patients with relapsed/refractory chronic lymphocytic leukemia (CLL). The primary end point was met: the complete response (CR) rate, defined as complete or nodular partial response, was significantly greater with OBL-FC than with FC (17% v 7%; P = .025). Among patients with CR, response duration was significantly longer with OBL-FC than with FC (median not reached; > 36 months v 22 months; P = .03). Maximum benefit with OBL-FC, including a four-fold increase in CR rate and a survival benefit with 3 years of follow-up (hazard ratio, 0.53; P = .05), was observed in patients with fludarabine-sensitive disease. We evaluated long-term survival and poststudy CLL therapy among all randomly assigned patients. Methods Poststudy CLL treatment information was collected. Patients were observed for survival for up to 5 years from the date of random assignment. Results Poststudy CLL treatment was balanced between arms. Intent-to-treat analysis of 5-year survival showed no significant between-treatment difference (hazard ratio, 0.87; P = .34). Among the greater than 40% of patients with complete or partial remission, a significant 5-year survival benefit was observed with OBL-FC (hazard ratio, 0.60; P = .038). Among patients with fludarabine-sensitive disease who had previously demonstrated maximum benefit with OBL-FC, the previously observed survival benefit improved: a 50% reduction in the risk of death was observed (P = .004). Conclusion In relapsed/refractory CLL, OBL combined with FC offers patients who achieve complete or partial remission, as well as those who have fludarabine-sensitive disease, a significant survival benefit. PMID:19738118

  18. Substantial Susceptibility of Chronic Lymphocytic Leukemia to BCL2 Inhibition: Results of a Phase I Study of Navitoclax in Patients With Relapsed or Refractory Disease

    PubMed Central

    Roberts, Andrew W.; Seymour, John F.; Brown, Jennifer R.; Wierda, William G.; Kipps, Thomas J.; Khaw, Seong Lin; Carney, Dennis A.; He, Simon Z.; Huang, David C.S.; Xiong, Hao; Cui, Yue; Busman, Todd A.; McKeegan, Evelyn M.; Krivoshik, Andrew P.; Enschede, Sari H.; Humerickhouse, Rod

    2012-01-01

    Purpose BCL2 overexpression is a hallmark of chronic lymphocytic leukemia (CLL). The novel BH3 mimetic navitoclax (ABT-263) specifically inhibits BCL2 and related proteins BCL-xl and BCL-w, potently inducing apoptosis of CLL cells in vitro. A phase I trial in patients with CLL was conducted to evaluate the safety, pharmacokinetics, and biologic activity of oral navitoclax. Patients and Methods Twenty-nine patients with relapsed or refractory CLL received daily navitoclax for 14 days (10, 110, 200, or 250 mg/d; n = 15) or 21 days (125, 200, 250, or 300 mg/d; n = 14) of each 21-day cycle. Dose escalation decisions were informed by continual reassessment methodology. Results Lymphocytosis was reduced by more than 50% in 19 of 21 patients with baseline lymphocytosis. Among 26 patients treated with navitoclax ≥ 110 mg/d, nine (35%) achieved a partial response and seven maintained stable disease for more than 6 months. Median treatment duration was 7 months (range, 1 to ≥ 29 months). Median progression-free survival was 25 months. Activity was observed in patients with fludarabine-refractory disease, bulky adenopathy, and del(17p) CLL. Thrombocytopenia due to BCL-xl inhibition was the major dose-limiting toxicity and was dose-related. Low MCL1 expression and high BIM:MCL1 or BIM:BCL2 ratios in leukemic cells correlated with response. We determined that the navitoclax dose of 250 mg/d in a continuous dosing schedule was optimal for phase II studies. Conclusion BCL2 is a valid therapeutic target in CLL, and its inhibition by navitoclax warrants further evaluation as monotherapy and in combination in this disease. PMID:22184378

  19. Romidepsin in Treating Patients With Lymphoma, Chronic Lymphocytic Leukemia, or Solid Tumors With Liver Dysfunction

    ClinicalTrials.gov

    2017-03-23

    Glioma; Lymphoma; Metastatic Malignant Solid Neoplasm; Neuroendocrine Neoplasm; Recurrent Adult Soft Tissue Sarcoma; Recurrent Bladder Carcinoma; Recurrent Breast Carcinoma; Recurrent Chronic Lymphocytic Leukemia; Recurrent Colorectal Carcinoma; Recurrent Cutaneous T-Cell Non-Hodgkin Lymphoma; Recurrent Head and Neck Carcinoma; Recurrent Lung Carcinoma; Recurrent Malignant Solid Neoplasm; Recurrent Melanoma; Recurrent Pancreatic Carcinoma; Recurrent Prostate Carcinoma; Recurrent Renal Cell Carcinoma; Recurrent Thyroid Gland Carcinoma; Refractory Chronic Lymphocytic Leukemia; Refractory Cutaneous T-Cell Non-Hodgkin Lymphoma; Refractory Mature T-Cell and NK-Cell Non-Hodgkin Lymphoma; Stage III Lung Cancer; Stage III Pancreatic Cancer; Stage III Prostate Cancer; Stage III Renal Cell Cancer; Stage III Soft Tissue Sarcoma; Stage IIIA Breast Cancer; Stage IIIA Colorectal Cancer; Stage IIIA Skin Melanoma; Stage IIIB Breast Cancer; Stage IIIB Colorectal Cancer; Stage IIIB Skin Melanoma; Stage IIIC Breast Cancer; Stage IIIC Colorectal Cancer; Stage IIIC Skin Melanoma; Stage IV Breast Cancer; Stage IV Lung Cancer; Stage IV Pancreatic Cancer; Stage IV Prostate Cancer; Stage IV Renal Cell Cancer; Stage IV Skin Melanoma; Stage IV Soft Tissue Sarcoma; Stage IVA Colorectal Cancer; Stage IVB Colorectal Cancer; Unresectable Solid Neoplasm

  20. Aberrant microRNA expression in Chinese patients with chronic lymphocytic leukemia.

    PubMed

    Zhu, Dan-Xia; Miao, Kou-Rong; Fang, Cheng; Fan, Lei; Zhu, Wei; Zhu, Hua-Yuan; Zhuang, Yun; Hong, Ming; Liu, Peng; Xu, Wei; Li, Jian-Yong

    2011-06-01

    MicroRNAs (miRNAs) are a class of small endogenous RNAs that play important regulatory roles by targeting mRNAs for cleavage or translational repression. Many reports have indicated that miRNAs play a critical role in malignancies, and regulations in the progression of leukemia. However, the miRNAs expression level in Chinese patients with chronic lymphocytic leukemia (CLL), and its prognostic value remain elusive. We identified various degrees of down-regulation of miR-15a, miR-16-1, miR-29b, miR-181a and miR-181b in CLL mononuclear cells. Moreover, we have identified miR-29b and miR-181a/b expression significantly correlated with IGHV mutational status. Transcript levels of predicted target genes BCL-2 and TCL-1 were also determined, and the expression levels were significantly upregulated in CLL patients compared with normal controls (P<0.001). Higher expression of TCL-1 was significantly correlated with aggressive disease features. In addition, an inverse correlation was observed in the CLL samples we examined between miRNAs (miR-16-1, miR-181a, miR-181b) and BCL-2 level; furthermore, an inverse correlation was also observed between miRNAs (miR-16-1, miR-181a, miR-181b) and TCL-1, which suggest that these miRNAs may implicate in negatively regulating target mRNA at transcriptional level. These different miRNAs may play an important role in the pathogenesis of CLL and might be applied for the assessment of prognosis in patients with CLL.

  1. Fludarabine, Cyclophosphamide, and Multiple-Dose Rituximab as Frontline Therapy for Chronic Lymphocytic Leukemia

    PubMed Central

    Short, Nicholas J.; Keating, Michael J.; Wierda, William G.; Faderl, Stefan; Ferrajoli, Alessandra; Estrov, Zeev; Smith, Susan C.; O'Brien, Susan M.

    2016-01-01

    Background Fludarabine, cyclophosphamide and rituximab (FCR) results in durable responses in patients with previously untreated chronic lymphocytic leukemia (CLL). Previous reports suggest that in patients with relapsed CLL a dose-intensified rituximab regimen increases response rates compared to standard-dose rituximab. It is unknown whether rituximab intensification of the FCR regimen will result in improved response rates and patient outcomes in patients with previously untreated CLL. Methods We conducted a single-arm study to evaluate the safety and efficacy of a modified FCR regimen with multiple-dose rituximab (FCR3) in 65 patients with previously untreated CLL. Results were compared to an historical cohort treated with FCR. Results The overall response rate to FCR3 was 97%, with 75% of patients achieving a complete remission. Minimal residual disease negativity was achieved in 62% of patients by flow cytometry. Median time to progression (TTP) was 81 months, and median overall survival (OS) was not reached, with 58% of patients still alive at a median survivor follow-up of 9.7 years. Grade 3-4 neutropenia, grade 3-4 thrombocytopenia and major infection were observed with 45%, 5% and 1.9% of FCR3 courses, respectively. Therapy-related myelodysplastic syndrome (t-MDS) or acute myelogenous leukemia (t-AML) developed in 7 patients (11%) (P <0.01 compared to the historical FCR cohort). Conclusions In patients with previously untreated CLL, FCR3 resulted in similar response rates, TTP and OS compared to a historical cohort of patients treated with FCR. FCR3 was associated with an increased incidence of t-MDS/AML. PMID:26218678

  2. 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

  3. Chronic myelogenous leukemia (CML)

    MedlinePlus

    CML; Chronic myeloid leukemia; Chronic granulocytic leukemia; Leukemia - chronic granulocytic ... nuclear disaster. It takes many years to develop leukemia from radiation exposure. Most people treated for cancer ...

  4. Activated Allogeneic NK Cells Preferentially Kill Poor Prognosis B-Cell Chronic Lymphocytic Leukemia Cells.

    PubMed

    Sánchez-Martínez, Diego; Lanuza, Pilar M; Gómez, Natalia; Muntasell, Aura; Cisneros, Elisa; Moraru, Manuela; Azaceta, Gemma; Anel, Alberto; Martínez-Lostao, Luis; Villalba, Martin; Palomera, Luis; Vilches, Carlos; García Marco, José A; Pardo, Julián

    2016-01-01

    Mutational status of TP53 together with expression of wild-type (wt) IGHV represents the most widely accepted biomarkers, establishing a very poor prognosis in B-cell chronic lymphocytic leukemia (B-CLL) patients. Adoptive cell therapy using allogeneic HLA-mismatched Natural killer (NK) cells has emerged as an effective and safe alternative in the treatment of acute myeloid and lymphoid leukemias that do not respond to traditional therapies. We have described that allogeneic activated NK cells eliminate hematological cancer cell lines with multidrug resistance acquired by mutations in the apoptotic machinery. This effect depends on the activation protocol, being B-lymphoblastoid cell lines (LCLs) the most effective stimulus to activate NK cells. Here, we have further analyzed the molecular determinants involved in allogeneic NK cell recognition and elimination of B-CLL cells, including the expression of ligands of the main NK cell-activating receptors (NKG2D and NCRs) and HLA mismatch. We present preliminary data suggesting that B-CLL susceptibility significantly correlates with HLA mismatch between NK cell donor and B-CLL patient. Moreover, we show that the sensitivity of B-CLL cells to NK cells depends on the prognosis based on TP53 and IGHV mutational status. Cells from patients with worse prognosis (mutated TP53 and wt IGHV) are the most susceptible to activated NK cells. Hence, B-CLL prognosis may predict the efficacy of allogenic activated NK cells, and, thus, NK cell transfer represents a good alternative to treat poor prognosis B-CLL patients who present a very short life expectancy due to lack of effective treatments.

  5. Activated Allogeneic NK Cells Preferentially Kill Poor Prognosis B-Cell Chronic Lymphocytic Leukemia Cells

    PubMed Central

    Sánchez-Martínez, Diego; Lanuza, Pilar M.; Gómez, Natalia; Muntasell, Aura; Cisneros, Elisa; Moraru, Manuela; Azaceta, Gemma; Anel, Alberto; Martínez-Lostao, Luis; Villalba, Martin; Palomera, Luis; Vilches, Carlos; García Marco, José A.; Pardo, Julián

    2016-01-01

    Mutational status of TP53 together with expression of wild-type (wt) IGHV represents the most widely accepted biomarkers, establishing a very poor prognosis in B-cell chronic lymphocytic leukemia (B-CLL) patients. Adoptive cell therapy using allogeneic HLA-mismatched Natural killer (NK) cells has emerged as an effective and safe alternative in the treatment of acute myeloid and lymphoid leukemias that do not respond to traditional therapies. We have described that allogeneic activated NK cells eliminate hematological cancer cell lines with multidrug resistance acquired by mutations in the apoptotic machinery. This effect depends on the activation protocol, being B-lymphoblastoid cell lines (LCLs) the most effective stimulus to activate NK cells. Here, we have further analyzed the molecular determinants involved in allogeneic NK cell recognition and elimination of B-CLL cells, including the expression of ligands of the main NK cell-activating receptors (NKG2D and NCRs) and HLA mismatch. We present preliminary data suggesting that B-CLL susceptibility significantly correlates with HLA mismatch between NK cell donor and B-CLL patient. Moreover, we show that the sensitivity of B-CLL cells to NK cells depends on the prognosis based on TP53 and IGHV mutational status. Cells from patients with worse prognosis (mutated TP53 and wt IGHV) are the most susceptible to activated NK cells. Hence, B-CLL prognosis may predict the efficacy of allogenic activated NK cells, and, thus, NK cell transfer represents a good alternative to treat poor prognosis B-CLL patients who present a very short life expectancy due to lack of effective treatments. PMID:27833611

  6. [Chemotherapy-free treatment of chronic lymphocytic leukemia?].

    PubMed

    Wendtner, C-M

    2013-10-01

    Treatment of CLL patients with conventional cytotoxic agents is often combined with significant toxicity that prevents broad application especially in elderly patients. In addition, relapse frequently occurs after application of conventional chemotherapy in CLL. Recently several new chemo-free treatment options have been introduced within clinical trials. Among them are monoclonal antibodies, most of them targeting the CD20 molecule: besides the licensed drugs rituximab and ofatumumab obinutuzumab, although in combination with chemotherapy, has recently shown high clinical efficacy in front-line treatment of elderly patients with CLL. Lenalidomide as monotherapy has demonstrated clinical efficacy in patients with relapsed disease and first data within clinical trials have been generated in the front-line setting. A promising class of novel agents has been designed to block aberrant signaling from the B-cell receptor. Ibrutinib acts by inhibiting the Bruton's tyrosine kinase (BTK) while idelalisib represents a first-in-class specific inhibitor of the phosphoinositol-3 kinase (PI3K) delta isoform. Another class of drugs with potential impact for chemo-free treatment strategies in CLL are the BH3-mimetic inhibitors of the Bcl-2 family of pro-survival proteins. Other interesting candidate drugs that are currently explored for CLL patients include small modular immunopharmaceutical (SMIP) proteins (e. g. TRU-016), CDK inhibitors (e. g. dinaciclib), HDAC inhibitors and others. Given all these novel agents and targets, chemo-free or at least chemo-reduced concepts may become reality in the near future for our patients suffering from CLL.

  7. Outcomes of Patients With Chronic Lymphocytic Leukemia and Richter's Transformation After Transplantation Failure

    PubMed Central

    Rozovski, Uri; Benjamini, Ohad; Jain, Preetesh; Thompson, Philip A.; Wierda, William G.; O'Brien, Susan; Burger, Jan A.; Ferrajoli, Alessandra; Faderl, Stefan; Shpall, Elizabeth; Hosing, Chitra; Khouri, Issa F.; Champlin, Richard; Keating, Michael J.; Estrov, Zeev

    2015-01-01

    Purpose Allogeneic stem-cell transplantation (SCT) induces long-term remission in a fraction of patients with high-risk chronic lymphocytic leukemia (CLL) or Richter's transformation (RT). Our purpose was to determine the outcomes of patients whose disease progressed after allogeneic SCT. Patients and Methods We retrospectively analyzed the outcomes of 72 patients (52 with CLL and 20 with RT) who underwent allogeneic SCT between 1998 and 2011 and had documented progression after transplantation. Twenty-two (31%) never had a response, and 50 (69%) had a response but experienced relapse after a median of 7 months (range, 2 to 85 months). Forty-eight patients who were receiving or were candidates to receive post-SCT cell-based therapies were not included in this analysis. Results The median age at time of transplantation was 58 years (range, 30 to 72 years). Sixty-two patients (86%) received more than two treatment regimens and 37 (51%) received more than three treatment regimens before SCT. Sixty-six patients (92%) had active disease at the time of transplantation. The 2- and 5-year survival rates were 67% and 38% (patients with CLL) and 36% and 0% (patients with RT). The patients who developed acute or chronic graft-versus-host disease had a longer overall survival (OS; P = .05). In a multivariable analysis, RT or low hemoglobin at the time of SCT predicted shorter OS. Chronic graft-versus-host disease and an initial response to SCT predicted longer OS. Conclusion Patients with CLL in whom allogeneic SCT fails may have a response to and benefit from salvage therapies, and their prognosis is relatively good. PMID:25847930

  8. Nonmyeloablative Allogeneic Stem Cell Transplantation in Relapsed/Refractory Chronic Lymphocytic Leukemia

    PubMed Central

    Khouri, Issa F.; Bassett, Roland; Poindexter, Nancy; O'Brien, Susan; Bueso-Ramos, Carlos E.; Hsu, Yvonne; Ferrajoli, Alessandra; Keating, Michael J.; Champlin, Richard; Fernandez-Vina, Marcelo

    2015-01-01

    BACKGROUND The role of nonmyeloablative allogeneic stem cell transplantation (NST) in the treatment of chronic lymphocytic leukemia (CLL) is not well established. The authors report on long-term experience with NST in relapsed/refractory CLL and define prognostic factors associated with outcome. METHODS The authors reviewed the outcome of 86 patients with relapsed/relapsed CLL enrolled in sequential NST protocols. RESULTS The median patient age was 58 years. Patients were heavily pretreated before transplantation, and 43 required immunomanipulation after NST for persistent or recurrent disease. Immunomanipulation included withdrawal of immunosuppression, rituximab, and step-wise donor lymphocyte infusions. Of 43 patients receiving immunomanipulation, 20 (47%) experienced a complete remission. Patients with human leukocyte antigen (HLA) genotype A1+/A2−/B44− were more likely to experience a complete remission (P ¼ .0009), with rates of 9%, 36%, 50%, and 91%, respectively, for 0, 1, 2, and 3 of these HLA factors. This resulted in significant improvement in progression-free-survival rates of 68.2% at 5 years for patients with all 3 HLA factors. Overall, the estimated 5-year survival rate was 51%. In a multivariate model, a CD4 count of <100/mm3 and a below normal serum immunoglobulin G level at study entry were associated with a short survival duration (P < .0001). CONCLUSIONS These results confirm the potential cure of relapsed/refractory CLL with NST and provide the first evidence that immunoglobulin G and CD4 levels are predictive of overall survival after NST in CLL and that human leukocyte antigen alleles predict response to immunomanipulation. PMID:21455998

  9. Single-Agent Lenalidomide in the Treatment of Previously Untreated Chronic Lymphocytic Leukemia

    PubMed Central

    Chen, Christine I.; Bergsagel, P. Leif; Paul, Harminder; Xu, Wei; Lau, Anthea; Dave, Nimisha; Kukreti, Vishal; Wei, Ellen; Leung-Hagesteijn, Chungyee; Li, Zhi Hua; Brandwein, Joseph; Pantoja, Mariela; Johnston, James; Gibson, Spencer; Hernandez, Tiffany; Spaner, David; Trudel, Suzanne

    2011-01-01

    Purpose Lenalidomide is an oral immunomodulatory drug with multiple effects on the immune system and tumor cell microenvironment leading to inhibition of malignant cell growth. Based on encouraging reports of lenalidomide in relapsed and refractory chronic lymphocytic leukemia (CLL), we investigated the first-line use of single-agent lenalidomide in CLL. Patients and Methods Using a starting dose of lenalidomide 10 mg/d for 21 days of a 28-day cycle and weekly 5-mg dose escalations to a target of 25 mg, we encountered severe toxicities (tumor lysis, fatal sepsis) in the first two patients enrolled. The study was halted and the protocol amended to a more conservative regimen: starting dose of lenalidomide 2.5 mg with monthly escalations to a target dose of 10 mg, and extended tumor lysis prophylaxis and monitoring. Gene expression profiles from patient samples before and after 7 days of lenalidomide were performed. Results Twenty-five patients were enrolled on the amended protocol. No further tumor lysis events were reported. Tumor flare was common (88%) but mild. Grade 3 to 4 neutropenia occurred in 72% of patients, with only five episodes of febrile neutropenia. The overall response rate was 56% (no complete responses). Although rapid peripheral lymphocyte reductions were observed, rebound lymphocytoses during the week off-therapy were common. Lenalidomide-induced molecular changes enriched for cytoskeletal and immune-related genes were identified. Conclusion Lenalidomide is clinically active as first-line CLL therapy and is well-tolerated if a conservative approach with slow dose escalation is used. A lenalidomide-induced molecular signature provides insights into its immunomodulatory mechanisms of action in CLL. PMID:21189385

  10. Cytokine-driven loss of plasmacytoid dendritic cell function in chronic lymphocytic leukemia

    PubMed Central

    Saulep-Easton, Damien; Vincent, Fabien B.; Le Page, Melanie; Wei, Andrew; Ting, Stephen B.; Croce, Carlo M.; Tam, Constantine; Mackay, Fabienne

    2014-01-01

    Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of CD5+CD19+ B cells in the peripheral blood, and in primary and secondary lymphoid organs. A major complication associated with CLL is severe recurrent infections, which are often fatal. Vulnerability to infection is due to a wide variety of immunological defects, yet the initiating events of immunodeficiency in CLL are unclear. Using CLL patient samples and a mouse model of CLL, we have discovered that plasmacytoid dendritic cells (pDCs), which underpin the activity of effector immune cells critical for anti-viral immunity and anti-tumor responses, are reduced in number and functionally impaired in progressive CLL. As a result, the levels of interferon alpha (IFNα) production, a cytokine critical for immunity, are markedly reduced. Lower pDC numbers with impaired IFNα production was due to the decreased expression of FMS-like tyrosine kinase 3 receptor (Flt3) and Toll-like receptor 9 (TLR9), respectively. Reduced Flt3 expression was reversed using inhibitors of TGF-β and TNF, an effect correlating with a reduction in tumor load. Defects in pDC numbers and function offer a new insight into mechanisms underpinning the profound immunodeficiency affecting CLL patients and provide a potentially novel avenue for restoring immuno-competency in CLL. PMID:24721775

  11. Profile of obinutuzumab for the treatment of patients with previously untreated chronic lymphocytic leukemia

    PubMed Central

    Hill, Brian T; Kalaycio, Matt

    2015-01-01

    Chronic lymphocytic leukemia (CLL) is a hematologic malignancy derived from a clonal population of mature B-lymphocytes characterized by relatively low CD20 antigen expression. Although the disease often takes an indolent course, the majority of patients will eventually require therapy. Standard treatment for medically fit patients includes purine analogs and/or alkylating agents in addition to the type I anti-CD20 monoclonal antibody, rituximab. This therapy is inherently myelosuppressive and can result in significant morbidity and even mortality in patients with impaired performance status due to age and/or medical comorbidities. Historically, treatment options for the elderly or frail patient population were limited to mono-therapy with the oral alkylating agent, chlorambucil, rituximab, or another type I anti-CD20 monoclonal antibody ofatumumab. Recently, a newer-generation anti-CD20 monoclonal antibody, obinutuzumab, was developed for patients with CLL. Obinutuzumab is a humanized type II monoclonal antibody that appears to have more direct antibody-dependent cell-mediated cytotoxicity (ADCC) and possibly more direct cytotoxicity in vitro than previously available type I antibodies. A large Phase III prospective randomized clinical trial for older patients with impaired renal function and/or significant medical comorbidities demonstrated that when compared to conventionally-dosed rituximab and chlorambucil, the combination of chlorambucil and obinutuzumab administered at a dose and schedule involving early loading doses improved response rates and progression-free survival without significantly increasing toxicity. Results of this pivotal trial led to the FDA (US Food and Drug Administration) approval of obinutuzumab in combination with chlorambucil for frontline treatment of CLL. Obinutuzumab expands the armamentarium of active and less-toxic targeted agents in the evolving treatment landscape of CLL, providing physicians and patients with an additional

  12. Profile of obinutuzumab for the treatment of patients with previously untreated chronic lymphocytic leukemia.

    PubMed

    Hill, Brian T; Kalaycio, Matt

    2015-01-01

    Chronic lymphocytic leukemia (CLL) is a hematologic malignancy derived from a clonal population of mature B-lymphocytes characterized by relatively low CD20 antigen expression. Although the disease often takes an indolent course, the majority of patients will eventually require therapy. Standard treatment for medically fit patients includes purine analogs and/or alkylating agents in addition to the type I anti-CD20 monoclonal antibody, rituximab. This therapy is inherently myelosuppressive and can result in significant morbidity and even mortality in patients with impaired performance status due to age and/or medical comorbidities. Historically, treatment options for the elderly or frail patient population were limited to mono-therapy with the oral alkylating agent, chlorambucil, rituximab, or another type I anti-CD20 monoclonal antibody ofatumumab. Recently, a newer-generation anti-CD20 monoclonal antibody, obinutuzumab, was developed for patients with CLL. Obinutuzumab is a humanized type II monoclonal antibody that appears to have more direct antibody-dependent cell-mediated cytotoxicity (ADCC) and possibly more direct cytotoxicity in vitro than previously available type I antibodies. A large Phase III prospective randomized clinical trial for older patients with impaired renal function and/or significant medical comorbidities demonstrated that when compared to conventionally-dosed rituximab and chlorambucil, the combination of chlorambucil and obinutuzumab administered at a dose and schedule involving early loading doses improved response rates and progression-free survival without significantly increasing toxicity. Results of this pivotal trial led to the FDA (US Food and Drug Administration) approval of obinutuzumab in combination with chlorambucil for frontline treatment of CLL. Obinutuzumab expands the armamentarium of active and less-toxic targeted agents in the evolving treatment landscape of CLL, providing physicians and patients with an additional

  13. Germ line mutations in shelterin complex genes are associated with familial chronic lymphocytic leukemia

    PubMed Central

    Speedy, Helen E.; Kinnersley, Ben; Chubb, Daniel; Broderick, Peter; Law, Philip J.; Litchfield, Kevin; Jayne, Sandrine; Dyer, Martin J. S.; Dearden, Claire; Follows, George A.; Catovsky, Daniel

    2016-01-01

    Chronic lymphocytic leukemia (CLL) can be familial; however, thus far no rare germ line disruptive alleles for CLL have been identified. We performed whole-exome sequencing of 66 CLL families, identifying 4 families where loss-of-function mutations in protection of telomeres 1 (POT1) co-segregated with CLL. The p.Tyr36Cys mutation is predicted to disrupt the interaction between POT1 and the telomeric overhang. The c.1164-1G>A splice-site, p.Gln358SerfsTer13 frameshift, and p.Gln376Arg missense mutations are likely to impact the interaction between POT1 and adrenocortical dysplasia homolog (ACD), which is a part of the telomere-capping shelterin complex. We also identified mutations in ACD (c.752-2A>C) and another shelterin component, telomeric repeat binding factor 2, interacting protein (p.Ala104Pro and p.Arg133Gln), in 3 CLL families. In a complementary analysis of 1083 cases and 5854 controls, the POT1 p.Gln376Arg variant, which has a global minor allele frequency of 0.0005, conferred a 3.61-fold increased risk of CLL (P = .009). This study further highlights telomere dysregulation as a key process in CLL development. PMID:27528712

  14. Lacrimal gland carcinoma ex pleomorphic adenoma with chronic lymphocytic leukemia infiltration

    PubMed Central

    Couceiro, Rita; Loureiro, Cláudia; Luís, Pedro; López-Presa, Dolores; Proença, Helena; Fonseca, Ana; Monteiro-Grillo, Manuel

    2014-01-01

    Purpose To report a rare case of lacrimal gland carcinoma ex pleomorphic adenoma (Ca ex PA) with chronic B-cell lymphocytic leukemia (B-CLL) infiltration in a patient without a previous diagnosis of B-CLL. Patient and methods We report a 66-year-old woman who presented with recent worsening of a long-standing right eye proptosis. Sequential orbital computed tomography imaging was performed over the course of 2 years, and biopsy specimens were analyzed. Results Initial computed tomography scans revealed a lacrimal gland lesion with stable dimensions for more than 1 year and no malignancy features on incisional biopsy. Subsequently, lesion volume growth and bone erosion were documented on orbital computed tomography. Lateral orbitectomy and lacrimal gland resection were performed. Pathology and immunohistochemistry detected Ca ex PA with B-CLL infiltration. Conclusion This case highlights the importance of persistent investigation of clinically suspicious orbital lesions. To our knowledge, this is the first description of a case of lacrimal gland Ca ex PA with B-CLL infiltration. PMID:25336906

  15. Tumor evolutionary directed graphs and the history of chronic lymphocytic leukemia

    PubMed Central

    Wang, Jiguang; Khiabanian, Hossein; Rossi, Davide; Fabbri, Giulia; Gattei, Valter; Forconi, Francesco; Laurenti, Luca; Marasca, Roberto; Del Poeta, Giovanni; Foà, Robin; Pasqualucci, Laura; Gaidano, Gianluca; Rabadan, Raul

    2014-01-01

    Cancer is a clonal evolutionary process, caused by successive accumulation of genetic alterations providing milestones of tumor initiation, progression, dissemination, and/or resistance to certain therapeutic regimes. To unravel these milestones we propose a framework, tumor evolutionary directed graphs (TEDG), which is able to characterize the history of genetic alterations by integrating longitudinal and cross-sectional genomic data. We applied TEDG to a chronic lymphocytic leukemia (CLL) cohort of 70 patients spanning 12 years and show that: (a) the evolution of CLL follows a time-ordered process represented as a global flow in TEDG that proceeds from initiating events to late events; (b) there are two distinct and mutually exclusive evolutionary paths of CLL evolution; (c) higher fitness clones are present in later stages of the disease, indicating a progressive clonal replacement with more aggressive clones. Our results suggest that TEDG may constitute an effective framework to recapitulate the evolutionary history of tumors. DOI: http://dx.doi.org/10.7554/eLife.02869.001 PMID:25496728

  16. Germline mutations in shelterin complex genes are associated with familial chronic lymphocytic leukemia.

    PubMed

    Speedy, Helen E; Kinnersley, Ben; Chubb, Daniel; Broderick, Peter; Law, Philip J; Litchfield, Kevin; Jayne, Sandrine; Dyer, Martin J S; Dearden, Claire; Follows, George A; Catovsky, Daniel; Houlston, Richard S

    2016-08-15

    Chronic lymphocytic leukemia (CLL) can be familial, however thus far no rare germline disruptive alleles for CLL have been identified. We performed whole-exome sequencing of 66 CLL families, identifying four families where loss-of-function mutations in POT1 co-segregated with CLL. The p.Tyr36Cys mutation is predicted to disrupt the interaction between POT1 and the telomeric overhang. The c.1164-1G>A splice-site, p.Gln358SerfsTer13 frameshift and p.Gln376Arg missense mutations are likely to impact the interaction between POT1 and ACD, part of the telomere-capping shelterin complex. We also identified mutations in ACD (c.752-2A>C) and another shelterin component, TERF2IP (p.Ala104Pro and p.Arg133Gln), in three CLL families. In a complementary analysis of 1,083 cases and 5,854 controls, the POT1 p.Gln376Arg variant, which has a global minor allele frequency of 0.0005, conferred a 3.61-fold increased risk of CLL (P=0.009). This study further highlights telomere dysregulation as a key process in CLL development.

  17. Lenalidomide in chronic lymphocytic leukemia: the present and future in the era of tyrosine kinase inhibitors.

    PubMed

    Maffei, Rossana; Colaci, Elisabetta; Fiorcari, Stefania; Martinelli, Silvia; Potenza, Leonardo; Luppi, Mario; Marasca, Roberto

    2016-01-01

    Lenalidomide is an immunomodulatory agent (IMiD) clinically active in chronic lymphocytic leukemia (CLL), both in heavily pre-treated patients and upfront. Lenalidomide has a unique mechanism of action in CLL. Its efficacy relies on a multifactorial mode-of-action (MOA), comprising a plethora of immunomodulatory actions, the disruption of mutualistic interactions inside CLL microenvironment and direct effects against leukemic cells. In the last few years, a number of new and highly effective drugs appeared in the scenario of CLL therapeutic options, i.e. tyrosine kinase inhibitors (TKIs), showing a good safety profile and impressive clinical response, also in high-risk patients. In this review, we describe the data from clinical studies about lenalidomide efficacy in CLL and we critically dissect the different mechanisms of action of this drug. We point the attention on open issues, including drug dosage and administration schedule, prediction of clinical response to lenalidomide, and combination therapeutic strategies. This overview would be useful to envision a possible role of lenalidomide in the treatment flow-chart of CLL, exploiting its peculiar MOA and also exploring the possible synergetic effect with new drugs.

  18. Prognostic signature and clonality pattern of recurrently mutated genes in inactive chronic lymphocytic leukemia

    PubMed Central

    Hurtado, A M; Chen-Liang, T-H; Przychodzen, B; Hamedi, C; Muñoz-Ballester, J; Dienes, B; García-Malo, M D; Antón, A I; de Arriba, F; Teruel-Montoya, R; Ortuño, F J; Vicente, V; Maciejewski, J P; Jerez, A

    2015-01-01

    An increasing numbers of patients are being diagnosed with asymptomatic early-stage chronic lymphocytic leukemia (CLL), with no treatment indication at baseline. We applied a high-throughput deep-targeted analysis, especially designed for covering widely TP53 and ATM genes, in 180 patients with inactive disease at diagnosis, to test the independent prognostic value of CLL somatic recurrent mutations. We found that 40/180 patients harbored at least one acquired variant with ATM (n=17, 9.4%), NOTCH1 (n=14, 7.7%), TP53 (n=14, 7.7%) and SF3B1 (n=10, 5.5%) as most prevalent mutated genes. Harboring one ‘sub-Sanger' TP53 mutation granted an independent 3.5-fold increase of probability of needing treatment. Those patients with a double-hit ATM lesion (mutation+11q deletion) had the shorter median time to first treatment (17 months). We found that a genomic variable: TP53 mutations, most of them under the sensitivity of conventional techniques; a cell phenotypic factor: CD38-positive expression; and a classical marker as β2-microglobulin, remained as the unique independent predictors of outcome. The high-throughput determination of TP53 status, particularly in this set of patients frequently lacking high-risk chromosomal aberrations, emerges as a key step, not only for prediction modeling, but also for exploring mutation-specific therapeutic approaches and minimal residual disease monitoring. PMID:26314984

  19. Cyclophosphamide, fludarabine, alemtuzumab, and rituximab as salvage therapy for heavily pretreated patients with chronic lymphocytic leukemia

    PubMed Central

    Badoux, Xavier C.; Keating, Michael J.; Wang, Xuemei; O'Brien, Susan M.; Ferrajoli, Alessandra; Faderl, Stefan; Burger, Jan; Koller, Charles; Lerner, Susan; Kantarjian, Hagop

    2011-01-01

    Patients with relapsed chronic lymphocytic leukemia (CLL) and high-risk features, such as fludarabine refractoriness, complex karyotype, or abnormalities of chromosome 17p, experience poor outcomes after standard fludaradine-based regimens. Alemtuzumab is a chimeric CD52 monoclonal antibody with activity in CLL patients with fludarabine-refractory disease and 17p deletion. We report the outcome for 80 relapsed or refractory patients with CLL enrolled in a phase 2 study of cyclophosphamide, fludarabine, alemtuzumab, and rituximab (CFAR). All patients were assessed for response and progression according to the 1996 CLL-working group criteria. For the intention-to-treat analysis, the overall response rate was 65%, including 29% complete response. The estimated progression-free survival was 10.6 months and median overall survival was 16.7 months. Although we noted higher complete response in high-risk patients after CFAR compared with a similar population who had received fludarabine, cyclophosphamide, and rituximab as salvage therapy, there was no significant improvement in progression-free survival and overall survival appeared worse. CFAR was associated with a high rate of infectious complications with 37 patients (46%) experiencing a serious infection during therapy and 28% of evaluable patients experiencing late serious infections. Although CFAR produced good response rates in this highly pretreated high-risk group of patients, there was no benefit in survival outcomes. PMID:21670470

  20. Lenalidomide induces complete and partial remissions in patients with relapsed and refractory chronic lymphocytic leukemia.

    PubMed

    Ferrajoli, Alessandra; Lee, Bang-Ning; Schlette, Ellen J; O'Brien, Susan M; Gao, Hui; Wen, Sijin; Wierda, William G; Estrov, Zeev; Faderl, Stefan; Cohen, Evan N; Li, Changping; Reuben, James M; Keating, Michael J

    2008-06-01

    This study investigated the activity of lenalidomide in patients with relapsed/refractory chronic lymphocytic leukemia (CLL). Lenalidomide was given at 10 mg daily with dose escalation up to 25 mg daily. Three patients (7%) achieved a complete response (CR), one a nodular partial remission, and 10 patients a partial remission (PR), for an overall response (OR) rate of 32%. Treatment with lenalidomide was associated with an OR rate of 31% in patients with 11q or 17p deletion, of 24% in patients with unmutated V(H), and of 25% in patients with fludarabine-refractory disease. The most common toxicity was myelosuppression, and the median daily dose of lenalidomide tolerated was 10 mg. Plasma levels of angiogenic factors, inflammatory cytokines, and cytokine receptors were measured at baseline, day 7, and day 28. There was a dramatic increase in median interleukin (IL)-6, IL-10, IL-2, and tumor necrosis factor receptor-1 levels on day 7, whereas no changes were observed in median vascular endothelial growth factor levels (20 patients studied). According to our experience, lenalidomide given as a continuous treatment has antitumor activity in heavily pretreated patients with CLL.

  1. Obinutuzumab in chronic lymphocytic leukemia: design, development and place in therapy

    PubMed Central

    Al-Sawaf, Othman; Fischer, Kirsten; Engelke, Anja; Pflug, Natali; Hallek, Michael; Goede, Valentin

    2017-01-01

    For decades, treatment of chronic lymphocytic leukemia (CLL) has been based on chemotherapy. This changed when the first CD20 antibody rituximab was introduced. Since 2008, the combination of chemotherapy and CD20 antibodies has become the standard of care for most patients, and a significant fraction of patients had very long-lasting remissions after chemoimmunotherapy. Despite the improvement of response rates and overall survival (OS) by the use of chemoimmunotherapy, most CLL patients will relapse eventually. One approach to achieve more durable responses was the development of obinutuzumab (GA101), a new type of CD20 antibody that has unique molecular and functional characteristics. Obinutuzumab is a type II fully humanized CD20 antibody that binds to a partly different epitope of the CD20 protein than rituximab and due to its glycoengineered design induces greater antibody-dependent cell-mediated cytotoxicity (ADCC). Initial preclinical observations of a more effective B-cell depletion have been successfully reproduced in clinical trials with CLL patients. This review summarizes results of preclinical as well as clinical studies with obinutuzumab and provides an outlook on its future role in the therapy of CLL. PMID:28182141

  2. Obinutuzumab in chronic lymphocytic leukemia: design, development and place in therapy.

    PubMed

    Al-Sawaf, Othman; Fischer, Kirsten; Engelke, Anja; Pflug, Natali; Hallek, Michael; Goede, Valentin

    2017-01-01

    For decades, treatment of chronic lymphocytic leukemia (CLL) has been based on chemotherapy. This changed when the first CD20 antibody rituximab was introduced. Since 2008, the combination of chemotherapy and CD20 antibodies has become the standard of care for most patients, and a significant fraction of patients had very long-lasting remissions after chemoimmunotherapy. Despite the improvement of response rates and overall survival (OS) by the use of chemoimmunotherapy, most CLL patients will relapse eventually. One approach to achieve more durable responses was the development of obinutuzumab (GA101), a new type of CD20 antibody that has unique molecular and functional characteristics. Obinutuzumab is a type II fully humanized CD20 antibody that binds to a partly different epitope of the CD20 protein than rituximab and due to its glycoengineered design induces greater antibody-dependent cell-mediated cytotoxicity (ADCC). Initial preclinical observations of a more effective B-cell depletion have been successfully reproduced in clinical trials with CLL patients. This review summarizes results of preclinical as well as clinical studies with obinutuzumab and provides an outlook on its future role in the therapy of CLL.

  3. Constitutive activation of NF-κB signaling by NOTCH1 mutations in chronic lymphocytic leukemia.

    PubMed

    Xu, Zhen-Shu; Zhang, Ju-Shun; Zhang, Jing-Yan; Wu, Shun-Quan; Xiong, Dong-Lian; Chen, Hui-Jun; Chen, Zhi-Zhe; Zhan, Rong

    2015-04-01

    NOTCH1 mutations occur in approximately 10% of patients with chronic lymphocytic leukemia (CLL). However, the relationship between the genetic aberrations and tumor cell drug resistance or disease progression remains unclear. Frameshift deletions were detected by gene sequencing in the NOTCH1 PEST domain in three naive CLL patients. These mutations were associated with chromosomal abnormalities including trisomy 12 or 13q deletion. Of note, one of the patients developed Richter's transformation during FCR treatment. Immunofluorescent and western blot analyses revealed a markedly higher intracellular domain of NOTCH (ICN) expression in the mutated cells compared with their unmutated counterparts and normal CD19+ B lymphocytes (P<0.01 and P<0.001, respectively). In addition, strong DNA-κB binding activities were observed in the mutant cells by gel shift assays. RT-PCR analysis revealed elevated RelA mRNA expression in the mutant cells, while RelB levels were variable. Reduced levels of RelA and RelB mRNA were observed in unmutated CLL and normal B cells. Compared to unmutated CLL and normal B cells, increased apoptosis occurred in the mutant cells in the presence of GSI (ICN inhibitor) and PDTC (NF-κB inhibitor), particularly under the synergistic effects of the two drugs (P=0.03). Moreover, IKKα and IKKβ, the active components in the NF-κB pathway, were markedly inhibited following prolonged treatment with GSI and PDTC. These results suggested that NOTCH1 mutations constitutively activate the NF-κB signaling pathway in CLL, which is likely related to ICN overexpression, indicating NOTCH1 and NF-κB as potential therapeutic targets in the treatment of CLL.

  4. Rapid induction of apoptosis in chronic lymphocytic leukemia cells by the microtubule disrupting agent BNC105

    PubMed Central

    Bates, Darcy; Feris, Edmond J.; Danilov, Alexey V.; Eastman, Alan

    2016-01-01

    ABSTRACT Microtubule targeting agents, such as vinblastine, are usually thought to arrest cells in mitosis and subsequently induce apoptosis. However, they can also cause rapid induction of apoptosis in a cell-cycle phase independent manner. BNC105 is a novel vascular and microtubule disrupting drug that also induces apoptosis rapidly but with markedly increased potency compared to vinca alkaloids and combretastatin A4. BNC105 binds to the colchicine-binding site on tubulin resulting in activation of c-Jun N-terminal kinase (JNK), phosphorylation of ATF2, and induction of ATF3 and Noxa leading to acute apoptosis in chronic lymphocytic leukemia (CLL) cells. Apoptosis induced by BNC105 is dependent upon both JNK activation and Noxa induction. Normal leukocytes and one CLL sample also exhibited JNK activation but not Noxa induction and were resistant to BNC105. This study emphasizes the importance of Noxa and JNK for induction of apoptosis in CLL cells by microtubule targeting drugs, and highlights the potential of BNC105 as a potent therapeutic to treat haematopoietic malignancies. PMID:26891146

  5. AID induces intraclonal diversity and genomic damage in CD86+ chronic lymphocytic leukemia cells

    PubMed Central

    Huemer, Michael; Rebhandl, Stefan; Zaborsky, Nadja; Gassner, Franz J; Hainzl, Stefan; Weiss, Lukas; Hebenstreit, Daniel; Greil, Richard; Geisberger, Roland

    2014-01-01

    The activation-induced cytidine deaminase (AID) mediates somatic hypermutation and class switch recombination of the Ig genes by directly deaminating cytosines to uracils. As AID causes a substantial amount of off-target mutations, its activity has been associated with lymphomagenesis and clonal evolution of B-cell malignancies. Although it has been shown that AID is expressed in B-cell chronic lymphocytic leukemia (CLL), a clear analysis of in vivo AID activity in this B-cell malignancy remained elusive. In this study performed on primary human CLL samples, we report that, despite the presence of a dominant VDJ heavy chain region, a substantial intraclonal diversity was observed at VDJ as well as at IgM switch regions (Sμ), showing ongoing AID activity in vivo during disease progression. This AID-mediated heterogeneity was higher in CLL subclones expressing CD86, which we identified as the proliferative CLL fraction. Finally, CD86 expression correlated with shortened time to first treatment and increased γ-H2AX focus formation. Our data demonstrate that AID is active in CLL in vivo and thus, AID likely contributes to clonal evolution of CLL. PMID:25179679

  6. Meta-analysis of genome-wide association studies discovers multiple loci for chronic lymphocytic leukemia

    PubMed Central

    Berndt, Sonja I.; Camp, Nicola J.; Skibola, Christine F.; Vijai, Joseph; Wang, Zhaoming; Gu, Jian; Nieters, Alexandra; Kelly, Rachel S.; Smedby, Karin E.; Monnereau, Alain; Cozen, Wendy; Cox, Angela; Wang, Sophia S.; Lan, Qing; Teras, Lauren R.; Machado, Moara; Yeager, Meredith; Brooks-Wilson, Angela R.; Hartge, Patricia; Purdue, Mark P.; Birmann, Brenda M.; Vajdic, Claire M.; Cocco, Pierluigi; Zhang, Yawei; Giles, Graham G.; Zeleniuch-Jacquotte, Anne; Lawrence, Charles; Montalvan, Rebecca; Burdett, Laurie; Hutchinson, Amy; Ye, Yuanqing; Call, Timothy G.; Shanafelt, Tait D.; Novak, Anne J.; Kay, Neil E.; Liebow, Mark; Cunningham, Julie M.; Allmer, Cristine; Hjalgrim, Henrik; Adami, Hans-Olov; Melbye, Mads; Glimelius, Bengt; Chang, Ellen T.; Glenn, Martha; Curtin, Karen; Cannon-Albright, Lisa A.; Diver, W Ryan; Link, Brian K.; Weiner, George J.; Conde, Lucia; Bracci, Paige M.; Riby, Jacques; Arnett, Donna K.; Zhi, Degui; Leach, Justin M.; Holly, Elizabeth A.; Jackson, Rebecca D.; Tinker, Lesley F.; Benavente, Yolanda; Sala, Núria; Casabonne, Delphine; Becker, Nikolaus; Boffetta, Paolo; Brennan, Paul; Foretova, Lenka; Maynadie, Marc; McKay, James; Staines, Anthony; Chaffee, Kari G.; Achenbach, Sara J.; Vachon, Celine M.; Goldin, Lynn R.; Strom, Sara S.; Leis, Jose F.; Weinberg, J. Brice; Caporaso, Neil E.; Norman, Aaron D.; De Roos, Anneclaire J.; Morton, Lindsay M.; Severson, Richard K.; Riboli, Elio; Vineis, Paolo; Kaaks, Rudolph; Masala, Giovanna; Weiderpass, Elisabete; Chirlaque, María- Dolores; Vermeulen, Roel C. H.; Travis, Ruth C.; Southey, Melissa C.; Milne, Roger L.; Albanes, Demetrius; Virtamo, Jarmo; Weinstein, Stephanie; Clavel, Jacqueline; Zheng, Tongzhang; Holford, Theodore R.; Villano, Danylo J.; Maria, Ann; Spinelli, John J.; Gascoyne, Randy D.; Connors, Joseph M.; Bertrand, Kimberly A.; Giovannucci, Edward; Kraft, Peter; Kricker, Anne; Turner, Jenny; Ennas, Maria Grazia; Ferri, Giovanni M.; Miligi, Lucia; Liang, Liming; Ma, Baoshan; Huang, Jinyan; Crouch, Simon; Park, Ju-Hyun; Chatterjee, Nilanjan; North, Kari E.; Snowden, John A.; Wright, Josh; Fraumeni, Joseph F.; Offit, Kenneth; Wu, Xifeng; de Sanjose, Silvia; Cerhan, James R.; Chanock, Stephen J.; Rothman, Nathaniel; Slager, Susan L.

    2016-01-01

    Chronic lymphocytic leukemia (CLL) is a common lymphoid malignancy with strong heritability. To further understand the genetic susceptibility for CLL and identify common loci associated with risk, we conducted a meta-analysis of four genome-wide association studies (GWAS) composed of 3,100 cases and 7,667 controls with follow-up replication in 1,958 cases and 5,530 controls. Here we report three new loci at 3p24.1 (rs9880772, EOMES, P=2.55 × 10−11), 6p25.2 (rs73718779, SERPINB6, P=1.97 × 10−8) and 3q28 (rs9815073, LPP, P=3.62 × 10−8), as well as a new independent SNP at the known 2q13 locus (rs9308731, BCL2L11, P=1.00 × 10−11) in the combined analysis. We find suggestive evidence (P<5 × 10−7) for two additional new loci at 4q24 (rs10028805, BANK1, P=7.19 × 10−8) and 3p22.2 (rs1274963, CSRNP1, P=2.12 × 10−7). Pathway analyses of new and known CLL loci consistently show a strong role for apoptosis, providing further evidence for the importance of this biological pathway in CLL susceptibility. PMID:26956414

  7. Meta-analysis of genome-wide association studies discovers multiple loci for chronic lymphocytic leukemia.

    PubMed

    Berndt, Sonja I; Camp, Nicola J; Skibola, Christine F; Vijai, Joseph; Wang, Zhaoming; Gu, Jian; Nieters, Alexandra; Kelly, Rachel S; Smedby, Karin E; Monnereau, Alain; Cozen, Wendy; Cox, Angela; Wang, Sophia S; Lan, Qing; Teras, Lauren R; Machado, Moara; Yeager, Meredith; Brooks-Wilson, Angela R; Hartge, Patricia; Purdue, Mark P; Birmann, Brenda M; Vajdic, Claire M; Cocco, Pierluigi; Zhang, Yawei; Giles, Graham G; Zeleniuch-Jacquotte, Anne; Lawrence, Charles; Montalvan, Rebecca; Burdett, Laurie; Hutchinson, Amy; Ye, Yuanqing; Call, Timothy G; Shanafelt, Tait D; Novak, Anne J; Kay, Neil E; Liebow, Mark; Cunningham, Julie M; Allmer, Cristine; Hjalgrim, Henrik; Adami, Hans-Olov; Melbye, Mads; Glimelius, Bengt; Chang, Ellen T; Glenn, Martha; Curtin, Karen; Cannon-Albright, Lisa A; Diver, W Ryan; Link, Brian K; Weiner, George J; Conde, Lucia; Bracci, Paige M; Riby, Jacques; Arnett, Donna K; Zhi, Degui; Leach, Justin M; Holly, Elizabeth A; Jackson, Rebecca D; Tinker, Lesley F; Benavente, Yolanda; Sala, Núria; Casabonne, Delphine; Becker, Nikolaus; Boffetta, Paolo; Brennan, Paul; Foretova, Lenka; Maynadie, Marc; McKay, James; Staines, Anthony; Chaffee, Kari G; Achenbach, Sara J; Vachon, Celine M; Goldin, Lynn R; Strom, Sara S; Leis, Jose F; Weinberg, J Brice; Caporaso, Neil E; Norman, Aaron D; De Roos, Anneclaire J; Morton, Lindsay M; Severson, Richard K; Riboli, Elio; Vineis, Paolo; Kaaks, Rudolph; Masala, Giovanna; Weiderpass, Elisabete; Chirlaque, María-Dolores; Vermeulen, Roel C H; Travis, Ruth C; Southey, Melissa C; Milne, Roger L; Albanes, Demetrius; Virtamo, Jarmo; Weinstein, Stephanie; Clavel, Jacqueline; Zheng, Tongzhang; Holford, Theodore R; Villano, Danylo J; Maria, Ann; Spinelli, John J; Gascoyne, Randy D; Connors, Joseph M; Bertrand, Kimberly A; Giovannucci, Edward; Kraft, Peter; Kricker, Anne; Turner, Jenny; Ennas, Maria Grazia; Ferri, Giovanni M; Miligi, Lucia; Liang, Liming; Ma, Baoshan; Huang, Jinyan; Crouch, Simon; Park, Ju-Hyun; Chatterjee, Nilanjan; North, Kari E; Snowden, John A; Wright, Josh; Fraumeni, Joseph F; Offit, Kenneth; Wu, Xifeng; de Sanjose, Silvia; Cerhan, James R; Chanock, Stephen J; Rothman, Nathaniel; Slager, Susan L

    2016-03-09

    Chronic lymphocytic leukemia (CLL) is a common lymphoid malignancy with strong heritability. To further understand the genetic susceptibility for CLL and identify common loci associated with risk, we conducted a meta-analysis of four genome-wide association studies (GWAS) composed of 3,100 cases and 7,667 controls with follow-up replication in 1,958 cases and 5,530 controls. Here we report three new loci at 3p24.1 (rs9880772, EOMES, P=2.55 × 10(-11)), 6p25.2 (rs73718779, SERPINB6, P=1.97 × 10(-8)) and 3q28 (rs9815073, LPP, P=3.62 × 10(-8)), as well as a new independent SNP at the known 2q13 locus (rs9308731, BCL2L11, P=1.00 × 10(-11)) in the combined analysis. We find suggestive evidence (P<5 × 10(-7)) for two additional new loci at 4q24 (rs10028805, BANK1, P=7.19 × 10(-8)) and 3p22.2 (rs1274963, CSRNP1, P=2.12 × 10(-7)). Pathway analyses of new and known CLL loci consistently show a strong role for apoptosis, providing further evidence for the importance of this biological pathway in CLL susceptibility.

  8. Selinexor is effective in acquired resistance to ibrutinib and synergizes with ibrutinib in chronic lymphocytic leukemia

    PubMed Central

    Hing, Zachary A.; Mantel, Rose; Beckwith, Kyle A.; Guinn, Daphne; Williams, Erich; Smith, Lisa L.; Williams, Katie; Johnson, Amy J.; Lehman, Amy M.; Byrd, John C.; Woyach, Jennifer A.

    2015-01-01

    Despite the therapeutic efficacy of ibrutinib in chronic lymphocytic leukemia (CLL), complete responses are infrequent, and acquired resistance to Bruton agammaglobulinemia tyrosine kinase (BTK) inhibition is being observed in an increasing number of patients. Combination regimens that increase frequency of complete remissions, accelerate time to remission, and overcome single agent resistance are of considerable interest. We previously showed that the XPO1 inhibitor selinexor is proapoptotic in CLL cells and disrupts B-cell receptor signaling via BTK depletion. Herein we show the combination of selinexor and ibrutinib elicits a synergistic cytotoxic effect in primary CLL cells and increases overall survival compared with ibrutinib alone in a mouse model of CLL. Selinexor is effective in cells isolated from patients with prolonged lymphocytosis following ibrutinib therapy. Finally, selinexor is effective in ibrutinib-refractory mice and in a cell line harboring the BTK C481S mutation. This is the first report describing the combined activity of ibrutinib and selinexor in CLL, which represents a new treatment paradigm and warrants further evaluation in clinical trials of CLL patients including those with acquired ibrutinib resistance. PMID:25838351

  9. Cross-resistance and synergy with bendamustine in chronic lymphocytic leukemia.

    PubMed

    Kost, Sara E F; Bouchard, Eric D J; LaBossière, Élise; Ye, Xibiao; Queau, Michelle L; Liang, William S; Banerji, Versha; Gibson, Spencer B; Katyal, Sachin; Johnston, James B

    2016-11-01

    Bendamustine (BEN) has structural similarities to an alkylating agent and a nucleoside analog, and effective against tumor cells that are resistant to standard therapy. In this study we compared the activities of BEN against that of the alkylating agent, chlorambucil (CLB), and the nucleoside analogs, fludarabine (FLU) and deoxyadenosine/pentostatin (dADO/PEN), in primary chronic lymphocytic leukemia (CLL) cells in vitro. Cross-resistance was observed between BEN, CLB and FLU, with previously treated patients or those with a deletion 17p being most resistant. In contrast, some resistant CLL cells retained moderate sensitivity to dADO/PEN. Like FLU and CLB, BEN induced apoptosis through both the mitochondrial and death receptor pathways. There was a greater increase in DNA double-strand breaks (DSB) following FLU, as compared to BEN and CLB. Synergistic cytotoxicity was seen on combining BEN or CLB with FLU or dADO/PEN, but not when combining BEN with CLB. These results demonstrate that BEN acts as an alkylating agent, demonstrates cross-resistance to CLB and FLU and resistance to cells with a del 17p. Synergistic cytotoxic activity was seen between BEN and dADO/PEN suggesting that the combination of BEN and PEN should be evaluated in the clinic.

  10. Interferon regulatory factor 4 attenuates Notch signaling to suppress the development of chronic lymphocytic leukemia.

    PubMed

    Shukla, Vipul; Shukla, Ashima; Joshi, Shantaram S; Lu, Runqing

    2016-07-05

    Molecular pathogenesis of Chronic Lymphocytic Leukemia (CLL) is not fully elucidated. Genome wide association studies have linked Interferon Regulatory Factor 4 (IRF4) to the development of CLL. We recently established a causal relationship between low levels of IRF4 and development of CLL. However, the molecular mechanism through which IRF4 suppresses CLL development remains unclear. Deregulation of Notch signaling pathway has been identified as one of the most recurrent molecular anomalies in the pathogenesis of CLL. Yet, the role of Notch signaling as well as its regulation during CLL development remains poorly understood. Previously, we demonstrated that IRF4 deficient mice expressing immunoglobulin heavy chain Vh11 (IRF4-/-Vh11) developed spontaneous CLL with complete penetrance. In this study, we show that elevated Notch2 expression and the resulting hyperactivation of Notch signaling are common features of IRF4-/-Vh11 CLL cells. Our studies further reveal that Notch signaling is indispensable for CLL development in the IRF4-/-Vh11 mice. Moreover, we identify E3 ubiquitin ligase Nedd4, which targets Notch for degradation, as a direct target of IRF4 in CLL cells and their precursors. Collectively, our studies provide the first in vivo evidence for an essential role of Notch signaling in the development of CLL and establish IRF4 as a critical regulator of Notch signaling during CLL development.

  11. Idelalisib and caffeine reduce suppression of T cell responses mediated by activated chronic lymphocytic leukemia cells

    PubMed Central

    Hock, Barry D.; MacPherson, Sean A.; McKenzie, Judith L.

    2017-01-01

    Chronic lymphocytic leukemia (CLL) is associated with T cell dysfunction. Activated CLL cells are found within the lymphoid tumor micro-environment and overcoming immuno-suppression induced by these cells may improve anti-CLL immune responses. However, the mechanisms by which activated CLL cells inhibit T cell responses, and reagents targeting such mechanisms have not been identified. Here we demonstrate that the ability of in vitro activated CLL cells to suppress T cell proliferation is not reversed by the presence of ecto-nuclease inhibitors or blockade of IL-10, PD-1 and CTLA-4 pathways. Caffeine is both an adenosine receptor antagonist and a phosphatidylinositol-3-kinase, p110δ (PI3Kδ) inhibitor and, at physiologically relevant levels, significantly reversed suppression. Significant reversal of suppression was also observed with the PI3Kδ specific inhibitor Idelalisib but not with adenosine receptor specific antagonists. Furthermore, addition of caffeine or Idelalisib to activated CLL cells significantly inhibited phosphorylation of AKT, a downstream kinase of PI3K, but did not affect CLL viability. These results suggest that caffeine, in common with Idelalisib, reduces the immuno-suppressive activity of activated CLL cells by inhibiting PI3Kδ. These findings raise the possibility that these compounds may provide a useful therapeutic adjunct by reducing immuno-suppression within the tumor micro-environment of CLL. PMID:28257435

  12. Targeting DNA repair with aphidicolin sensitizes primary chronic lymphocytic leukemia cells to purine analogs

    PubMed Central

    Starczewska, Eliza; Beyaert, Maxime; Michaux, Lucienne; Vekemans, Marie-Christiane; Saussoy, Pascale; Bol, Vanesa; Echarri, Ainhoa Arana; Smal, Caroline; Van Den Neste, Eric; Bontemps, Françoise

    2016-01-01

    Purine analogs are among the most effective chemotherapeutic drugs for the treatment of chronic lymphocytic leukemia (CLL). However, chemoresistance and toxicity limit their clinical use. Here, we report that the DNA polymerase inhibitor aphidicolin, which displayed negligible cytotoxicity as a single agent in primary CLL cells, markedly synergizes with fludarabine and cladribine via enhanced apoptosis. Importantly, synergy was recorded regardless of CLL prognostic markers. At the molecular level, aphidicolin enhanced purine analog-induced phosphorylation of p53 and accumulation of γH2AX, consistent with increase in DNA damage. In addition, aphidicolin delayed γH2AX disappearance that arises after removal of purine analogs, suggesting that aphidicolin causes an increase in DNA damage by impeding DNA damage repair. Similarly, aphidicolin inhibited UV-induced DNA repair known to occur primarily through the nucleotide excision repair (NER) pathway. Finally, we showed that fludarabine induced nuclear import of XPA, an indispensable factor for NER, and that XPA silencing sensitized cell lines to undergo apoptosis in response to fludarabine. Together, our data indicate that aphidicolin potentiates the cytotoxicity of purine analogs by inhibiting a DNA repair pathway that involves DNA polymerases, most likely NER, and provide a rationale for manipulating it to therapeutic advantage. PMID:27223263

  13. Lenalidomide induces long-lasting responses in elderly patients with chronic lymphocytic leukemia

    PubMed Central

    Strati, Paolo; Keating, Michael J.; Wierda, William G.; Badoux, Xavier C.; Calin, Steliana; Reuben, James M.; O’Brien, Susan; Kornblau, Steven M.; Kantarjian, Hagop M.; Gao, Hui

    2013-01-01

    We evaluated long-term outcomes of 60 patients with chronic lymphocytic leukemia treated with an initial therapy of lenalidomide. At a median follow-up of 4 years, time-to-treatment failure has not been reached and overall survival is 82%. Thirty-five (58%) patients had a response lasting >36 months (long-term responders [LTRs]). Best LTR responses consisted of 25 (71%) complete remissions and 10 (29%) partial remissions. In addition to clinical responses, an increase in IgA, IgG, and IgM levels of >50% from baseline was reported in 61%, 45%, and 42% of LTRs. Normalization in the percentage of CD4+ and CD8+ cells and T-cell numbers was observed in 48%, 71% and 99% of LTRs. Compared with other patients in the study, LTRs had lower baseline plasma levels of β-2-microglobulin, were more likely to have trisomy 12, and less likely to have deletion 17p. This trial was registered at http://clinicaltrials.gov as # NCT00535873. PMID:23801633

  14. Frontline chemoimmunotherapy with fludarabine, cyclophosphamide, alemtuzumab, and rituximab for high-risk chronic lymphocytic leukemia

    PubMed Central

    Parikh, Sameer A.; Keating, Michael J.; O'Brien, Susan; Wang, Xuemei; Ferrajoli, Alessandra; Faderl, Stefan; Burger, Jan; Koller, Charles; Estrov, Zeev; Badoux, Xavier; Lerner, Susan

    2011-01-01

    Frontline chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR) is associated with superior overall survival (OS) for patients with chronic lymphocytic leukemia (CLL). Alemtuzumab (A) was added to FCR (CFAR) in a phase 2 trial for high-risk untreated patients < 70 years with serum β-2 microglobulin (β2M) ≥ 4 mg/L. Sixty patients were enrolled; median age was 59 years (range, 42-69); 75% were male; median β2M was 5.1 mg/L (range, 4-11.6); and 51% were Rai III-IV. Complete remission (CR) was achieved in 70%, partial remission (PR) in 18%, nodular PR in 3%, for an overall response of 92%. Of 14 patients with 17p deletion, CR was achieved by 8 (57%). Of 57 BM samples evaluated by 3-color flow cytometry at the end of treatment, 41 (72%) were negative for residual disease. Grade 3-4 neutropenia and thrombocytopenia occurred with 33% and 13% courses, respectively. The median progression-free survival was 38 months and median OS was not reached. In conclusion, CFAR is an active frontline regimen for high-risk CLL. Response rates and survival are comparable with historic high-risk FCR-treated patients. CFAR may be a useful frontline regimen to achieve CR in patients with 17p deletion before allogeneic stem cell transplantation. PMID:21750315

  15. FCR and Bevacizumab (FCR-B) Treatment in Patients with Relapsed Chronic Lymphocytic Leukemia (CLL)

    PubMed Central

    Jain, Preetesh; Lee, Hun Ju; Qiao, Wei; Wierda, William; Benjamini, Ohad; Burger, Jan; Ferrajoli, Alessandra; Estrov, Zeev; Kantarjian, Hagop; Keating, Michael; O’Brien, Susan

    2014-01-01

    Patients with relapsed chronic lymphocytic leukemia (CLL) often achieve response with chemoimmunotherapy but have short remission durations. Studies have shown that patients with CLL have increased angiogenesis in the microenvironment; levels of pro-angiogenic growth factors such as VEGF and/or angiopoietin-2 (Ang-2) are also elevated. Increased angiogenesis correlates with poor outcome in CLL. Bevacizumab (B) is a humanized monoclonal antibody targeting VEGF-A. In this study, we analysed whether a combination of bevacizumab (B) with FCR chemoimmunotherapy (FCR-B) could improve outcomes in patients with relapsed CLL. Sixty-two patients were enrolled. The median age of the patients was 60 years (range, 31–84 years) and 40% had received >1 prior therapy for CLL. Sixty-one patients were evaluable for toxicity and 57 were evaluable for response. Six cycles were planned; 36 (59%) patients completed ≥ 4–6 cycles of the regimen. The overall response rate (ORR) was 79% with 13 (23%) complete remissions (CR), 8 (14%) nodular partial remissions (nPR) and 24 (43%) partial remissions (PR). The median progression free survival (PFS) and overall survival (OS) rates were 13.5 and 45 months, respectively. Grade 3 or 4 toxicities included febrile neutropenia (n=40), infections (n=21), thrombocytopenia (n=18) and anemia (n=9). Results with FCR-B were similar to those observed with an historical cohort of relapsed patients treated with FCR. PMID:25043749

  16. Multivariable Model for Time to First Treatment in Patients With Chronic Lymphocytic Leukemia

    PubMed Central

    Wierda, William G.; O'Brien, Susan; Wang, Xuemei; Faderl, Stefan; Ferrajoli, Alessandra; Do, Kim-Anh; Garcia-Manero, Guillermo; Cortes, Jorge; Thomas, Deborah; Koller, Charles A.; Burger, Jan A.; Lerner, Susan; Schlette, Ellen; Abruzzo, Lynne; Kantarjian, Hagop M.; Keating, Michael J.

    2011-01-01

    Purpose The clinical course for patients with chronic lymphocytic leukemia (CLL) is diverse; some patients have indolent disease, never needing treatment, whereas others have aggressive disease requiring early treatment. We continue to use criteria for active disease to initiate therapy. Multivariable analysis was performed to identify prognostic factors independently associated with time to first treatment for patients with CLL. Patients and Methods Traditional laboratory, clinical prognostic, and newer prognostic factors such as fluorescent in situ hybridization (FISH), IGHV mutation status, and ZAP-70 expression evaluated at first patient visit to MD Anderson Cancer Center were correlated by multivariable analysis with time to first treatment. This multivariable model was used to develop a nomogram—a weighted tool to calculate 2- and 4-year probability of treatment and estimate median time to first treatment. Results There were 930 previously untreated patients who had traditional and new prognostic factors evaluated; they did not have active CLL requiring initiation of treatment within 3 months of first visit and were observed for time to first treatment. The following were independently associated with shorter time to first treatment: three involved lymph node sites, increased size of cervical lymph nodes, presence of 17p deletion or 11q deletion by FISH, increased serum lactate dehydrogenase, and unmutated IGHV mutation status. Conclusion We developed a multivariable model that incorporates traditional and newer prognostic factors to identify patients at high risk for progression to treatment. This model may be useful to identify patients for early interventional trials. PMID:21969505

  17. Functional Differences between IgM and IgD Signaling in Chronic Lymphocytic Leukemia.

    PubMed

    Ten Hacken, Elisa; Sivina, Mariela; Kim, Ekaterina; O'Brien, Susan; Wierda, William G; Ferrajoli, Alessandra; Estrov, Zeev; Keating, Michael J; Oellerich, Thomas; Scielzo, Cristina; Ghia, Paolo; Caligaris-Cappio, Federico; Burger, Jan A

    2016-09-15

    BCR signaling is a central pathogenetic pathway in chronic lymphocytic leukemia (CLL). Most CLL cells express BCRs of IgM and IgD isotypes, but the contribution of these isotypes to functional responses remains incompletely defined. We therefore investigated differences between IgM and IgD signaling in freshly isolated peripheral blood CLL cells and in CLL cells cultured with nurselike cells, a model that mimics the lymph node microenvironment. IgM signaling induced prolonged activation of ERK kinases and promoted CLL cell survival, CCL3 and CCL4 chemokine secretion, and downregulation of BCL6, the transcriptional repressor of CCL3 In contrast, IgD signaling induced activation of the cytoskeletal protein HS1, along with F-actin polymerization, which resulted in rapid receptor internalization and failure to support downstream responses, including CLL cell survival and chemokine secretion. IgM and IgD receptor downmodulation, HS1 and ERK activation, chemokine secretion, and BCL6 downregulation were also observed when CLL cells were cocultured with nurselike cells. The Bruton's tyrosine kinase inhibitor ibrutinib effectively inhibited both IgM and IgD isotype signaling. In conclusion, through a variety of functional readouts, we demonstrate very distinct outcomes of IgM and IgD isotype activation in CLL cells, providing novel insight into the regulation of BCR signaling in CLL.

  18. Fludarabine in resistant or relapsing B-cell chronic lymphocytic leukemia: the Spanish Group experience.

    PubMed

    Montserrat, E; Lopez-Lorenzo, J L; Manso, F; Martin, A; Prieto, E; Arias-Sampedro, J; Fernandez, M N; Oyarzabal, F J; Odriozola, J; Alcala, A; Garcia-Conde, J; Guardia, R; Bosch, F

    1996-05-01

    Fludarabine produces high response rates in patients with B-cell chronic lymphocytic leukemia (CLL). Nevertheless, response to fludarabine of patients with previously treated CLL varies from 17% to 74% (0% to 38% CR). In 68 patients with heavily pretreated and advanced CLL, an overall response rate to fludarabine of 28% (4% CR) was observed. Response correlated with sensitivity of the disease to previous treatments (relapsing vs. refractory disease) (62% vs. 20%; p = 0.005) and, albeit not significantly, with the number of cycles of fludarabine (>3 vs. < or = 3) that patients could receive (36% vs. 15%; p = NS). Responding patients had a longer survival (median, not reached) than those not responding (median, 11 months) (p = 0.03). Severe toxicity was observed in some cases. It is concluded that fludarabine is a highly useful agent in CLL. However, in order to improve its effectiveness and decrease its toxicity, fludarabine should be given as soon as a lack of response to front-line therapy is observed and before the disease becomes completely resistant to therapy.

  19. No evidence of transmission of chronic lymphocytic leukemia through blood transfusion.

    PubMed

    Hjalgrim, Henrik; Rostgaard, Klaus; Vasan, Senthil K; Ullum, Henrik; Erikstrup, Christian; Pedersen, Ole B V; Nielsen, Kaspar R; Titlestad, Kjell-Einar; Melbye, Mads; Nyrén, Olof; Edgren, Gustaf

    2015-10-22

    Monoclonal B-cell lymphocytosis (MBL) is a precursor of chronic lymphocytic leukemia (CLL). Observations of MBL in blood donors raise concern that transmitted MBL may cause recipient CLL. Using a database with health information on 1.5 million donors and 2.1 million recipients, we compared CLL occurrence among 7413 recipients of blood from 796 donors diagnosed with CLL after donation cessation, and among 80, 431 recipients of blood from 7477 matched CLL-free donors. During follow-up, 12 and 107 cases of CLL occurred among the exposed and unexposed recipients, respectively, yielding a relative risk of 0.94 (95% confidence interval, 0.52-1.71). Analyses using the entire database showed no evidence of CLL clustering among recipients of blood from individual donors. In conclusion, when donor MBL was approximated by subsequent donor CLL diagnosis, data from 2 countries' entire computerized transfusion experience over more than 30 years indicate that MBL/CLL transmission does not contribute importantly to recipient CLL risk.

  20. Association of peripheral CD4+ CXCR5+ T cells with chronic lymphocytic leukemia.

    PubMed

    Cha, Zhanshan; Zang, Yan; Guo, Huijun; Rechlic, James R; Olasnova, Lindsay M; Gu, Haihui; Tu, Xiaohua; Song, Haihan; Qian, Baohua

    2013-12-01

    Accumulating evidences indicate that immune dysregulation plays a key role in both lymphomagenesis and patient outcome of chronic lymphocytic leukemia (CLL). Peripheral blood CD4+ CXCR5+ T cells, known as circulating follicular helper T cells (Tfh), can induce B cell activation and production of specific antibody responses. The aim of the study was to investigate changes of circulating Tfh in CLL. Tfh and it subtypes were tested by measuring CD4, CXCR5, CXCR3, and CCR6 in 72 CLL cases and 86 healthy controls using flow cytometry. Data showed that the percentage of Tfh in the peripheral CD4+ T cells was significantly increased in CLL (25.1%) than in controls (8.4%) (p < 0.001). Further analysis revealed that the upregulation of Tfh was contributed by Tfh-th2 subtype and Tfh-th17 subtype. Investigating staging of the cases demonstrated that the prevalence of Tfh was significantly elevated in cases with Binet stage C (37.3%) than those with stage A (20.1 %) or stage B (23.9 %). In addition, we analyzed Tfh in patients with immunoglobulin variable heavy chain (IGHV) gene mutational status. Results presented that Tfh-th17 subtype had clearly higher frequency in patients with IGHV mutation compared to the unmutated cases (p = 0.035). This study suggested the involvement of Tfh in the pathogenesis and progression of CLL, and provided a potential target for treating this disease.

  1. BIRC3 alterations in chronic and B-cell acute lymphocytic leukemia patients

    PubMed Central

    ALHOURANI, EYAD; OTHMAN, MONEEB A.K.; MELO, JOANA B.; CARREIRA, ISABEL M.; GRYGALEWICZ, BEATA; VUJIĆ, DRAGANA; ZECEVIĆ, ZELJKO; JOKSIĆ, GORDANA; GLASER, ANITA; POHLE, BEATE; SCHLIE, CORDULA; HAUKE, SVEN; LIEHR, THOMAS

    2016-01-01

    Deletions within chromosome 11q22-23, are considered among the most common chromosomal aberrations in chronic lymphocytic leukemia (CLL), and are associated with a poor outcome. In addition to the ataxia telangiectasia mutated (ATM) gene, the baculoviral IAP repeat-containing 3 (BIRC3) gene is also located in the region. BIRC3 encodes a negative regulator of the non-canonical nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) protein. Disruption of BIRC3 is known to be restricted to CLL fludarabine-refractory patients. The aim of the present study was to determine the frequency of copy number changes of BIRC3 and to assess its association with two known predictors of negative CLL outcome, ATM and tumor protein 53 (TP53) gene deletions. To evaluate the specificity of BIRC3 alterations to CLL, BIRC3 copy numbers were assessed in 117 CLL patients in addition to 45 B-cell acute lymphocytic leukemia (B-ALL) patients. A commercially available multiplex ligation dependent probe amplification kit, which includes four probes for the detection of TP53 and four probes for ATM gene region, was applied. Interphase-directed fluorescence in situ hybridization was used to apply commercially available probes for BIRC3, ATM and TP53. High resolution array-comparative genomic hybridization was conducted in selected cases. Genetic abnormalities of BIRC3 were detected in 23/117 (~20%) of CLL and 2/45 (~4%) of B-ALL cases. Overall, 20 patients with CLL and 1 with B-ALL possessed a BIRC3 deletion, whilst 3 patients with CLL and 1 with B-ALL harbored a BIRC3 duplication. All patients with an ATM deletion also carried a BIRC3 deletion. Only 2 CLL cases possessed deletions in BIRC3, ATM and TP53 simultaneously. Evidently, the deletion or duplication of BIRC3 may be observed rarely in B-ALL patients. BIRC3 duplication may occur in CLL patients, for which the prognosis requires additional studies in the future. The likelihood that TP53 deletions occur simultaneously with

  2. Concepts of Chronic Lymphocytic Leukemia Pathogenesis: DNA Damage Response and Tumor Microenvironment.

    PubMed

    Frenzel, Lukas P; Reinhardt, H Christian; Pallasch, Christian P

    2016-01-01

    Pathogenesis of chronic lymphocytic leukemia (CLL) is characterized by specific genetic aberrations and alterations of cellular signaling pathways. In particular, a disturbed DNA damage response (DDR) and an activated B-cell receptor signaling pathway play a major role in promoting CLL cell survival. External stimuli are similarly essential for CLL cell survival and lead to activation of the PI3K/AKT and MAPK pathways. Activation of nuclear factor-kappa B (NFkB) influences the disturbed anti-apoptotic balance of CLL cells. Losses or disabling mutations in TP53 and ATM are frequent events in chemotherapy-naïve patients and are further enriched in chemotherapy-resistant patients. As these lesions define key regulatory elements of the DDR pathway, they also determine treatment response to genotoxic therapy. Novel therapeutic strategies therefore try to circumvent defective DDR signaling and to suppress the pro-survival stimuli received from the tumor microenvironment. With increasing knowledge on specific genetic alterations of CLL, we may be able to target CLL cells more efficiently even in the situation of mutated DDR pathways or protection by microenvironmental stimuli.

  3. Macrophage-mediated chronic lymphocytic leukemia cell survival is independent of APRIL signaling

    PubMed Central

    van Attekum, MHA; Terpstra, S; Reinen, E; Kater, AP; Eldering, E

    2016-01-01

    Survival of chronic lymphocytic leukemia (CLL) cells is mainly driven by interactions within the lymph node (LN) microenvironment with bystander cells such as T cells or cells from the monocytic lineage. Although the survival effect by T cells is largely governed by the TNFR ligand family member CD40L, the exact mechanism of monocyte-derived cell-induced survival is not known. An important role has been attributed to the TNFR ligand, a proliferation-inducing ligand (APRIL), although the exact mechanism remained unclear. Since we detected that APRIL was expressed by CD68+ cells in CLL LN, we addressed its relevance in various aspects of CLL biology, using a novel APRIL overexpressing co-culture system, recombinant APRIL, and APRIL reporter cells. Unexpectedly, we found, that in these various systems, APRIL had no effect on survival of CLL cells, and activation of NF-κB was not enhanced on APRIL stimulation. Moreover, APRIL stity mulation did not affect CLL proliferation, neither as single stimulus nor in combination with known CLL proliferation stimuli. Furthermore, the survival effect conveyed by macrophages to CLL cells was not affected by transmembrane activator and CAML interactor-Fc, an APRIL decoy receptor. We conclude that the direct role ascribed to APRIL in CLL cell survival might be overestimated due to application of supraphysiological levels of recombinant APRIL. PMID:27551513

  4. Ibrutinib modifies the function of monocyte/macrophage population in chronic lymphocytic leukemia

    PubMed Central

    Audrito, Valentina; Martinelli, Silvia; Hacken, Elisa ten; Zucchini, Patrizia; Grisendi, Giulia; Potenza, Leonardo; Luppi, Mario; Burger, Jan A.; Deaglio, Silvia; Marasca, Roberto

    2016-01-01

    In lymphoid organs, nurse-like cells (NLCs) show properties of tumor-associated macrophages, playing a crucial role in chronic lymphocytic leukemia (CLL) cell survival. Ibrutinib, a potent inhibitor of Bruton's tyrosine kinase (BTK), is able to counteract pro-survival signals in CLL cells. Since the effects on CLL cells have been studied in the last years, less is known about the influence of ibrutinib on NLCs properties. We sought to determine how ibrutinib modifies NLCs functions focusing on the balance between immunosuppressive and inflammatory features. Our data show that ibrutinib targets BTK expressed by NLCs modifying their phenotype and function. Treatment with ibrutinib reduces the phagocytic ability and increases the immunosuppressive profile of NLCs exacerbating the expression of M2 markers. Accordingly, ibrutinib hampers LPS-mediated signaling, decreasing STAT1 phosphorylation, while allows IL-4-mediated STAT6 phosphorylation. In addition, NLCs treated with ibrutinib are able to protect CLL cells from drug-induced apoptosis partially through the secretion of IL-10. Results from patient samples obtained prior and after 1 month of treatment with ibrutinib show an accentuation of CD206, CD11b and Tie2 in the monocytic population in the peripheral blood. Our study provides new insights into the immunomodulatory action of ibrutinib on monocyte/macrophage population in CLL. PMID:27602755

  5. At High Levels, Constitutively Activated STAT3 Induces Apoptosis of Chronic Lymphocytic Leukemia Cells.

    PubMed

    Rozovski, Uri; Harris, David M; Li, Ping; Liu, Zhiming; Wu, Ji Yuan; Grgurevic, Srdana; Faderl, Stefan; Ferrajoli, Alessandra; Wierda, William G; Martinez, Matthew; Verstovsek, Srdan; Keating, Michael J; Estrov, Zeev

    2016-05-15

    In chronic lymphocytic leukemia (CLL), the increment in PBLs is slower than the expected increment calculated from the cells' proliferation rate, suggesting that cellular proliferation and apoptosis are concurrent. Exploring this phenomenon, we found overexpression of caspase-3, higher cleaved poly (ADP-ribose) polymerase levels (p < 0.007), and a higher apoptosis rate in cells from patients with high counts compared with cells from patients with low counts. Although we previously found that STAT3 protects CLL cells from apoptosis, STAT3 levels were significantly higher in cells from patients with high counts than in cells from patients with low counts. Furthermore, overexpression of STAT3 did not protect the cells. Rather, it upregulated caspase-3 and induced apoptosis. Remarkably, putative STAT3 binding sites were identified in the caspase-3 promoter, and a luciferase assay, chromatin immunoprecipitation, and an EMSA revealed that STAT3 activated caspase-3 However, caspase-3 levels increased only when STAT3 levels were sufficiently high. Using chromatin immunoprecipitation and EMSA, we found that STAT3 binds with low affinity to the caspase-3 promoter, suggesting that at high levels, STAT3 activates proapoptotic mechanisms and induces apoptosis in CLL cells.

  6. Impaired bactericidal but not fungicidal activity of polymorphonuclear neutrophils in patients with chronic lymphocytic leukemia.

    PubMed

    Kontoyiannis, Dimitrios P; Georgiadou, Sarah P; Wierda, William G; Wright, Susan; Albert, Nathaniel D; Ferrajoli, Alessandra; Keating, Michael; Lewis, Russell E

    2013-08-01

    We examined the qualitative polymorphonuclear neutrophil (PMN)-associated immune impairment in patients with chronic lymphocytic leukemia (CLL) by characterizing phagocytic killing of key non-opsonized bacterial (Staphylococcus aureus and Pseudomonas aeruginosa) and fungal (Candida albicans and Aspergillus fumigatus) pathogens. Neutrophils were collected from 47 non-neutropenic patients with CLL (PMN count > 1000/mm(3)) and age-matched and young healthy controls (five each). A subset of patients (13%) had prior or subsequent infections. We found that the patients with CLL had diminished PMN microbicidal response against bacteria but not against fungi compared with the controls. Compared to patients with effective PMN responses, we did not identify differences of basal PMN pathogen-associated molecular pattern receptor gene expression, soluble pathogen-associated molecular pattern gene expression or inflammatory cytokine signatures in patients with impaired PMN responses when PMNs were analyzed in multiplex real-time polymerase chain reaction assays. However, differences in PMN microbicidal response against A. fumigatus in patients with CLL were associated with the degree of hypogammaglobulinemia.

  7. Impaired bactericidal but not fungicidal activity of polymorphonuclear neutrophils in patients with chronic lymphocytic leukemia

    PubMed Central

    Kontoyiannis, Dimitrios P.; Georgiadou, Sarah P.; Wierda, William G.; Wright, Susan; Albert, Nathaniel D.; Ferrajoli, Alessandra; Keating, Michael; Lewis, Russell E.

    2013-01-01

    We examined the qualitative polymorphonuclear neutrophil (PMN)-associated immune impairment in patients with chronic lymphocytic leukemia (CLL) by characterizing phagocytic killing of key nonopsonized bacterial (Staphylococcus aureus and Pseudomonas aeruginosa) and fungal (Candida albicans and Aspergillus fumigatus) pathogens. Neutrophils were collected from 47 nonneutropenic CLL patients (PMN count > 1000/mm3), and age-matched and young healthy controls (five each). A subset of patients (13%) had prior or subsequent infections. We found that the CLL patients had diminished PMN microbicidal response against bacteria but not against fungi than did the controls. Compared to patients with effective PMN responses, we did not identify differences of basal PMN pathogen-associated molecular pattern receptor gene expression, soluble pathogen-associated molecular pattern gene expression, or inflammatory cytokine signatures in patients with impaired PMN responses when PMNs were analyzed in multiplex real-time polymerase chain reaction assays. However, differences in PMN microbicidal response against A. fumigatus in CLL patients were associated with the degree of hypogammaglobulinemia. PMID:23163595

  8. Lenalidomide as initial therapy of elderly patients with chronic lymphocytic leukemia.

    PubMed

    Badoux, Xavier C; Keating, Michael J; Wen, Sijin; Lee, Bang-Ning; Sivina, Mariela; Reuben, James; Wierda, William G; O'Brien, Susan M; Faderl, Stefan; Kornblau, Steven M; Burger, Jan A; Ferrajoli, Alessandra

    2011-09-29

    The best initial therapy for elderly patients with chronic lymphocytic leukemia (CLL) has not yet been defined. We investigated the activity of lenalidomide as initial therapy for elderly patients with CLL. Sixty patients with CLL 65 years of age and older received treatment with lenalidomide orally 5 mg daily for 56 days, then titrated up to 25 mg/d as tolerated. Treatment was continued until disease progression. At a median follow-up of 29 months, 53 patients (88%) are alive and 32 patients (53%) remain on therapy. Estimated 2-year progression-free survival is 60%. The overall response rate to lenalidomide therapy is 65%, including 10% complete response, 5% complete response with residual cytopenia, 7% nodular partial response, and 43% partial response. Neutropenia is the most common grade 3 or 4 treatment-related toxicity observed in 34% of treatment cycles. Major infections or neutropenic fever occurred in 13% of patients. Compared with baseline levels, we noted an increase in serum immunoglobulin levels across all classes, and a reduction in CCL3 and CCL4 plasma levels was noted in responding patients. Lenalidomide therapy was well tolerated and induced durable remissions in this population of elderly, symptomatic patients with CLL. This study was registered at www.clinicaltrials.gov as #NCT00535873.

  9. Lenalidomide as initial therapy of elderly patients with chronic lymphocytic leukemia

    PubMed Central

    Badoux, Xavier C.; Keating, Michael J.; Wen, Sijin; Lee, Bang-Ning; Sivina, Mariela; Reuben, James; Wierda, William G.; O'Brien, Susan M.; Faderl, Stefan; Kornblau, Steven M.; Burger, Jan A.

    2011-01-01

    The best initial therapy for elderly patients with chronic lymphocytic leukemia (CLL) has not yet been defined. We investigated the activity of lenalidomide as initial therapy for elderly patients with CLL. Sixty patients with CLL 65 years of age and older received treatment with lenalidomide orally 5 mg daily for 56 days, then titrated up to 25 mg/d as tolerated. Treatment was continued until disease progression. At a median follow-up of 29 months, 53 patients (88%) are alive and 32 patients (53%) remain on therapy. Estimated 2-year progression-free survival is 60%. The overall response rate to lenalidomide therapy is 65%, including 10% complete response, 5% complete response with residual cytopenia, 7% nodular partial response, and 43% partial response. Neutropenia is the most common grade 3 or 4 treatment-related toxicity observed in 34% of treatment cycles. Major infections or neutropenic fever occurred in 13% of patients. Compared with baseline levels, we noted an increase in serum immunoglobulin levels across all classes, and a reduction in CCL3 and CCL4 plasma levels was noted in responding patients. Lenalidomide therapy was well tolerated and induced durable remissions in this population of elderly, symptomatic patients with CLL. This study was registered at www.clinicaltrials.gov as #NCT00535873. PMID:21725050

  10. MicroRNA as biomarkers and regulators in B-cell chronic lymphocytic leukemia

    PubMed Central

    Moussay, Etienne; Wang, Kai; Cho, Ji-Hoon; van Moer, Kris; Pierson, Sandrine; Paggetti, Jérôme; Nazarov, Petr V.; Palissot, Valérie; Hood, Leroy E.; Berchem, Guy; Galas, David J.

    2011-01-01

    Early cancer detection and disease stratification or classification are critical to successful treatment. Accessible, reliable, and informative cancer biomarkers can be medically valuable and can provide some relevant insights into cancer biology. Recent studies have suggested improvements in detecting malignancies by the use of specific extracellular microRNAs (miRNAs) in plasma. In chronic lymphocytic leukemia (CLL), an incurable hematologic disorder, sensitive, early, and noninvasive diagnosis and better disease classification would be very useful for more effective therapies. We show here that circulating miRNAs can be sensitive biomarkers for CLL, because certain extracellular miRNAs are present in CLL patient plasma at levels significantly different from healthy controls and from patients affected by other hematologic malignancies. The levels of several of these circulating miRNAs also displayed significant differences between zeta-associated protein 70 (ZAP-70)+ and ZAP-70− CLL. We also determined that the level of circulating miR-20a correlates reliably with diagnosis-to-treatment time. Network analysis of our data, suggests a regulatory network associated with BCL2 and ZAP-70 expression in CLL. This hypothesis suggests the possibility of using the levels of specific miRNAs in plasma to detect CLL and to determine the ZAP-70 status. PMID:21460253

  11. Obinutuzumab for the treatment of patients with previously untreated chronic lymphocytic leukemia: overview and perspective.

    PubMed

    Owen, Carolyn J; Stewart, Douglas A

    2015-08-01

    Chronic lymphocytic leukemia (CLL) is the most common lymphoproliferative disorder in the Western world and predominantly affects older people. Until recently, most studies in CLL focused on younger patients in whom intensive therapy with the addition of rituximab to fludarabine and cyclophosphamide was shown to improve survival. Obinutuzumab is a novel type II anti-CD20 monoclonal antibody (mAb) that recently demonstrated an overall survival advantage when combined with chemotherapy in previously untreated older patients with CLL and comorbidities. Obinutuzumab was superior to rituximab in this same study in terms of response rates and progression-free survival. Several preclinical and early phase clinical studies also support the efficacy of obinutuzumab. The most frequent adverse event noted with obinutuzumab is infusion-related reactions, which occur more frequently than with rituximab and are typically restricted to the first cycle of therapy. Based on these results, obinutuzumab should be considered the gold standard mAb for combination with chemotherapy in previously untreated patients with CLL and comorbidities. The marked efficacy of obinutuzumab with a weak chemotherapy backbone implies significant potency of this mAb, making it the ideal partner for combination studies with other agents in CLL.

  12. FCR front-line therapy and quality of life in patients with chronic lymphocytic leukemia.

    PubMed

    Kutsch, Nadine; Busch, Raymonde; Bahlo, Jasmin; Mayer, Jiri; Hensel, Manfred; Hopfinger, Georg; Hess, Georg; von Grünhagen, Ulrich; Wendtner, Clemens-Martin; Maria Fink, Anna; Fischer, Kirsten; Hallek, Michael; Eichhorst, Barbara

    2017-02-01

    The chemoimmunotherapy FCR (fludarabine and cyclophosphamide with rituximab) is the standard first-line treatment for physically fit chronic lymphocytic leukemia (CLL) patients. To assess the risks and benefits, we investigated health-related quality of life (HRQOL). 817 untreated CLL patients received either FC or FCR within the GCLLSG CLL8 trial. The European Organization for Research and Treatment of Cancer Quality of life Questionnaire C30 was sent to all patients at baseline, after 3, 6, and 12 months and then yearly as follow-up. A total of 769 (94%) of 817 patients completed at least one questionnaire. Comparing HRQOL of CLL patients with the general German population, CLL patients' health declined in most scales except for global health and pain. No major differences in HRQOL were found during treatment or follow-up between both treatment arms. Females were more likely to have treatment-related symptoms than males. Although FCR was associated with more side effects, this did not influence HRQOL. During follow-up after FCR only minor improvement of HRQOL compared with FC was assessed.

  13. Adoptive cellular therapy for chronic lymphocytic leukemia and B cell malignancies. CARs and more.

    PubMed

    Castro, Januario E; Kipps, Thomas J

    2016-03-01

    Treatment of patients with chronic lymphocytic leukemia and other B cell malignancies is evolving very rapidly. We have observed the quick transition during the last couple of years, from chemo-immunotherapy based treatments to oral targeted therapies based on B cell receptor signaling and Bcl-2 inhibitors, as well as the increasing use of second generation glyco-engineered antibodies. The next wave of revolution in the treatment for this conditions is approaching and it will be based on strategies that harness the power of the immune system to fight cancer. In the center of this biotechnological revolution is cellular engineering, the field that had made possible to redirect the immune system effector cells to achieve a more effective and targeted adoptive cellular therapy. In this chapter, we will review the historical context of these scientific developments, the most recent basic and clinical research in the field and some opinions regarding the future of adoptive cellular therapy in CLL and other B cell malignancies.

  14. Incorporating the use of GM-CSF in the treatment of chronic lymphocytic leukemia.

    PubMed

    Ferrajoli, Alessandra

    2009-03-01

    We evaluated the clinical activity of GM-CSF in combination with standard dose rituximab in patients with chronic lymphocytic leukemia (CLL). The rationale for exploring this combination is provided by the ability of GM-CSF to increase surface expression of CD20 in CLL cells and potentially render them a better target for rituximab. GM-CSF also enhances antibody-dependent cellular cytotoxicity against CLL cells. The combination of GM-CSF and rituximab was evaluated as initial treatment in elderly patients with indication for treatment and in patients at high risk for progression identified by elevated beta(2) microglobulin. This combination was also evaluated in patients with recurrent CLL. On the basis of the results of 118 patients, we observed an overall response rate of 65 and 9% complete remission and these results compare favourably with the results obtained with rituximab single agent. This combination was well tolerated with the most common toxicity consisting in mild GM-CSF injection site erythema. On the basis of this experience, we are currently evaluating the use of GM-CSF in combination with the chemoimmunotherapy regimen fludarabine, cyclophosphamide and rituximab.

  15. Profile of venetoclax and its potential in the context of treatment of relapsed or refractory chronic lymphocytic leukemia.

    PubMed

    Huber, Henriette; Edenhofer, Simone; Estenfelder, Sven; Stilgenbauer, Stephan

    2017-01-01

    Over the last few years, dramatic changes have occurred in the treatment of chronic lymphocytic leukemia (CLL). The current standard for young and fit patients with CLL remains chemoimmunotherapy, namely the fludarabine, cyclophosphamide, and rituximab (FCR) regimen. However, novel oral therapies are presently being introduced and represent a considerable breakthrough concerning effectiveness and safety profile. In particular, the very high-risk group of CLL patients, defined by the genetic aberration del(17p) and/or TP53 mutation, benefit from the new agents. These genetic abnormalities are the most relevant negative prognostic markers in the context of chemoimmunotherapy. New targeted therapies allow different approaches to improve outcomes.

  16. Profile of venetoclax and its potential in the context of treatment of relapsed or refractory chronic lymphocytic leukemia

    PubMed Central

    Huber, Henriette; Edenhofer, Simone; Estenfelder, Sven; Stilgenbauer, Stephan

    2017-01-01

    Over the last few years, dramatic changes have occurred in the treatment of chronic lymphocytic leukemia (CLL). The current standard for young and fit patients with CLL remains chemoimmunotherapy, namely the fludarabine, cyclophosphamide, and rituximab (FCR) regimen. However, novel oral therapies are presently being introduced and represent a considerable breakthrough concerning effectiveness and safety profile. In particular, the very high-risk group of CLL patients, defined by the genetic aberration del(17p) and/or TP53 mutation, benefit from the new agents. These genetic abnormalities are the most relevant negative prognostic markers in the context of chemoimmunotherapy. New targeted therapies allow different approaches to improve outcomes. PMID:28223822

  17. Serum Soluble TACI, a BLyS Receptor, Is a Powerful Prognostic Marker of Outcome in Chronic Lymphocytic Leukemia

    PubMed Central

    Kyrtsonis, Marie-Christine; Sarris, Katerina; Koulieris, Efstathios; Maltezas, Dimitrios; Nikolaou, Eftychia; Angelopoulou, Maria K.; Bartzis, Vassiliki; Tzenou, Tatiana; Dimou, Maria; Siakandaris, Mariana P.; Viniou, Nora A.; Sachanas, Sotirios; Kalpadakis, Christina; Sfikakis, Petros P.; Pangalis, Gerassimos A.; Panayiotidis, Panayiotis

    2014-01-01

    BLyS is involved in CLL biology and its low soluble serum levels related to a shorter time to first treatment (TFT). TACI is a BLyS receptor and can be shed from cells' surface and circulate in soluble form (sTACI). We investigated the impact of serum BLyS and sTACI levels at diagnosis in CLL patients and their relationship with disease parameters and patients' outcome. Serum BLyS was determined in 73 patients, while sTACI in 60. Frozen sera drawn at diagnosis were tested by ELISA. sTACI concentrations correlated with BLyS (P = −0.000021), b2-microglobulin (P = 0.005), anemia (P = −0.03), thrombocytopenia (P = 0.04), Binet stage (P = 0.02), and free light chains ratio (P = 0.0003). Soluble BLyS levels below median and sTACI values above median were related to shorter TFT (P = 0.0003 and 0.007). During a ten-year followup, sTACI levels, but not BLyS, correlated with survival (P = 0.048). In conclusion, we confirmed the prognostic significance of soluble BLyS levels with regard to TFT in CLL patients, and, more importantly, we showed for the first time that sTACI is a powerful prognostic marker, related to parameters of disease activity and staging and, more importantly, to TFT and OS. PMID:25162001

  18. What Is Chronic Myeloid Leukemia?

    MedlinePlus

    ... About Chronic Myeloid Leukemia What Is Chronic Myeloid Leukemia? Cancer starts when cells in the body begin ... is the same as for adults. What is leukemia? Leukemia is a cancer that starts in the ...

  19. Bendamustine and rituximab combination in the management of chronic lymphocytic leukemia-associated autoimmune hemolytic anemia: a multicentric retrospective study of the French CLL intergroup (GCFLLC/MW and GOELAMS).

    PubMed

    Quinquenel, Anne; Willekens, Christophe; Dupuis, Jehan; Royer, Bruno; Ysebaert, Loic; De Guibert, S; Michallet, Anne-Sophie; Feugier, Pierre; Guieze, Romain; Levy, Vincent; Delmer, Alain

    2015-03-01

    We report our experience on bendamustine and rituximab (BR) combination in 26 patients with chronic lymphocytic leukemia (CLL) complicated by autoimmune hemolytic anemia (AIHA). At the time of BR initiation, 88% of the patients had already been treated for AIHA and CLL was progressive regardless of AIHA in all patients but one. Overall response rates were 81% for AIHA and 77% for CLL. Median time to next treatment was 28.3 months and 26.2 months for AIHA and CLL, respectively. BR therapy may represent a good and safe therapeutic option in this setting where adequate control of CLL seems important for long-term AIHA response.

  20. Novel Biomarker Proteins in Chronic Lymphocytic Leukemia: Impact on Diagnosis, Prognosis and Treatment

    PubMed Central

    Admoni-Elisha, Lee; Nakdimon, Itay; Shteinfer, Anna; Prezma, Tal; Arif, Tasleem; Arbel, Nir; Melkov, Anna; Zelichov, Ori; Levi, Itai; Shoshan-Barmatz, Varda

    2016-01-01

    In many cancers, cells undergo re-programming of metabolism, cell survival and anti-apoptotic defense strategies, with the proteins mediating this reprogramming representing potential biomarkers. Here, we searched for novel biomarker proteins in chronic lymphocytic leukemia (CLL) that can impact diagnosis, treatment and prognosis by comparing the protein expression profiles of peripheral blood mononuclear cells from CLL patients and healthy donors using specific antibodies, mass spectrometry and binary logistic regression analyses and other bioinformatics tools. Mass spectrometry (LC-HR-MS/MS) analysis identified 1,360 proteins whose expression levels were modified in CLL-derived lymphocytes. Some of these proteins were previously connected to different cancer types, including CLL, while four other highly expressed proteins were not previously reported to be associated with cancer, and here, for the first time, DDX46 and AK3 are linked to CLL. Down-regulation expression of two of these proteins resulted in cell growth inhibition. High DDX46 expression levels were associated with shorter survival of CLL patients and thus can serve as a prognosis marker. The proteins with modified expression include proteins involved in RNA splicing and translation and particularly mitochondrial proteins involved in apoptosis and metabolism. Thus, we focused on several metabolism- and apoptosis-modulating proteins, particularly on the voltage-dependent anion channel 1 (VDAC1), regulating both metabolism and apoptosis. Expression levels of Bcl-2, VDAC1, MAVS, AIF and SMAC/Diablo were markedly increased in CLL-derived lymphocytes. VDAC1 levels were highly correlated with the amount of CLL-cancerous CD19+/CD5+ cells and with the levels of all other apoptosis-modulating proteins tested. Binary logistic regression analysis demonstrated the ability to predict probability of disease with over 90% accuracy. Finally, based on the changes in the levels of several proteins in CLL patients, as

  1. Integration of Chinese Herbal Medicine Therapy Improves Survival of Patients With Chronic Lymphocytic Leukemia: A Nationwide Population-Based Cohort Study.

    PubMed

    Fleischer, Tom; Chang, Tung-Ti; Chiang, Jen-Huai; Hsieh, Ching-Yun; Sun, Mao-Feng; Yen, Hung-Rong

    2016-05-01

    Utilization of Chinese Medicine (CM) is not uncommon in patients with chronic lymphocytic leukemia (CLL). However, the current knowledge of the usage and efficacy of CM among CLL patients is limited. The aim of this study was to determine the impact of integrative Chinese Herbal Medicine (CHM) on the disease course of CLL and ascertain the herbal products most commonly prescribed to patients with CLL.A Taiwanese nationwide population-based study involving the use of Western medicine and CM services provided by the National Health Insurance (NHI) was conducted.An NHI Research Database-based cohort study was performed; the timeframe of the study was January 2000 to December 2010. The end of the follow-up period was defined as December 31, 2011.A total of 808 patients were diagnosed with CLL in Taiwan within the defined study period. After randomly matching for age and sex and excluding patients younger than 18 years of age, data from 616 patients were analyzed.The 2 study groups both received standard of care treatment. In addition, 1 group also received CHM. Patients who were registered as receiving other forms of CM, such as acupuncture, were excluded.Hazard ratios of mortality were used to determine the influence of CHM and the therapeutic potential of herbal products.In total, 616 CLL patients were included in the analyses. We found that the HR associated with the adjunctive use of CHM was less than half when compared to the non-CHM group (0.43, 95% CI 0.33-0.55, P < 0.0001) and that treatment-naive patients who used CHM had the lowest HR. We also established that this association between reduction in HR and CHM was dose-dependent, and the longer CHM users received prescriptions, the lower the HR (P < 0.001).We supplied data from a relatively large population that spanned a significant amount of time. Our data suggests that the treatment of CLL with adjunctive CHM may have a substantial positive impact on mortality, especially for treatment-naive patients

  2. Rho and Rap guanosine triphosphatase signaling in B cells and chronic lymphocytic leukemia.

    PubMed

    Mele, Silvia; Devereux, Stephen; Ridley, Anne J

    2014-09-01

    Chronic lymphocytic leukemia (CLL) cells proliferate predominantly in niches in the lymph nodes, where signaling from the B cell receptor (BCR) and the surrounding microenvironment are critical for disease progression. In addition, leukemic cells traffic constantly from the bloodstream into the lymph nodes, migrate within lymphatic tissues and egress back to the bloodstream. These processes are driven by chemokines and their receptors, and depend on changes in cell migration and integrin-mediated adhesion. Here we describe how Rho and Rap guanosine triphosphatases (GTPases) contribute to both BCR signaling and chemokine receptor signaling, particularly by regulating cytoskeletal dynamics and integrin activity. We propose that new inhibitors of BCR-activated kinases are likely to affect CLL cell trafficking via Rho and Rap GTPases, and that upstream regulators or downstream effectors could be good targets for therapeutic intervention in CLL.

  3. Association of various risk factors with chronic lymphocytic leukemia and its cytogenetic characteristics.

    PubMed

    Karakosta, Maria; Delicha, Eumorfia-Maria; Kouraklis, Gregory; Manola, Kalliopi N

    2016-11-01

    This study aimed to investigate whether occupational and environmental exposures, lifestyle, family, and medical history are associated with chronic lymphocytic leukemia (CLL) risk and its chromosomal abnormalities. The study included 138 CLL cases and 141 age- and sex-matched controls. Information data were collected through in-person interviews from cases and controls. Cytogenetic analysis was performed on CLL bone marrow cells. Positive associations were found between CLL and cancer family history, smoking, pneumonia, and exposure to petroleum, metals, pesticides/chemical fertilizers, detergents, and medical radiation. Chromosome deletions of 11q and 13q were more frequent in patients exposed to pesticides and rubber, respectively. This study investigated for the first time specific risk factors in relation to CLL aberrations and presented positive correlations. Moreover, it indicates the possible involvement of specific occupational and lifestyle risk factors in the onset of CLL.

  4. The Development and Current Use of BCL-2 Inhibitors for the Treatment of Chronic Lymphocytic Leukemia.

    PubMed

    Lampson, Benjamin L; Davids, Matthew S

    2017-01-23

    The BCL-2 family of proteins integrates pro- and anti-apoptotic signals within the cell and is responsible for initiation of caspase-dependent apoptosis. Chronic lymphocytic leukemia (CLL) cells are particularly dependent on the anti-apoptotic protein BCL-2 for their survival, making this an attractive therapeutic target in CLL. Several early efforts to create inhibitors of the anti-apoptotic family members faced significant challenges, but eventually, the BCL-2 specific inhibitor venetoclax moved forward in CLL. Overall and complete response rates to venetoclax monotherapy in relapsed, refractory CLL are approximately 80 and 20%, respectively, even in patients with high-risk 17p deletion. Toxicities have been manageable and include neutropenia, diarrhea, and nausea. The risk of tumor lysis syndrome (TLS), seen in early experience with the drug, has been mitigated by the use of appropriate TLS risk assessment, prophylaxis, and management. Future studies of venetoclax will focus on combination approaches, predictive biomarker discovery, and mechanisms of resistance.

  5. Phase I dose escalation trial of the novel proteasome inhibitor carfilzomib in patients with relapsed chronic lymphocytic leukemia and small lymphocytic lymphoma.

    PubMed

    Awan, Farrukh T; Flynn, Joseph M; Jones, Jeffrey A; Andritsos, Leslie A; Maddocks, Kami J; Sass, Ellen J; Lucas, Margaret S; Chase, Weihong; Waymer, Sharon; Ling, Yonghua; Jiang, Yao; Phelps, Mitch A; Byrd, John C; Lucas, David M; Woyach, Jennifer A

    2015-01-01

    The proteasome complex degrades proteins involved in a variety of cellular processes and is a powerful therapeutic target in several malignancies. Carfilzomib is a potent proteasome inhibitor which induces rapid chronic lymphocytic leukemia (CLL) cell apoptosis in vitro. We conducted a phase I dose-escalation trial to determine the safety and tolerability of carfilzomib in relapsed/refractory CLL or small lymphocytic lymphoma (SLL). Nineteen patients were treated with carfilzomib initially at 20 mg/m(2), then escalated in four cohorts (27, 36, 45 and 56 mg/m(2)) on days 1, 2, 8, 9, 15 and 16 of 28-day cycles. Therapy was generally well tolerated, and no dose limiting toxicities were observed. The most common hematologic toxicities were thrombocytopenia and neutropenia. All patients evaluable for response had stable disease, including patients with del17p13 and fludarabine-resistant disease. This trial shows acceptable tolerability and limited preliminary efficacy of carfilzomib in CLL and SLL.

  6. IGHV-unmutated and IGHV-mutated chronic lymphocytic leukemia cells produce activation-induced deaminase protein with a full range of biologic functions.

    PubMed

    Patten, Piers E M; Chu, Charles C; Albesiano, Emilia; Damle, Rajendra N; Yan, Xiao-Jie; Kim, Dorothy; Zhang, Lu; Magli, Amanda R; Barrientos, Jacqueline; Kolitz, Jonathan E; Allen, Steven L; Rai, Kanti R; Roa, Sergio; Mongini, Patricia K; MacCarthy, Thomas; Scharff, Matthew D; Chiorazzi, Nicholas

    2012-12-06

    Clonal evolution occurs during the course of chronic lymphocytic leukemia (CLL) and activation-induced deaminase (AID) could influence this process. However, this possibility has been questioned in CLL because the number of circulating AID mRNA(+) cells is exceedingly low; synthesis of AID protein by blood CLL cells has not been demonstrated; the full range of AID functions is lacking in unmutated CLL (U-CLL), and no prospective analysis linking AID expression and disease severity has been reported. The results of the present study show that circulating CLL cells and those within secondary lymphoid tissues can make AID mRNA and protein. This production is related to cell division because more AID mRNA was detected in recently divided cells and AID protein was limited to the dividing fraction and was up-regulated on induction of cell division. AID protein was functional because AID(+) dividing cells exhibited more double-stranded DNA breaks, IGH class switching, and new IGHV-D-J mutations. Each of these actions was documented in U-CLL and mutated CLL (M-CLL). Furthermore, AID protein was associated with worse patient outcome and adverse cytogenetics. We conclude that the production of fully functional AID protein by U-CLL and M-CLL cells could be involved in clonal evolution of the disease.

  7. The Family Physician's Role in Managing Chronic Leukemia

    PubMed Central

    Galbraith, Peter R.

    1988-01-01

    This article provides a brief update on the clinical approach to chronic myelogenous leukemia and chronic lymphocytic leukemia, based on advances in pathbiology and the effect of new concepts on treatment policies. These disorders were selected because family physicians take most responsibility for the day-to-day management of these most common forms of chronic leukemias. PMID:21253119

  8. Whole-exome sequencing in relapsing chronic lymphocytic leukemia: clinical impact of recurrent RPS15 mutations

    PubMed Central

    Ljungström, Viktor; Cortese, Diego; Young, Emma; Pandzic, Tatjana; Mansouri, Larry; Plevova, Karla; Ntoufa, Stavroula; Baliakas, Panagiotis; Clifford, Ruth; Sutton, Lesley-Ann; Blakemore, Stuart J.; Stavroyianni, Niki; Agathangelidis, Andreas; Rossi, Davide; Höglund, Martin; Kotaskova, Jana; Juliusson, Gunnar; Belessi, Chrysoula; Chiorazzi, Nicholas; Panagiotidis, Panagiotis; Langerak, Anton W.; Smedby, Karin E.; Oscier, David; Gaidano, Gianluca; Schuh, Anna; Davi, Frederic; Pott, Christiane; Strefford, Jonathan C.; Trentin, Livio; Pospisilova, Sarka; Ghia, Paolo; Stamatopoulos, Kostas; Sjöblom, Tobias

    2016-01-01

    Fludarabine, cyclophosphamide, and rituximab (FCR) is first-line treatment of medically fit chronic lymphocytic leukemia (CLL) patients; however, despite good response rates, many patients eventually relapse. Although recent high-throughput studies have identified novel recurrent genetic lesions in adverse prognostic CLL, the mechanisms leading to relapse after FCR therapy are not completely understood. To gain insight into this issue, we performed whole-exome sequencing of sequential samples from 41 CLL patients who were uniformly treated with FCR but relapsed after a median of 2 years. In addition to mutations with known adverse-prognostic impact (TP53, NOTCH1, ATM, SF3B1, NFKBIE, and BIRC3), a large proportion of cases (19.5%) harbored mutations in RPS15, a gene encoding a component of the 40S ribosomal subunit. Extended screening, totaling 1119 patients, supported a role for RPS15 mutations in aggressive CLL, with one-third of RPS15-mutant cases also carrying TP53 aberrations. In most cases, selection of dominant, relapse-specific subclones was observed over time. However, RPS15 mutations were clonal before treatment and remained stable at relapse. Notably, all RPS15 mutations represented somatic missense variants and resided within a 7 amino-acid, evolutionarily conserved region. We confirmed the recently postulated direct interaction between RPS15 and MDM2/MDMX and transient expression of mutant RPS15 revealed defective regulation of endogenous p53 compared with wild-type RPS15. In summary, we provide novel insights into the heterogeneous genetic landscape of CLL relapsing after FCR treatment and highlight a novel mechanism underlying clinical aggressiveness involving a mutated ribosomal protein, potentially representing an early genetic lesion in CLL pathobiology. PMID:26675346

  9. The p53 transcriptional pathway is preserved in ATMmutated and NOTCH1mutated chronic lymphocytic leukemias

    PubMed Central

    Rigolin, Gian Matteo; Agnoletto, Chiara; Voltan, Rebecca; Vozzi, Diego; Piscianz, Elisa; Segat, Ludovica; Dal Monego, Simeone; Cuneo, Antonio; Secchiero, Paola; Zauli, Giorgio

    2014-01-01

    By using next generation sequencing, we have analyzed 108 B chronic lymphocytic leukemia (B-CLL) patients. Among genes involved in the TP53 pathway, we found frequent mutations in ATM (n=18), TP53 (n=10) and NOTCH1 (n=10) genes, rare mutations of NOTCH2 (n=2) and CDKN1A/p21 (n=1) and no mutations in BAX, MDM2, TNFRSF10A and TNFRSF10B genes. The in vitro treatment of primary B-CLL cells with the activator of p53 Nutlin-3 induced the transcription of p53 target genes, without significant differences between the B-CLL without mutations and those harboring either ATM or NOTCH1 mutations. On the other hand, the subgroup of TP53mutated B-CLL exhibited a significantly lower induction of the p53 target genes in response to Nutlin-3 as compared to the other B-CLL samples. However, among the TP53mutated B-CLL, those showing mutations in the high hot spot region of the DNA binding domain [273-280 aa] maintained a significantly higher p53-dependent transcriptional activity as compared to the other TP53mutated B-CLL samples. Since the ability to elicit a p53-dependent transcriptional activity in vitro has a positive prognostic significance, our data suggest that ATMmutated, NOTCH1mutated and surprisingly, also a subset of TP53mutated B-CLL patients might benefit from therapeutic combinations including small molecule activator of the p53 pathway. PMID:25587027

  10. Clinical Predictors of Venetoclax Pharmacokinetics in Chronic Lymphocytic Leukemia and Non-Hodgkin's Lymphoma Patients: a Pooled Population Pharmacokinetic Analysis.

    PubMed

    Jones, Aksana K; Freise, Kevin J; Agarwal, Suresh K; Humerickhouse, Rod A; Wong, Shekman L; Salem, Ahmed Hamed

    2016-09-01

    Venetoclax (ABT-199/GDC-0199) is a selective, potent, first-in-class BCL-2 inhibitor that restores apoptosis in cancer cells and has demonstrated clinical efficacy in a variety of hematological malignancies. The objective of this analysis was to characterize the population pharmacokinetics of venetoclax and identify demographic, pathophysiologic, and treatment factors that influence its pharmacokinetics. Plasma concentration samples from 505 subjects enrolled in 8 clinical studies were analyzed using non-linear mixed-effects modeling. Venetoclax plasma concentrations were best described by a two-compartment PK model with first-order absorption and elimination. The terminal half-life in cancer subjects was estimated to be approximately 26 h. Moderate and strong CYP3A inhibitors decreased venetoclax apparent clearance by 19% and 84%, respectively, while weak CYP3A inhibitors and inducers did not affect clearance. Additionally, concomitant rituximab administration was estimated to increase venetoclax apparent clearance by 21%. Gastric acid-reducing agent co-administration had no impact on the rate or extent of venetoclax absorption. Females had 32% lower central volume of distribution when compared to males. Food increased the bioavailability by 2.99- to 4.25-fold when compared to the fasting state. Mild and moderate renal and hepatic impairment, body weight, age, race, weak CYP3A inhibitors and inducers as well as OATP1B1 transporter phenotype and P-gp, BCRP, and OATP1B1/OATP1B3 modulators had no impact on venetoclax pharmacokinetics. Venetoclax showed minimal accumulation with accumulation ratio of 1.30-1.44. In conclusion, the concomitant administration of moderate and strong CYP3A inhibitors and rituximab as well as food were the main factors impacting venetoclax pharmacokinetics, while patient characteristics had only minimal impact.

  11. Droplet digital PCR analysis of NOTCH1 gene mutations in chronic lymphocytic leukemia

    PubMed Central

    Anelli, Luisa; Zagaria, Antonella; Casieri, Paola; Coccaro, Nicoletta; Cumbo, Cosimo; Tota, Giuseppina; Impera, Luciana; Orsini, Paola; Brunetti, Claudia; Giordano, Annamaria; Specchia, Giorgina; Albano, Francesco

    2016-01-01

    In chronic lymphocytic leukemia (CLL), NOTCH1 gene mutations (NOTCH1mut) have been associated with adverse prognostic features but the independence of these as a prognostic factor is still controversial. In our study we validated a c.7541-7542delCT NOTCH1 mutation assay based on droplet digital PCR (ddPCR); we also analyzed the NOTCH1mut allelic burden, expressed as fractional abundance (FA), in 88 CLL patients at diagnosis to assess its prognostic role and made a longitudinal ddPCR analysis in 10 cases harboring NOTCH1mut to verify the FA variation over time. Our data revealed that with the ddPCR approach the incidence of NOTCH1mut in CLL was much higher (53.4%) than expected. However, longitudinal ddPCR analysis of CLL cases showed a statistically significant reduction of the NOTCH1mut FA detected at diagnosis after treatment (median FA 11.67 % vs 0.09 %, respectively, p = 0.01); the same difference, in terms of NOTCH1mut FA, was observed in the relapsed cases compared to the NOTCH1mut allelic fraction observed in patients in complete or partial remission (median FA 4.75% vs 0.43%, respectively, p = 0.007). Our study demonstrated a much higher incidence of NOTCH1mut in CLL than has previously been reported, and showed that the NOTCH1mut allelic burden evaluation by ddPCR might identify patients in need of a closer clinical follow-up during the “watch and wait” interval and after standard chemotherapy. PMID:27835908

  12. The Prognostic Difference of Monoallelic Versus Biallelic Deletion of 13q in Chronic Lymphocytic Leukemia

    PubMed Central

    Garg, Ravin; Wierda, William; Ferrajoli, Alessandra; Abruzzo, Lynne; Pierce, Sherry; Lerner, Susan; Keating, Michael; O’Brien, Susan

    2015-01-01

    BACKGROUND Fluorescence in situ hybridization can detect genomic abnormalities in up to 80% of cases and provides prognostic information on patients with chronic lymphocytic leukemia (CLL). Although 13q deletion as the sole abnormality has been found to confer a favorable prognosis, there are little data as to whether there is a difference in prognostic value between monoallelic versus biallelic deletion of 13q. METHODS The authors reviewed the electronic database for patients with CLL who carried the 13q deletion as the sole abnormality and presented to The University of Texas MD Anderson Cancer Center (MDACC). Untreated patients were separated into 2 groups: those having monoallelic versus those with biallelic deletion of 13q. Using Mann-Whitney, chi-square, and Kaplan-Meier analysis, the baseline quantitative and qualitative variables for each group, along with the time from presentation to MDACC to treatment, were compared. RESULTS A total of 176 patients were identified; 143 patients had a monoallelic deletion of 13q, whereas 33 patients had a biallelic deletion. The only significantly different values between the groups were albumin (4.5 g/dL vs 4.4 g/dL; P = .01) and zeta-chain-associated protein kinase 70 (ZAP70) expression (1.7% vs 4.8%; P = .010). The median time from fluorescence in situ hybridization analysis to treatment in both the monoallelic and biallelic groups had not been reached (P = not significant). CONCLUSIONS Except for inconsequential differences in albumin and ZAP70 expression, there was no difference in the baseline characteristics between patients with CLL who had monoallelic or biallelic deletion of 13q. In addition, there was no significant difference in endpoints, including time to treatment. PMID:22139735

  13. Phenotypic alteration of CD8+ T cells in chronic lymphocytic leukemia is associated with epigenetic reprogramming

    PubMed Central

    Wu, Jiazhu; Xu, Xiaojing; Lee, Eun-Joon; Shull, Austin Y.; Pei, Lirong; Awan, Farrukh; Wang, Xiaoling; Choi, Jeong-Hyeon; Deng, Libin; Xin, Hong-Bo; Zhong, Wenxun; Liang, Jinhua; Miao, Yi; Wu, Yujie; Fan, Lei; Li, Jianyong; Xu, Wei; Shi, Huidong

    2016-01-01

    Immunosuppression is a prevalent clinical feature in chronic lymphocytic leukemia (CLL) patients, with many patients demonstrating increased susceptibility to infections as well as increased failure of an antitumor immune response. However, much is currently not understood regarding the precise mechanisms that attribute to this immunosuppressive phenotype in CLL. To provide further clarity to this particular phenomenon, we analyzed the T-cell profile of CLL patient samples within a large cohort and observed that patients with an inverted CD4/CD8 ratio had a shorter time to first treatment as well as overall survival. These observations coincided with higher expression of the immune checkpoint receptor PD-1 in CLL patient CD8+ T cells when compared to age-matched healthy donors. Interestingly, we discovered that increased PD-1 expression in CD8+ T cells corresponds with decreased DNA methylation levels in a distal upstream locus of the PD-1 gene PDCD1. Further analysis using luciferase reporter assays suggests that the identified PDCD1 distal upstream region acts as an enhancer for PDCD1 transcription and this region becomes demethylated during activation of naïve CD8+ T cells by anti-CD3/anti-CD28 antibodies and IL2. Finally, we conducted a genome-wide DNA methylation analysis comparing CD8+ T cells from CLL patients against healthy donors and identified additional differentially methylated genes with known immune regulatory functions including CCR6 and KLRG1. Taken together, our findings reveal the occurrence of epigenetic reprogramming taking place within CLL patient CD8+ T cells and highlight the potential mechanism of how immunosuppression is accomplished in CLL. PMID:27302925

  14. Randomized phase 2 study of obinutuzumab monotherapy in symptomatic, previously untreated chronic lymphocytic leukemia

    PubMed Central

    Flynn, Joseph M.; Kipps, Thomas J.; Boxer, Michael; Kolibaba, Kathryn S.; Carlile, David J.; Fingerle-Rowson, Guenter; Tyson, Nicola; Hirata, Jamie; Sharman, Jeff P.

    2016-01-01

    Obinutuzumab is a glycoengineered, type 2 anti-CD20 humanized antibody with single-agent activity in relapsed chronic lymphocytic leukemia (CLL). With other CD20 antibodies, a dose-response relationship has been shown. We therefore performed a randomized phase 2 study in symptomatic, untreated CLL patients to evaluate if an obinutuzumab dose response exists. Obinutuzumab was given at a dose of 1000 mg (100 mg IV day 1, 900 mg day 2, 1000 mg day 8 and day 15 of cycle 1; 1000 mg day 1 of cycles 2-8) or 2000 mg (100 mg IV day 1, 900 mg day 2, 1000 mg day 3, 2000 mg day 8 and day 15 of cycle 1; 2000 mg day 1 of cycles 2-8). The primary end point was overall response rate (ORR). Eighty patients were enrolled with similar demographics: median age 67 years, 41% high-risk Rai disease, and 10% del(17p)(13.1). ORR (67% vs 49%, P = .08) and complete response (CR) or CR with incomplete cytopenia response (20% vs 5%) favored 2000 mg obinutuzumab. Overall, therapy was well tolerated, and infusion events were manageable. This study demonstrates significant efficacy of obinutuzumab monotherapy, for 1000 mg as well as for 2000 mg, in untreated CLL patients with acceptable toxicity. Although exploratory, a dose-response relationship may exist, but its relevance to improving progression-free survival is uncertain and will require further follow-up. This trial was registered at www.clinicaltrials.gov as #NCT01414205. PMID:26472752

  15. Randomized phase 2 study of obinutuzumab monotherapy in symptomatic, previously untreated chronic lymphocytic leukemia.

    PubMed

    Byrd, John C; Flynn, Joseph M; Kipps, Thomas J; Boxer, Michael; Kolibaba, Kathryn S; Carlile, David J; Fingerle-Rowson, Guenter; Tyson, Nicola; Hirata, Jamie; Sharman, Jeff P

    2016-01-07

    Obinutuzumab is a glycoengineered, type 2 anti-CD20 humanized antibody with single-agent activity in relapsed chronic lymphocytic leukemia (CLL). With other CD20 antibodies, a dose-response relationship has been shown. We therefore performed a randomized phase 2 study in symptomatic, untreated CLL patients to evaluate if an obinutuzumab dose response exists. Obinutuzumab was given at a dose of 1000 mg (100 mg IV day 1, 900 mg day 2, 1000 mg day 8 and day 15 of cycle 1; 1000 mg day 1 of cycles 2-8) or 2000 mg (100 mg IV day 1, 900 mg day 2, 1000 mg day 3, 2000 mg day 8 and day 15 of cycle 1; 2000 mg day 1 of cycles 2-8). The primary end point was overall response rate (ORR). Eighty patients were enrolled with similar demographics: median age 67 years, 41% high-risk Rai disease, and 10% del(17p)(13.1). ORR (67% vs 49%, P = .08) and complete response (CR) or CR with incomplete cytopenia response (20% vs 5%) favored 2000 mg obinutuzumab. Overall, therapy was well tolerated, and infusion events were manageable. This study demonstrates significant efficacy of obinutuzumab monotherapy, for 1000 mg as well as for 2000 mg, in untreated CLL patients with acceptable toxicity. Although exploratory, a dose-response relationship may exist, but its relevance to improving progression-free survival is uncertain and will require further follow-up. This trial was registered at www.clinicaltrials.gov as #NCT01414205.

  16. High-resolution genomic profiling of chronic lymphocytic leukemia reveals new recurrent genomic alterations.

    PubMed

    Edelmann, Jennifer; Holzmann, Karlheinz; Miller, Florian; Winkler, Dirk; Bühler, Andreas; Zenz, Thorsten; Bullinger, Lars; Kühn, Michael W M; Gerhardinger, Andreas; Bloehdorn, Johannes; Radtke, Ina; Su, Xiaoping; Ma, Jing; Pounds, Stanley; Hallek, Michael; Lichter, Peter; Korbel, Jan; Busch, Raymonde; Mertens, Daniel; Downing, James R; Stilgenbauer, Stephan; Döhner, Hartmut

    2012-12-06

    To identify genomic alterations in chronic lymphocytic leukemia (CLL), we performed single-nucleotide polymorphism-array analysis using Affymetrix Version 6.0 on 353 samples from untreated patients entered in the CLL8 treatment trial. Based on paired-sample analysis (n = 144), a mean of 1.8 copy number alterations per patient were identified; approximately 60% of patients carried no copy number alterations other than those detected by fluorescence in situ hybridization analysis. Copy-neutral loss-of-heterozygosity was detected in 6% of CLL patients and was found most frequently on 13q, 17p, and 11q. Minimally deleted regions were refined on 13q14 (deleted in 61% of patients) to the DLEU1 and DLEU2 genes, on 11q22.3 (27% of patients) to ATM, on 2p16.1-2p15 (gained in 7% of patients) to a 1.9-Mb fragment containing 9 genes, and on 8q24.21 (5% of patients) to a segment 486 kb proximal to the MYC locus. 13q deletions exhibited proximal and distal breakpoint cluster regions. Among the most common novel lesions were deletions at 15q15.1 (4% of patients), with the smallest deletion (70.48 kb) found in the MGA locus. Sequence analysis of MGA in 59 samples revealed a truncating mutation in one CLL patient lacking a 15q deletion. MNT at 17p13.3, which in addition to MGA and MYC encodes for the network of MAX-interacting proteins, was also deleted recurrently.

  17. Chronic Lymphocytic Leukemia with Translocation (2;14)(p16;q32): A Case Report and Review of the Literature

    PubMed Central

    Insuasti-Beltran, Giovanni; Henrich Lobo, Rodolfo; Atrash, Shebli; Sasapu, Appalanaidu

    2016-01-01

    We report the case of a young African American male with no significant past medical history presenting with low back and bilateral leg pain; presenting CBC and chemistries revealed elevated white blood cell count of 250,000, with anemia (Hb 6.8 g/dL) and thrombocytopenia (platelets 9 K/μL), and elevated LDH, 1008. Physical examination findings were notable for diffuse lymphadenopathy and lower extremity skin nodules. Interestingly the bone marrow biopsy revealed involvement by CLL/SLL with translocation (2;14)(p16;q32) and trisomy 12. The patient was treated with fludarabine-based chemotherapy and steroids for CLL-related ITP with excellent response. After three cycles of chemotherapy, all the enlarged lymph nodes and skin nodules disappeared, and patient had achieved complete hematologic response. In this paper we also reviewed the available literature of CLL patients with translocation (2;14). PMID:27885349

  18. Ibrutinib synergizes with MDM-2 inhibitors in promoting cytotoxicity in B chronic lymphocytic leukemia

    PubMed Central

    Melloni, Elisabetta; Rigolin, Gian Matteo; Casciano, Fabio; Arcidiacono, Maria Vittoria; Celeghini, Claudio; Cuneo, Antonio; Zauli, Giorgio; Secchiero, Paola

    2016-01-01

    Objective The aim of this study was to investigate the anti-leukemic activity of the Bruton tyrosine kinase inhibitor Ibrutinib in combination with the small molecule MDM-2 inhibitor Nutlin-3 in preclinical models. Methods The potential efficacy of the Ibrutinib/Nutlin-3 combination was evaluated in vitro in a panel of B leukemic cell lines (EHEB, JVM-2, JVM-3, MEC-1, MEC-2) and in primary B-chronic lymphocytic leukemia (B-CLL) patient samples, by assessing cell viability, cell cycle profile, apoptosis and intracellular pathway modulations. Validation of the combination therapy was assessed in a B leukemic xenograft mouse model. Results Ibrutinib exhibited variable anti-leukemic activity in vitro and the combination with Nutlin-3 synergistically enhanced the induction of apoptosis independently from the p53 status. Indeed, the Ibrutinib/Nutlin-3 combination was effective in promoting cytotoxicity also in primary B-CLL samples carrying 17p13 deletion and/or TP53 mutations, already in therapy with Ibrutinib. Molecular analyses performed on both B-leukemic cell lines as well as on primary B-CLL samples, while confirming the switch-off of the MAPK and PI3K pro-survival pathways by Ibrutinib, indicated that the synergism of action with Nutlin-3 was independent by p53 pathway and was accompanied by the activation of the DNA damage cascade signaling through the phosphorylation of the histone protein H2A.X. This observation was confirmed also in the JVM-2 B leukemic xenograft mouse model. Conclusions Taken together, our data emphasize that the Ibrutinib/Nutlin-3 combination merits to be further evaluated as a therapeutic option for B-CLL. PMID:27661115

  19. Myelosuppression After Frontline Fludarabine, Cyclophosphamide, and Rituximab in Patients With Chronic Lymphocytic Leukemia

    PubMed Central

    Strati, Paolo; Wierda, William; Burger, Jan; Ferrajoli, Alessandra; Tam, Constantine; Lerner, Susan; Keating, Michael J.; O’Brien, Susan

    2015-01-01

    BACKGROUND The combination of fludarabine, cyclophosphamide, and rituximab (FCR) has produced improved response rates and a prolonged survival in patients with chronic lymphocytic leukemia (CLL). However, its therapeutic power is counterbalanced by significant hematologic toxicity. Persistent and new-onset cytopenia after the completion of FCR raise concern about disease recurrence, the development of therapy-related myeloid malignancies (TRMM), and infections. METHODS A total of 207 patients with CLL who achieved complete response, complete response with incomplete bone marrow recovery, or nodular partial remission were analyzed after frontline FCR therapy. RESULTS Three months after the completion of therapy, 35% of patients had developed grade 2 to 4 cytopenia (according to Common Terminology Criteria for Adverse Events [version 4.0]). Factors found to be associated with cytopenia at 3 months after therapy were older age, advanced Rai stage disease, and lower baseline blood counts. Moreover, patients with cytopenia were less likely to have completed 6 courses of therapy with FCR. At 6 months and 9 months after therapy, the prevalence of grade 2 to 4 cytopenia was 24% and 12%, respectively. No differences in progression-free survival and overall survival were noted between cytopenic and noncytopenic patients or between patients with persistent and new-onset cytopenia. The prevalence of TRMM was 2.3% and did not differ significantly between cytopenic and noncytopenic patients or between those with persistent and new-onset disease. Late infections were more common in patients who were cytopenic at 9 months (38%) and were mostly bacterial (67%). CONCLUSIONS Cytopenia after the completion of therapy is a common complication of frontline FCR that improves over time, particularly for new-onset cases. The presence of persistent cytopenia (lasting up to 9 months after the completion of therapy) should not raise concern about CLL recurrence of the development of TRMM, but

  20. Factors predicting survival in chronic lymphocytic leukemia patients developing Richter syndrome transformation into Hodgkin lymphoma.

    PubMed

    Mauro, Francesca Romana; Galieni, Piero; Tedeschi, Alessandra; Laurenti, Luca; Del Poeta, Giovanni; Reda, Gianluigi; Motta, Marina; Gozzetti, Alessandro; Murru, Roberta; Caputo, Maria Denise; Campanelli, Melissa; Frustaci, Anna Maria; Innocenti, Idanna; Raponi, Sara; Guarini, Anna; Morabito, Fortunato; Foà, Robin; Gentile, Massimo

    2017-03-10

    We hereby report the clinical and biologic features of 33 of 4680 (0.7%) patients with chronic lymphocytic leukemia (CLL), managed at 10 Italian centers, who developed Hodgkin lymphoma (HL), a rare variant of Richter syndrome. The median age at CLL and at HL diagnosis were 61 years (range 41-80) and 70 years (range 46-82), respectively, with a median interval from CLL to the diagnosis of HL of 90 months (range 0-258). In 3 cases, CLL and HL were diagnosed simultaneously. Hl was characterized by advanced stage in 79% of cases, International Prognostic Score (IPS) ≥4 in 50%, extranodal involvement in 39%, B symptoms in 70%. Prior treatment for CLL had been received by 82% of patients and included fludarabine in 67%. Coexistence of CLL and HL was detected in the same bioptic tissue in 87% of cases. The most common administered treatment was the ABVD regimen given to 22 patients (66.6%). The complete response (CR) rate after ABVD was 68%, and was influenced by the IPS (p=.03) and interval from the last CLL treatment (p=.057). Survival from HL was also influenced by the IPS (p=.006) and time from the last CLL treatment (p=.047). The achievement of CR with ABVD was the only significant and independent factor predicting survival (p=.037). Taken together, our results show that the IPS and the interval from the prior CLL treatment influence the likelihood of achieving CR after ABVD, which is the most important factor predicting survival of patients with CLL developing HL. This article is protected by copyright. All rights reserved.

  1. Occupation and risk of non-Hodgkin's lymphoma and chronic lymphocytic leukemia.

    PubMed

    Zheng, Tongzhang; Blair, Aaron; Zhang, Yawei; Weisenburger, Dennis D; Zahm, Shelia H

    2002-05-01

    To investigate the association between occupation and the risk of non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL), and to test whether the associations may vary by histological type of NHL, we analyzed data from two population-based, case-control studies of NHL performed in Kansas and Nebraska. A total of 555 incident NHL cases, 56 CLL cases, and 2380 population-based controls were included in the analysis. Information on occupation and other confounding factors was collected through telephone interviews. Study pathologists reviewed slides of tumor tissues in all cases. In men, we found an increased risk of NHL and CLL for those working in agricultural, forestry, and logging industries (odds ratio [OR], 1.6; 95% confidence interval [CI], 1.2 to 2.1). The OR was 1.9 (95% CI, 1.4 to 2.6) for those producing crops. An increased risk was also observed for industries involving metalworking machinery and equipment (OR, 8.4; 95% CI, 1.4 to 50.6), motor vehicles and motor vehicle equipment (OR, 4.2; 95% CI, 1.3 to 13.9), and telephone communications (OR, 3.1; 95% CI, 1.2 to 8.0), and for teachers (OR, 2.5; 95% CI, 1.0 to 6.5), farmers (OR, 2.0; 95% CI, 1.5 to 2.8), and welders and solderers (OR, 2.9; 95% CI, 1.2 to 6.9). The risks for these associations increased by duration of employment and seem to vary by histological type. Work in the printing and publishing industry was also associated with an increased risk of NHL among women. These data suggest that the workers employed in these industries or occupations experienced an increased risk of NHL and CLL, and the risks associated with these industries or occupations may vary by histological type of NHL.

  2. Clinical Characteristics, Response to Therapy, and Survival of African American Patients Diagnosed With Chronic Lymphocytic Leukemia

    PubMed Central

    Falchi, Lorenzo; Keating, Michael J.; Wang, Xuemei; Coombs, Catherine C.; Lanasa, Mark C.; Strom, Sara; Wierda, William G.; Ferrajoli, Alessandra

    2015-01-01

    Background Little is known regarding racial disparities in characteristics and outcomes among patients with chronic lymphocytic leukemia (CLL). Methods The characteristics and outcomes of untreated African American (AA) patients with CLL (n=84) were analyzed and compared with a reference nonblack (NB) patient population (n=1571). Results At the time of presentation, AA patients had lower median hemoglobin levels (12.9 g/dL vs 13.7 g/dL), higher β2 microglobulin levels (2.7 mg/dL vs 2.4 mg/dL), greater frequency of constitutional symptoms (27% vs 10%), unmutated immunoglobulin heavy-chain variable region (IGHV) mutation status (65% vs 47%), ζ-chain-associated protein kinase 70 (ZAP70) expression (58% vs 32%), and deletion of chromosome 17p or chromosome 11q (28% vs 17%; P ≤ 02 for each comparison). Fifty-one percent of AA patients and 39% of NB patients required first-line therapy and 91% and 88%, respectively, received chemoimmunotherapy. Overall response rates to treatment were 85% for AA patients and 94% for NB patients (P=.06); and the complete response rates were 56% and 58%, respectively (P=.87). The median survival of AA patients was shorter compared with that of NB patients (event-free survival: 36 months vs 61 months; P=.007; overall survival: 152 months vs not reached; P=.0001). AA race was an independent predictor of shorter event-free and overall survival in multivariable regression models. Conclusions The current results indicated that AA patients with CLL have more unfavorable prognostic characteristics and shorter survival compared with their NB counterparts. PMID:24022787

  3. Aberrant histone modification in CD19+ B cells of patients with chronic lymphocytic leukemia

    PubMed Central

    Zhou, Keshu; Zhang, Qing; Liu, Yanyan; Xiong, Yuanyuan; Wu, Shengsheng; Yang, Jingke; Zhou, Hu; Liu, Xinjian; Wei, Xudong; Song, Yongping

    2017-01-01

    The aim of this study was to detect the alterations in histone methylation and acetylation in patients with chronic lymphocytic leukemia (CLL). Global histone H3/H4 acetylation and H3K4/H3K9 methylation were detected by the EpiQuik™ global histone H3/H4 acetylation and H3K4/H3K9 methylation assay kits. The mRNA expression of selected chromatin modifier genes was measured by real-time polymerase chain reaction (RT-PCR). Our results found that the global histone H3/H4 hypoacetylation in the CD19+ B cells of patients with CLL (P=0.028 and P=0.03, respectively) and the global histone H3K9 methylation in patients with CLL were significantly increased compared with controls (P=0.02), while there was no significant difference in the global histone H3K4 methylation between the two groups. The level of SIRT1 and EZH2 mRNA expression was upregulated in patients with CLL (P=0.03 and P=0.02, respectively), which increased significantly with progression from Binet stage A to stage C (P=0.015 and P=0.01, respectively) and Rai good to high risk stage (P=0.007 and P=0.008, respectively). The level of HDAC1 and HDAC7 mRNA expression was significantly increased (P=0.02 and P=0.008, respectively) and HDAC2 and P300 mRNA expression was reduced in patients with CLL (P=0.002 and P=0.001, respectively). In conclusion, it is observed that the aberrant histone modification plays an important role in the pathogenesis of CLL. PMID:28260932

  4. Functional invariant natural killer T-cell and CD1d axis in chronic lymphocytic leukemia: implications for immunotherapy.

    PubMed

    Weinkove, Robert; Brooks, Collin R; Carter, John M; Hermans, Ian F; Ronchese, Franca

    2013-03-01

    Invariant natural killer T cells recognize glycolipid antigens such as α-galactosylceramide presented by CD1d. In preclinical models of B-cell malignancies, α-galactosylceramide is an adjuvant to tumor vaccination, enhancing tumor-specific T-cell responses and prolonging survival. However, numerical and functional invariant natural killer T-cell defects exist in patients with some cancers. Our aim was to assess this axis in patients with chronic lymphocytic leukemia. The numbers of circulating invariant natural killer T cells and the expression of CD1d on antigen-presenting cells were evaluated in patients with chronic lymphocytic leukemia and age-matched controls. Cytokine profile and in vitro proliferative capacity were determined. Patient- and control-derived invariant natural killer T-cell lines were generated and characterized, and allogeneic and autologous responses to α-galactosylce-ramide-treated leukemia cells were assessed. Absolute numbers and phenotype of invariant natural killer T cells were normal in patients with untreated chronic lymphocytic leukemia, and cytokine profile and proliferative capacity were intact. Chemotherapy-treated patients had reduced numbers of invariant natural killer T cells and myeloid dendritic cells, but α-galactosylceramide-induced proliferation was preserved. Invariant natural killer T-cell lines from patients lysed CD1d-expressing targets. Irradiated α-galactosylceramide-treated leukemic cells elicited allogeneic and autologous invariant natural killer T-cell proliferation, and α-galactosylceramide treatment led to increased proliferation of conventional T cells in response to tumor. In conclusion, the invariant natural killer T-cell and CD1d axis is fundamentally intact in patients with early-stage chronic lymphocytic leukemia and, despite reduced circulating numbers, function is retained in fludarabine-treated patients. Immunotherapies exploiting the adjuvant effect of α-galactosylceramide may be feasible.

  5. TCL1 targeting miR-3676 is codeleted with tumor protein p53 in chronic lymphocytic leukemia.

    PubMed

    Balatti, Veronica; Rizzotto, Lara; Miller, Cecelia; Palamarchuk, Alexey; Fadda, Paolo; Pandolfo, Rosantony; Rassenti, Laura Z; Hertlein, Erin; Ruppert, Amy S; Lozanski, Arletta; Lozanski, Gerard; Kipps, Thomas J; Byrd, John C; Croce, Carlo M; Pekarsky, Yuri

    2015-02-17

    B-cell chronic lymphocytic leukemia (CLL) is the most common human leukemia and dysregulation of the T-cell leukemia/lymphoma 1 (TCL1) oncogene is a contributing event in the pathogenesis of the aggressive form of this disease based on transgenic mouse studies. To determine a role of microRNAs on the pathogenesis of the aggressive form of CLL we studied regulation of TCL1 expression in CLL by microRNAs. We identified miR-3676 as a regulator of TCL1 expression. We demonstrated that miR-3676 targets three consecutive 28-bp repeats within 3'UTR of TCL1 and showed that miR-3676 is a powerful inhibitor of TCL1. We further showed that miR-3676 expression is significantly down-regulated in four groups of CLL carrying the 11q deletions, 13q deletions, 17p deletions, or a normal karyotype compared with normal CD19(+) cord blood and peripheral blood B cells. In addition, the sequencing of 539 CLL samples revealed five germ-line mutations in six samples (1%) in miR-3676. Two of these mutations were loss-of-function mutations. Because miR-3676 is located at 17p13, only 500-kb centromeric of tumor protein p53 (Tp53), and is codeleted with Tp53, we propose that loss of miR-3676 causes high levels of TCL1 expression contributing to CLL progression.

  6. TCL1 targeting miR-3676 is codeleted with tumor protein p53 in chronic lymphocytic leukemia

    PubMed Central

    Balatti, Veronica; Rizzotto, Lara; Miller, Cecelia; Palamarchuk, Alexey; Fadda, Paolo; Pandolfo, Rosantony; Rassenti, Laura Z.; Hertlein, Erin; Ruppert, Amy S.; Lozanski, Arletta; Lozanski, Gerard; Kipps, Thomas J.; Byrd, John C.; Croce, Carlo M.; Pekarsky, Yuri

    2015-01-01

    B-cell chronic lymphocytic leukemia (CLL) is the most common human leukemia and dysregulation of the T-cell leukemia/lymphoma 1 (TCL1) oncogene is a contributing event in the pathogenesis of the aggressive form of this disease based on transgenic mouse studies. To determine a role of microRNAs on the pathogenesis of the aggressive form of CLL we studied regulation of TCL1 expression in CLL by microRNAs. We identified miR-3676 as a regulator of TCL1 expression. We demonstrated that miR-3676 targets three consecutive 28-bp repeats within 3′UTR of TCL1 and showed that miR-3676 is a powerful inhibitor of TCL1. We further showed that miR-3676 expression is significantly down-regulated in four groups of CLL carrying the 11q deletions, 13q deletions, 17p deletions, or a normal karyotype compared with normal CD19+ cord blood and peripheral blood B cells. In addition, the sequencing of 539 CLL samples revealed five germ-line mutations in six samples (1%) in miR-3676. Two of these mutations were loss-of-function mutations. Because miR-3676 is located at 17p13, only 500-kb centromeric of tumor protein p53 (Tp53), and is codeleted with Tp53, we propose that loss of miR-3676 causes high levels of TCL1 expression contributing to CLL progression. PMID:25646413

  7. Exome sequencing identifies recurrent mutations of the splicing factor SF3B1 gene in chronic lymphocytic leukemia.

    PubMed

    Quesada, Víctor; Conde, Laura; Villamor, Neus; Ordóñez, Gonzalo R; Jares, Pedro; Bassaganyas, Laia; Ramsay, Andrew J; Beà, Sílvia; Pinyol, Magda; Martínez-Trillos, Alejandra; López-Guerra, Mónica; Colomer, Dolors; Navarro, Alba; Baumann, Tycho; Aymerich, Marta; Rozman, María; Delgado, Julio; Giné, Eva; Hernández, Jesús M; González-Díaz, Marcos; Puente, Diana A; Velasco, Gloria; Freije, José M P; Tubío, José M C; Royo, Romina; Gelpí, Josep L; Orozco, Modesto; Pisano, David G; Zamora, Jorge; Vázquez, Miguel; Valencia, Alfonso; Himmelbauer, Heinz; Bayés, Mónica; Heath, Simon; Gut, Marta; Gut, Ivo; Estivill, Xavier; López-Guillermo, Armando; Puente, Xose S; Campo, Elías; López-Otín, Carlos

    2011-12-11

    Here we perform whole-exome sequencing of samples from 105 individuals with chronic lymphocytic leukemia (CLL), the most frequent leukemia in adults in Western countries. We found 1,246 somatic mutations potentially affecting gene function and identified 78 genes with predicted functional alterations in more than one tumor sample. Among these genes, SF3B1, encoding a subunit of the spliceosomal U2 small nuclear ribonucleoprotein (snRNP), is somatically mutated in 9.7% of affected individuals. Further analysis in 279 individuals with CLL showed that SF3B1 mutations were associated with faster disease progression and poor overall survival. This work provides the first comprehensive catalog of somatic mutations in CLL with relevant clinical correlates and defines a large set of new genes that may drive the development of this common form of leukemia. The results reinforce the idea that targeting several well-known genetic pathways, including mRNA splicing, could be useful in the treatment of CLL and other malignancies.

  8. Monoclonal B-cell lymphocytosis in individuals from sporadic (non-familial) chronic lymphocytic leukemia families persists over time, but does not progress to chronic B-cell lymphoproliferative diseases

    PubMed Central

    Matos, Daniel Mazza; Furtado, Felipe Magalhães; Falcão, Roberto Passetto

    2015-01-01

    Background Monoclonal B-cell lymphocytosis is classified as ‘high-count or clinical’ monoclonal B-cell lymphocytosis and ‘low-count or population’ monoclonal B-cell lymphocytosis. Previously, 167 first-degree relatives pertaining to sporadic (non-familial) chronic lymphocytic leukemia families were studied and the presence of seven monoclonal B-cell lymphocytosis individuals was reported. Objective The aim of this report is to describe the outcomes of five of the original monoclonal B-cell lymphocytosis individuals. Methods Flow cytometry analysis was performed on mononuclear cells previously isolated from peripheral blood samples. A strategy of sequential gating designed to identify the population of CD19+/CD5+ B-lymphocytes was used and, subsequently, the monoclonal B-cell lymphocytosis cells were characterized by the CD20weak/CD79bweak/negative phenotype. Results The monoclonal B-cell lymphocytosis clone showed consistent stability over time with little variations in size. After a median follow-up of 7.6 years, none of the five monoclonal B-cell lymphocytosis individuals progressed to chronic lymphocytic leukemia or other B-cell lymphoproliferative disease. Conclusions The data of this study suggest that chronic lymphocytic leukemia-like monoclonal B-cell lymphocytosis detected in the context of sporadic chronic lymphocytic leukemia families is not prone to clinical evolution and could be just a sign of immune senescence. PMID:26408361

  9. Integration of Chinese Herbal Medicine Therapy Improves Survival of Patients With Chronic Lymphocytic Leukemia

    PubMed Central

    Fleischer, Tom; Chang, Tung-Ti; Chiang, Jen-Huai; Hsieh, Ching-Yun; Sun, Mao-Feng; Yen, Hung-Rong

    2016-01-01

    Abstract Utilization of Chinese Medicine (CM) is not uncommon in patients with chronic lymphocytic leukemia (CLL). However, the current knowledge of the usage and efficacy of CM among CLL patients is limited. The aim of this study was to determine the impact of integrative Chinese Herbal Medicine (CHM) on the disease course of CLL and ascertain the herbal products most commonly prescribed to patients with CLL. A Taiwanese nationwide population-based study involving the use of Western medicine and CM services provided by the National Health Insurance (NHI) was conducted. An NHI Research Database-based cohort study was performed; the timeframe of the study was January 2000 to December 2010. The end of the follow-up period was defined as December 31, 2011. A total of 808 patients were diagnosed with CLL in Taiwan within the defined study period. After randomly matching for age and sex and excluding patients younger than 18 years of age, data from 616 patients were analyzed. The 2 study groups both received standard of care treatment. In addition, 1 group also received CHM. Patients who were registered as receiving other forms of CM, such as acupuncture, were excluded. Hazard ratios of mortality were used to determine the influence of CHM and the therapeutic potential of herbal products. In total, 616 CLL patients were included in the analyses. We found that the HR associated with the adjunctive use of CHM was less than half when compared to the non-CHM group (0.43, 95% CI 0.33–0.55, P < 0.0001) and that treatment-naive patients who used CHM had the lowest HR. We also established that this association between reduction in HR and CHM was dose-dependent, and the longer CHM users received prescriptions, the lower the HR (P < 0.001). We supplied data from a relatively large population that spanned a significant amount of time. Our data suggests that the treatment of CLL with adjunctive CHM may have a substantial positive impact on mortality, especially for

  10. Genomic Profile of Chronic Lymphocytic Leukemia in Korea Identified by Targeted Sequencing

    PubMed Central

    Park, Si Nae; Huh, Sunghoon; Im, Kyongok; Choi, Sungbin; Chung, Hye Yoon; Huh, JooRyung; Seo, Eul-Ju; Lee, Je-Hwan; Bang, Duhee; Lee, Dong Soon

    2016-01-01

    Chronic lymphocytic leukemia (CLL) is extremely rare in Asian countries and there has been one report on genetic changes for 5 genes (TP53, SF3B1, NOTCH1, MYD88, and BIRC3) by Sanger sequencing in Chinese CLL. Yet studies of CLL in Asian countries using Next generation sequencing have not been reported. We aimed to characterize the genomic profiles of Korean CLL and to find out ethnic differences in somatic mutations with prognostic implications. We performed targeted sequencing for 87 gene panel using next-generation sequencing along with G-banding and fluorescent in situ hybridization (FISH) for chromosome 12, 13q14.3 deletion, 17p13 deletion, and 11q22 deletion. Overall, 36 out of 48 patients (75%) harbored at least one mutation and mean number of mutation per patient was 1.6 (range 0–6). Aberrant karyotypes were observed in 30.4% by G-banding and 66.7% by FISH. Most recurrent mutation (>10% frequency) was ATM (20.8%) followed by TP53 (14.6%), SF3B1 (10.4%), KLHL6 (8.3%), and BCOR (6.25%). Mutations of MYD88 was associated with moderate adverse prognosis by multiple comparisons (P = 0.055). Mutation frequencies of MYD88, SAMHD1, EGR2, DDX3X, ZMYM3, and MED12 showed similar incidence with Caucasians, while mutation frequencies of ATM, TP53, KLHL6, BCOR and CDKN2A tend to be higher in Koreans than in Caucasians. Especially, ATM mutation showed 1.5 fold higher incidence than Caucasians, while mutation frequencies of SF3B1, NOTCH1, CHD2 and POT1 tend to be lower in Koreans than in Caucasians. However, mutation frequencies between Caucasians and Koreans were not significantly different statistically, probably due to low number of patients. Collectively, mutational profile and adverse prognostic genes in Korean CLL were different from those of Caucasians, suggesting an ethnic difference, while profile of cytogenetic aberrations was similar to those of Caucasians. PMID:27959900

  11. Autologous Peripheral Blood Stem Cell Transplant Followed by Donor Bone Marrow Transplant in Treating Patients With High-Risk Hodgkin Lymphoma, Non-Hodgkin Lymphoma, Multiple Myeloma, or Chronic Lymphocytic Leukemia

    ClinicalTrials.gov

    2017-01-06

    B-Cell Prolymphocytic Leukemia; Hypodiploidy; Loss of Chromosome 17p; Plasma Cell Leukemia; Progression of Multiple Myeloma or Plasma Cell Leukemia; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Non-Hodgkin Lymphoma; Recurrent Childhood Hodgkin Lymphoma; Recurrent Childhood Non-Hodgkin Lymphoma; Recurrent Chronic Lymphocytic Leukemia; Recurrent Plasma Cell Myeloma; Recurrent Small Lymphocytic Lymphoma; Refractory Childhood Hodgkin Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Non-Hodgkin Lymphoma; Refractory Plasma Cell Myeloma; Refractory Small Lymphocytic Lymphoma; t(14;16); t(4;14); T-Cell Prolymphocytic Leukemia; Waldenstrom Macroglobulinemia

  12. Fludarabine, cyclophosphamide and rituximab plus granulocyte macrophage colony-stimulating factor as frontline treatment for patients with chronic lymphocytic leukemia.

    PubMed

    Strati, Paolo; Ferrajoli, Alessandra; Lerner, Susan; O'Brien, Susan; Wierda, William; Keating, Michael J; Faderl, Stefan

    2014-04-01

    Fludarabine, cyclophosphamide and rituximab (FCR), the standard of care for the frontline treatment of patients with chronic lymphocytic leukemia (CLL), is associated with a high rate of neutropenia and infectious complications. Granulocyte macrophage colony-stimulating factor (GM-CSF) reduces myelosuppression and can potentiate rituximab activity. We conducted a clinical trial combining GM-CSF with FCR for frontline treatment of 60 patients with CLL. Eighty-six percent completed all six courses and 18% discontinued GM-CSF for toxicity: grade 3-4 neutropenia was observed in 30% of cycles, and severe infections in 16% of cases. The overall response rate was 100%. Both median event-free survival (EFS) and overall survival (OS) have not been reached. Longer EFS was associated with favorable cytogenetics. GM-CSF led to a lower frequency of infectious complications than in the historical FCR group, albeit similar EFS and OS.

  13. Common variation at 6p21.31 (BAK1) influences the risk of chronic lymphocytic leukemia

    PubMed Central

    Di Bernardo, Maria Chiara; Conde, Lucia; Broderick, Peter; McDonnell, Shannon K.; Goldin, Lynn R.; Croft, Naomi; Holroyd, Amy; Harris, Shelley; Riby, Jacques; Serie, Daniel J.; Kay, Neil E.; Call, Timothy G.; Bracci, Paige M.; Halperin, Eran; Lanasa, Mark C.; Cunningham, Julie M.; Leis, Jose F.; Morrison, Vicki A.; Spector, Logan G.; Vachon, Celine M.; Shanafelt, Tait D.; Strom, Sara S.; Camp, Nicola J.; Weinberg, J. Brice; Matutes, Estella; Caporaso, Neil E.; Wade, Rachel; Dyer, Martin J. S.; Dearden, Claire; Cerhan, James R.; Catovsky, Daniel

    2012-01-01

    We performed a meta-analysis of 3 genome-wide association studies to identify additional common variants influencing chronic lymphocytic leukemia (CLL) risk. The discovery phase was composed of genome-wide association study data from 1121 cases and 3745 controls. Replication analysis was performed in 861 cases and 2033 controls. We identified a novel CLL risk locus at 6p21.33 (rs210142; intronic to the BAK1 gene, BCL2 antagonist killer 1; P = 9.47 × 10−16). A strong relationship between risk genotype and reduced BAK1 expression was shown in lymphoblastoid cell lines. This finding provides additional support for polygenic inheritance to CLL and provides further insight into the biologic basis of disease development. PMID:22700719

  14. IgD cross-linking induces gene expression profiling changes and enhances apoptosis in chronic lymphocytic leukemia cells.

    PubMed

    Tavolaro, Simona; Peragine, Nadia; Chiaretti, Sabina; Ricciardi, Maria Rosaria; Raponi, Sara; Messina, Monica; Santangelo, Simona; Marinelli, Marilisa; Di Maio, Valeria; Mauro, Francesca Romana; Del Giudice, Ilaria; Foà, Robin; Guarini, Anna

    2013-04-01

    Gene profile and functional changes upon IgD cross-linking were evaluated in chronic lymphocytic leukemia (CLL). Microarrays highlighted responsiveness to IgD in all cases, independently of clinico-biological characteristics. Stimulated samples exhibited the down-regulation of transcripts of B-cell receptor signaling and cell-adhesion at 24h and the up-modulation of differentiation and apoptosis genes at 48 h. A significant increase in apoptosis upon ligation was also documented. Furthermore, comparison between IgD and IgM stimulation displayed a differential transcriptional/functional response. In conclusion, CLL respond to IgD displaying expression changes and cell-death enhancement, indicating the apoptosis induction via-IgD as an alternative approach for CLL management.

  15. Autoantigenic targets of B-cell receptors derived from chronic lymphocytic leukemias bind to and induce proliferation of leukemic cells.

    PubMed

    Zwick, Carsten; Fadle, Natalie; Regitz, Evi; Kemele, Maria; Stilgenbauer, Stephan; Bühler, Andreas; Pfreundschuh, Michael; Preuss, Klaus-Dieter

    2013-06-06

    Antigenic targets of the B-cell receptor (BCR) derived from malignant cells in chronic lymphocytic leukemia (CLL) might play a role in the pathogenesis of this neoplasm. We screened human tissue-derived protein macroarrays with antigen-binding fragments derived from 47 consecutive cases of CLL. An autoantigenic target was identified for 12/47 (25.5%) of the cases, with 3 autoantigens being the target of the BCRs from 2 patients each. Recombinantly expressed autoantigens bound specifically to the CLL cells from which the BCR used for the identification of the respective autoantigen was derived. Moreover, binding of the autoantigen to the respective leukemic cells induced a specific activation and proliferation of these cells. In conclusion, autoantigens are frequent targets of CLL-BCRs. Their specific binding to and induction of proliferation in the respective leukemic cells provide the most convincing evidence to date for the long-time hypothesized role of autoantigens in the pathogenesis of CLL.

  16. Targeting p53-deficient chronic lymphocytic leukemia cells in vitro and in vivo by ROS-mediated mechanism

    PubMed Central

    Liu, Jinyun; Chen, Gang; Pelicano, Helene; Liao, Jianwei; Huang, Jie; Feng, Li; Keating, Michael J.; Huang, Peng

    2016-01-01

    Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in Western countries. Loss of p53 function in CLL cells due to chromosome 17p deletion or p53 mutations often leads to a more malignant disease phenotype and is associated with drug resistance and poor clinical outcome. Thus, development of novel therapeutic strategies to effectively target CLL cells with p53 deficiency is clinically important. Here we showed that p53-null CLL cells were highly sensitive to ROS-mediated cell killing due to their intrinsic ROS stress. We further demonstrated that a natural compound phenethyl isothiocyanate (PEITC) was able to effectively kill CLL cells with loss of p53, even under the protection of stromal cells. In p53-defficient CLL cells, PEITC induced a rapid depletion of glutathione and a severe accumulation of ROS, leading to massive leukemia cell death in the stromal microenvironment. The drug-induced cell death was associated with a significant decrease of in MCL-1 survival molecule. We further showed that ROS-mediated cell death was the key mechanism by which PEITC induced cytotoxicity, since such cell death could be prevented by addition of antioxidant NAC. Importantly, in vivo study showed that PEITC was able to induce substantial leukemia cell death in mice. Treatment of CLL mice harboring TCL1-Tg:p53−/− genotype with PEITC significantly prolonged the median survival time of the animals. Our study identifies a vulnerability of p53-null CLL cells with high sensitivity to ROS-generating agents, and suggests that PEITC may potentially be useful for clinical treatment of CLL with 17p deletion and p53 mutations. PMID:27655686

  17. The first MCL-1-selective BH3 mimetics have therapeutic potential for chronic lymphocytic leukemia.

    PubMed

    Besbes, Samaher; Pocard, Marc; Mirshahi, Massoud; Billard, Christian

    2016-04-01

    Small-molecule BH3 mimetics are designed to mimic the BH3 domain of BH3-only BCL-2 family members which are antagonists of the prosurvival members (such as BCL-2, BCL-XL and MCL-1). The BH3 mimetics are intended to bind with high affinity to prosurvival proteins, in order to inhibit their functional activity and hence to induce apoptosis in cancer cells. Both navitoclax (BCL-2/BCL-XL antagonist) and ABT-199/venetoclax (BCL-2-selective inhibitor) have demonstrated therapeutic efficacy especially in chronic lymphocytic leukemia (CLL). However, these BH3 mimetics cannot antagonize the prosurvival protein MCL-1 that is overexpressed and involved in therapeutic resistance in CLL. Furthermore, until now, none of the reported small-molecule MCL-1 inhibitors bound to their target with high affinity. The first MCL-1-selective BH3 mimetics capable of high-affinity binding and inducing apoptosis in cancer cells through an on-target mechanism have just been identified. This discovery should advance the translational research to implement novel drugs in treating CLL.

  18. Atypical aleukemic presentation of large granular lymphocytic leukemia: a case report

    PubMed Central

    Bagacean, Cristina; Tempescul, Adrian; Patiu, Mariana; Fetica, Bogdan; Bumbea, Horia; Zdrenghea, Mihnea

    2017-01-01

    Large granular lymphocytic leukemia (LGLL) is a rare lymphoproliferative disorder of transformed natural killer or T-cells attributed to chronic exposure to the proinflammatory cytokine IL-15. Diagnosis of the majority of T-cell LGLL is established by documenting clonal large granular lymphocytes (LGLs) in peripheral blood, by morphology and immunophenotype. The proteasome inhibitor bortezomib is known to target molecular pathways downstream of the IL-15 receptor signaling and has been proposed as a therapy in these patients. We report an uncommon presentation of LGLL with chronic neutropenia lacking typical blood LGLs, which failed to respond to bortezomib but obtained a very good partial remission with a classical methotrexate regimen. PMID:28031720

  19. Outcomes for Patients with Chronic Lymphocytic Leukemia (CLL) and Acute Leukemia or Myelodysplastic Syndrome

    PubMed Central

    Tambaro, Francesco Paolo; Garcia-Manero, Guillermo; O’Brien, Susan M.; Faderl, Stefan H.; Ferrajoli, Alessandra; Burger, Jan A.; Pierce, Sherry; Wang, Xuemei; Do, Kim-Anh; Kantarjian, Hagop M.; Keating, Michael J.; Wierda, William G.

    2016-01-01

    Acute leukemia (AL) and myelodysplastic syndrome (MDS) are uncommon in CLL. We retrospectively identified 95 patients with CLL also diagnosed with AL (n=38) or MDS (n=57), either concurrently (n=5) or subsequent (n=90) to CLL diagnosis and report their outcomes. Median number of CLL treatments prior to AL and MDS was 2(0–9) and 1(0–8), respectively; the most common regimen was purine analogue combined with alkylating agent±CD20 mAb. Twelve had no prior CLL treatment. Among 38 with AL, 33 had AML, 3 had ALL (1Ph+), 1 had biphenotypic, and 1 had extramedullary (bladder) AML. Unfavorable AML karyotype was noted in 26, intermediate-risk in 7. There was no association between survival from AL and number of prior CLL regimens or karyotype. Expression of CD7 on blasts was associated with shorter survival. Among MDS cases, all IPSS were represented; karyotype was unfavorable in 36, intermediate in 6, and favorable in 12 patients; 10 experienced transformation to AML. Shorter survival from MDS correlated with higher-risk IPSS, poor-risk karyotype, and increased number of prior CLL treatments. Overall, outcomes for patients with CLL subsequently diagnosed with AL or MDS were poor; AL/MDS occurred without prior CLL treatment. Effective therapies for these patients are desperately needed. PMID:26290497

  20. Different spectra of recurrent gene mutations in subsets of chronic lymphocytic leukemia harboring stereotyped B-cell receptors

    PubMed Central

    Sutton, Lesley-Ann; Young, Emma; Baliakas, Panagiotis; Hadzidimitriou, Anastasia; Moysiadis, Theodoros; Plevova, Karla; Rossi, Davide; Kminkova, Jana; Stalika, Evangelia; Pedersen, Lone Bredo; Malcikova, Jitka; Agathangelidis, Andreas; Davis, Zadie; Mansouri, Larry; Scarfò, Lydia; Boudjoghra, Myriam; Navarro, Alba; Muggen, Alice F.; Yan, Xiao-Jie; Nguyen-Khac, Florence; Larrayoz, Marta; Panagiotidis, Panagiotis; Chiorazzi, Nicholas; Niemann, Carsten Utoft; Belessi, Chrysoula; Campo, Elias; Strefford, Jonathan C.; Langerak, Anton W.; Oscier, David; Gaidano, Gianluca; Pospisilova, Sarka; Davi, Frederic; Ghia, Paolo; Stamatopoulos, Kostas; Rosenquist, Richard

    2016-01-01

    We report on markedly different frequencies of genetic lesions within subsets of chronic lymphocytic leukemia patients carrying mutated or unmutated stereotyped B-cell receptor immunoglobulins in the largest cohort (n=565) studied for this purpose. By combining data on recurrent gene mutations (BIRC3, MYD88, NOTCH1, SF3B1 and TP53) and cytogenetic aberrations, we reveal a subset-biased acquisition of gene mutations. More specifically, the frequency of NOTCH1 mutations was found to be enriched in subsets expressing unmutated immunoglobulin genes, i.e. #1, #6, #8 and #59 (22–34%), often in association with trisomy 12, and was significantly different (P<0.001) to the frequency observed in subset #2 (4%, aggressive disease, variable somatic hypermutation status) and subset #4 (1%, indolent disease, mutated immunoglobulin genes). Interestingly, subsets harboring a high frequency of NOTCH1 mutations were found to carry few (if any) SF3B1 mutations. This starkly contrasts with subsets #2 and #3 where, despite their immunogenetic differences, SF3B1 mutations occurred in 45% and 46% of cases, respectively. In addition, mutations within TP53, whilst enriched in subset #1 (16%), were rare in subsets #2 and #8 (both 2%), despite all being clinically aggressive. All subsets were negative for MYD88 mutations, whereas BIRC3 mutations were infrequent. Collectively, this striking bias and skewed distribution of mutations and cytogenetic aberrations within specific chronic lymphocytic leukemia subsets implies that the mechanisms underlying clinical aggressiveness are not uniform, but rather support the existence of distinct genetic pathways of clonal evolution governed by a particular stereotyped B-cell receptor selecting a certain molecular lesion(s). PMID:27198719

  1. [Review of evidence of thalidomide and lenalidomide in different hematological diseases: chronic lymphocytic leukemia, primary amyloidosis, myelofibrosis and syndrome myelodysplastic].

    PubMed

    Jiménez Lozano, I; Juárez Jiménez, J C

    2013-01-01

    Lenalidomide is an immunomodulatory drug approved by the AEMPS and the EMA, in combination with dexamethasone, for the treatment of multiple myeloma in adult patients who have received at least one prior therapy. Moreover, it has recently been approved for the treatment of patients with transfusion-dependent anaemia due to low- or intermediate-1-risk myelodysplastic syndromes associated with an isolated deletion 5q cytogenetic abnormality when other therapeutic options are insufficient or inadequate. It has also shown to be active in other hematologic and no hematologic diseases. Growing evidence of its use entails a challenge when situating the drug in a cost-effective way to treat these diseases. On this article we review the available evidence on the use of lenalidomide in the second line treatment of patients with chronic lymphocytic leukemia, primary amyloidosis and primary myelofibrosis, and in the first line treatment of patients with myelodysplastic syndrome, and also the evidence of other immunomodulators. Different clinical practice guidelines and scientific evidence portals consider lenalidomide a valid alternative in the first-line treatment of patients with myelodysplastic syndromes, specially those with the deletion of 5q, and in second line for patients with chronic lymphocytic leukemia. However, the available evidence of lenalidomide in the treatment of patients with primary amyloidosis and primary myelofibrosis is limited, ant thus is not considered as the first choice treatment. In any case, the treatment of choice should consider the safety profile in each patient, the previous treatments that has received and the own therapeutic protocols of each center.

  2. Evidence-based mini-review: the role of alkylating agents in the initial treatment of chronic lymphocytic leukemia patients with the 11q deletion.

    PubMed

    Ding, Wei; Ferrajoli, Alessandra

    2010-01-01

    A 55-year-old man presented with fever, night sweats, and weight loss of about 20 lbs. in the prior 6 months. Physical examination revealed multiple cervical, axillary, and inguinal lymphadenopathy. The spleen was enlarged. A complete blood count revealed leukocytosis with absolute lymphocytosis: 30,000/μL. Peripheral blood-flow cytometric analysis showed a clonal lymphocyte population with immunophenotypes positive for CD5, CD20(dim), and monotypic kappa light chain. Fluorescence in situ hybridization (FISH) analysis revealed del(11q22.3), but negative for t(11:14). What should be used to treat his chronic lymphocytic leukemia (CLL) disease?

  3. Detection of t(12;14)(p13;q32) in a patient with IGH-CCND1 negative mantle cell lymphoma resembling ultra-high risk chronic lymphocytic leukemia.

    PubMed

    Miao, Yi; Wang, Rong; Fan, Lei; Qiu, Hairong; Wu, Yujie; Chen, Yaoyu; Xu, Wei; Li, Jianyong

    2015-01-01

    T(12;14)(p13;q32) is a rare recurrent chromosomal translocation, which has only been identified in a small subgroup of mantle cell lymphoma (MCL) without typical t(11;14)(q13;q32). This rearrangement causes aberrant over-expression of cyclin D2 (CCND2), which disrupts the normal cell cycle. Here we report a subtle case of MCL with t(12;14)(p13;q32) that was initially misdiagnosed as ultra-high risk chronic lymphocytic leukemia (CLL). A 60-year-old male patient presented with obvious leukocytosis and progressive weakness. Morphology of peripheral blood and immunophenotyping by flow cytometry pointed to a diagnosis of chronic lymphocytic leukemia. Fluorescence in situ hybridization (FISH) using IGH-CCND1 probe was negative for CCND1 abnormality, but demonstrated IGH breakapart signals. The initial diagnosis of CLL was established and the patient was treated with six courses of immunochemotherpy with fludarabine, cyclophosphamide and rituximab (FCR). Complete remission (CR) was achieved at the end of treatment, but disease relapsed quickly. The patient was transferred to our hospital, flow cytometry using additional markers showed that the clonal cells were CD200+(dim), CD148+(strong), and chromosome analysis revealed a complex karyotype, 47, XY, t(12;14)(p13;q32), +12, del(9p21), which indicated over-expression of CCND2, and immunostaining showed strong positivity of SOX11 further confirming the characteristics of CCND1-negtive MCL. The final diagnosis was revised to rare subtype of MCL with CCND2 translocation and intensive regimens were employed. This confusable MCL case illustrates the importance of cytogenetic analysis and clinicopathologic diagnosis of this rare category of MCL.

  4. Selective Anticancer Activity of Acacetin Against Chronic Lymphocytic Leukemia Using Both In Vivo and In Vitro Methods: Key Role of Oxidative Stress and Cancerous Mitochondria.

    PubMed

    Salimi, Ahmad; Roudkenar, Mehryar Habibi; Sadeghi, Leila; Mohseni, Alireza; Seydi, Enayatollah; Pirahmadi, Nahal; Pourahmad, Jalal

    2016-01-01

    The present study investigates the in vitro and in vivo effect of acacetin (4'-methoxy-5,7-dihydroxyflavone) on chronic lymphocytic leukemia (CLL) B-lymphocytes and mitochondria. CLL B-lymphocytes and healthy B-lymphocytes were obtained from CLL patients and healthy donors, respectively. Mitochondria were isolated from B-lymphocytes of both groups. Xenografts in severe combined immune deficient mice were used to examine the toxicity and anti CLL activity of acacetin. We evaluated and compared the mechanism of action of acacetin on CLL and healthy B-lymphocytes and their mitochondria. We have found that acacetin (10 μM) can selectively induce apoptosis on CLL B-lymphocyte (25% at 24 h) by directly targeting mitochondria, through increased reactive oxygen species (ROS) formation, MMP collapse, MPT, release of cytochrome c, caspase 3 activation, and finally apoptosis, while sparing normal healthy B-lymphocytes unaffected at similar concentrations. Besides, oral administration of acacetin showed a potent in vivo anticancer activity in CLL xenograft mouse models. Our in vivo findings indicate that acacetin accumulates and kills CLL B-lymphocyte in a rather selective way through targeting cancerous mitochondria and ROS formation, which ends in CLL therapy. Finally, we can recommend acacetin as a promising compound for further drug development assays for the CLL treatment.

  5. A non-invasive approach to monitor chronic lymphocytic leukemia engraftment in a xenograft mouse model using ultra-small superparamagnetic iron oxide-magnetic resonance imaging (USPIO-MRI).

    PubMed

    Valdora, Francesca; Cutrona, Giovanna; Matis, Serena; Morabito, Fortunato; Massucco, Carlotta; Emionite, Laura; Boccardo, Simona; Basso, Luca; Recchia, Anna Grazia; Salvi, Sandra; Rosa, Francesca; Gentile, Massimo; Ravina, Marco; Pace, Daniele; Castronovo, Angela; Cilli, Michele; Truini, Mauro; Calabrese, Massimo; Neri, Antonino; Neumaier, Carlo Emanuele; Fais, Franco; Baio, Gabriella; Ferrarini, Manlio

    2016-11-01

    Chronic lymphocytic leukemia (CLL) is the most prevalent leukemia among adults. Despite its indolent nature, CLL remains an incurable disease. Herein we aimed to monitor CLL disease engraftment and, progression/regression in a xenograft CLL mouse model using ultra-small superparamagnetic iron oxide-magnetic resonance imaging (USPIO-MRI). Spleen contrast enhancement, quantified as percentage change in signal intensity upon USPIO administration, demonstrated a difference due to a reduced USPIO uptake, in the spleens of mice injected with CLL cells (NSG-CLL, n=71) compared to controls (NSG-CTR, n=17). These differences were statistically significant both after 2 and 4weeks from CLL cells injection. In addition comparison of mice treated with rituximab with untreated controls for changes in spleen iron uptake confirmed that it is possible to monitor treatment efficacy in this mouse model of CLL using USPIO-enhanced MRI. Further applications could include the preclinical in vivo monitoring of new therapies and the clinical evaluation of CLL patients.

  6. Tumor antigen ROR1 targeted drug delivery mediated selective leukemic but not normal B cell cytotoxicity in chronic lymphocytic leukemia

    PubMed Central

    Mani, Rajeswaran; Mao, Yicheng; Frissora, Frank W.; Chiang, Chi-Ling; Wang, Jiang; Zhao, Yuan; Wu, Yun; Yu, Bo; Yan, Ribai; Mo, Xiaokui; Yu, Lianbo; Flynn, Joseph; Jones, Jeffrey; Andritsos, Leslie; Baskar, Sivasubramanian; Rader, Christoph; Phelps, Mitch A; Chen, Ching-Shih; Lee, Robert J.; Byrd, John C.; Lee, L. James; Muthusamy, Natarajan

    2014-01-01

    Selective cytotoxicity to cancer cells without compromising their normal counterparts pose a huge challenge for traditional drug design. Here we developed a tumor antigen targeted delivery of immunonanoparticle carrying a novel non-immunosuppressive FTY720 derivative OSU-2S with potent cytotoxicity against leukemic B cells. OSU-2S induces activation of protein phosphatase 2A, phosphorylation and nuclear translocation of SHP1S591 and deregulation of multiple cellular processes in chronic lymphocytic leukemia (CLL) resulting in potent cytotoxicity. To preclude OSU-2S mediated effects on these ubiquitous phosphatases in unintended cells and avoid potential adverse effects we developed a OSU-2S targeted delivery immunonanoparticles (2A2-OSU-2S-ILP), that mediated selective cytotoxicity of CLL but not normal B cells through targeting receptor tyrosine kinase ROR1 expressed in leukemic but not normal B cells. Developing a novel spontaneous CLL mouse model expressing human ROR1 (hROR1) in all leukemic B cells, we demonstrate the therapeutic benefit of enhanced survival with 2A2-OSU-2S-ILP in-vivo. The newly developed non-immunosuppressive OSU-2S, its delivery using human CLL directed immunonanoparticles and the novel transgenic mouse model of CLL that expresses hROR1 exclusively in leukemic B cell surface are highly innovative and can be applied to CLL and other ROR1+ malignancies including mantle cell lymphoma and acute lymphoblastic leukemia. PMID:24947019

  7. Progress in the treatment of elderly/unfit chronic lymphocytic leukemia patients: results of the German CLL-11 trial.

    PubMed

    Molica, Stefano

    2015-01-01

    Chronic lymphocytic leukemia (CLL) is the most prevalent type of leukemia and affects mostly the elderly. Chemoimmunotherapy with fludarabine, cyclophosphamide and rituximab is generally considered a standard treatment for younger fit patients with CLL. In a recent randomized Phase III study of patients with newly diagnosed CLL and coexisting conditions, obinutuzumab, a humanized anti-CD20 glycoengineered type 2 antibody, used in combination with chlorambucil, demonstrated significant improvement in progression-free survival and several other outcome parameters, in comparison to rituximab plus chlorambucil. Grade 3-4 infusion-related reactions and neutropenia occurred more frequently in patients who received obinutuzumab compared with those who received rituximab; however, the rate of serious infections was similar. Results of this trial clearly established that obinutuzumab in combination with chlorambucil represent the new first-line standard of treatment in this setting. A broad range of novel agents with different mechanisms of action have already proven their efficacy in CLL. New drugs targeting specific molecular features, such as ibrutinib, idelalisib or ABT-199, are being tested at present, and their advent is very likely to change the future treatment paradigm of CLL that relies today on chemoimmunotherapy for both fit and elderly/unfit patients.

  8. Hsp90 inhibition increases SOCS3 transcript and regulates migration and cell death in chronic lymphocytic leukemia

    PubMed Central

    Chen, Timothy L.; Gupta, Nikhil; Lehman, Amy; Ruppert, Amy S.; Yu, Lianbo; Oakes, Christopher C.; Claus, Rainer; Plass, Christoph; Maddocks, Kami J.; Andritsos, Leslie; Jones, Jeffery A.; Lucas, David M.; Johnson, Amy J.; Byrd, John C.; Hertlein, Erin

    2016-01-01

    Epigenetic or transcriptional silencing of important tumor suppressors has been described to contribute to cell survival and tumorigenesis in chronic lymphocytic leukemia (CLL). Using gene expression microarray analysis, we found that thousands of genes are repressed more than 2-fold in CLL compared to normal B cells; however therapeutic approaches to reverse this have been limited in CLL. Following treatment with the Hsp90 inhibitor 17-DMAG, a significant number of these repressed genes were significantly re-expressed. One of the genes significantly repressed in CLL and up-regulated by 17-DMAG was suppressor of cytokine signaling 3, (SOCS3). SOCS3 has been shown to be silenced in solid tumors as well as myeloid leukemia; however little is known about the regulation in CLL. We found that 17-DMAG induces expression of SOCS3 by via the activation of p38 signaling, and subsequently inhibits AKT and STAT3 phosphorylation resulting in downstream effects on cell migration and survival. We therefore suggest that SOCS3 is an important signaling protein in CLL, and Hsp90 inhibitors represent a novel approach to target transcriptional repression in B cell lymphoproliferative disorders which exhibit a substantial degree of gene repression. PMID:27107422

  9. Hsp90 inhibition increases SOCS3 transcript and regulates migration and cell death in chronic lymphocytic leukemia.

    PubMed

    Chen, Timothy L; Gupta, Nikhil; Lehman, Amy; Ruppert, Amy S; Yu, Lianbo; Oakes, Christopher C; Claus, Rainer; Plass, Christoph; Maddocks, Kami J; Andritsos, Leslie; Jones, Jeffery A; Lucas, David M; Johnson, Amy J; Byrd, John C; Hertlein, Erin

    2016-05-10

    Epigenetic or transcriptional silencing of important tumor suppressors has been described to contribute to cell survival and tumorigenesis in chronic lymphocytic leukemia (CLL). Using gene expression microarray analysis, we found that thousands of genes are repressed more than 2-fold in CLL compared to normal B cells; however therapeutic approaches to reverse this have been limited in CLL. Following treatment with the Hsp90 inhibitor 17-DMAG, a significant number of these repressed genes were significantly re-expressed. One of the genes significantly repressed in CLL and up-regulated by 17-DMAG was suppressor of cytokine signaling 3, (SOCS3). SOCS3 has been shown to be silenced in solid tumors as well as myeloid leukemia; however little is known about the regulation in CLL. We found that 17-DMAG induces expression of SOCS3 by via the activation of p38 signaling, and subsequently inhibits AKT and STAT3 phosphorylation resulting in downstream effects on cell migration and survival. We therefore suggest that SOCS3 is an important signaling protein in CLL, and Hsp90 inhibitors represent a novel approach to target transcriptional repression in B cell lymphoproliferative disorders which exhibit a substantial degree of gene repression.

  10. The isopeptidase inhibitor 2cPE triggers proteotoxic stress and ATM activation in chronic lymphocytic leukemia cells

    PubMed Central

    Tomasella, Andrea; Picco, Raffaella; Ciotti, Sonia; Sgorbissa, Andrea; Bianchi, Elisa; Manfredini, Rossella; Benedetti, Fabio; Trimarco, Valentina; Frezzato, Federica; Trentin, Livio; Semenzato, Gianpietro; Delia, Domenico; Brancolini, Claudio

    2016-01-01

    Relapse after treatment is a common and unresolved problem for patients suffering of the B-cell chronic lymphocytic leukemia (B-CLL). Here we investigated the ability of the isopeptidase inhibitor 2cPE to trigger apoptosis in leukemia cells in comparison with bortezomib, another inhibitor of the ubiquitin-proteasome system (UPS). Both inhibitors trigger apoptosis in CLL B cells and gene expression profiles studies denoted how a substantial part of genes up-regulated by these compounds are elements of adaptive responses, aimed to sustain cell survival. 2cPE treatment elicits the up-regulation of chaperones, proteasomal subunits and elements of the anti-oxidant response. Selective inhibition of these responses augments apoptosis in response to 2cPE treatment. We have also observed that the product of the ataxia telangiectasia mutated gene (ATM) is activated in 2cPE treated cells. Stimulation of ATM signaling is possibly dependent on the alteration of the redox homeostasis. Importantly ATM inhibition, mutations or down-modulation increase cell death in response to 2cPE. Overall this work suggests that 2cPE could offer new opportunities for the treatment of B-CLL. PMID:27259251

  11. Ionizing Radiation and Risk of Chronic Lymphocytic Leukemia in the 15-Country Study of Nuclear Industry Workers

    PubMed Central

    Vrijheid, Martine; Cardis, Elisabeth; Ashmore, Patrick; Auvinen, Anssi; Gilbert, Ethel; Habib, Rima R.; Malker, Hans; Muirhead, Colin R.; Richardson, David B.; Rogel, Agnes; Schubauer-Berigan, Mary; Tardy, Hélène; Telle-Lamberton, Maylis

    2014-01-01

    In contrast to other types of leukemia, chronic lymphocytic leukemia (CLL) has long been regarded as non-radiogenic, i.e. not caused by ionizing radiation. However, the justification for this view has been challenged. We therefore report on the relationship between CLL mortality and external ionizing radiation dose within the 15-country nuclear workers cohort study. The analyses included, in seven countries with CLL deaths, a total of 295,963 workers with more than 4.5 million person-years of follow-up and an average cumulative bone marrow dose of 15 mSv; there were 65 CLL deaths in this cohort. The relative risk (RR) at an occupational dose of 100 mSv compared to 0 mSv was 0.84 (95% CI 0.39, 1.48) under the assumption of a 10-year exposure lag. Analyses of longer lag periods showed little variation in the RR, but they included very small numbers of cases with relatively high doses. In conclusion, the largest nuclear workers cohort study to date finds little evidence for an association between low doses of external ionizing radiation and CLL mortality. This study had little power due to low doses, short follow-up periods, and uncertainties in CLL ascertainment from death certificates; an extended follow-up of the cohorts is merited and would ideally include incident cancer cases. PMID:18959468

  12. Bruton's tyrosine kinase inhibition increases BCL-2 dependence and enhances sensitivity to venetoclax in chronic lymphocytic leukemia.

    PubMed

    Deng, J; Isik, E; Fernandes, S M; Brown, J R; Letai, A; Davids, M S

    2017-02-14

    Although the BTK inhibitor ibrutinib has transformed the management of patients with chronic lymphocytic leukemia (CLL), it does not induce substantial apoptosis in vitro, and as such the mechanisms underlying its ability to kill CLL cells are not well understood. Acalabrutinib, a more specific BTK inhibitor now in development, also appears to be highly effective in CLL, but the connection of its mechanism with CLL cell death is also unclear. Using dynamic BH3 profiling, we analyzed alterations in the function of the mitochondrial apoptotic pathway induced by ibrutinib and acalabrutinib. We studied CLL patient samples treated ex vivo with both drugs, as well as primary samples from CLL patients on clinical trials of both drugs. We found that BTK inhibition enhances mitochondrial BCL-2 dependence without significantly altering overall mitochondrial priming. Enhancement of BCL-2 dependence was accompanied by an increase in the pro-apoptotic protein BIM. In contrast, treatment with the selective BCL-2 inhibitor venetoclax enhanced overall mitochondrial priming without increasing BCL-2 dependence. Pre-treatment of CLL cells with either BTK inhibitor, whether ex vivo or in vivo in patients, enhanced killing by venetoclax. Our data suggest that BTK inhibition enhances mitochondrial BCL-2 dependence, supporting the ongoing development of clinical trials combining BTK and BCL-2 inhibition.Leukemia advance online publication, 14 February 2017; doi:10.1038/leu.2017.32.

  13. What Are the Key Statistics about Acute Lymphocytic Leukemia?

    MedlinePlus

    ... Leukemia (ALL) What Are the Key Statistics About Acute Lymphocytic Leukemia? The American Cancer Society’s estimates for acute lymphocytic ... Acute Lymphocytic Leukemia Research and Treatment? More In Acute Lymphocytic Leukemia About Acute Lymphocytic Leukemia Causes, Risk Factors, and ...

  14. Immunoglobulin transcript sequence and somatic hypermutation computation from unselected RNA-seq reads in chronic lymphocytic leukemia

    PubMed Central

    Blachly, James S.; Ruppert, Amy S.; Zhao, Weiqiang; Long, Susan; Flynn, Joseph; Flinn, Ian; Jones, Jeffrey; Maddocks, Kami; Andritsos, Leslie; Ghia, Emanuela M.; Rassenti, Laura Z.; Kipps, Thomas J.; de la Chapelle, Albert; Byrd, John C.

    2015-01-01

    Immunoglobulins (Ig) are produced by B lymphocytes as secreted antibodies or as part of the B-cell receptor. There is tremendous diversity of potential Ig transcripts (>1 × 1012) as a result of hundreds of germ-line gene segments, random nucleotide incorporation during joining of gene segments into a complete transcript, and the process of somatic hypermutation at individual nucleotides. This recombination and mutation process takes place in the maturing B cell and is responsible for the diversity of potential epitope recognition. Cancers arising from mature B cells are characterized by clonal production of Ig heavy (IGH@) and light chain transcripts, although whether the sequence has undergone somatic hypermutation is dependent on the maturation stage at which the neoplastic clone arose. Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults and arises from a mature B cell with either mutated or unmutated IGH@ transcripts, the latter having worse prognosis and the assessment of which is routinely performed in the clinic. Currently, IGHV mutation status is assessed by Sanger sequencing and comparing the transcript to known germ-line genes. In this paper, we demonstrate that complete IGH@ V-D-J sequences can be computed from unselected RNA-seq reads with results equal or superior to the clinical procedure: in the only discordant case, the clinical transcript was out-of-frame. Therefore, a single RNA-seq assay can simultaneously yield gene expression profile, SNP and mutation information, as well as IGHV mutation status, and may one day be performed as a general test to capture multidimensional clinically relevant data in CLL. PMID:25787252

  15. The novel antisense Bcl-2 inhibitor SPC2996 causes rapid leukemic cell clearance and immune activation in chronic lymphocytic leukemia.

    PubMed

    Dürig, J; Dührsen, U; Klein-Hitpass, L; Worm, J; Hansen, J B Rode; Ørum, H; Wissenbach, M

    2011-04-01

    SPC2996 is a novel locked nucleic acid phosphorothioate antisense molecule targeting the mRNA of the Bcl-2 oncoprotein. We investigated the mechanism of action of SPC2996 and the basis for its clinically observed immunostimulatory effects in chronic lymphocytic leukemia (CLL). Patients with relapsed CLL were treated with a maximum of six doses of SPC2996 (0.2-6 mg/kg) in a multicenter phase I trial. Microarray-based transcriptional profiling of circulating CLL cells was carried out before and after the first infusion of SPC2996 in 18 patients. Statistically significant transcriptomic changes were observed at doses 4 mg/kg and occurred as early as 24 h after the first infusion of the oligonucleotide. SPC2996 induced the upregulation of 466 genes including a large number of immune response and apoptotic regulator molecules, which were enriched for Toll-like receptor response genes. Serum measurements confirmed the release of pro-inflammatory cytokines including chemokine (C-C motif) ligand 3 (macrophage inflammatory protein 1α) and tumor necrosis factor-α, thereby validating the in vivo transcriptomic data at the protein level. SPC2996 caused a 50% reduction of circulating lymphocytes in five of 18 (28%) patients, which was found to be independent of its immunostimulatory and anti-Bcl-2 effects.

  16. Feasibility of Telomerase-Specific Adoptive T-cell Therapy for B-cell Chronic Lymphocytic Leukemia and Solid Malignancies.

    PubMed

    Sandri, Sara; Bobisse, Sara; Moxley, Kelly; Lamolinara, Alessia; De Sanctis, Francesco; Boschi, Federico; Sbarbati, Andrea; Fracasso, Giulio; Ferrarini, Giovanna; Hendriks, Rudi W; Cavallini, Chiara; Scupoli, Maria Teresa; Sartoris, Silvia; Iezzi, Manuela; Nishimura, Michael I; Bronte, Vincenzo; Ugel, Stefano

    2016-05-01

    Telomerase (TERT) is overexpressed in 80% to 90% of primary tumors and contributes to sustaining the transformed phenotype. The identification of several TERT epitopes in tumor cells has elevated the status of TERT as a potential universal target for selective and broad adoptive immunotherapy. TERT-specific cytotoxic T lymphocytes (CTL) have been detected in the peripheral blood of B-cell chronic lymphocytic leukemia (B-CLL) patients, but display low functional avidity, which limits their clinical utility in adoptive cell transfer approaches. To overcome this key obstacle hindering effective immunotherapy, we isolated an HLA-A2-restricted T-cell receptor (TCR) with high avidity for human TERT from vaccinated HLA-A*0201 transgenic mice. Using several relevant humanized mouse models, we demonstrate that TCR-transduced T cells were able to control human B-CLL progression in vivo and limited tumor growth in several human, solid transplantable cancers. TERT-based adoptive immunotherapy selectively eliminated tumor cells, failed to trigger a self-MHC-restricted fratricide of T cells, and was associated with toxicity against mature granulocytes, but not toward human hematopoietic progenitors in humanized immune reconstituted mice. These data support the feasibility of TERT-based adoptive immunotherapy in clinical oncology, highlighting, for the first time, the possibility of utilizing a high-avidity TCR specific for human TERT. Cancer Res; 76(9); 2540-51. ©2016 AACR.

  17. Microenvironment interactions and B-cell receptor signaling in Chronic Lymphocytic Leukemia: implications for disease pathogenesis and treatment

    PubMed Central

    ten Hacken, Elisa; Burger, Jan A.

    2015-01-01

    Chronic Lymphocytic Leukemia (CLL) is a malignancy of mature B lymphocytes which are highly dependent on interactions with the tissue microenvironment for their survival and proliferation. Critical components of the microenvironment are monocyte-derived nurselike cells (NLCs), mesenchymal stromal cells, T cells and NK cells, which communicate with CLL cells through a complex network of adhesion molecules, chemokine receptors, tumor necrosis factor (TNF) family members, and soluble factors. (Auto-) antigens and/or autonomous mechanisms activate the B-cell receptor (BCR) and its downstream signaling cascade in secondary lymphatic tissues, playing a central pathogenetic role in CLL. Novel small molecule inhibitors, including the Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib and the phosphoinositide-3-kinase delta (PI3Kδ) inhibitor idelalisib, target BCR signaling and have become the most successful new therapeutics in this disease. We here review the cellular and molecular characteristics of CLL cells, and discuss the cellular components and key pathways involved in the cross-talk with their microenvironment. We also highlight the relevant novel treatment strategies, focusing on immunomodulatory agents and BCR signaling inhibitors and how these treatments disrupt CLL-microenvironment interactions. PMID:26193078

  18. Biological analysis of chronic lymphocytic leukemia: integration of mRNA and microRNA expression profiles.

    PubMed

    Dong, L; Bi, K H; Huang, N; Chen, C Y

    2016-01-08

    Chronic lymphocytic leukemia (CLL) is a disease that involves progressive accumulation of nonfunctioning lymphocytes and has a low cure rate. There is an urgent requirement to determine the molecular mechanism underlying this disease in order to improve the early diagnosis and treatment of CLL. In this study, genes differentially expressed between CLL samples and age-matched controls were identified using microRNA (miRNA) and mRNA expression profiles. Differentially expressed (DE) miRNA targets were predicted by combining five algorithms. Common genes were obtained on overlapping the DE mRNA and DE miRNA targets. Then, network and module analyses were performed. A total of 239 miRNA targets were predicted and 357 DE mRNAs were obtained. On intersecting miRNA targets and DE mRNAs, 33 common genes were obtained. The protein-protein interaction network and module analysis identified several crucial genes and modules that might be associated with the development of CLL. These DE mRNAs were significantly enriched in the hematopoietic cell lineage (P = 2.58E-4), mitogen-activated protein kinase signaling pathway (P = 0.0025), and leukocyte transendothelial migration pathway (P = 0.0026). Thus, we conducted biological analysis on integration of DE mRNAs and DE miRNAs in CLL, determined gene expression patterns, and screened out several important genes that might be related to CLL.

  19. CD160 signaling mediates PI3K-dependent survival and growth signals in chronic lymphocytic leukemia

    PubMed Central

    Liu, Feng-Ting; Giustiniani, Jerome; Farren, Timothy; Jia, Li; Bensussan, Armand; Gribben, John G.

    2010-01-01

    B-cell chronic lymphocytic leukemia (CLL) expresses CD160, a glycosylphosphatidylinositol-linked receptor found on normal natural killer (NK) and T cells, but not B cells. CD160 is a multifunctional molecule in normal lymphocytes, but its role in CLL biology is unknown. In vitro, CLL cells undergo rapid spontaneous apoptosis, which CD160 activation protected against—mean cell viability increased from 67% to 79% (P < .001). This was associated with up-regulation of Bcl-2, Bcl-xL, and Mcl-1, but not Bax. As expected from these changes in Bcl-2/Bax and Bcl-xL/Bax ratios, CD160 triggering reduced mitochondrial membrane potential collapse and cytochrome c release. CD160 stimulation also induced DNA synthesis, cell cycle progression, and proliferation. B-cell antigen receptor (BCR)–induced CLL proliferation was generally greater than with CD160, but marked variation was seen. Both BCR and CD160 signaling led to CLL secretion of interleukin-6 (IL-6) and IL-8, although CD160 induced greater increases of IL-6 (51-fold) and IL-8 (15-fold). Survival and activation signals mediated by CD160 showed dose-dependent suppression by phosphoinositide-3 kinase (PI3K) inhibitors. Thus, in vitro, CLL cells can use the CD160 pathway for survival and activation, mimicking CD160 signaling in normal NK and CD8+ T cells. Establishing the pathophysiologic relevance of these findings may reveal new therapeutic targets. PMID:20164468

  20. Polymer-coated surface enhanced Raman scattering (SERS) gold nanoparticles for multiplexed labeling of chronic lymphocytic leukemia cells

    NASA Astrophysics Data System (ADS)

    MacLaughlin, Christina M.; Parker, Edward P. K.; Walker, Gilbert C.; Wang, Chen

    2012-01-01

    The ease and flexibility of functionalization and inherent light scattering properties of plasmonic nanoparticles make them suitable contrast agents for measurement of cell surface markers. Immunophenotyping of lymphoproliferative disorders is traditionally undertaken using fluorescence detection methods which have a number of limitations. Herein, surface-enhanced Raman scattering (SERS) gold nanoparticles conjugated to monoclonal antibodies are used for the selective targeting of CD molecules on the surface of chronic lymphocytic leukemia (CLL) cells. Raman-active reporters were physisorbed on to the surface of 60 nm spherical Au nanoparticles, the particles were coated with 5kDa polyethylene glycol (PEG) including functionalities for conjugation to monoclonal IgG1 antibodies. A novel method for quantifying the number of antibodies bound to SERS probes on an individual basis as opposed to obtaining averages from solution was demonstrated using metal dots in transmission electron microscopy (TEM). The specificity of the interaction between SERS probes and surface CD molecules of CLL cells was assessed using Raman spectroscopy and dark field microscopy. An in-depth study of SERS probe targeting to B lymphocyte marker CD20 was undertaken, and proof-of-concept targeting using different SERS nanoparticle dyes specific for cell surface CD19, CD45 and CD5 demonstrated using SERS spectroscopy.

  1. Vascular Endothelial Growth Factor A (VEGFA) Gene Polymorphisms Have an Impact on Survival in a Subgroup of Indolent Patients with Chronic Lymphocytic Leukemia

    PubMed Central

    Lozano-Santos, Carol; Martinez-Velasquez, Jimena; Fernandez-Cuevas, Belen; Polo, Natividad; Navarro, Belen; Millan, Isabel; Garcia, Jose Miguel; Collado, Rosa; Sanchez-Godoy, Pedro; Carbonell, Felix; Garcia-Vela, Jose Antonio

    2014-01-01

    Vascular endothelial growth factor (VEGF)-mediated angiogenesis contributes to the pathogenesis of B-cell chronic lymphocytic leukaemia (CLL). We investigated the impact of VEGFA gene diversity on the clinical outcome of patients with this disease. A VEGFA haplotype conformed by positions rs699947 (–1540C>A), rs833061 (–460T>C) and rs2010963 (405C>G) and two additional single-nucleotide polymorphisms (SNPs), rs3025039 (936C>T) and rs25648 (1032C>T), were analysed in 239 patients at the time of their CLL diagnosis. Here, we showed that homozygosity for rs699947/rs833061/rs2010963 ACG haplotype (ACG+/+ genotype) correlated with a reduced survival in CLL patients (ACG+/+ vs other genotypes: HR = 2.3, p = 0.002; recessive model). In multivariate analysis, the ACG+/+ genotype was identified as a novel independent prognostic factor (HR = 2.1, p = 0.005). Moreover, ACG homozygosity subdivided patients with CLL with otherwise indolent parameters into prognostic subgroups with different outcomes. Specifically, patients carrying the ACG+/+ genotype with mutated IgVH, very low and low-risk cytogenetics, initial clinical stage, CD38 negative status or early age at diagnosis showed a shorter survival (ACG+/+ vs other genotypes: HR = 3.5, p = 0.035; HR = 3.4, p = 0.001; HR = 2.2, p = 0.035; HR = 3.4, p = 0.0001 and HR = 3.1, p = 0.009, respectively). In conclusion, VEGFA ACG+/+ genotype confers an adverse effect in overall survival in CLL patients with an indolent course of the disease. These observations support the biological and prognostic implications of VEGFA genetics in CLL. PMID:24971577

  2. Hsa-miR-15a and Hsa-miR-16-1 Expression Is Not Related to Proliferation Centers Abundance and Other Prognostic Factors in Chronic Lymphocytic Leukemia

    PubMed Central

    Agostinelli, Claudio; Righi, Simona; Laginestra, Maria Antonella; Gazzola, Anna; Mannu, Claudia; Cuneo, Antonio; Pileri, Stefano

    2013-01-01

    Chronic lymphocytic leukemia/small lymph