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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. 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

  5. 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.

  6. Bendamustine Plus Alemtuzumab for Refractory Chronic Lymphocytic Leukemia (CLL)

    ClinicalTrials.gov

    2013-08-20

    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

  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

    2017-04-24

    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. 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

  16. 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 ...

  17. 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.

  18. 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.

  19. 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.

  20. A case of SRSF2 mutation in chronic lymphocytic leukemia.

    PubMed

    Garza, Eduardo; Del Poeta, Giovanni; Martínez-Losada, Carmen; Catalano, Gianfranco; Borgia, Loredana; Piredda, Maria Liliana; Fabiani, Emiliano; Gattei, Valter; Lo-Coco, Francesco; Noguera, Nélida I

    2016-01-01

    Chronic lymphocytic leukemia (CLL) is characterized by extremely variable clinical course indicating substantial differences in the biology of the disease. Molecular characterization provides new insights useful for treatment decision making. We report on a patient diagnosed with CLL, whose disease was characterized by episodes of rapid progression and disease stabilization, and in which a SRSF2 gene mutation was identified in the absence of other commonly known mutations of CLL. To the best of our knowledge this is the first case of SRSF2 gene mutation ever reported in CLL.

  1. 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. ...

  2. 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

  3. [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.

  4. Cholesterol Homeostasis in Isolated Lymphocytes: a Differential Correlation Between Male Control and Chronic Lymphocytic Leukemia Subjects

    PubMed Central

    Sankanagoudar, Shrimanjunath; Singh, Govind; Mahapatra, Manaranjan; Kumar, Lalit; Chandra, Nimai Chand

    2017-01-01

    Background: This study was performed to investigate any association between cellular cholesterol homeostasis and chronic lymphocytic leukemia (CLL). CLL is characterized primarily by an abnormal accumulation of neoplastic B cells in the blood, bone marrow, lymph nodes and spleen. Methods: Men aged >50 years participated in this study. Enzyme-based plasma lipid profile estimations, peripheral blood lymphocyte isolation, lysate preparations, SDS-PAGE, western blotting, dil-LDL uptake and ultracentrifugation were employed. Results: Our study demonstrated hypocholesterolemia in lymphocytic leukemia in addition to hyper-expression of LDLRs in leukemic lymphocytes. Breakdown of intracellular cholesterol homeostasis and failure to maintain the feedback mechanism normally processed by the transcription factor SREBP-2 in the cytoplasm was apparent. The presence of cholesterol in the nucleus was noted in leukemic lymphocytes. A comparison of cholesterol homeostasis between healthy controls and CLL subjects showed that cholesterol may contribute to lymphocytic leukemia. While plasma cholesterol levels decreased (p < 0.0005), hyper-expression of LDLR (p=0.0001), SREBP-2 (transcription factor of LDLR) (p=0.0001) and PBR (nuclear cholesterol channel protein) (p=0.016) was observed in lymphocytes isolated from CLL subjects in association with a significant increase in intracellular cholesterol in the nuclear (p=0.036) and cytoplasmic (p=0.004) compartments. Conclusion: This study provided insights into cholesterol homeostasis in CLL subjects regarding LDLR, SREBP-2 and PBR. Cholesterol may enter the nucleus through highly expressed PBR and may be involved in development of leukemia by influencing cell cycle mechanisms in the lymphocytes of CLL subjects. PMID:28240002

  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. Tositumomab and Iodine I 131 Tositumomab in Treating Patients With Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma in First Remission

    ClinicalTrials.gov

    2015-08-04

    Lymphoid Leukemia in Remission; Stage I Chronic Lymphocytic Leukemia; 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

  7. 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.

  8. 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

  9. Chronic lymphocytic leukemia (CLL)

    MedlinePlus

    ... CLL, unless you have: A high-risk or aggressive (grows quickly) type of CLL Infections that keep ... to severe Other cancers, including a much more aggressive lymphoma (Richter's transformation) Side effects of chemotherapy

  10. 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.

  11. 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.

  12. A role for oleoylethanolamide in chronic lymphocytic leukemia.

    PubMed

    Masoodi, M; Lee, E; Eiden, M; Bahlo, A; Shi, Y; Ceddia, R B; Baccei, C; Prasit, P; Spaner, D E

    2014-07-01

    Oleoylethanolamide (OEA) is a bioactive lipid that stimulates nuclear and G protein-coupled receptors and regulates appetite and fat metabolism. It has not previously been shown to have a role in cancer. However, a mass spectrometry-based lipidomics platform revealed the presence of high amounts of OEA in the plasma of chronic lymphocytic leukemia (CLL) patients compared with normal donors. CLL cells produced OEA and the magnitude of plasma OEA levels was related directly to the circulating leukemic cell number. OEA from CLL cells was increased by URB-597, an inhibitor of fatty acid amide hydrolase (FAAH), and decreased by inflammatory mediators that downregulate expression of N-acylphosphatidylethanolamine-specific phospholipase D (NAPE-PLD). These enzymes degrade and synthesize OEA, respectively. Nonphysiologic doses of OEA prevented spontaneous apoptosis of CLL cells in a receptor-independent manner that was mimicked by its free fatty acid (FFA) derivative oleate. However, OEA-containing supernatants from CLL cells induced lipolysis in adipocytes, lipid products from adipocytes protected CLL cells from cytotoxic chemotherapy, and increased levels of FFAs were found in CLL plasma that correlated with OEA. We suggest OEA is a lipolytic factor produced by CLL cells to fuel their growth with a potential role in drug resistance and cancer cachexia.

  13. 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

  14. 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

  15. Coexistence of chronic lymphocytic leukemia and polycythemia vera: a case report and review of the literature.

    PubMed

    Korkmaz, Serdal; Kulakoglu, Sinan; Gorkem, Hasan; Aygun, Bilal; Cetinkaya, Ali

    2016-01-01

    Polycythemia vera is a Philadelphia chromosome-negative myeloproliferative neoplasm. Chronic lymphocytic leukemia is a monoclonal expansion of a CD5+ CD19+ B lymphocytes. Chronic myeloproliferative neoplasms may coexist with indolent B-cell malignant lymphomas of various types. The association of chronic lymphocytic leukemia with polycythemia vera is a rare event with only a few cases of coexistence ever reported. We report a 56-year-old man in whom these two disorders were diagnosed concomitantly. Possible etiopathogenic relationships between both disorders are discussed in this case report. 6.

  16. 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

  17. 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.

  18. 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

  19. 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.

  20. 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

  1. 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.

  2. Vorinostat, Fludarabine Phosphate, Cyclophosphamide, and Rituximab in Treating Patients With Previously Untreated Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

    ClinicalTrials.gov

    2017-02-21

    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

  3. Chronic lymphocytic leukemia: a clinical and molecular heterogenous disease.

    PubMed

    Rodríguez-Vicente, Ana E; Díaz, Marcos González; Hernández-Rivas, Jesús M

    2013-03-01

    The clinical heterogeneity that characterizes chronic lymphocytic leukemia (CLL), with survival times ranging from months to decades, reflects its biological diversity. Our understanding of the biology of CLL has helped us identify several markers of prognostic significance, by which CLL can be differentiated into several distinct diseases. The presence of specific chromosomal abnormalities is a prognostic indicator of disease progression and survival. Conventional cytogenetic analyses have revealed chromosomal aberrations in 40-50% of patients, but the detection of abnormalities is limited by the low mitotic activity of CLL cells. Metaphase analysis has recently undergone a "revival" because the metaphase yield has been improved by stimulation of CLL cells with alternative methods. Fluorescence in situ hybridization identifies chromosomal changes in approximately 80% of patients with CLL, and comparative genomic hybridization using high-density arrays (i.e., array comparative genomic hybridization [aCGH]) enables high-resolution genome-wide scanning for detecting copy number alterations in a single hybridization. The mutational status of the immunoglobulin heavy chain variable (IGHV) genes identifies two subsets of CLL with different outcomes. Unfortunately, the determination of IGHV mutation status may not be practical in all laboratories, and for this reason characteristics that are correlated with IGHV mutation status are needed-zeta-chain associated (TCR) protein kinase 70 kDa (ZAP-70) being that most commonly used currently in routine clinical practice. Whole genome sequencing has offered new insights into the mutational status of the disease, highlighting the role of several genes previously unrelated to CLL. Of these, NOTCH1 and SF3B1 are the most frequently mutated genes that predict poor prognosis. MicroRNA alterations are also involved in the initiation and progression of CLL, and the expression levels of some microRNAs correlate with previously

  4. [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.

  5. 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.

  6. 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

  7. 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

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

    ClinicalTrials.gov

    2017-09-04

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

  9. 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.

  10. Presentation of Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma in a Warthin Tumor: Case Report and Literature Review.

    PubMed

    Jawad, Hadeel; McCarthy, Peter; O'Leary, Gerard; Heffron, Cynthia C

    2017-10-01

    Warthin tumor is the second most common salivary gland neoplasm. It occurs more commonly in males than in females. Malignant transformation in Warthin tumor is a rare but well-recognized phenomenon; however, the development or presentation of lymphoma in a Warthin tumor is rare. An 80-year-old man presented with painless mass of the right parotid gland of 2 years duration with recent ulceration of the overlying skin and right cervical lymphadenopathy underwent a surgical resection of parotid mass and biopsy of the periglandular lymph nodes. The histological diagnosis was malignant lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma, present within the stroma of a Warthin tumor, and also present within the adjacent lymph node. This case is the third reported case describing a collision of Warthin tumor and chronic lymphocytic leukemia/small lymphocytic lymphoma. It also emphasizes the importance of careful examination of the lymphoid stroma of these tumors.

  11. Legionella feeleii Serotype 2 Pneumonia in a Man with Chronic Lymphocytic Leukemia: a Challenging Diagnosis ▿

    PubMed Central

    Siegel, Marc O.; Fedorko, Daniel P.; Drake, Steven K.; Calhoun, Leslie B.; Holland, Steven M.

    2010-01-01

    Legionella feeleii has rarely been reported as causing pneumonia in patients with hematologic malignancies. We present a case of Legionella feeleii serotype 2 pneumonia with empyema in a man with chronic lymphocytic leukemia and describe the methods of identifying this organism using both standard methods and newer diagnostic techniques. PMID:20357216

  12. Legionella feeleii serotype 2 pneumonia in a man with chronic lymphocytic leukemia: a challenging diagnosis.

    PubMed

    Siegel, Marc O; Fedorko, Daniel P; Drake, Steven K; Calhoun, Leslie B; Holland, Steven M

    2010-06-01

    Legionella feeleii has rarely been reported as causing pneumonia in patients with hematologic malignancies. We present a case of Legionella feeleii serotype 2 pneumonia with empyema in a man with chronic lymphocytic leukemia and describe the methods of identifying this organism using both standard methods and newer diagnostic techniques.

  13. 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.

  14. 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.

  15. 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.

  16. 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.

  17. CD38 and chronic lymphocytic leukemia: a decade later

    PubMed Central

    Deaglio, Silvia; Damle, Rajendra; Cutrona, Giovanna; Ferrarini, Manlio; Chiorazzi, Nicholas

    2011-01-01

    This review highlights a decade of investigations into the role of CD38 in CLL. CD38 is accepted as a dependable marker of unfavorable prognosis and as an indicator of activation and proliferation of cells when tested. Leukemic clones with higher numbers of CD38+ cells are more responsive to BCR signaling and are characterized by enhanced migration. In vitro activation through CD38 drives CLL proliferation and chemotaxis via a signaling pathway that includes ZAP-70 and ERK1/2. Finally, CD38 is under a polymorphic transcriptional control after external signals. Consequently, CD38 appears to be a global molecular bridge to the environment, promoting survival/proliferation over apoptosis. Together, this evidence contributes to the current view of CLL as a chronic disease in which the host's microenvironment promotes leukemic cell growth and also controls the sequential acquisition and accumulation of genetic alterations. This view relies on the existence of a set of surface molecules, including CD38, which support proliferation and survival of B cells on their way to and after neoplastic transformation. The second decade of studies on CD38 in CLL will tell if the molecule is an effective target for antibody-mediated therapy in this currently incurable leukemia. PMID:21765022

  18. 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.

  19. 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

  20. 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

  1. 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.

  2. 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.

  3. Monoclonal Antibody Therapy in Treating Patients With Chronic Lymphocytic Leukemia, Lymphocytic Lymphoma, Acute Lymphoblastic Leukemia, or Acute Myeloid Leukemia

    ClinicalTrials.gov

    2013-06-03

    Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Nodal Marginal Zone B-cell Lymphoma; Noncontiguous Stage II Marginal Zone Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Marginal Zone Lymphoma; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Splenic Marginal Zone Lymphoma; Stage III Marginal Zone Lymphoma; Stage III Small Lymphocytic Lymphoma; Stage IV Marginal Zone Lymphoma; Stage IV Small Lymphocytic Lymphoma

  4. 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.

  5. 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

  6. Apoptosis inducers in chronic lymphocytic leukemia

    PubMed Central

    Billard, Christian

    2014-01-01

    Chronic lymphocytic leukemia (CLL) is characterized by a typical defect in apoptosis and is still an incurable disease. Numerous apoptosis inducers have been described. These synthetic compounds and natural products (mainly derived from plants) display antileukemic properties in vitro and in vivo and some have even been tested in the clinic in CLL. They act through several different mechanisms. Most of them involve proteins of the Bcl-2 family, which are the key regulators in triggering the mitochondrial pathway of caspase-dependent apoptosis. Thus, the Mcl-1/Noxa axis appeared as a target. Here I overview natural and synthetic apoptosis inducers and their mechanisms of action in CLL cells. Opportunities for developing novel, apoptosis-based therapeutics are presented. PMID:24525395

  7. 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

  8. 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

  9. 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.

  10. 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.

  11. 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

  12. 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.

  13. 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.

  14. 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

  15. 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.

  16. 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

  17. 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

  18. 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

  19. 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.

  20. 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

  1. 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

  2. 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

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. 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

  8. 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).

  9. Diagnostic problems among chronic lymphocytic leukemia and other indolent B-cell leukemias in a Japanese population.

    PubMed

    Isobe, Yasushi; Tomomatsu, Junichi; Tsukune, Yutaka; Tsukada, Nobuhiro; Sasaki, Makoto; Sugimoto, Koichi; Komatsu, Norio

    2012-01-01

    Japanese chronic lymphocytic leukemia (CLL) provides a diagnostic dilemma due to the low incidence and the heterogeneity shown in its morphology and immunophenotype. We clarified the diagnostic problems in Japanese CLL through our retrospective observation. Between 2006 and 2011, we found a total of 48 cases with CLL and other indolent B-cell leukemias. We made a diagnosis of true CLL based on clinical, laboratory, immunophenotypic and cytogenetic data. Among the 48 cases, only 28 cases (58.3%) were diagnosed with true CLL. Morphologic evaluation using a forced-air dried preparation alone is not helpful to distinguish CLL from other indolent B-cell leukemias, including hairy cell leukemia, mantle cell lymphoma, lymphoplasmacytic lymphoma, and splenic marginal zone lymphoma. CLL immunophenotypic score should be more strictly applied in Japan than in Western countries. Fluorescence in situ hybridization for CCND1/IGH, the presence of leukocytosis and lymphadenopathy at diagnosis, and the morphological evaluation using naturally air dried preparations are important clues to make a correct diagnosis of Japanese CLL.

  10. 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

  11. 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.

  12. 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.

  13. A Genomic Approach to Improve Prognosis and Predict Therapeutic Response in Chronic Lymphocytic Leukemia

    PubMed Central

    Friedman, Daphne R.; Weinberg, J. Brice; Barry, William T.; Goodman, Barbara K.; Volkheimer, Alicia D.; Bond, Karen M.; Chen, Youwei; Jiang, Ning; Moore, Joseph O.; Gockerman, Jon P.; Diehl, Louis F.; Decastro, Carlos M.; Potti, Anil; Nevins, Joseph R.

    2009-01-01

    Purpose Chronic lymphocytic leukemia (CLL) is a B-cell malignancy characterized by a variable clinical course. Several parameters have prognostic capabilities but are associated with altered response to therapy in only a small subset of patients. Experimental Design We used gene expression profiling methods to generate predictors of therapy response and prognosis. Genomic signatures that reflect progressive disease and responses to chemotherapy or chemo-immunotherapy were created using cancer cell lines and patient leukemia cell samples. We validated and applied these three signatures to independent clinical data from four cohorts representing a total of 301 CLL patients. Results A genomic signature of prognosis created from patient leukemic cell gene expression data coupled with clinical parameters significantly differentiated patients with stable disease from those with progressive disease in the training dataset. The progression signature was validated in two independent datasets, demonstrating a capacity to accurately identify patients at risk for progressive disease. In addition, genomic signatures that predict response to chlorambucil or pentostatin, cyclophosphamide, and rituximab were generated and could accurately distinguish responding and non-responding CLL patients. Conclusions Thus, microarray analysis of CLL lymphocytes can be used to refine prognosis and predict response to different therapies. These results have implications for standard and investigational therapeutics in CLL patients. PMID:19861443

  14. Chronic lymphocytic leukemia/small lymphocytic lymphoma involving the aortic valve.

    PubMed

    Chisté, Marcela; Vrotsos, Elena; Zamora, Carlos; Martinez, Antonio

    2013-06-01

    Chronic lymphocytic leukemia/small lymphocytic lymphoma is a neoplasm composed of monomorphic small B lymphocytes in the peripheral blood, bone marrow, spleen, and lymph nodes, forming proliferation centers in tissue infiltrates (Muller-Hermelink HK, Montserrat E, Catovsky D, et al. Chronic lymphocytic leukaemia/small lymphocytic lymphoma, in Swerdlow SH (ed). WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France, International Agency for Research on Cancer, 2008, pp. 180-182). We report a case of a 77-year-old man with a medical history of chronic lymphocytic leukemia who presented with worsening chest pain over 8 weeks. Imaging studies revealed severe aortic stenosis and moderate mitral regurgitation. He subsequently underwent minimally invasive aortic valve replacement and mitral repair at our institution. Grossly, the specimen consisted of a trileaflet valve with multiple yellow-white focally hemorrhagic and calcified nodules over its surface. Histologically, a lymphocytic infiltrate composed of monotonous small cells with scant cytoplasm was seen as well as calcification and fibrosis. Immunohistochemical stains were positive for CD20, PAX5, CD5, and CD23. To our knowledge, this is the first reported case of an immunohistochemically documented chronic lymphocytic leukemia/small lymphocytic lymphoma to involve a cardiac valve. Copyright © 2013 Elsevier Inc. All rights reserved.

  15. 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.

  16. 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.

  17. Identification of Therapeutic Candidates for Chronic Lymphocytic Leukemia from a Library of Approved Drugs

    PubMed Central

    Shen, Min; Zhang, Yaqin; Saba, Nakhle; Austin, Christopher P.; Wiestner, Adrian; Auld, Douglas S.

    2013-01-01

    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. In this study, we used a luminescent cell viability assay based on ATP levels to find compounds that were potent and efficacious in killing CLL cells. We employed an in-house process of quantitative high throughput screening (qHTS) to assess 8 concentrations of each member of a 2,816 compound library (including FDA-approved drugs and those known to be bio-active from commercial suppliers). Using qHTS we generated potency values on each compound in lymphocytes donated from each of six individuals with CLL and five unaffected individuals. We found 102 compounds efficacious against cells from all six individuals with CLL (“consensus” drugs) with five of these showing low or no activity on lymphocytes from a majority of normal donors, suggesting some degree of specificity for the leukemic cells. To our knowledge, this is the first study to screen a drug library against primary CLL cells to identify candidate agents for anti-cancer therapy. The results presented here offer possibilities for the development of novel drug candidates for therapeutic uses to treat CLL and other diseases. PMID:24073257

  18. 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.

  19. 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).

  20. 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.

  1. 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

  2. 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.

  3. 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.

  4. The Spectrum of Kidney Pathology in B-Cell Chronic Lymphocytic Leukemia / Small Lymphocytic Lymphoma: A 25-Year Multicenter Experience

    PubMed Central

    Poitou-Verkinder, Anne-Laure; Francois, Arnaud; Drieux, Fanny; Lepretre, Stéphane; Legallicier, Bruno; Moulin, Bruno; Godin, Michel; Guerrot, Dominique

    2015-01-01

    Background Chronic lymphocytic leukemia and small lymphocytic lymphoma are 2 different presentations of the most common B-cell neoplasm in western countries (CLL/SLL). In this disease, kidney involvement is usually silent, and is rarely reported in the literature. This study provides a clinicopathological analysis of all-cause kidney disease in CLL/SLL patients. Methods Fifteen CLL/SLL patients with kidney biopsy were identified retrospectively. Demographic, clinical, pathological and laboratory data were assessed at biopsy, and during follow-up. Results At biopsy 11 patients presented impaired renal function, 7 patients nephrotic syndrome, 6 patients dysproteinemia, and 3 patients cryoglobulinemia. Kidney pathology revealed CLL/SLL-specific monoclonal infiltrate in 10 biopsies, glomerulopathy in 9 biopsies (5 membranoproliferative glomerulonephritis, 2 minimal change disease, 1 glomerulonephritis with organized microtubular monoclonal immunoglobulin deposits, 1 AHL amyloidosis). Five patients presented interstitial granulomas attributed to CLL/SLL. After treatment of the hematological disease, improvement of renal function was observed in 7/11 patients, and remission of nephrotic syndrome in 5/7 patients. During follow-up, aggravation of the kidney disease systematically occurred in the absence of favorable response to hematological treatment. Conclusions A broad spectrum of kidney diseases is associated with CLL/SLL. In this setting, kidney biopsy can provide important information for diagnosis and therapeutic guidance. PMID:25811382

  5. Expression and function of the TL1A/DR3 axis in chronic lymphocytic leukemia

    PubMed Central

    Cavallini, Chiara; Lovato, Ornella; Bertolaso, Anna; Zoratti, Elisa; Malpeli, Giorgio; Mimiola, Elda; Tinelli, Martina; Aprili, Fiorenza; Tecchio, Cristina; Perbellini, Omar; Scarpa, Aldo; Zamò, Alberto; Cassatella, Marco Antonio; Pizzolo, Giovanni; Scupoli, Maria Teresa

    2015-01-01

    TNF-like ligand 1A (TL1A) and its unique receptor death receptor 3 (DR3) acts as broad T-cell costimulator involved in regulatory mechanisms of adaptive immune response under physiological and pathological settings. Moreover, we have recently shown that TL1A negatively regulates B-cell proliferation. Despite increasing interest on the TL1A/DR3-axis functions, very little is known on its expression and role in leukemia. In this study, we investigated the expression and function of TL1A/DR3 axis in chronic lymphocytic leukemia (CLL). DR3 was differentially expressed in activated CLL cells and predominantly detected in patients with early clinical stage disease. Soluble TL1A has been revealed in the sera of CLL patients where higher TL1A levels were associated with early stage disease. T cells, monocytes and leukemic B cells have been identified as major sources of TL1A in CLL. The relevance of these findings has been sustained by functional data showing that exogenous TL1A reduces CLL proliferation induced by stimulation of the B cell receptor. Overall, these data document the expression of the TL1A/DR3 axis in early-stage CLL. They also identify a novel function for TL1A as a negative regulator of leukemic cell proliferation that may influence the CLL physiopathology and clinical outcome at an early-stage disease. PMID:26393680

  6. Expression and function of the TL1A/DR3 axis in chronic lymphocytic leukemia.

    PubMed

    Cavallini, Chiara; Lovato, Ornella; Bertolaso, Anna; Zoratti, Elisa; Malpeli, Giorgio; Mimiola, Elda; Tinelli, Martina; Aprili, Fiorenza; Tecchio, Cristina; Perbellini, Omar; Scarpa, Aldo; Zamò, Alberto; Cassatella, Marco Antonio; Pizzolo, Giovanni; Scupoli, Maria Teresa

    2015-10-13

    TNF-like ligand 1A (TL1A) and its unique receptor death receptor 3 (DR3) acts as broad T-cell costimulator involved in regulatory mechanisms of adaptive immune response under physiological and pathological settings. Moreover, we have recently shown that TL1A negatively regulates B-cell proliferation. Despite increasing interest on the TL1A/DR3-axis functions, very little is known on its expression and role in leukemia. In this study, we investigated the expression and function of TL1A/DR3 axis in chronic lymphocytic leukemia (CLL). DR3 was differentially expressed in activated CLL cells and predominantly detected in patients with early clinical stage disease. Soluble TL1A has been revealed in the sera of CLL patients where higher TL1A levels were associated with early stage disease. T cells, monocytes and leukemic B cells have been identified as major sources of TL1A in CLL. The relevance of these findings has been sustained by functional data showing that exogenous TL1A reduces CLL proliferation induced by stimulation of the B cell receptor. Overall, these data document the expression of the TL1A/DR3 axis in early-stage CLL. They also identify a novel function for TL1A as a negative regulator of leukemic cell proliferation that may influence the CLL physiopathology and clinical outcome at an early-stage disease.

  7. 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

  8. 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

  9. Quantification of newly produced B and T lymphocytes in untreated chronic lymphocytic leukemia patients

    PubMed Central

    2010-01-01

    Background The immune defects occurring in chronic lymphocytic leukemia are responsible for the frequent occurrence of infections and autoimmune phenomena, and may be involved in the initiation and maintenance of the malignant clone. Here, we evaluated the quantitative defects of newly produced B and T lymphocytes. Methods The output of B and T lymphocytes from the production and maturation sites was analyzed in chronic lymphocytic leukemia patients and healthy controls by quantifying kappa-deleting recombination excision circles (KRECs) and T-cell receptor excision circles (TRECs) by a Real-Time PCR assay that simultaneously detects both targets. T-lymphocyte subsets were analyzed by six-color flow cytometric analysis. Data comparison was performed by two-sided Mann-Whitney test. Results KRECs level was reduced in untreated chronic lymphocytic leukemia patients studied at the very early stage of the disease, whereas the release of TRECs+ cells was preserved. Furthermore, the observed increase of CD4+ lymphocytes could be ascribed to the accumulation of CD4+ cells with effector memory phenotype. Conclusions The decreased number of newly produced B lymphocytes in these patients is likely related to a homeostatic mechanism by which the immune system balances the abnormal B-cell expansion. This feature may precede the profound defect of humoral immunity characterizing the later stages of the disease. PMID:21054858

  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. 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

  12. 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.

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

    PubMed Central

    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.

    2013-01-01

    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/m2 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). PMID:23645694

  14. Lenalidomide and Rituximab for the Initial Treatment of Patients With Chronic Lymphocytic Leukemia: A Multicenter Clinical-Translational Study From the Chronic Lymphocytic Leukemia Research Consortium

    PubMed Central

    James, Danelle F.; Werner, Lillian; Brown, Jennifer R.; Wierda, William G.; Barrientos, Jacqueline C.; Castro, Januario E.; Greaves, Andrew; Johnson, Amy J.; Rassenti, Laura Z.; Rai, Kanti R.; Neuberg, Donna; Kipps, Thomas J.

    2014-01-01

    Purpose Lenalidomide is an immunomodulatory agent with therapeutic activity in chronic lymphocytic leukemia (CLL). In preclinical models, lenalidomide acted synergistically with rituximab. The CLL Research Consortium initiated a phase II study to evaluate this combination in treatment-naive patients. Patients and Methods Lenalidomide was initiated at 2.5 mg/day and was escalated based on treatment tolerability to a maximum of 10 mg/day, for 21 days/cycle, for a maximum of seven cycles. Rituximab was administered at the end of cycle 1 and was continued for seven cycles. Patients received allopurinol and aspirin for prophylaxis. Results Sixty-nine patients enrolled onto one of two age-specific strata; patients' median age was 56 and 70 years for arms A and B, respectively. Patients in the older-patient stratum more frequently had elevated serum beta-2 microglobulin levels, high-risk Rai stage, and were less likely to complete the maximum planned therapy. Adverse events were similar in the two arms. Nonhematologic toxicity was predominantly at grade 1/2, and neutropenia was the most common hematologic adverse event. The response rate for arm A was 95%, with 20% complete responses (CRs) and 20% nodular partial responses. Of arm B patients, 78% achieved a response, of which 11% were CRs. Median progression-free survival (PFS) was 19 months for the younger cohort and 20 months for the older cohort. Conclusion Intrapatient dose-escalation was safe. The majority of patients reached the maximum lenalidomide dose and experienced a response to a defined seven-cycle course of lenalidomide and rituximab therapy. Despite differences in baseline characteristics and the response rate between the two strata, the PFS did not differ. PMID:24868031

  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. 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

  17. 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.

  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. Composite Mantle Cell Lymphoma and Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: A Clinicopathologic and Molecular Study

    PubMed Central

    Hoeller, Sylvia; Zhou, Yi; Kanagal-Shamanna, Rashmi; Xu-Monette, Zijun Y.; Hoehn, Daniela; Bihl, Michel; Swerdlow, Steven H.; Rosenwald, Andreas; Ott, German; Said, Jonathan; Dunphy, Cherie H.; Bueso-Ramos, Carlos E.; Lin, Pei; Miranda, Roberto N.; Tzankov, Alexander; Medeiros, L. Jeffrey; Young, Ken H.

    2013-01-01

    Mantle cell lymphoma (MCL) and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) share many features and both arise from CD5+ B-cells, their distinction is critical as MCL is a much more aggressive neoplasm. Rarely, composite MCL and CLL/SLL have been reported. Little is known, about the nature of these cases and in particular the clonal relationship of the two lymphomas. Eleven composite MCL and CLL/SLL cases were identified. The clinical, morphologic and immunophenotypic features of the MCL and CLL/SLL were characterized. Immunoglobulin heavy chain (IGH) gene analysis was performed on microdissected MCL and CLL/SLL components to assess their clonal relationship. Ten patients had lymphadenopathy, and 7 patients had bone marrow involvement. The MCL component had the following growth patterns: in situ (n=1), mantle zone (n=3), nodular and diffuse (n=3), diffuse (n=3), and interstitial in the bone marrow (the only patient without lymphadenopathy) (n=1); 6 MCL had blastoid or pleomorphic and 5 classical cytologic features. The CLL/SLL component was internodular (n=9) or diffuse (n=2). All MCL were CD5+ and cyclin D1+ with t(11;14) translocation. All CLL/SLL were CD5+, CD23+ and negative for cyclin D1 or t(11;14). IGH gene analysis showed that the MCL and CLL/SLL components displayed different sized fragments, indicating that the MCL and CLL/SLL are likely derived from different neoplastic B-cell clones. The lack of a clonal relationship between the MCL and CLL/SLL components suggests that the MCL and CLL/SLL represent distinct disease processes and do not share a common progenitor B-cell. PMID:22944294

  2. 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

  3. A rare coexistence--Chronic lymphocytic leukemia and Kaposi sarcoma: Case report and review of the literature.

    PubMed

    Hacioglu, Muhammet Bekir; Sahin, Suleyman; Karatas, Fatih; Aytekin, Aydın

    2015-01-01

    Chronic lymphocytic leukemia (CLL) is the most common leukemia worldwide. Skin lesions associated with CLL mostly develop on the bases of infectious or a hemorrhagic origin with an estimated incidence of 25% of all the cases. Kaposi sarcoma (KS)-associated with human herpes virus-8 infection is a spindle-cell, malignant, low-grade tumor originating from vascular and lymphatic endothelium. KS mostly presents with skin lesions as the initial presentation. The relation between these two pathologies has not yet been clarified up to date. Herein, we report a case of KS along with CLL to illustrate the possible relation between these two pathologies.

  4. Chronic Lymphocytic Leukemia With Hodgkin and Reed-Sternberg (HRS) Cells: A Potential Diagnostic Pitfall in Lymph Node Biopsies.

    PubMed

    Agrawal, Parimal; Bal, Amanjit; Das, Ashim; Sachdeva, ManUpdesh; Prakash, Gaurav

    2017-01-01

    Chronic lymphocytic leukemia (CLL) is known to undergo Richter transformation in a proportion of cases. Transformation into Hodgkin lymphoma has been described in a minority of the cases. However, CLL rarely also shows Hodgkin and Reed-Sternberg cells with a classic morphology and the immunophenotype of Hodgkin lymphoma, even when not in transformation. The presence of these Hodgkin and Reed-Sternberg cells in CLL can cause a diagnostic dilemma.

  5. 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

  6. 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.

  7. 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

  8. Lenalidomide interferes with tumor-promoting properties of nurse-like cells in chronic lymphocytic leukemia

    PubMed Central

    Fiorcari, Stefania; Martinelli, Silvia; Bulgarelli, Jenny; Audrito, Valentina; Zucchini, Patrizia; Colaci, Elisabetta; Potenza, Leonardo; Narni, Franco; Luppi, Mario; Deaglio, Silvia; Marasca, Roberto; Maffei, Rossana

    2015-01-01

    Lenalidomide is an immunomodulatory agent clinically active in chronic lymphocytic leukemia patients. The specific mechanism of action is still undefined, but includes modulation of the microenvironment. In chronic lymphocytic leukemia patients, nurse-like cells differentiate from CD14+ mononuclear cells and protect chronic lymphocytic leukemia cells from apoptosis. Nurse-like cells resemble M2 macrophages with potent immunosuppressive functions. Here, we examined the effect of lenalidomide on the monocyte/macrophage population in chronic lymphocytic leukemia patients. We found that lenalidomide induces high actin polymerization on CD14+ monocytes through activation of small GTPases, RhoA, Rac1 and Rap1 that correlated with increased adhesion and impaired monocyte migration in response to CCL2, CCL3 and CXCL12. We observed that lenalidomide increases the number of nurse-like cells that lost the ability to nurture chronic lymphocytic leukemia cells, acquired properties of phagocytosis and promoted T-cell proliferation. Gene expression signature, induced by lenalidomide in nurse-like cells, indicated a reduction of pivotal pro-survival signals for chronic lymphocytic leukemia, such as CCL2, IGF1, CXCL12, HGF1, and supported a modulation towards M1 phenotype with high IL2 and low IL10, IL8 and CD163. Our data provide new insights into the mechanism of action of lenalidomide that mediates a pro-inflammatory switch of nurse-like cells affecting the protective microenvironment generated by chronic lymphocytic leukemia into tissues. PMID:25398834

  9. Bruton's tyrosine kinase mediated signaling enhances leukemogenesis in a mouse model for chronic lymphocytic leukemia.

    PubMed

    Kil, Laurens P; de Bruijn, Marjolein Jw; van Hulst, Jennifer Ac; Langerak, Anton W; Yuvaraj, Saravanan; Hendriks, Rudi W

    2013-01-01

    In chronic lymphocytic leukemia (CLL) signals from the B cell receptor (BCR) play a major role in disease development and progression. In this light, new therapies that specifically target signaling molecules downstream of the BCR continue to be developed. While first studies on the selective small molecule inhibitor of Bruton's tyrosine kinase (Btk), Ibrutinib (PCI-32765), demonstrated that Btk inhibition sensitizes CLL cells to apoptosis and alters their migratory behavior, these studies however did not address whether Btk-mediated signaling is involved in the process of CLL leukemogenesis. To investigate the requirement of Btk signaling for CLL development, we modulated Btk expression in the IgH.ETμ CLL mouse model, which is based on sporadic expression of the simian oncovirus SV40 T-antigen in mature B cells. To this end, we crossed IgH.ETμ mice on a Btk-deficient background or introduced a human Btk transgene (CD19-hBtk). Here we show that Btk deficiency fully abrogates CLL formation in IgH.ETμ mice, and that leukemias formed in Btk haplo-insufficient mice selectively expressed the wild-type Btk allele on their active X chromosome. Conversely, Btk overexpression accelerated CLL onset, increased mortality, and was associated with selection of non-stereotypical BCRs into CLL clones. Taken together, these data show that Btk expression represents an absolute prerequisite for CLL development and that Btk mediated signaling enhances leukemogenesis in mice. We therefore conclude that in CLL Btk expression levels set the threshold for malignant transformation.

  10. Targeting the Ataxia Telangiectasia Mutated-null phenotype in chronic lymphocytic leukemia with pro-oxidants

    PubMed Central

    Agathanggelou, Angelo; Weston, Victoria J.; Perry, Tracey; Davies, Nicholas J.; Skowronska, Anna; Payne, Daniel T.; Fossey, John S.; Oldreive, Ceri E.; Wei, Wenbin; Pratt, Guy; Parry, Helen; Oscier, David; Coles, Steve J.; Hole, Paul S.; Darley, Richard L.; McMahon, Michael; Hayes, John D.; Moss, Paul; Stewart, Grant S.; Taylor, A. Malcolm R.; Stankovic, Tatjana

    2015-01-01

    Inactivation of the Ataxia Telangiectasia Mutated gene in chronic lymphocytic leukemia results in resistance to p53-dependent apoptosis and inferior responses to treatment with DNA damaging agents. Hence, p53-independent strategies are required to target Ataxia Telangiectasia Mutated-deficient chronic lymphocytic leukemia. As Ataxia Telangiectasia Mutated has been implicated in redox homeostasis, we investigated the effect of the Ataxia Telangiectasia Mutated-null chronic lymphocytic leukemia genotype on cellular responses to oxidative stress with a view to therapeutic targeting. We found that in comparison to Ataxia Telangiectasia Mutated-wild type chronic lymphocytic leukemia, pro-oxidant treatment of Ataxia Telangiectasia Mutated-null cells led to reduced binding of NF-E2 p45-related factor-2 to antioxidant response elements and thus decreased expression of target genes. Furthermore, Ataxia Telangiectasia Mutated-null chronic lymphocytic leukemia cells contained lower levels of antioxidants and elevated mitochondrial reactive oxygen species. Consequently, Ataxia Telangiectasia Mutated-null chronic lymphocytic leukemia, but not tumors with 11q deletion or TP53 mutations, exhibited differentially increased sensitivity to pro-oxidants both in vitro and in vivo. We found that cell death was mediated by a p53- and caspase-independent mechanism associated with apoptosis inducing factor activity. Together, these data suggest that defective redox-homeostasis represents an attractive therapeutic target for Ataxia Telangiectasia Mutated-null chronic lymphocytic leukemia. PMID:25840602

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

    ClinicalTrials.gov

    2017-09-13

    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

  12. 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

  13. A Novel Assay for the Identification of NOTCH1 PEST Domain Mutations in Chronic Lymphocytic Leukemia

    PubMed Central

    Petroni, Roberta Cardoso; Muto, Nair Hideko; Sitnik, Roberta; de Carvalho, Flavia Pereira; Bacal, Nydia Strachman; Velloso, Elvira Deolinda Rodrigues Pereira; Oliveira, Gislaine Borba; Pinho, João Renato Rebello; Torres, Davi Coe; Mansur, Marcela Braga; Hassan, Rocio; Lorand-Metze, Irene Gyongyvér Heidemarie; Chiattone, Carlos Sérgio; Hamerschlak, Nelson; Mangueira, Cristovão Luis Pitangueira

    2016-01-01

    Aims. To develop a fast and robust DNA-based assay to detect insertions and deletions mutations in exon 34 that encodes the PEST domain of NOTCH1 in order to evaluate patients with chronic lymphocytic leukemia (CLL). Methods. We designed a multiplexed allele-specific polymerase chain reaction (PCR) combined with a fragment analysis assay to detect specifically the mutation c.7544_7545delCT and possibly other insertions and deletions in exon 34 of NOTCH1. Results. We evaluated our assay in peripheral blood samples from two cohorts of patients with CLL. The frequency of NOTCH1 mutations was 8.4% in the first cohort of 71 unselected CLL patients. We then evaluated a second cohort of 26 CLL patients with known cytogenetic abnormalities that were enriched for patients with trisomy 12. NOTCH1 mutations were detected in 43.7% of the patients with trisomy 12. Conclusions. We have developed a fast and robust assay combining allele-specific PCR and fragment analysis able to detect NOTCH1 PEST domain insertions and deletions. PMID:28074183

  14. 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

  15. EGR2 mutations define a new clinically aggressive subgroup of chronic lymphocytic leukemia.

    PubMed

    Young, E; Noerenberg, D; Mansouri, L; Ljungström, V; Frick, M; Sutton, L-A; Blakemore, S J; Galan-Sousa, J; Plevova, K; Baliakas, P; Rossi, D; Clifford, R; Roos-Weil, D; Navrkalova, V; Dörken, B; Schmitt, C A; Smedby, K E; Juliusson, G; Giacopelli, B; Blachly, J S; Belessi, C; Panagiotidis, P; Chiorazzi, N; Davi, F; Langerak, A W; Oscier, D; Schuh, A; Gaidano, G; Ghia, P; Xu, W; Fan, L; Bernard, O A; Nguyen-Khac, F; Rassenti, L; Li, J; Kipps, T J; Stamatopoulos, K; Pospisilova, S; Zenz, T; Oakes, C C; Strefford, J C; Rosenquist, R; Damm, F

    2017-07-01

    Recurrent mutations within EGR2 were recently reported in advanced-stage chronic lymphocytic leukemia (CLL) patients and associated with a worse outcome. To study their prognostic impact, 2403 CLL patients were examined for mutations in the EGR2 hotspot region including a screening (n=1283) and two validation cohorts (UK CLL4 trial patients, n=366; CLL Research Consortium (CRC) patients, n=490). Targeted deep-sequencing of 27 known/postulated CLL driver genes was also performed in 38 EGR2-mutated patients to assess concurrent mutations. EGR2 mutations were detected in 91/2403 (3.8%) investigated cases, and associated with younger age at diagnosis, advanced clinical stage, high CD38 expression and unmutated IGHV genes. EGR2-mutated patients frequently carried ATM lesions (42%), TP53 aberrations (18%) and NOTCH1/FBXW7 mutations (16%). EGR2 mutations independently predicted shorter time-to-first-treatment (TTFT) and overall survival (OS) in the screening cohort; they were confirmed associated with reduced TTFT and OS in the CRC cohort and independently predicted short OS from randomization in the UK CLL4 cohort. A particularly dismal outcome was observed among EGR2-mutated patients who also carried TP53 aberrations. In summary, EGR2 mutations were independently associated with an unfavorable prognosis, comparable to CLL patients carrying TP53 aberrations, suggesting that EGR2-mutated patients represent a new patient subgroup with very poor outcome.

  16. A systematic approach for peptide characterization of B-cell receptor in chronic lymphocytic leukemia cells

    PubMed Central

    Díez, Paula; Ibarrola, Nieves; Dégano, Rosa M.; Lécrevisse, Quentin; Rodriguez-Caballero, Arancha; Criado, Ignacio; Nieto, Wendy G.; Góngora, Rafael; González, Marcos; Almeida, Julia; Orfao, Alberto; Fuentes, Manuel

    2017-01-01

    A wide variety of immunoglobulins (Ig) is produced by the immune system thanks to different mechanisms (V(D)J recombination, somatic hypermutation, and antigen selection). The profiling of Ig sequences (at both DNA and peptide levels) are of great relevance to developing targeted vaccines or treatments for specific diseases or infections. Thus, genomics and proteomics techniques (such as Next-Generation Sequencing (NGS) and mass spectrometry (MS)) have notably increased the knowledge in Ig sequencing and serum Ig peptide profiling in a high-throughput manner. However, the peptide characterization of membrane-bound Ig (e.g., B-cell receptors, BCR) is still a challenge mainly due to the poor recovery of mentioned Ig. Herein, we have evaluated three different sample processing methods for peptide sequencing of BCR belonging to chronic lymphocytic leukemia (CLL) B cells identifying up to 426 different peptide sequences (MS/MS data are available via ProteomeXchange with identifier PXD004466). Moreover, as a consequence of the results here obtained, recommended guidelines have been described for BCR-sequencing of B-CLL samples by MS approaches. For this purpose, an in–house algorithm has been designed and developed to compare the MS/MS results with those obtained by molecular biology in order to integrate both proteomics and genomics results and establish the steps to follow when sequencing membrane-bound Ig by MS/MS. PMID:28467808

  17. A putative "hepitype" in the ATM gene associated with chronic lymphocytic leukemia risk.

    PubMed

    Martín-Guerrero, Idoia; Enjuanes, Anna; Richter, Julia; Ammerpohl, Ole; Colomer, Dolors; Ardanaz, Maite; Marco, Fernando; Salas, Antonio; Campo, Elias; Siebert, Reiner; García-Orad, Africa

    2011-11-01

    Chronic lymphocytic leukemia (CLL) cells are characterized by several chromosomal lesions. Some of these aberrations imply chromosome breaks as a result of unrepaired double strand breaks (DSBs) in the DNA. The ATM (ataxia telangiectasia-mutated) protein is the principal integrator of cellular responses to DSBs. ATM deletion is also an adverse prognostic factor in CLL. Taking this into account, we evaluated if genetic and/or epigenetic variation in the ATM gene may modulate the individual susceptibility to develop CLL. Our case-control association study was performed in a large Spanish population of 1,503 individuals, including 742 patients with CLL and 761 controls. We identified one haplotype within the ATM gene that confers an increased risk of CLL development (OR = 1.33; 95% CI: 1.10-1.60). Two polymorphisms of this ATM haplotype eliminated one CpG site each in Introns 15 and 61, causing changes in DNA methylation pattern. These data provide the first evidence for the existence of a putative "hepitype" in the ATM gene associated with CLL risk. Copyright © 2011 Wiley-Liss, Inc.

  18. Clinical roundtable monograph: unmet needs in the treatment of chronic lymphocytic leukemia: integrating a targeted approach.

    PubMed

    O'Brien, Susan M; Furman, Richard R; Byrd, John C; Smith, Ashbel

    2014-01-01

    Chronic lymphocytic leukemia (CLL) is the most frequently diagnosed hematologic malignancy in the United States. Although several features can be useful in the diagnosis of CLL, the most important is the immunophenotype.Two staging systems--the Binet system and the Rai classification--are used to assess risk. After diagnosis, the first major therapeutic decision is when to initiate therapy, as a watchful waiting approach is often appropriate for patients with asymptomatic disease. Once a patient has met the criteria for treatment, the choice of therapy is the next major decision. Younger patients (<65 years) often receive more aggressive treatment that typically consists of cytotoxic chemotherapy. There is a great unmet need concerning treatment of older patients with CLL, who often present with more comorbid conditions that can decrease their ability to tolerate particular regimens. The current standard of care for older patients with CLL is rituximab plus chlorambucil. The concept of targeted agents is currently an area of intense interest in CLL. The Bruton’s tyrosine kinase inhibitor ibrutinib is the targeted agent that is furthest along in clinical development. It is associated with an overall survival rate of 83%. Idelalisib targets the phosphatidyl inositol 3-kinase and is under evaluation in pivotal trials. Targeted agents offer much promise in terms of efficacy, toxicity, and oral availability. They will change the management of patients with CLL.

  19. 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. Copyright 2009 ISFM and AAFP. Published by Elsevier Ltd. All rights reserved.

  20. 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

  1. 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.

  2. 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.

  3. 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

  4. 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.

  5. Chronic lymphocytic leukemia in young (≤ 55 years) patients: a comprehensive analysis of prognostic factors and outcomes

    PubMed Central

    Parikh, Sameer A.; Rabe, Kari G.; Kay, Neil E.; Call, Timothy G.; Ding, Wei; Schwager, Susan M.; Bowen, Deborah A.; Conte, Michael; Jelinek, Diane F.; Slager, Susan L.; Shanafelt, Tait D.

    2014-01-01

    The clinical characteristics and outcomes of younger (≤55 years) patients with chronic lymphocytic leukemia in the era of modern prognostic biomarkers and chemoimmunotherapy are not well understood. Baseline characteristics and outcomes of patients with chronic lymphocytic leukemia ≤55 years who were seen at the Mayo Clinic between January 1995 and April 2012 were compared with those of patients >55 years. The overall survival of patients ≤55 years was compared to that of the age- and sex-matched normal population. The characteristics of 844 newly diagnosed chronic lymphocytic leukemia patients ≤55 years old (median, 50 years) were compared to those of 2324 patients >55 years old (median, 67 years). Younger patients were more likely to have Rai stage I or II disease (P<0.0001), be IGHV unmutated (P=0.002) and express ZAP-70 (P=0.009). These differences became more pronounced when the ≤55 age group was sub-stratified into age ≤45, 46–50 and 51–55 years. After a median follow-up of 5.5 years, 426 (51%) patients ≤55 years old had received treatment, and 192 (23%) had died. The time to treatment was shorter in patients ≤55 years than in those older than 55 years (4.0 years versus 5.2 years; P=0.001) and those ≤55 years had longer survival (12.5 years versus 9.5 years; P<0.0001). However, patients ≤55 years had significantly shorter survival than the age- and sex-matched normal population (12.5 years versus not reached; P<0.0001). Our study is the first comprehensive analysis of younger patients with chronic lymphocytic leukemia in the modern era. Adverse prognostic markers appear more common among young patients. Although the survival of young chronic lymphocytic leukemia patients is longer than that of those >55 years old, their survival relative to the age- and sex-matched normal population is profoundly shortened. PMID:23911703

  6. Chronic lymphocytic leukemia in young (≤ 55 years) patients: a comprehensive analysis of prognostic factors and outcomes.

    PubMed

    Parikh, Sameer A; Rabe, Kari G; Kay, Neil E; Call, Timothy G; Ding, Wei; Schwager, Susan M; Bowen, Deborah A; Conte, Michael; Jelinek, Diane F; Slager, Susan L; Shanafelt, Tait D

    2014-01-01

    The clinical characteristics and outcomes of younger (≤ 55 years) patients with chronic lymphocytic leukemia in the era of modern prognostic biomarkers and chemoimmunotherapy are not well understood. Baseline characteristics and outcomes of patients with chronic lymphocytic leukemia ≤ 55 years who were seen at the Mayo Clinic between January 1995 and April 2012 were compared with those of patients >55 years. The overall survival of patients ≤ 55 years was compared to that of the age- and sex-matched normal population. The characteristics of 844 newly diagnosed chronic lymphocytic leukemia patients ≤ 55 years old (median, 50 years) were compared to those of 2324 patients >55 years old (median, 67 years). Younger patients were more likely to have Rai stage I or II disease (P<0.0001), be IGHV unmutated (P=0.002) and express ZAP-70 (P=0.009). These differences became more pronounced when the ≤ 55 age group was sub-stratified into age ≤ 45, 46-50 and 51-55 years. After a median follow-up of 5.5 years, 426 (51%) patients ≤ 55 years old had received treatment, and 192 (23%) had died. The time to treatment was shorter in patients ≤ 55 years than in those older than 55 years (4.0 years versus 5.2 years; P=0.001) and those ≤ 55 years had longer survival (12.5 years versus 9.5 years; P<0.0001). However, patients ≤ 55 years had significantly shorter survival than the age- and sex-matched normal population (12.5 years versus not reached; P<0.0001). Our study is the first comprehensive analysis of younger patients with chronic lymphocytic leukemia in the modern era. Adverse prognostic markers appear more common among young patients. Although the survival of young chronic lymphocytic leukemia patients is longer than that of those >55 years old, their survival relative to the age- and sex-matched normal population is profoundly shortened.

  7. 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.

  8. Treatment Options by Stage (Chronic Lymphocytic Leukemia)

    MedlinePlus

    ... is a type of cancer in which the bone marrow makes too many lymphocytes (a type of white ... no known reason. Tests that examine the blood, bone marrow, and lymph nodes are used to detect (find) ...

  9. Chronic lymphocytic leukemia: state of the art and beyond.

    PubMed

    Byrd, John C

    2014-05-01

    In the treatment of chronic lymphocytic leukemia (CLL), select genomic studies can assist in risk stratification of newly diagnosed patients. Chemoimmunotherapy targeting CD20 offers a survival advantage in symptomatic patients both with and without these high-risk genetic features, though patients with del(17p13.1) have poor outcomes and require specific intervention. Obinutuzumab plus chlorambucil is a treatment standard for untreated elderly patients and is superior to rituximab plus chlorambucil. In the setting of relapsed CLL, the new kinase inhibitors have the potential to completely change the treatment paradigm of CLL. Copyright © 2014 by the National Comprehensive Cancer Network.

  10. 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.

  11. 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.

  12. 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.

  13. 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.

  14. 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

  15. 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

  16. 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.

  17. SJG-136 in Treating Patients With Relapsed or Refractory Acute Leukemia, Myelodysplastic Syndromes, Blastic Phase Chronic Myelogenous Leukemia, or Chronic Lymphocytic Leukemia

    ClinicalTrials.gov

    2013-09-27

    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; de Novo Myelodysplastic Syndromes; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Refractory Chronic Lymphocytic Leukemia; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes

  18. 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

  19. Concept Elicitation Within Patient-Powered Research Networks: A Feasibility Study in Chronic Lymphocytic Leukemia.

    PubMed

    McCarrier, Kelly P; Bull, Scott; Fleming, Sarah; Simacek, Kristina; Wicks, Paul; Cella, David; Pierson, Renee

    2016-01-01

    To explore the feasibility of using social media-based patient networks to gather qualitative data on patient-reported outcome (PRO) concepts relevant to chronic lymphocytic leukemia (CLL). Between August and November 2013, US-residing members of the PatientsLikeMe online CLL patient community completed open-ended web-based surveys designed to elicit descriptions of CLL symptoms, impacts, and treatment-related perceptions. Qualitative telephone follow-up interviews were conducted with a subsample of respondents. Survey responses and interview transcripts were coded for qualitative analysis using Atlas.ti. Fifty survey responses were included in the analyses. Participants were age 60.5 ± 6.9 years, 54% female, and 96% white. When surveyed, 20% were receiving current treatment, 16% were in remission, and 64% were treatment-naïve. Among respondents, 369 descriptions of CLL symptoms were coded. Fatigue-related symptoms were expressed most frequently, with 54% reporting "fatigue," "tiredness," or both in their responses. These concepts were followed by night sweats (38%), swollen lymph nodes (32%), and frequent infections (28%). Among impacts of CLL, worry and fear (66% of respondents), depressed feelings (52%), and work limitations (50%) were noted most frequently. Survey results identified constitutional symptoms of CLL included in existing PRO instruments and the literature. Although the findings suggest that qualitative data obtained through social media applications can be potentially useful in supporting concept identification for newly developed PRO instruments, they also indicate that online approaches alone may not be sufficient to achieve efficient and exhaustive concept elicitation. Further research is needed to identify whether the results can support content validity in the same way as established qualitative research methods. Copyright © 2016. Published by Elsevier Inc.

  20. A comprehensive review of occupational and general population cancer risk: 1,3-Butadiene exposure-response modeling for all leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, myeloid neoplasm and lymphoid neoplasm.

    PubMed

    Sielken, Robert L; Valdez-Flores, Ciriaco

    2015-11-05

    Excess cancer risks associated with 1,3-butadiene (BD) inhalation exposures are calculated using an extensive data set developed by the University of Alabama at Birmingham (UAB) from an epidemiology study of North American workers in the styrene butadiene rubber (SBR) industry. While the UAB study followed SBR workers, risk calculations can be adapted to estimate both occupational and general population risks. The data from the UAB SBR study offer an opportunity to quantitatively evaluate the association between cumulative exposure to BD and different types of cancer, accounting for the number of tasks involving high-intensity exposures to BD as well as confounding associated with the exposures to the multiple other chemicals in the SBR industry. Quantitative associations of BD exposure and cancer, specifically leukemia, can be further characterized by leukemia type, including potential associations with acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), and chronic myelogenous leukemia (CML), and the groups of lymphoid and myeloid neoplasms. Collectively, these multiple evaluations lead to a comprehensive analysis that makes use of all of the available information and is consistent with the risk assessment goals of the USEPA and other regulatory agencies, and in line with the recommendations of the USEPA Science Advisory Board. While a range of cancer risk values can result from these multiple factors, a preferred case for occupational and general population risk is highlighted. Cox proportional hazards models are used to fit exposure-response models to the most recent UAB data. The slope of the model with cumulative BD ppm-years as the predictor variable is not statistically significantly greater than zero for CML, AML, or, when any one of eight exposure covariates is added to the model, for all leukemias combined. The slope for CLL is statistically significantly different from zero. The slope for myeloid neoplasms is not statistically

  1. ATM gene alterations in chronic lymphocytic leukemia patients induce a distinct gene expression profile and predict disease progression.

    PubMed

    Guarini, Anna; Marinelli, Marilisa; Tavolaro, Simona; Bellacchio, Emanuele; Magliozzi, Monia; Chiaretti, Sabina; De Propris, Maria Stefania; Peragine, Nadia; Santangelo, Simona; Paoloni, Francesca; Nanni, Mauro; Del Giudice, Ilaria; Mauro, Francesca Romana; Torrente, Isabella; Foà, Robin

    2012-01-01

    The genetic characterization of chronic lymphocytic leukemia cells correlates with the behavior, progression and response to treatment of the disease. Our aim was to investigate the role of ATM gene alterations, their biological consequences and their value in predicting disease progression. The ATM gene was analyzed by denaturing high performance liquid chromatography and multiplex ligation probe amplification in a series of patients at diagnosis. The results were correlated with immunoglobulin gene mutations, cytogenetic abnormalities, ZAP-70 and CD38 expression, TP53 mutations, gene expression profile and treatment-free interval. Mutational screening of the ATM gene identified point mutations in 8/57 cases (14%). Multiplex ligation probe amplification analysis identified six patients with 11q deletion: all of them had at least 20% of deleted cells, analyzed by fluorescent in situ hybridization. Overall, ATM point mutations and deletions were detected in 14/57 (24.6%) cases at presentation, representing the most common unfavorable genetic anomalies in chronic lymphocytic leukemia, also in stage A patients. Patients with deleted or mutated ATM had a significantly shorter treatment-free interval compared to patients without ATM alterations. ATM-mutated cases had a peculiar gene expression profile characterized by the deregulation of genes involved in apoptosis and DNA repair. Finally, definition of the structure of the ATM-mutated protein led to a hypothesis that functional abnormalities are responsible for the unfavorable clinical course of patients carrying these point mutations. ATM alterations are present at diagnosis in about 25% of individuals with chronic lymphocytic leukemia; these alterations are associated with a peculiar gene expression pattern and a shorter treatment-free interval.

  2. ATM gene alterations in chronic lymphocytic leukemia patients induce a distinct gene expression profile and predict disease progression

    PubMed Central

    Guarini, Anna; Marinelli, Marilisa; Tavolaro, Simona; Bellacchio, Emanuele; Magliozzi, Monia; Chiaretti, Sabina; De Propris, Maria Stefania; Peragine, Nadia; Santangelo, Simona; Paoloni, Francesca; Nanni, Mauro; Del Giudice, Ilaria; Mauro, Francesca Romana; Torrente, Isabella; Foà, Robin

    2012-01-01

    Background The genetic characterization of chronic lymphocytic leukemia cells correlates with the behavior, progression and response to treatment of the disease. Design and Methods Our aim was to investigate the role of ATM gene alterations, their biological consequences and their value in predicting disease progression. The ATM gene was analyzed by denaturing high performance liquid chromatography and multiplex ligation probe amplification in a series of patients at diagnosis. The results were correlated with immunoglobulin gene mutations, cytogenetic abnormalities, ZAP-70 and CD38 expression, TP53 mutations, gene expression profile and treatment-free interval. Results Mutational screening of the ATM gene identified point mutations in 8/57 cases (14%). Multiplex ligation probe amplification analysis identified six patients with 11q deletion: all of them had at least 20% of deleted cells, analyzed by fluorescent in situ hybridization. Overall, ATM point mutations and deletions were detected in 14/57 (24.6%) cases at presentation, representing the most common unfavorable genetic anomalies in chronic lymphocytic leukemia, also in stage A patients. Patients with deleted or mutated ATM had a significantly shorter treatment-free interval compared to patients without ATM alterations. ATM-mutated cases had a peculiar gene expression profile characterized by the deregulation of genes involved in apoptosis and DNA repair. Finally, definition of the structure of the ATM-mutated protein led to a hypothesis that functional abnormalities are responsible for the unfavorable clinical course of patients carrying these point mutations. Conclusions ATM alterations are present at diagnosis in about 25% of individuals with chronic lymphocytic leukemia; these alterations are associated with a peculiar gene expression pattern and a shorter treatment-free interval. PMID:21993670

  3. Molecular Characterization of Chronic Lymphocytic Leukemia Patients with a High Number of Losses in 13q14

    PubMed Central

    Rodríguez, Ana Eugenia; Hernández, Jose Ángel; Benito, Rocío; Gutiérrez, Norma C.; García, Juan Luis; Hernández-Sánchez, María; Risueño, Alberto; Sarasquete, M. Eugenia; Fermiñán, Encarna; Fisac, Rosa; de Coca, Alfonso García; Martín-Núñez, Guillermo; de las Heras, Natalia; Recio, Isabel; Gutiérrez, Oliver; De Las Rivas, Javier; González, Marcos; Hernández-Rivas, Jesús M.

    2012-01-01

    Background Patients with chronic lymphocytic leukemia and 13q deletion as their only FISH abnormality could have a different outcome depending on the number of cells displaying this aberration. Thus, cases with a high number of 13q- cells (13q-H) had both shorter overall survival and time to first therapy. The goal of the study was to analyze the genetic profile of 13q-H patients. Design and Methods: A total of 102 samples were studied, 32 of which served as a validation cohort and five were healthy donors. Results Chronic lymphocytic leukemia patients with higher percentages of 13q- cells (>80%) showed a different level of gene expression as compared to patients with lower percentages (<80%, 13q-L). This deregulation affected genes involved in apoptosis and proliferation (BCR and NFkB signaling), leading to increased proliferation and decreased apoptosis in 13q-H patients. Deregulation of several microRNAs, such as miR-15a, miR-155, miR-29a and miR-223, was also observed in these patients. In addition, our study also suggests that the gene expression pattern of 13q-H cases could be similar to the patients with 11q- or 17p-. Conclusions This study provides new evidence regarding the heterogeneity of 13q deletion in chronic lymphocytic leukemia patients, showing that apoptosis, proliferation as well as miRNA regulation are involved in cases with higher percentages of 13q- cells. PMID:23152777

  4. 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.

  5. 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

  6. Saliva is a reliable and practical source of germline DNA for genome-wide studies in chronic lymphocytic leukemia.

    PubMed

    Rasi, Silvia; Bruscaggin, Alessio; Rinaldi, Andrea; Cresta, Stefania; Fangazio, Marco; De Paoli, Lorenzo; Monti, Sara; Gargiulo, Ernesto; Kwee, Ivo; Foà, Robin; Bertoni, Francesco; Gaidano, Gianluca; Rossi, Davide

    2011-10-01

    High-throughput genomics requires tumor DNA matched to germline DNA, that cannot be easily obtained in the context of leukemia. Using chronic lymphocytic leukemia as a model, saliva DNA was frequently devoid of tumor DNA also during overt disease, and passed quality controls for SNP-array (77/102, 75.4%) and next generation sequencing (71/102, 69.6%). Compared to saliva, urine provides germline DNA of similar quality but in lower amounts. Saliva DNA was successfully run on SNP 6.0 arrays, and passed quality control call rate thresholds. On these bases, saliva represents a useful source of germline DNA for high-throughput genomic studies of hematologic neoplasia. Copyright © 2011 Elsevier Ltd. All rights reserved.

  7. 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

  8. Safety and Tolerability Study of PCI-32765 in B Cell Lymphoma and Chronic Lymphocytic Leukemia

    ClinicalTrials.gov

    2017-10-09

    B-cell Chronic Lymphocytic Leukemia; Small Lymphocytic Lymphoma; Diffuse Well-differentiated Lymphocytic Lymphoma; B Cell Lymphoma; Follicular Lymphoma; Mantle Cell Lymphoma; Non-Hodgkin's Lymphoma; Waldenstrom Macroglobulinemia; Burkitt Lymphoma; B-Cell Diffuse Lymphoma

  9. 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

  10. 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

  11. Autologous bone marrow transplantation in chronic lymphocytic leukemia (CLL).

    PubMed

    Mangoni, L; Rizzoli, V

    1996-01-01

    Chronic lymphocytic leukemia (CLL) is an indolent disease characterized by an abnormal proliferation of monoclonal lymphocytes in the bone marrow and lymphoid tissues. Most of the cases (> 90%) belong to the B-lymphocyte lineage and the course of the disease is variable depending on the presence of poor prognostic factors at diagnosis. Therefore optimal treatment is still questioned; presently there are no proven cures for CLL, but the natural history of the disease and the advanced age of the majority of patients makes prolongation of survival a reasonable therapeutic goal in most cases. The traditional therapeutic approach has been based on the activity of alkylating agents and corticosteroid, while patients resistant have been treated with nucleoside analogs. However, patients ultimately relapse and the choice of salvage therapy by conventional methods does not offer many chances. Particularly in younger patients, with poor prognostic factors, the therapeutic options may substantially change in the near future, based on alternative and innovative approaches aimed at achieving cure or long disease-free-survival. The results of high-dose therapy followed by reinfusion of hematopoietic stem cells, either from bone marrow or peripheral blood, will be presented and discussed.

  12. 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.

  13. 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

  14. 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

  15. 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.

  16. 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.

  17. Bilateral Tonsillar Enlargement as a First Manifestation of Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma with an Unusual Interfollicular Pattern of Infiltration.

    PubMed

    Duggal, Rajan; Rana, Alka; Vaid, Ashok; Sood, Nitin; Handa, Kumud Kumar

    2016-06-01

    Tonsillar lymphoma usually presents as unilateral or bilateral enlargement or as an ulcerative or fungating lesions. Most lymphomas that involve the tonsils are diffuse large B-cell lymphomas and primary low grade lymphomas are exceptional. We report a case of primary B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) affecting tonsils with interfollicular pattern of infiltration in a 54-year-old female who clinically presented with bilateral tonsillar enlargement, sore throat, dysphagia and respiratory difficulty, unresponsive to the conservative treatment. To the best of our knowledge, till date only six cases of CLL/SLL infiltrating tonsils have been reported in the English literature, three of these were known cases of CLL/SLL prior to tonsillectomy. In the present case diagnosis of CLL/SLL was first time established on tonsillar histomorphology and that too with an unusual interfollicular pattern of infiltration.

  18. 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

  19. 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

    2017-10-05

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

  20. 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.

  1. 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

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

    PubMed Central

    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. PMID:26109852

  3. 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.

  4. 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

  5. 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.

  6. 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.

  7. 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

  8. 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.

  9. Suppression of chronic lymphocytic leukemia progression by CXCR4 inhibitor WZ811

    PubMed Central

    Li, Shi Hui; Dong, Wen Chuan; Fan, Li; Wang, Guang Sheng

    2016-01-01

    CXCR4 is a chemokine and chemokine receptor pair playing critical roles in tumorigenesis. Overexpression of C-X-C chemokine receptor type 4 (CXCR4) is a hallmark of many hematological malignancies including acute myeloid leukemia, chronic lymphocytic leukemia and non-Hodgkin’s lymphoma, and generally correlates with a poor prognosis. A highly potent competitive antagonist of CXCR4, WZ811, recently has been identified with suppression of cancer cells aggressive in a variety of cancers. However, the effects of WZ811 on chronic lymphocytic leukemia cells have not yet been defined. The effect of WZ811 on chronic lymphocytic leukemia cells TF-1 and UT-7 cells in proliferation, colony formation, and cell migration in vitro were measured respectively. Decreased in cell viability, colony formation, migration, and survival with cell cycle arrest and higher sensitivity to docetaxel in vitro was observed upon WZ811 treatment. In mouse xenograft models developed with human leukemia cells, WZ811 exhibited tumor growth inhibition. Collectively, we have demonstrated that CXCR4 inhibition by WZ811 has the potential for the treatment of human hematological malignancies. This study demonstrated that WZ811 may be a novel approach in the treatment of chronic lymphocytic leukemia. PMID:27725861

  10. 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

  11. 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

  12. Targeting BTK with Ibrutinib in Relapsed Chronic Lymphocytic Leukemia

    PubMed Central

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

    2013-01-01

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

  13. 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.

  14. 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

  15. 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.

  16. Asymptomatic diffuse "encephalitic" cerebral toxoplasmosis in a patient with chronic lymphocytic leukemia: case report and review of the literature.

    PubMed

    Abedalthagafi, Malak; Rushing, Elisabeth J; Garvin, David; Cheson, Bruce; Ozdemirli, Metin

    2009-03-15

    Opportunistic infections account for the majority of central nervous system lesions in adult immunosuppressed patients. In this setting, toxoplasmosis typically manifests as multiple abscesses readily seen on routine neuroimaging studies. Asymptomatic, widely disseminated Toxoplasma cysts without parenchymal reaction are also recognized. In contrast, widespread parasites in the brain parenchyma with an inflammatory "encephalitic" reaction and little or no necrosis have been reported in only four patients with acquired immune deficiency syndrome (AIDS). We describe a 70 year old male with stage IV chronic lymphocytic leukemia complicated by aplastic anemia. Neurological examination and imaging revealed no significant abnormalities. At autopsy, the brain revealed multifocal cysts and free tachyzoites of Toxoplasma gondii with diffuse microglial nodules and no necrosis. To the best of our knowledge, this case represents the first report of the "encephalitic" form of toxoplasmosis in a non-AIDS patient.

  17. 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

  18. 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.

  19. 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.

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

    PubMed Central

    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

    ABSTRACT 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. PMID:27853650

  1. 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.

  2. 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.

  3. 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. Copyright © 2015 John Wiley & Sons, Ltd.

  4. 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.

  5. 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

  6. 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 ...

  7. Ibrutinib as Initial Therapy for Patients with Chronic Lymphocytic Leukemia.

    PubMed

    Burger, Jan A; Tedeschi, Alessandra; Barr, Paul M; Robak, Tadeusz; Owen, Carolyn; Ghia, Paolo; Bairey, Osnat; Hillmen, Peter; Bartlett, Nancy L; Li, Jianyong; Simpson, David; Grosicki, Sebastian; Devereux, Stephen; McCarthy, Helen; Coutre, Steven; Quach, Hang; Gaidano, Gianluca; Maslyak, Zvenyslava; Stevens, Don A; Janssens, Ann; Offner, Fritz; Mayer, Jiří; O'Dwyer, Michael; Hellmann, Andrzej; Schuh, Anna; Siddiqi, Tanya; Polliack, Aaron; Tam, Constantine S; Suri, Deepali; Cheng, Mei; Clow, Fong; Styles, Lori; James, Danelle F; Kipps, Thomas J

    2015-12-17

    Chronic lymphocytic leukemia (CLL) primarily affects older persons who often have coexisting conditions in addition to disease-related immunosuppression and myelosuppression. We conducted an international, open-label, randomized phase 3 trial to compare two oral agents, ibrutinib and chlorambucil, in previously untreated older patients with CLL or small lymphocytic lymphoma. We randomly assigned 269 previously untreated patients who were 65 years of age or older and had CLL or small lymphocytic lymphoma to receive ibrutinib or chlorambucil. The primary end point was progression-free survival as assessed by an independent review committee. The median age of the patients was 73 years. During a median follow-up period of 18.4 months, ibrutinib resulted in significantly longer progression-free survival than did chlorambucil (median, not reached vs. 18.9 months), with a risk of progression or death that was 84% lower with ibrutinib than that with chlorambucil (hazard ratio, 0.16; P<0.001). Ibrutinib significantly prolonged overall survival; the estimated survival rate at 24 months was 98% with ibrutinib versus 85% with chlorambucil, with a relative risk of death that was 84% lower in the ibrutinib group than in the chlorambucil group (hazard ratio, 0.16; P=0.001). The overall response rate was higher with ibrutinib than with chlorambucil (86% vs. 35%, P<0.001). The rates of sustained increases from baseline values in the hemoglobin and platelet levels were higher with ibrutinib. Adverse events of any grade that occurred in at least 20% of the patients receiving ibrutinib included diarrhea, fatigue, cough, and nausea; adverse events occurring in at least 20% of those receiving chlorambucil included nausea, fatigue, neutropenia, anemia, and vomiting. In the ibrutinib group, four patients had a grade 3 hemorrhage and one had a grade 4 hemorrhage. A total of 87% of the patients in the ibrutinib group are continuing to take ibrutinib. Ibrutinib was superior to chlorambucil

  8. Ibrutinib as Initial Therapy for Patients with Chronic Lymphocytic Leukemia

    PubMed Central

    Burger, Jan A.; Tedeschi, Alessandra; Barr, Paul M.; Robak, Tadeusz; Owen, Carolyn; Ghia, Paolo; Bairey, Osnat; Hillmen, Peter; Bartlett, Nancy L.; Li, Jianyong; Simpson, David; Grosicki, Sebastian; Devereux, Stephen; McCarthy, Helen; Coutre, Steven; Quach, Hang; Gaidano, Gianluca; Maslyak, Zvenyslava; Stevens, Don A.; Janssens, Ann; Offner, Fritz; Mayer, Jiří; O'Dwyer, Michael; Hellmann, Andrzej; Schuh, Anna; Siddiqi, Tanya; Polliack, Aaron; Tam, Constantine S.; Suri, Deepali; Cheng, Mei; Clow, Fong; Styles, Lori; James, Danelle F.; Kipps, Thomas J.

    2016-01-01

    BACKGROUND Chronic lymphocytic leukemia (CLL) primarily affects older persons who often have coexisting conditions in addition to disease-related immunosuppression and myelosuppression. We conducted an international, open-label, randomized phase 3 trial to compare two oral agents, ibrutinib and chlorambucil, in previously untreated older patients with CLL or small lymphocytic lymphoma. METHODS We randomly assigned 269 previously untreated patients who were 65 years of age or older and had CLL or small lymphocytic lymphoma to receive ibrutinib or chlorambucil. The primary end point was progression-free survival as assessed by an independent review committee. RESULTS The median age of the patients was 73 years. During a median follow-up period of 18.4 months, ibrutinib resulted in significantly longer progression-free survival than did chlorambucil (median, not reached vs. 18.9 months), with a risk of progression or death that was 84% lower with ibrutinib than that with chlorambucil (hazard ratio, 0.16; P<0.001). Ibrutinib significantly prolonged overall survival; the estimated survival rate at 24 months was 98% with ibrutinib versus 85% with chlorambucil, with a relative risk of death that was 84% lower in the ibrutinib group than in the chlorambucil group (hazard ratio, 0.16; P=0.001). The overall response rate was higher with ibrutinib than with chlorambucil (86% vs. 35%, P<0.001). The rates of sustained increases from baseline values in the hemoglobin and platelet levels were higher with ibrutinib. Adverse events of any grade that occurred in at least 20% of the patients receiving ibrutinib included diarrhea, fatigue, cough, and nausea; adverse events occurring in at least 20% of those receiving chlorambucil included nausea, fatigue, neutropenia, anemia, and vomiting. In the ibrutinib group, four patients had a grade 3 hemorrhage and one had a grade 4 hemorrhage. A total of 87% of the patients in the ibrutinib group are continuing to take ibrutinib. CONCLUSIONS

  9. 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

  10. Monoclonal B-cell lymphocytosis and chronic lymphocytic leukemia.

    PubMed

    Rawstron, Andy C; Bennett, Fiona L; O'Connor, Sheila J M; Kwok, Marwan; Fenton, James A L; Plummer, Marieth; de Tute, Ruth; Owen, Roger G; Richards, Stephen J; Jack, Andrew S; Hillmen, Peter

    2008-08-07

    A diagnosis of chronic lymphocytic leukemia (CLL) requires a count of over 5000 circulating CLL-phenotype cells per cubic millimeter. Asymptomatic persons with fewer CLL-phenotype cells have monoclonal B-cell lymphocytosis (MBL). The goal of this study was to investigate the relation between MBL and CLL. We investigated 1520 subjects who were 62 to 80 years of age with a normal blood count and 2228 subjects with lymphocytosis (>4000 lymphocytes per cubic millimeter) for the presence of MBL, using flow cytometry. Monoclonal B cells were further characterized by means of cytogenetic and molecular analyses. A representative cohort of 185 subjects with CLL-phenotype MBL and lymphocytosis were monitored for a median of 6.7 years (range, 0.2 to 11.8). Monoclonal CLL-phenotype B cells were detected in 5.1% of subjects (78 of 1520) with a normal blood count and 13.9% (309 of 2228) with lymphocytosis. CLL-phenotype MBL had a frequency of 13q14 deletion and trisomy 12 similar to that of CLL and showed a skewed repertoire of the immunoglobulin heavy variable group (IGHV) genes. Among 185 subjects presenting with lymphocytosis, progressive lymphocytosis occurred in 51 (28%), progressive CLL developed in 28 (15%), and chemotherapy was required in 13 (7%). The absolute B-cell count was the only independent prognostic factor associated with progressive lymphocytosis. During follow-up over a median of 6.7 years, 34% of subjects (62 of 185) died, but only 4 of these deaths were due to CLL. Age above 68 years and hemoglobin level below 12.5 g per deciliter were the only independent prognostic factors for death. The CLL-phenotype cells found in the general population and in subjects with lymphocytosis have features in common with CLL cells. CLL requiring treatment develops in subjects with CLL-phenotype MBL and with lymphocytosis at the rate of 1.1% per year. 2008 Massachusetts Medical Society

  11. 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

  12. T-cell chronic lymphocytic leukemia or small-cell variant of T-cell prolymphocytic leukemia: a historical perspective and search for consensus.

    PubMed

    Rashidi, Armin; Fisher, Stephen I

    2015-09-01

    There is a rich history behind the extinct entity 'T-cell chronic lymphocytic leukemia (T-CLL)' and the now-established replacement, small-cell variant of T-cell prolymphocytic leukemia (T-PLL-sv). Herein, we review the history of the events, observations, and discussions that led to this replacement. We also provide a systematic analysis of all previously reported cases of T-PLL-sv as well as our four new additional cases. Despite the higher frequency of a normal karyotype and perhaps an overrepresented CD4(-) CD8(-) immunophenotype among these patients (compared to T-PLL in general) as well as bland morphology (that makes them superficially appear more similar to B-CLL), we argue that the current World Health Organization (WHO)-based classification as T-PLL-sv is adequate and should continue for the time being. Morphologically, T-PLL-sv represents approximately one-fifth of all T-PLL cases. However, morphology alone does not determine the clinical course and should not be the basis for clinical decision making and prognostication. We propose a clonal evolution model in which mature T-cell leukemias classified in the past as T-CLL are perhaps T-PLL diagnosed early in the course of the disease. Future research using next-generation sequencing, comparative genomic hybridization, and molecular array studies, including serial analyses of individual cases over time, is needed to better identify this rarely diagnosed, inherently controversial form of T-cell leukemia. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  13. 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

  14. 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

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

    PubMed

    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

    2014-04-10

    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.

  16. 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

  17. 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.

  18. 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

  19. 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.

  20. 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

  1. 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.

  2. 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.

  3. 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

  4. [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.

  5. Bruton's tyrosine kinase inhibitors in chronic lymphocytic leukemia and lymphoma.

    PubMed

    Varma, Gaurav; Johnson, Tyler P; Advani, Ranjana H

    2016-07-01

    The development of Bruton's tyrosine kinase (BTK) inhibitors and their introduction into clinical practice represent a major advance in the treatment of chronic lymphocytic leukemia (CLL) and other B-cell lymphomas. Although ibrutinib is the only BTK inhibitor that has been approved by the US Food and Drug Administration, several others are under investigation. Ibrutinib is currently approved for use in relapsed/refractory CLL, CLL with 17p deletion (del[17p]), relapsed or refractory mantle cell lymphoma, and Waldenström macroglobulinemia. Although it is clear that ibrutinib has altered treatment paradigms and outcomes in these diseases, several questions remain regarding (1) its role in frontline vs salvage therapy; (2) its use as a single agent vs in combination with biologic agents, other small molecules, or traditional chemoimmunotherapy; (3) the optimal duration of treatment; and (4) the treatment of patients who cannot tolerate or have disease resistant to ibrutinib. Because sparse clinical data are available on other BTK inhibitors, it is unclear at present whether their clinical efficacy and toxicity will differ from those of ibrutinib.

  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. 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

  9. Venetoclax for the treatment of chronic lymphocytic leukemia.

    PubMed

    Gentile, Massimo; Petrungaro, Annamaria; Uccello, Giuseppina; Vigna, Ernesto; Recchia, Anna Grazia; Caruso, Nadia; Bossio, Sabrina; De Stefano, Laura; Palummo, Angela; Storino, Francesca; Martino, Massimo; Morabito, Fortunato

    2017-10-03

    Venetoclax, an orally bioavailable inhibitor of BCL-2, was approved in 2016 by the United States Food and Drug Administration (FDA) for the treatment of chronic lymphocytic leukemia (CLL) patients with 17p deletion [del(17p)], who have received at least one prior therapy. Areas covered: We focus on the mechanism of action of venetoclax and on the clinical trial data that led to approval of venetoclax for CLL patients. We also review the studies in which this drug has being explored in combination with other anti-CLL drugs. Expert opinion: Data from early clinical trials have shown that venetoclax, as a single agent, is highly effective for relapsed/refractory CLL patients, including those cases with high-risk features. Furthermore, venetoclax seems to be an appropriate option for patients who progress on B-cell receptor (BCR) pathway kinase inhibitors. Venetoclax is also safe, with the most common serious adverse events being neutropenia. The risk of tumor lysis syndrome (TLS) can be reduced by a slow dose ramp-up, careful monitoring and adequate prophylaxis. Ongoing trials will further clarify the safety and efficacy of venetoclax in combination with other drugs in both relapsed/refractory and untreated CLL patients.

  10. 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.

  11. Genetic differences between Asian and Caucasian chronic lymphocytic leukemia

    PubMed Central

    KAWAMATA, NORIHIKO; MOREILHON, CHIMENE; SAITOH, TAKAYUKI; KARASAWA, MASAMITSU; BERNSTEIN, BRIAN K.; SATO-OTSUBO, AIKO; OGAWA, SEISHI; RAYNAUD, SOPHIE; KOEFFLER, H. PHILLIP

    2013-01-01

    Chronic lymphocytic leukemia (CLL) is a common hematological malignancy in Western countries. However, this disease is very rare in Asian countries. It is not clear whether the mechanisms of development of CLL in Caucasians and Asians are the same. We compared genetic abnormalities in Asian and Caucasian CLL using 250k GeneChip arrays. Both Asian and Caucasian CLL had four common genetic abnormalities: deletion of 13q14.3, trisomy 12, abnormalities of ATM (11q) and abnormalities of 17p. Interestingly, trisomy 12 and deletion of 13q14.3 were mutually exclusive in both groups. We also found that deletions of miR 34b/34c (11q), caspase 1/4/5 (11q), Rb1 (13q) and DLC1 (8p) are common in both ethnic groups. Asian CLL more frequently had gain of 3q and 18q. These suggest that classic genomic changes in the Asian and Caucasina CLL are same. Further, we found amplification of IRF4 and deletion of the SP140/SP100 genes; these genes have been reported as CLL-associated genes by previous genome-wide-association study. We have found classic genomic abnormalities in Asian CLL as well as novel genomic alteration in CLL. PMID:23708256

  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. 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

  14. 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.

  15. 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

  16. A phase I study of imatinib mesylate in combination with chlorambucil in previously treated chronic lymphocytic leukemia patients.

    PubMed

    Hebb, Jonathan; Assouline, Sarit; Rousseau, Caroline; Desjardins, Pierre; Caplan, Stephen; Egorin, Merrill J; Amrein, Lilian; Aloyz, Raquel; Panasci, Lawrence

    2011-09-01

    The tyrosine kinase inhibitor, imatinib, has the potential to indirectly inhibit DNA repair. This mechanism of action has been shown to mediate sensitization to chlorambucil in chronic lymphocytic leukemia (CLL). To evaluate this effect in vivo, we performed a phase I study of chlorambucil combined with imatinib in relapsed CLL patients. The three dose levels studied included imatinib at 300, 400, or 600 mg/day. Imatinib was given on days 1-10, and chlorambucil (8 mg/m(2) daily) was given on days 3-7 of a 28-day cycle (up to 6 cycles). Eleven patients participated in this study. Low-grade gastrointestinal toxicities were observed in a dose-dependent manner. Forty-five percent of patients responded (two unconfirmed CRs and three PRs). Two responding patients were fludarabine refractory. The in vitro IC(50) of chlorambucil alone or in the presence of 5 μM imatinib in CLL lymphocytes correlated with the decrease in lymphocyte counts on day 15. Imatinib plasma concentrations achieved in patients were in the range of those effective in in vitro sensitization studies. The combination of chlorambucil and imatinib in patients with previously treated CLL was well tolerated and showed evidence of clinical efficacy. Based on our results, we recommend the 400 mg daily dose of imatinib on days 1-10 with 8 mg/m(3) chlorambucil on days 3-7 every 28 days as the phase II dose. This represents the first clinical trial examining the potential synergy between a tyrosine kinase inhibitor and a conventional alkylating agent for the treatment of CLL.

  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. Actinic granuloma occurring in an unusual association with cutaneous B-cell chronic lymphocytic leukemia.

    PubMed

    Kauffman, Julia A; Ivan, Doina; Cutlan, Jonathan E; Hymes, Sharon R

    2012-02-01

    Granulomatous cutaneous reactions are well described in association with T-cell non-Hodgkin lymphoma and Hodgkin lymphoma, but are rarely seen in association with B-cell non-Hodgkin lymphoma or leukemia. We report a case of a 65-year-old woman with B-cell chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) who presented with multiple, tender, firm pink papules on the face, upper trunk and upper extremities 6 years after diagnosis of CLL. Biopsy revealed both palisading granulomatous dermatitis consistent with actinic granuloma and a dense perivascular lymphocytic infiltrate consistent with the patient's known history of leukemia. This is an unusual manifestation of cutaneous B-cell CLL that is rarely seen. Copyright © 2011 John Wiley & Sons A/S.

  19. 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.

  20. CAR T Cell Therapy in Acute Lymphoblastic Leukemia and Potential for Chronic Lymphocytic Leukemia.

    PubMed

    Singh, Nathan; Frey, Noelle V; Grupp, Stephan A; Maude, Shannon L

    2016-06-01

    Adoptive transfer of autologous T cells engineered to express a chimeric antigen receptor (CAR) represents a powerful targeted immunotherapy that has shown great promise in some of the most refractory leukemias. CAR-modified T cells directed against CD19 have led the way, setting a high standard with remission rates as high as 90 % in clinical trials for relapsed/refractory acute lymphoblastic leukemia (ALL). Yet, the first demonstration of efficacy was in another disease, chronic lymphocytic leukemia (CLL), in which CD19-targeted CAR T cells eradicated bulky, highly refractory disease. Despite early encouraging results, clinical trials in CLL have yielded lower response rates, revealing disease-specific differences in response in this form of immunotherapy. Ongoing research focused on identifying and overcoming these limitations, promises to improve response rates. Beyond the induction of remission, the transformative impact of engineered T cell therapy lies in its potential for long-term disease control. With longer follow-up and durable T cell persistence now reported, we are closer to answering the question of whether sustained remissions are possible with CAR T cell monotherapy. As might be expected with a highly effective therapy using a single mechanism of action, escape pathways have emerged. Combinatorial approaches are needed to anticipate and prevent this mode of relapse. Lastly, toxicity management is vital to ensure the safety of this exciting cancer immunotherapy.

  1. 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

  2. Novel treatments for chronic lymphocytic leukemia and moving forward.

    PubMed

    Brown, Jennifer R; Porter, David L; O'Brien, Susan M

    2014-01-01

    The last several years have seen an explosion of novel therapies for chronic lymphocytic leukemia (CLL). These include the antibody obintutuzumab (GA-101), as well as small-molecule inhibitors of key pathways involved in the pathogenesis of CLL, specifically the B-cell receptor (BCR) pathway (especially Bruton's tyrosine kinase [BTK] and P13K), and the antiapoptotic pathway (especially BCL-2). We will consider each in turn, focusing on the molecules most advanced in clinical development. There has also been extensive development in rewiring the patient's own immune system to treat CLL. This has been done through modifying autologous T cells to express a chimeric antigen receptor (CAR). Thus far all CAR-T preparations have targeted the CD19 antigen. This is a good rational for B-cell malignancies as CD19 expression is limited to B-cell malignancies and normal B cells. The in vivo amplification of the transduced T cells relies on signaling and co-signaling domains and provides significant killing of CLL cells. As exciting as these novel agents and approaches are, they obviously beg the question, will chemotherapy as a treatment for CLL soon be obsolete? Although chemotherapy is associated with known short-term toxicities, it has the advantage of being completed in a short period of time and being relatively inexpensive in comparison to novel therapies. In addition, long-term follow-up of results with chemoimmunotherapy have now identified a group of patients whose remissions are maintained for more than 10 years. An important question that will arise going forward is how to incorporate novel agents without eliminating the long term benefits possible with chemoimmunotherapy in a subset of patients with CLL.

  3. Small nucleolar RNAs as new biomarkers in chronic lymphocytic leukemia

    PubMed Central

    2013-01-01

    Background Small nucleolar RNAs (snoRNAs) and small Cajal body-specific RNAs are non-coding RNAs involved in the maturation of other RNA molecules. Alterations of sno/scaRNA expression may play a role in cancerogenesis. This study elucidates the patterns of sno/scaRNA expression in 211 chronic lymphocytic leukemia (CLL) patients (Binet stage A) also in comparison with those of different normal B-cell subsets. Methods The patterns of sno/scaRNA expression in highly purified CD19+ B-cells of 211 CLL patients and in 18 normal B-cell samples - 6 from peripheral blood, and 12 from tonsils (4 germinal center, 2 marginal zone, 3 switched memory and 3 naïve B-cells) - were analyzed on the Affymetrix GeneChip® Human Gene 1.0 ST array. Results CLLs display a sno/scaRNAs expression profile similar to normal memory, naïve and marginal-zone B-cells, with the exception of a few down-regulated transcripts (SNORA31, -6, -62, and -71C). Our analyses also suggest some heterogeneity in the pattern of sno/scaRNAs expression which is apparently unrelated to the major biological (ZAP-70 and CD38), molecular (IGHV mutation) and cytogenetic markers. Moreover, we found that SNORA70F was significantly down-regulated in poor prognostic subgroups and this phenomenon was associated with the down-regulation of its host gene COBLL1. Finally, we generated an independent model based on SNORA74A and SNORD116-18 expression, which appears to distinguish two different prognostic CLL groups. Conclusions These data extend the view of sno/scaRNAs deregulation in cancer and may contribute to discover novel biomarkers associated with the disease and potentially useful to predict the clinical outcome of early stage CLL patients. PMID:24004562

  4. Alemtuzumab in chronic lymphocytic leukemia: final results of a large observational multicenter study in mostly pretreated patients.

    PubMed

    Fiegl, M; Stauder, R; Steurer, M; Mian, M; Hopfinger, G; Brychtova, Y; Skrabs, C; Zabernigg, A; Schmid, F; Haslbaur, F; Winder, G; Walder, A; Lang, A; Voskova, D; Greil, R; Mayer, J; Gastl, G

    2014-02-01

    This retrospective study evaluated the benefit of alemtuzumab monotherapy in unselected patients with advanced B-cell chronic lymphocytic leukemia (CLL) and prolymphocytic leukemia (B-PLL) to definitely describe the impact of this antibody in clinical routine use. Data were collected from 208 consecutive, mainly pretreated, patients with CLL (n = 202), and B-PLL (n = 6) who had received alemtuzumab. Response, progression-free survival (PFS), and overall survival (OS) in various settings were assessed, and toxicities were documented. In these routine patients, a comparably low cumulative dose of alemtuzumab (median, 403 mg) was applied. In CLL, overall response rate was 32 %, and various pre-therapeutic parameters were predictive for inferior response, among them, the prior administration of ≥3 therapy lines (P < 0.001), refractoriness to fludarabine (P = 0.002), and bulky lymphadenopathy (P = 0.003). PFS and OS after start of alemtuzumab were 6.2 and 21.0 months, respectively. Bulky lymphadenopathy was the prominent risk factor for both inferior PFS (P < 0.001) and OS (P = 0.002). In B-PLL, four patients experienced a fatal outcome, whereas two patients had some benefit with alemtuzumab. The main adverse effects were CMV reactivation (20 %) and a broad spectrum of infections, which together were the main reasons for treatment interruption and/or premature termination. In conclusion, alemtuzumab administered even at low dose levels was effective but overall considerably toxic in routine CLL patients. We emphasize that alemtuzumab remains an important therapeutic option in subsets of CLL patients.

  5. 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.

  6. 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

  7. 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

  8. Predicting Prognosis in Chronic Lymphocytic Leukemia in the Contemporary Era.

    PubMed

    Nabhan, Chadi; Raca, Gordana; Wang, Y Lynn

    2015-10-01

    Next-generation sequencing has identified new genetic markers that have altered prognosis for patients with chronic lymphocytic leukemia (CLL) at diagnosis. Understanding the significance of these prognostic indicators and recognizing their potential impact on treatment selection and patients' outcomes is critical for clinicians and investigators. To review novel prognostic factors at CLL diagnosis that have shown an impact on the prognosis and outcomes of this disease. Literature from January 2004 through December 2014 was searched in PubMed, Cochrane Central Register of Controlled Trials, and Scopus to identify English-language, peer-reviewed articles on clinical and prognostic factors for CLL (TP53, ATM, NOTCH1, SF3B1, BIRC3, and MYD88). Reference lists were subsequently reviewed for additional articles. A total of 450 articles was identified, and 48 articles meeting inclusion criteria were reviewed. Among prognostic markers reviewed, chromosomal aberrations have been validated and are currently used clinically to predict prognosis. Patients with 17p13.1 deletion have poor response to chemoimmunotherapy and are treated differently, with some undergoing allogeneic transplantation in first remission. CD38 and ZAP-70 status of malignant cells and unmutated immunoglobulin variable heavy chain gene have similarly been validated to predict adverse prognosis, but their implications on treatment selection have not been proven. The presence of TP53 and ATM mutations predicts worse prognosis, which has been corroborated in various studies. Patients with TP53 mutations have lower responses to chemoimmunotherapy. Furthermore, patients with TP53 and ATM mutations have inferior progression-free survival and overall survival, independent of other factors. Patients carrying the NOTCH1 and SF3B1 mutations have worse prognosis; patients with the NOTCH1 mutation have lower response rates to standard chemoimmunotherapy. The impact of BIRC3 on prognosis and survival requires further

  9. 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.

  10. Gene Expression Profiling of B Cell Chronic Lymphocytic Leukemia Reveals a Homogeneous Phenotype Related to Memory B Cells〉

    PubMed Central

    Klein, Ulf; Tu, Yuhai; Stolovitzky, Gustavo A.; Mattioli, Michela; Cattoretti, Giorgio; Husson, Hervé; Freedman, Arnold; Inghirami, Giorgio; Cro, Lilla; Baldini, Luca; Neri, Antonino; Califano, Andrea; Dalla-Favera, Riccardo

    2001-01-01

    B cell–derived chronic lymphocytic leukemia (B-CLL) represents a common malignancy whose cell derivation and pathogenesis are unknown. Recent studies have shown that >50% of CLLs display hypermutated immunoglobulin variable region (IgV) sequences and a more favorable prognosis, suggesting that they may represent a distinct subset of CLLs which have transited through germinal centers (GCs), the physiologic site of IgV hypermutation. To further investigate the phenotype of CLLs, their cellular derivation and their relationship to normal B cells, we have analyzed their gene expression profiles using oligonucleotide-based DNA chip microarrays representative of ∼12,000 genes. The results show that CLLs display a common and characteristic gene expression profile that is largely independent of their IgV genotype. Nevertheless, a restricted number of genes (<30) have been identified whose differential expression can distinguish IgV mutated versus unmutated cases and identify them in independent panels of cases. Comparison of CLL profiles with those of purified normal B cell subpopulations indicates that the common CLL profile is more related to memory B cells than to those derived from naive B cells, CD5+ B cells, and GC centroblasts and centrocytes. Finally, this analysis has identified a subset of genes specifically expressed by CLL cells of potential pathogenetic and clinical relevance. PMID:11733577

  11. 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

  12. 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.

  13. 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

  14. 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.

  15. A high-density SNP genome-wide linkage search of 206 families identifies susceptibility loci for chronic lymphocytic leukemia

    PubMed Central

    Sellick, Gabrielle S.; Goldin, Lynn R.; Wild, Ruth W.; Slager, Susan L.; Ressenti, Laura; Strom, Sara S.; Dyer, Martin J. S.; Mauro, Francesca R.; Marti, Gerald E.; Fuller, Stephen; Lyttelton, Matthew; Kipps, Thomas J.; Keating, Michael J.; Call, Timothy G.; Catovsky, Daniel

    2007-01-01

    Chronic lymphocytic leukemia (CLL) and other B-cell lymphoproliferative disorders display familial aggregation. To identify a susceptibility gene for CLL, we assembled families from the major European (ICLLC) and American (GEC) consortia to conduct a genome-wide linkage analysis of 101 new CLL pedigrees using a high-density single nucleotide polymorphism (SNP) array and combined the results with data from our previously reported analysis of 105 families. Here, we report on the combined analysis of the 206 families. Multipoint linkage analyses were undertaken using both nonparametric (model-free) and parametric (model-based) methods. After the removal of high linkage disequilibrium SNPs, we obtained a maximum nonparametric linkage (NPL) score of 3.02 (P = .001) on chromosome 2q21.2. The same genomic position also yielded the highest multipoint heterogeneity LOD (HLOD) score under a common recessive model of disease susceptibility (HLOD = 3.11; P = 7.7 × 10−5), which was significant at the genome-wide level. In addition, 2 other chromosomal positions, 6p22.1 (corresponding to the major histocompatibility locus) and 18q21.1, displayed HLOD scores higher than 2.1 (P < .002). None of the regions coincided with areas of common chromosomal abnormalities frequently observed in CLL. These findings provide direct evidence for Mendelian predisposition to CLL and evidence for the location of disease loci. PMID:17687107

  16. 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.

  17. 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.

  18. Significance of bone marrow reticulin fibrosis in chronic lymphocytic leukemia at diagnosis: a study of 176 patients with prognostic implications.

    PubMed

    Tadmor, Tamar; Shvidel, Lev; Aviv, Ariel; Ruchlemer, Rosa; Bairey, Osnat; Yuklea, Mona; Herishanu, Yair; Braester, Andre; Rahimi-Levene, Naomi; Levene, Naomi; Vernea, Fiona; Ben-Ezra, Jonathan; Bejar, Jacob; Polliack, Aaron

    2013-05-15

    Bone marrow (BM) biopsies from patients with chronic lymphocytic leukemia (CLL) may show reticulin fibrosis at diagnosis, but its significance remains unclear. This study sought to assess the prognostic impact of BM reticulin fibrosis in patients with previously untreated CLL. Data was reviewed from untreated CLL patients in the national Israel CLL database, followed during 1987 to 2012. All bone marrow biopsies were graded for reticulin fibrosis using a modified scoring system containing 4 grades (0-3), based on the European consensus report. Grade of reticulin fibrosis was correlated with overall survival (OS), outcome, and a number of well-recognized prognostic factors for CLL. The final cohort included 176 patients (122 males and 51 females). Median age was 63 years (range, 32-86 years) and the 5-year OS was 77.1%. Grade of BM reticulin fibrosis correlated with OS (P < .0001) and mortality (P = .001), and separated patients into 2 groups with different survival curves. Advanced reticulin fibrosis (grades 2-3) was associated with thrombocytopenia (platelet counts of < 100,000/mm(3) ) (P = .025), anemia (P = .018), elevated β2-microglobulin < 4000 μg/mL (P = .048), and the presence of 11q deletion (P = .0015). There was a significant correlation between poor survival and grade of BM reticulin fibrosis. This staining procedure is easy to perform and can readily be added routinely when examining BM biopsies in CLL, because the findings do have prognostic implications. Copyright © 2013 American Cancer Society.

  19. 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

  20. 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.

  1. 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.

  2. 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

  3. 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.

  4. 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. ...

  5. 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

  6. 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.

  7. Chronic lymphocytic leukemia/small lymphocytic lymphoma: another neoplasm related to the B-cell follicle?

    PubMed

    Tandon, Bevan; Swerdlow, Steven H; Hasserjian, Robert P; Surti, Urvashi; Gibson, Sarah E

    2015-01-01

    Although there has been increased attention paid to the critical nature of nodal involvement in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), the B-cell compartment it is most closely related to and its relationship to the follicle remain uncertain. A clinicopathologic investigation of 60 extramedullary biopsies of LEF1+ CLL/SLL, including 29 cases with perifollicular/follicular (PF/F) growth, was therefore performed. A subset of PF/F cases demonstrated inner mantle zone preservation or intra-mantle zone growth. All PF/F and 16/31 other cases contained CD21+ follicular dendritic cells. No cytogenetic, IGHV mutational or gene usage differences were seen between PF/F and diffuse cases. PF/F cases were more often kappa positive (p<0.03) and had fewer involved nodal sites (p=0.0004). These findings suggest that at least a subset of bona fide CLL/SLL is related to the follicle, most likely the outer mantle zone, and that at least a subset of the diffuse cases may represent "later" disease.

  8. 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.

  9. T cells in chronic lymphocytic leukemia display dysregulated expression of immune checkpoints and activation markers

    PubMed Central

    Palma, Marzia; Gentilcore, Giusy; Heimersson, Kia; Mozaffari, Fariba; Näsman-Glaser, Barbro; Young, Emma; Rosenquist, Richard; Hansson, Lotta; Österborg, Anders; Mellstedt, Håkan

    2017-01-01

    Chronic lymphocytic leukemia is characterized by impaired immune functions largely due to profound T-cell defects. T-cell functions also depend on co-signaling receptors, inhibitory or stimulatory, known as immune checkpoints, including cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) and programmed death-1 (PD-1). Here we analyzed the T-cell phenotype focusing on immune checkpoints and activation markers in chronic lymphocytic leukemia patients (n=80) with different clinical characteristics and compared them to healthy controls. In general, patients had higher absolute numbers of CD3+ cells and the CD8+ subset was particularly expanded in previously treated patients. Progressive patients had higher numbers of CD4+ and CD8+ cells expressing PD-1 compared to healthy controls, which was more pronounced in previously treated patients (P=0.0003 and P=0.001, respectively). A significant increase in antigen-experienced T cells was observed in patients within both the CD4+ and CD8+ subsets, with a significantly higher PD-1 expression. Higher numbers of CD4+ and CD8+ cells with intracellular CTLA-4 were observed in patients, as well as high numbers of proliferating (Ki67+) and activated (CD69+) CD4+ and CD8+ cells, more pronounced in patients with active disease. The numbers of Th1, Th2, Th17 and regulatory T cells were substantially increased in patients compared to controls (P<0.05), albeit decreasing to low levels in pre-treated patients. In conclusion, chronic lymphocytic leukemia T cells display increased expression of immune checkpoints, abnormal subset distribution, and a higher proportion of proliferating cells compared to healthy T cells. Disease activity and previous treatment shape the T-cell profile of chronic lymphocytic leukemia patients in different ways. PMID:27927767

  10. T cells in chronic lymphocytic leukemia display dysregulated expression of immune checkpoints and activation markers.

    PubMed

    Palma, Marzia; Gentilcore, Giusy; Heimersson, Kia; Mozaffari, Fariba; Näsman-Glaser, Barbro; Young, Emma; Rosenquist, Richard; Hansson, Lotta; Österborg, Anders; Mellstedt, Håkan

    2017-03-01

    Chronic lymphocytic leukemia is characterized by impaired immune functions largely due to profound T-cell defects. T-cell functions also depend on co-signaling receptors, inhibitory or stimulatory, known as immune checkpoints, including cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) and programmed death-1 (PD-1). Here we analyzed the T-cell phenotype focusing on immune checkpoints and activation markers in chronic lymphocytic leukemia patients (n=80) with different clinical characteristics and compared them to healthy controls. In general, patients had higher absolute numbers of CD3(+) cells and the CD8(+) subset was particularly expanded in previously treated patients. Progressive patients had higher numbers of CD4(+) and CD8(+) cells expressing PD-1 compared to healthy controls, which was more pronounced in previously treated patients (P=0.0003 and P=0.001, respectively). A significant increase in antigen-experienced T cells was observed in patients within both the CD4(+) and CD8(+) subsets, with a significantly higher PD-1 expression. Higher numbers of CD4(+) and CD8(+) cells with intracellular CTLA-4 were observed in patients, as well as high numbers of proliferating (Ki67(+)) and activated (CD69(+)) CD4(+) and CD8(+) cells, more pronounced in patients with active disease. The numbers of Th1, Th2, Th17 and regulatory T cells were substantially increased in patients compared to controls (P<0.05), albeit decreasing to low levels in pre-treated patients. In conclusion, chronic lymphocytic leukemia T cells display increased expression of immune checkpoints, abnormal subset distribution, and a higher proportion of proliferating cells compared to healthy T cells. Disease activity and previous treatment shape the T-cell profile of chronic lymphocytic leukemia patients in different ways. Copyright© Ferrata Storti Foundation.

  11. 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

  12. 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

  13. Resistance to Dasatinib in primary chronic lymphocytic leukemia lymphocytes involves AMPK-mediated energetic re-programming.

    PubMed

    Martinez Marignac, Veronica L; Smith, Sarah; Toban, Nader; Bazile, Miguel; Aloyz, Raquel

    2013-12-01

    Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults in the western world. Although promising new therapies for this incurable disease are being tested in clinical trials, the therapeutic relevance of metabolic rewiring in chronic lymphocytic leukemia (CLL) is poorly understood. The aim of this study was to identify targetable metabolic differences in primary CLL lymphocytes by the use of Dasatinib. Dasatinib is a multi-tyrosine kinase inhibitor used to treat chronic myelogenous leukemia (CML) and is being tested in clinical trials for several cancers including CLL. This drug has been shown to be beneficial to CML patients suffering from diabetes by reducing their glucose plasma levels. In keeping with this previous observation, we report that Dasatinib induced glucose use while reducing lactate production, suggesting that this tyrosine kinase inhibitor decreases aerobic glycolysis and shifts glucose use in primary CLL lymphocytes. Our results suggest that primary CLL lymphocytes (independently of traditional prognostic factors) can be stratified in two subsets by their sensitivity to Dasatinib in vitro. Increased glucose use induced by Dasatinib or by inhibition of mitochondrial respiration was not sufficient to sustain survival and ATP levels in CLL samples sensitive to Dasatinib. The two subsets of primary CLL lymphocytes are characterized as well by a differential dependency on mitochondrial respiration and the use of anabolic or catabolic processes to cope with induced metabolic/energetic stress. Differential metabolic reprogramming between subsets is supported by the contrasting effect on the survival of Dasatinib treated CLL lymphocytes with pharmacological inhibition of two master metabolic regulators (mTorc1 and AMPK) as well as induced autophagy. Alternative metabolic organization between subsets is further supported by the differential basal expression (freshly purified lymphocytes) of active AMPK, regulators of glucose metabolism and

  14. 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

  15. 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

  16. 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.

  17. 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.

  18. Estimating outcomes and cost effectiveness using a single-arm clinical trial: ofatumumab for double-refractory chronic lymphocytic leukemia.

    PubMed

    Hatswell, Anthony J; Thompson, Gwilym J; Maroudas, Penny A; Sofrygin, Oleg; Delea, Thomas E

    2017-01-01

    Ofatumumab (Arzerra(®), Novartis) is a treatment for chronic lymphocytic leukemia refractory to fludarabine and alemtuzumab [double refractory (DR-CLL)]. Ofatumumab was licensed on the basis of an uncontrolled Phase II study, Hx-CD20-406, in which patients receiving ofatumumab survived for a median of 13.9 months. However, the lack of an internal control arm presents an obstacle for the estimation of comparative effectiveness. The objective of the study was to present a method to estimate the cost effectiveness of ofatumumab in the treatment of DR-CLL. As no suitable historical control was available for modelling, the outcomes from non-responders to ofatumumab were used to model the effect of best supportive care (BSC). This was done via a Cox regression to control for differences in baseline characteristics between groups. This analysis was included in a partitioned survival model built in Microsoft(®) Excel with utilities and costs taken from published sources, with costs and quality-adjusted life years (QALYs) were discounted at a rate of 3.5% per annum. Using the outcomes seen in non-responders, ofatumumab is expected to add approximately 0.62 life years (1.50 vs. 0.88). Using published utility values this translates to an additional 0.30 QALYs (0.77 vs. 0.47). At the list price, ofatumumab had a cost per QALY of £130,563, and a cost per life year of £63,542. The model was sensitive to changes in assumptions regarding overall survival estimates and utility values. This study demonstrates the potential of using data for non-responders to model outcomes for BSC in cost-effectiveness evaluations based on single-arm trials. Further research is needed on the estimation of comparative effectiveness using uncontrolled clinical studies.

  19. 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.

  20. 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

  1. 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.

  2. Opticin, a small leucine-rich proteoglycan, is uniquely expressed and translocated to the nucleus of chronic lymphocytic leukemia cells

    PubMed Central

    2013-01-01

    Background Opticin (OPTC) is a member of the small leucine-rich proteoglycan (SLRP) family and is localized particularly in certain extracellular matrices. We have previously reported the unique expression of another SLRP, fibromodulin (FMOD) in the leukemic cells of patients with chronic lymphocytic leukemia (CLL). OPTC is located in the same region as FMOD on chromosome 1 (1q32.1). Cluster up-regulation of genes may be observed in malignancies and the aim of the present study was to analyze the expression of OPTC in CLL cells. Methods The expression of OPTC was tested by RT-PCR and realtime qPCR in PBMC from CLL patients, other hematological malignancies and healthy controls. The presence of OPTC protein, and its subcellular localization, was investigated using fractionation methods where the obtained lysate fractions were analyzed by Western blotting. Deglycosylation experiments were performed to investigate the glycosylation status of the CLL OPTC. Results OPTC was expressed at the gene level in all patients with CLL (n = 90) and in 2/8 patients with mantle cell lymphoma (MCL) but not in blood mononuclear cells of healthy control donors (n = 20) or in tumor samples from nine other types of hematological malignancies. OPTC was detected by Western blot in all CLL samples analyzed (n = 30) but not in normal leukocytes (n = 10). Further analysis revealed a CLL-unique unglycosylated 37 kDa core protein that was found to be located preferentially in the cell nucleus and endoplasmic reticulum (ER) of the CLL cells. Conclusions A 37 kDa unglycosylated OPTC protein was detected in ER and in the nucleus of CLL cells and not in healthy control donors. The function of this OPTC core protein remains unclear but its CLL-specific expression and subcellular localization warrants further investigations in the pathobiology of CLL. PMID:24499526

  3. 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.

  4. 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

  5. Human chronic lymphocytic leukemia modeled in mouse by targeted TCL1 expression

    PubMed Central

    Bichi, Roberta; Shinton, Susan A.; Martin, Eric S.; Koval, Anatoliy; Calin, George A.; Cesari, Rossano; Russo, Giandomenico; Hardy, Richard R.; Croce, Carlo M.

    2002-01-01

    The TCL1 gene at 14q32.1 is involved in chromosomal translocations and inversions in mature T cell leukemias. These leukemias are classified either as T prolymphocytic leukemias, which occur very late in life, or as T chronic lymphocytic leukemias, which often arise in patients with ataxia telangiectasia (AT) at a young age. In transgenic animals, the deregulated expression of TCL1 leads to mature T cell leukemia, demonstrating the role of TCL1 in the initiation of malignant transformation in T cell neoplasia. Expression of high levels of Tcl1 have also been found in a variety of human tumor-derived B cell lines ranging from pre-B cell to mature B cell. Here we describe the phenotype of transgenic mice, Eμ-TCL1, established with TCL1 under the control of a VH promoter-IgH-Eμ enhancer to target TCL1 expression to immature and mature B cells. Flow cytometric analysis reveals a markedly expanded CD5+ population in the peritoneal cavity of Eμ-TCL1 mice starting at 2 mo of age that becomes evident in the spleen by 3–5 mo and in the bone marrow by 5–8 mo. Analysis of Ig gene rearrangements indicates monoclonality or oligoclonality in these populations, suggesting a preneoplastic expansion of CD5+ B cell clones, with the elder mice eventually developing a chronic lymphocytic leukemia (CLL)-like disorder resembling human B-CLL. Our findings provide an animal model for CLL, the most common human leukemia, and demonstrate that deregulation of the Tcl1 pathway plays a crucial role in CLL pathogenesis. PMID:12011454

  6. 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

  7. 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.

  8. Treatment Emergent Agranulocytosis with Skin and Gingival Lesions in a Chronic Lymphocytic Leukemia Patient: A Case Report

    PubMed Central

    Zade, Varun; Boddun, Meenakshi; Gupta, Rolly; Kumari, Micky; Suryawanshi, Hema

    2016-01-01

    Chronic Lymphocytic Leukaemia (CLL) is a monoclonal lymphoid malignancy characterized by progressive accumulation of small, mature but functionally incompetent neoplastic lymphocytes in the peripheral blood, bone marrow and lymphoid organs. Patients present a variable course and may not require early intervention unlike other malignancies. Patients with rapidly deteriorating blood counts, and organomegaly need treatment. Alkylating agent live Bendamustine combined with Rituximab, anti-CD 20 monoclonal antibody have shown promising results in such patients. Anaemia, neutropenia and thrombocytopenia have been reported as treatment emergent events with this combination therapy. Neutrophils are the major innate defense and their depletion can result in a wide range of opportunistic infections. This case report discusess the oral and dermal lesions which emerged with the Rituximab and Bendamustine combination therapy in a patient with CLL and their management. PMID:27891482

  9. 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. PMID:28408842

  10. 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

  11. 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.

  12. TRAF2 deficiency in B lymphocytes predisposes to chronic lymphocytic leukemia/small lymphocytic lymphoma in mice1

    PubMed Central

    Pérez-Chacón, Gema; Llobet, David; Pardo, Constanza; Pindado, Jose; Choi, Yongwon; Reed, John C.; Zapata, Juan M.

    2012-01-01

    We have previously shown that transgenic mice expressing in B lymphocytes both BCL-2 and a TRAF2 mutant lacking the RING and zinc finger domains (TRAF2DN) develop small lymphocytic lymphoma (SLL) and chronic lymphocytic leukemia (CLL) with high incidence. Further analysis of the expression of TRAF2 and TRAF2DN in purified B cells demonstrated that expression of both endogenous TRAF2 and transgenic TRAF2DN was negligible in Traf2DN-tg B cells compared to wild-type mice. This was the result of proteasome-dependent degradation, and rendered TRAF2DN B cells as bona fide TRAF2 deficient B cells. Similar to B cells with targeted Traf2 deletion, Traf2DN-tg mice show expanded marginal zone (MZ) B cell population and have constitutive p100 NF- κ B2 processing. Also, TRAF3, XIAP and Bcl-XL expression levels were increased, while cIAP1/2 levels were drastically reduced compared to those found in wild-type B cells. Moreover, consistent with previous results, we also show that TRAF2 was required for efficient JNK and ERK activation in response to CD40 engagement. However, TRAF2 was deleterious for BCR-mediated activation of these kinases. In contrast, TRAF2 deficiency had no effect on CD40-mediated p38 MAPK activation but significantly reduced BCR-mediated p38 activation. Finally, we further confirm that TRAF2 was required for CD40-mediated proliferation, but its absence relieved B cells of the need for BAFF for survival. Altogether, our results suggest that TRAF2 deficiency cooperates with BCL-2 in promoting CLL/SLL in mice, possibly by specifically enforcing MZ B cell accumulation, increasing XIAP expression, and rendering B cells independent of BAFF for survival. PMID:22711886

  13. 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.

  14. 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

  15. 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

  16. Evaluation of ZAP-70 expression by flow cytometry in chronic lymphocytic leukemia: A multicentric international harmonization process.

    PubMed

    Letestu, Remi; Rawstron, Andy; Ghia, Paolo; Villamor, Neus; Boeckx, Nancy; Leuven, Nancy Boeckx; Boettcher, Sebastian; Buhl, Anne Mette; Duerig, Jan; Ibbotson, Rachel; Kroeber, Alexander; Langerak, Anton; Le Garff-Tavernier, Magali; Mockridge, Ian; Morilla, Alison; Padmore, Ruth; Rassenti, Laura; Ritgen, Matthias; Shehata, Medhat; Smolewski, Piotr; Staib, Peter; Ticchioni, Michel; Walker, Clare; Ajchenbaum-Cymbalista, Florence

    2006-07-15

    The clinical course of patients with chronic lymphocytic leukemia (CLL) is heterogeneous with some patients requiring early therapy whereas others will not be treated for years. The evaluation of an individual CLL patient's prognosis remains a problematic issue. The presence or absence of somatic mutations in the IgVH genes is currently the gold-standard prognostic factor, but this technique is labor intensive and costly. Genomic studies uncovered that 70 kDa zeta-associated protein (ZAP-70) expression was associated with unmutated IgVH genes and ZAP-70 protein expression was proposed as a surrogate for somatic mutational status. Among the available techniques for ZAP-70 detection, flow cytometry is most preferable as it allows the simultaneous quantification of ZAP-70 protein expression levels in CLL cells and residual normal lymphocyte subsets. However, several factors introduce variability in the results reported from different laboratories; these factors include the anti-ZAP-70 antibody clone and conjugate, the staining procedure, the gating strategy, and the method of reporting the results. The need for standardization of the approach led to the organization of an international working group focused on harmonizing all aspects of the technique. During this workshop, a technical consensus was reached on the methods for cell permeabilization and immunophenotyping procedures. An assay was then designed that allowed comparison of two clones of anti-ZAP-70 antibody and the identification of the expression of this molecule in B, T, and NK cells identified in a four multicolor analysis. This procedure was applied to three stabilized blood samples, provided by the UK NEQAS group to all participating members of this study, in order to minimize variability caused by sample storage and shipment. Analysis was performed in 20 laboratories providing interpretable data from 14 centers. Various gating strategies were used and the ZAP-70 levels were expressed as percentage

  17. 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

  18. 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.

  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. 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

  1. 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.

  2. 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.

  3. 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.

  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. 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

  7. 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. PMID:28396813

  8. 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.

  9. The cytotoxic activity of Aplidin in chronic lymphocytic leukemia (CLL) is mediated by a direct effect on leukemic cells and an indirect effect on monocyte-derived cells.

    PubMed

    Morande, Pablo E; Zanetti, Samanta R; Borge, Mercedes; Nannini, Paula; Jancic, Carolina; Bezares, Raimundo F; Bitsmans, Alicia; González, Miguel; Rodríguez, Andrea L; Galmarini, Carlos M; Gamberale, Romina; Giordano, Mirta

    2012-10-01

    Aplidin is a novel cyclic depsipeptide, currently in Phase II/III clinical trials for solid and hematologic malignancies. The aim of this study was to evaluate the effect of Aplidin in chronic lymphocytic leukemia (CLL), the most common leukemia in the adult. Although there have been considerable advances in the treatment of CLL over the last decade, drug resistance and immunosuppression limit the use of current therapy and warrant the development of novel agents. Here we report that Aplidin induced a dose- and time-dependent cytotoxicity on peripheral blood mononuclear cells (PBMC) from CLL patients. Interestingly, Aplidin effect was markedly higher on monocytes compared to T lymphocytes, NK cells or the malignant B-cell clone. Hence, we next evaluated Aplidin activity on nurse-like cells (NLC) which represent a cell subset differentiated from monocytes that favors leukemic cell progression through pro-survival signals. NLC were highly sensitive to Aplidin and, more importantly, their death indirectly decreased neoplasic clone viability. The mechanisms of Aplidin-induced cell death in monocytic cells involved activation of caspase-3 and subsequent PARP fragmentation, indicative of death via apoptosis. Aplidin also showed synergistic activity when combined with fludarabine or cyclophosphamide. Taken together, our results show that Aplidin affects the viability of leukemic cells in two different ways: inducing a direct effect on the malignant B-CLL clone; and indirectly, by modifying the microenvironment that allows tumor growth.

  10. 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

  11. 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.

  12. Correction: Bruton's tyrosine kinase inhibitors in chronic lymphocytic leukemia and lymphoma.

    PubMed

    2016-09-01

    An article in the July 2016 issue, "Bruton's tyrosine kinase inhibitors in chronic lymphocytic leukemia and lymphoma" by Gaurav Varma, MSPH, Tyler P. Johnson, MD, and Ranjana H. Advani, MD, described ONO/GS-4059 as a "reversible" inhibitor of BTK when it is in fact an "irreversible" inhibitor. We have made the correction to pages 546 and 552 of the online version at www.hematologyandoncology.net. Many thanks to an astute reader for pointing out the error. This corrects the article pmid:27379948.

  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. 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

  15. 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.

  16. 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

  17. 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

  18. 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.

  19. 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.

  20. 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

  1. 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.

  2. 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.

  3. 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.

  4. 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

  5. Rapid progression of pulmonary blastomycosis in an untreated patient of chronic lymphocytic leukemia.

    PubMed

    Sarkar, Pralay K; Malhotra, Paras; Sriram, P S

    2014-01-01

    Chronic lymphocytic leukemia (CLL) is associated with a state of immunosuppression characterized by hypogammaglobulinemia as well as B and T lymphocyte dysfunction. Though opportunistic infections are common in CLL patients, particularly after treatment, reports of infections by endemic dimorphic fungi are very few. Here we report a case of pulmonary blastomycosis in a CLL patient who initially presented with an indolent pulmonary mass lesion. The pulmonary lesions progressed rapidly over a two-week period. The diagnosis was established by transbronchial lung biopsy. He was treated with Amphotericin B lipid complex followed by oral itraconazole and recovered uneventfully. This case illustrates the importance of a timely diagnosis and treatment. The presentation of blastomycosis in immunocompromised patients, diagnosis, and treatment are discussed.

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

    PubMed Central

    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. PMID:25733804

  7. 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.

  8. Role of chemokines and their receptors in chronic lymphocytic leukemia: function in microenvironment and targeted therapy.

    PubMed

    Han, Ting-Ting; Fan, Lei; Li, Jian-Yong; Xu, Wei

    2014-01-01

    Chemokines produced in distinct tissue microenvironments sustain migration of mature lymphocytes in lymphoglandula. Chemokine receptors expressed on chronic lymphocytic leukemia (CLL) cells regulate the migration of the leukemia cells within the bone marrow (BM), lymphoid organs in collaboration with chemokines. Chemokines form a pro-survival circuitry by regulating leukocyte trafficking, maintaining extended lymphocyte survival. Therefore, chemokines in tumor cell-microenvironment interactions represent a target for treatment of CLL. AMD3100 disrupts the CLL/microenvironment interactions and influences CXCL12/CXCR4 survival signaling. Fostamatinib, ibrutinib, and GS-1101 as B-cell receptor (BCR)-related kinase inhibitors inhibit BCR- and chemokine-receptor-signal-regulated kinase and have a good clinical response in CLL. Lenalidomide, sorafenib, and dasatinib are other additional drugs associated with chemokine in microenvironment. Inhibiting signaling through chemokine and microenvironment associated signaling are emerging as innovative therapeutic targets in CLL. In this article, we reviewed the role of chemokines in CLL microenvironment and novel therapeutics targeting CLL microenvironment.

  9. 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

  10. Rituximab and subcutaneous cladribine in chronic lymphocytic leukemia for newly diagnosed and relapsed patients.

    PubMed

    Bertazzoni, Paola; Rabascio, Cristina; Gigli, Federica; Calabrese, Liliana; Radice, Davide; Calleri, Angelica; Gregato, Giuliana; Negri, Mara; Liptrott, Sarah J; Bassi, Simona; Nassi, Luca; Sammassimo, Simona; Laszlo, Daniele; Preda, Lorenzo; Pruneri, Giancarlo; Orlando, Laura; Martinelli, Giovanni

    2010-08-01

    The aim of this study was to investigate the efficacy of combined treatment with rituximab and subcutaneous cladribine in patients with newly diagnosed and relapsed chronic lymphocytic leukemia (CLL). Forty-three patients with active CLL or small lymphocytic lymphoma received rituximab 375 mg/m(2) on day 1 and cladribine 0.1 mg/kg subcutaneously on days 2-6. The treatment was repeated every 4 weeks for a total of four cycles. Sixteen patients were pretreated. The overall response rate was 88% (50% complete remission and 38% partial remission). The median time to treatment failure was 37.9 months. Grade 4 neutropenia developed in 5% of patients. The data indicate that combination therapy with rituximab and cladribine is a valuable and safe treatment for patients with CLL.

  11. 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.

  12. 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

  13. 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

  14. 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.

  15. 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

  16. Use of hair coloring products and the risk of lymphoma, multiple myeloma, and chronic lymphocytic leukemia.

    PubMed Central

    Zahm, S H; Weisenburger, D D; Babbitt, P A; Saal, R C; Vaught, J B; Blair, A

    1992-01-01

    OBJECTIVES. Hair coloring products are widely used and contain components that are mutagenic and carcinogenic. An association between occupational exposure to hair coloring products and hematopoietic cancers has been reported, but the risk for these cancers among users has not been carefully evaluated. METHODS. We conducted a population-based, case-control study with telephone interviews from 385 with telephone interviews from 385 non-Hodgkin's lymphoma cases, 70 Hodgkin's disease cases, 72 multiple myeloma cases, 56 chronic lymphocytic leukemia cases, and 1432 controls. RESULTS. Among women, use was associated with odds ratios of 1.5 for non-Hodgkin's lymphoma, 1.7 for Hodgkin's disease, 1.8 for multiple myeloma, and 1.0 for chronic lymphocytic leukemia. Risk was higher for permanent hair coloring products than for semi- or nonpermanent products, particularly for dark colors. Long duration and early age of first use tended to increase risk, but the patterns were inconsistent. Use was much less common in men and did not significantly increase risk. CONCLUSIONS. The use of hair coloring products appears to increase the risk of non-Hodgkin's lymphoma. Multiple myeloma and Hodgkin's disease were also associated, although based on far fewer subjects. If these results represent a causal association, use of hair coloring products would account for 35% of non-Hodgkin's lymphoma cases in exposed women and 20% in all women. PMID:1609918

  17. 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

  18. Bendamustine versus chlorambucil for the first-line treatment of chronic lymphocytic leukemia in England and Wales: a cost-utility analysis.

    PubMed

    Woods, Beth; Hawkins, Neil; Dunlop, William; O'Toole, Alison; Bramham-Jones, Steve

    2012-01-01

    To evaluate the cost-effectiveness of bendamustine compared with chlorambucil as first-line treatment for patients with chronic lymphocytic leukemia who would be considered unsuitable for treatment with fludarabine combination chemotherapy regimens. A semi-Markov approach was used to estimate time in each health state. The model was parameterized primarily by using data from a phase III randomized, open-label trial comparing bendamustine with chlorambucil. It captured the increased progression-free survival and improved response rates with bendamustine, and the cost and quality of life impacts of postprogression treatments. The analysis was conducted from the perspective of the National Health Service in England and Wales. A lifetime (35-year) time horizon was used. Deterministic sensitivity analyses, probabilistic sensitivity analyses, and subgroup analyses in older patients and patients with poor performance status were carried out. The estimated incremental cost-effectiveness ratio was £ 11,960 per quality-adjusted life-year. None of the deterministic sensitivity analyses increased the incremental cost-effectiveness ratio by more than £ 2000. Subgroup analyses showed that bendamustine remained cost-effective across different patient groups. Probabilistic sensitivity analysis showed that at the £ 20,000 threshold, bendamustine has a 90% probability of being cost-effective. Bendamustine represents good value for first-line treatment of patients with chronic lymphocytic leukemia who are unsuitable for treatment with fludarabine combination chemotherapy. The incremental cost-effectiveness ratio is below the thresholds commonly applied in England and Wales (£ 20,000-£ 30,000 per quality-adjusted life-year). Copyright © 2012 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.

  19. 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

  20. 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.

  1. Clinical significance of bax/bcl-2 ratio in chronic lymphocytic leukemia.

    PubMed

    Del Principe, Maria Ilaria; Dal Bo, Michele; Bittolo, Tamara; Buccisano, Francesco; Rossi, Francesca Maria; Zucchetto, Antonella; Rossi, Davide; Bomben, Riccardo; Maurillo, Luca; Cefalo, Mariagiovanna; De Santis, Giovanna; Venditti, Adriano; Gaidano, Gianluca; Amadori, Sergio; de Fabritiis, Paolo; Gattei, Valter; Del Poeta, Giovanni

    2016-01-01

    In chronic lymphocytic leukemia the balance between the pro-apoptotic and anti-apoptotic members of the bcl-2 family is involved in the pathogenesis, chemorefractoriness and clinical outcome. Moreover, the recently proposed anti-bcl-2 molecules, such as ABT-199, have emphasized the potential role of of bcl-2 family proteins in the context of target therapies. We investigated bax/bcl-2 ratio by flow cytometry in 502 patients and identified a cut off of 1.50 to correlate bax/bcl-2 ratio with well-established clinical and biological prognosticators. Bax/bcl-2 was 1.50 or over in 263 patients (52%) with chronic lymphocytic leukemia. Higher bax/bcl-2 was associated with low Rai stage, lymphocyte doubling time over 12 months, beta-2 microglobulin less than 2.2 mg/dL, soluble CD23 less than 70 U/mL and a low risk cytogenetic profile (P<0.0001). On the other hand, lower bax/bcl-2 was correlated with unmutated IGHV (P<0.0001), mutated NOTCH1 (P<0.0001) and mutated TP53 (P=0.00007). Significant shorter progression-free survival and overall survival were observed in patients with lower bax/bcl-2 (P<0.0001). Moreover, within IGHV unmutated (168 patients) and TP53 mutated (37 patients) subgroups, higher bax/bcl-2 identified cases with significant longer PFS (P=0.00002 and P=0.039). In multivariate analysis of progression-free survival and overall survival, bax/bcl-2 was an independent prognostic factor (P=0.0002 and P=0.002). In conclusion, we defined the prognostic power of bax/bcl-2 ratio, as determined by a flow cytometric approach, and highlighted a correlation with chemoresistance and outcome in chronic lymphocytic leukemia. Finally, the recently proposed new therapies employing bcl-2 inhibitors prompted the potential use of bax/bcl-2 ratio to identify patients putatively resistant to these molecules. Copyright© Ferrata Storti Foundation.

  2. 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.

  3. 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

  4. S100-A9 protein in exosomes from chronic lymphocytic leukemia cells promotes NF-κB activity during disease progression.

    PubMed

    Prieto, Daniel; Sotelo, Natalia; Seija, Noé; Sernbo, Sandra; Abreu, Cecilia; Durán, Rosario; Gil, Magdalena; Sicco, Estefanía; Irigoin, Victoria; Oliver, Carolina; Landoni, Ana Inés; Gabus, Raúl; Dighiero, Guillermo; Oppezzo, Pablo

    2017-08-10

    Chronic lymphocytic leukemia (CLL) is an incurable disease characterized by accumulation of clonal B lymphocytes, resulting from a complex balance between cell proliferation and apoptotic death. Continuous crosstalk between cancer cells and local/distant host environment is required for effective tumor growth. Among the main actors of this dynamic interplay between tumoral cells and their microenvironment are the nano-sized vesicles called exosomes. Emerging evidence indicates that secretion, composition, and functional capacity of exosomes are altered as tumors progress to an aggressive phenotype. In CLL, no data exist exploring the specific changes in the proteomic profile of plasma-derived exosomes from patients during disease evolution. We hereby report for the first time different proteomic profiles of plasma exosomes, both between indolent and progressive CLLs as well as within the individual patients at the onset of disease and during its progression. Next, we focus on the changes of the exosome protein cargoes, which are found exclusively in patients with progressive CLL after disease progression. The alterations in the proteomic cargoes underline different networks specific for leukemia progression related to inflammation, oxidative stress, and NF-κB and phosphatidylinositol 3-kinase/AKT pathway activation. Finally, our results suggest a preponderant role for the protein S100-A9 as an activator of the NFκB pathway during CLL progression and suggest that the leukemic clone can generate an autoactivation loop through S100-A9 expression, NF-κB activation, and exosome secretion. Collectively, our data propose a new pathway for NF-κB activation in CLL and highlight the importance of exosomes as extracellular mediators promoting tumor progression in CLL. © 2017 by The American Society of Hematology.

  5. 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.

  6. 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

  7. 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.

  8. 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

  9. Expression and regulation of COP1 in chronic lymphocytic leukemia cells for promotion of cell proliferation and tumorigenicity.

    PubMed

    Fu, Chunling; Gong, Yanqing; Shi, Xuanxuan; Shi, Hengliang; Wan, Yan; Wu, Qingyun; Xu, Kailin

    2016-03-01

    Chronic lymphocytic leukemia (CLL) is the most common leukemia in Western countries, and mainly originates from an accumulation of abnormal B cells caused by the dysregulation of cell proliferation and apoptosis. The aberration of proliferation-related gene in CLL cells induces cell arrest at G0/G1 phase, or a small section shows rapid cell growth, which further complicates the pathogenesis of CLL. The constitutively photomorphogenic 1 (COP1), as an E3 ubiquitin ligase, is involved in many biological processes in mammalian cells, but its role in chronic lymphocytic leukemia (CLL) progression remains unclear. In the present study, we analyzed the expression of COP1 in peripheral blood mononuclear cells (PBMCs) from 23 CLL patients and 3 healthy donors. The observed upregulated expression of COP1 in CLL patients was positively correlated with CLL clinical stage and ZAP-70 expression, but not del(13q14) and del(17q-). Overexpression of COP1 significantly promoted cell colony formation and proliferation, especially contributing to the accumulation of cells in S-phase by inhibition of FoxO1 and p21. Moreover, overexpression of COP1 accelerated tumorigenicity of HG3 cells and promoted xenograft growth. Therefore, the present study revealed that COP1 plays an important role in CLL cell proliferation and tumorigenicity, and may be a useful indicator of the chronic lymphocytic leukemia processes.

  10. Possible prognostic value of nucleolar morphology in pathologic cells of B-chronic lymphocytic leukemia.

    PubMed

    Klobusicka, M; Kusenda, J; Stevulova, L; Kovarikova, A; Babusikova, O

    2010-01-01

    B-cell chronic lymphocytic leukemia (B-CLL) represents a heterogeneous disease with a very variable outcome. The reliable prognosis of this disease at the time of initial diagnosis is difficult to predict. The purpose of this preliminary study was to utilize the nucleolar morphology and to investigate the incidence of main nucleolar types in leukemic lymphocytes in B-CLL patients to assess their possible predictive value for the disease outcome, in correlation with immunophenotype parameters. The evaluation of nucleolar morphology of pathologic lymphocytes was performed at diagnosis and during the course of disease. Median follow up period of patients was 16.4 months (range from 2 to 32 months) from diagnosis. The nucleoli were visualized by a simple cytochemical demonstration of RNA and the proportion of main nucleolar types in pathologic lymphocyte population infiltrating bone marrow of 84 patients suffering from B-CLL was analyzed. The presence of ring shaped and compact nucleoli in leukemic lymphocytes divided patients into two subgroups with different outcome of the disease. Malignant lymphocytes of the majority of patients (Group 1, 71 patients, 84.5%) mostly contained ring shaped nucleoli. These patients were in stable phase and did not require any treatment during the follow up. The population of leukemic cells of a small group of B-CLL patients (Group 2, 13 patients, 15.4%) was characterized by the presence of various proportions of pathologic lymphocytes with one large compact nucleolus.Different response to the therapy discriminated the B-CLL patients whose leukemic lymphocytes revealed evident compact nucleoli at presentation, to next two subsets. Four of these patients (Group 2, 4/13, 31%) appeared to be resistant to chemotherapy, others (9/13, 69%) showed response to therapy, though the response time was variable. Leukemic cells with compact nucleolus morphologically resembled prolymphocytes, but hematologically and immunophenotypically did not

  11. [Chronic lymphocytic leukemia in Iceland from 2003 to 2013: Incidence, presentation and diagnosis].

    PubMed

    Olafsson, Gunnar Bjorn; Steingrimsdottir, Hlif; Vidarsson, Brynjar; Halldorsdottir, Anna Margret

    2016-04-01

    Chronic lymphocytic leukemia (CLL) is characterized by the proliferation of monoclonal B-lymphocytes. MBL (monoclonal B-cell lymphocytosis) is considered a precursor state of the disease. Although CLL is incurable it is an indolent disorder and often detected incidentally on routine blood counts. Until now little information has been available on CLL in Iceland, including the incidence, diagnosis, symptoms or MBL precursor state. This is a retrospective, descriptive study including CLL patients diagnosed in Iceland over the years 2003-2013. Registries of patients with a CLL diagnosis were obtained from the Icelandic Cancer Registry, Landspitali National University Hospital and the Medical Center in Mjódd. Medical records were reviewed for information on symptoms, diagnosis and treatment. Survival data and causes of death were obtained from national registries. The number of patients diagnosed with CLL over the study period was 161 (109 males, 52 females). The calculated incidence was 4.55/100,000, and the age-standardized incidence was 3.00/100,000. Mean age at diagnosis was 70.9 years (range 35-96 years). The Icelandic Cancer Registry lacked information on 28 patients (17.4%). The initial diagnosis of CLL was obtained exclusively with flow cytometry in 47.2% of cases. Symptoms were present at diagnosis in 67 of 151 patients (44.4%). One third of the group received chemotherapy and the average time to treatment was 1.3 years. Five-year survival was 70% and median survival was 9.4 years. Elevated lymphocyte counts (≥4,0x109/L) in peripheral blood prior (0.1 to 13.4 years) to diagnosis of CLL was identified in 85 of 99 CLL patients (85.9%). The incidence of CLL in Iceland is similar to other Western countries. The registration of CLL cases in the Icelandic Cancer Registry must be improved, especially in cases where diagnosis is based solely on flow cytometry. Elevated lymphocyte counts were present in a large proportion of cases prior to the diagnosis of CLL

  12. 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.

  13. Radiation and the risk of chronic lymphocytic and other leukemias among chornobyl cleanup workers.

    PubMed

    Zablotska, Lydia B; Bazyka, Dimitry; Lubin, Jay H; Gudzenko, Nataliya; Little, Mark P; Hatch, Maureen; Finch, Stuart; Dyagil, Irina; Reiss, Robert F; Chumak, Vadim V; Bouville, Andre; Drozdovitch, Vladimir; Kryuchkov, Victor P; Golovanov, Ivan; Bakhanova, Elena; Babkina, Nataliya; Lubarets, Tatiana; Bebeshko, Volodymyr; Romanenko, Anatoly; Mabuchi, Kiyohiko

    2013-01-01

    Risks of most types of leukemia from exposure to acute high doses of ionizing radiation are well known, but risks associated with protracted exposures, as well as associations between radiation and chronic lymphocytic leukemia (CLL), are not clear. We estimated relative risks of CLL and non-CLL from protracted exposures to low-dose ionizing radiation. A nested case-control study was conducted in a cohort of 110,645 Ukrainian cleanup workers of the 1986 Chornobyl nuclear power plant accident. Cases of incident leukemia diagnosed in 1986-2006 were confirmed by a panel of expert hematologists/hematopathologists. Controls were matched to cases on place of residence and year of birth. We estimated individual bone marrow radiation doses by the Realistic Analytical Dose Reconstruction with Uncertainty Estimation (RADRUE) method. We then used a conditional logistic regression model to estimate excess relative risk of leukemia per gray (ERR/Gy) of radiation dose. We found a significant linear dose response for all leukemia [137 cases, ERR/Gy = 1.26 (95% CI: 0.03, 3.58]. There were nonsignificant positive dose responses for both CLL and non-CLL (ERR/Gy = 0.76 and 1.87, respectively). In our primary analysis excluding 20 cases with direct in-person interviews < 2 years from start of chemotherapy with an anomalous finding of ERR/Gy = -0.47 (95% CI: < -0.47, 1.02), the ERR/Gy for the remaining 117 cases was 2.38 (95% CI: 0.49, 5.87). For CLL, the ERR/Gy was 2.58 (95% CI: 0.02, 8.43), and for non-CLL, ERR/Gy was 2.21 (95% CI: 0.05, 7.61). Altogether, 16% of leukemia cases (18% of CLL, 15% of non-CLL) were attributed to radiation exposure. Exposure to low doses and to low dose-rates of radiation from post-Chornobyl cleanup work was associated with a significant increase in risk of leukemia, which was statistically consistent with estimates for the Japanese atomic bomb survivors. Based on the primary analysis, we conclude that CLL and non-CLL are both radiosensitive.

  14. Prognostic and predictive significance of smudge cell percentage on routine blood smear in chronic lymphocytic leukemia.

    PubMed

    Gogia, Ajay; Raina, Vinod; Gupta, Ritu; Gajendra, Smeeta; Kumar, Lalit; Sharma, Atul; Kumar, Rajive; Vishnubhatla, Sreeniwas

    2014-12-01

    Smudge cells are ruptured lymphocytes present on routine blood smears of chronic lymphocytic leukemia (CLL) patients. We evaluated prognostic and predictive significance of smudge cell percentage on a blood smear in CLL patients. We calculated smudge cell percentages (ratio of smudged to intact cells plus smudged lymphocytes) on archived blood smears of 222 untreated CLL patients registered at Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi over the past 12 years. The male:female ratio was 3:1, and median age 60 (range, 28-90) years. Median absolute lymphocyte count was 42 × 10(9)/L. The median smudge cell percentage was 29.6% (range, 4%-79%). We found no correlation of proportion of smudge cells with age, sex, lymphocyte count, organomegaly, or response to therapy, although there was a significant correlation with the Rai stage at diagnosis. Median smudge cell percentage in stage 0 and I was 33% (range, 12%-79%), in stage II 31% (range, 12%-61%), and stage III and IV 21% (range, 4%-51%) (P < .001). Patients with ≤ 30% smudge cells had a shorter median progression-free period (PFP) of 30 months compared with patients who had more than 30% smudge cells (PFP, 45 months; P = .01). The 5-year survival rate was 51% for patients with 30% or fewer smudge cells, and it was 81% for patients with more than 30% smudge cells (P < .001) at a median follow-up of 3.5 years. Simple and inexpensive detection of smudge cells on routine blood smears seems useful in predicting progression-free and overall survival in CLL patients and might be beneficial in countries with limited resources. Copyright © 2014 Elsevier Inc. All rights reserved.

  15. 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.

  16. 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

  17. 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.

  18. 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.

  19. ZAP-70 intron1 DNA methylation status: determination by pyrosequencing in B chronic lymphocytic leukemia.

    PubMed

    Chantepie, Sylvain P; Vaur, Dominique; Grunau, Christoph; Salaün, Véronique; Briand, Mélanie; Parienti, Jean-Jacques; Heutte, Natacha; Cheze, Stéphane; Roussel, Mikel; Gauduchon, Pascal; Leporrier, Michel; Krieger, Sophie

    2010-06-01

    ZAP-70 expression is a strong prognostic indicator in chronic lymphocytic leukemia. However, ZAP-70 quantification by flow cytometry lacks sufficient standardization. Based upon the correlation between ZAP-70 expression and its gene methylation status, we have developed a quantitative pyrosequencing assay for the determination of ZAP-70 methylation adapted for routine use. Methylation in four CpG pairs (C-223, C-243, C-254, and C-267) in the first intron of ZAP-70 is associated with repression of ZAP-70. Moreover, it correlates with CD38 expression (n=111, p<.0001), IgHv mutation status (n=106, p<.0001), time to treatment (p<.0001), and overall survival (p=.0014). Pyrosequencing of ZAP-70 provides a good alternative to flow cytometry. Copyright 2009 Elsevier Ltd. All rights reserved.

  20. 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

  1. 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.

  2. 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.

  3. 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.

  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. Fetuin-A levels and free leptin index are reduced in patients with chronic lymphocytic leukemia: a hospital-based case-control study.

    PubMed

    Dalamaga, Maria; Polyzos, Stergios A; Karmaniolas, Konstantinos; Chamberland, John; Lekka, Antigoni; Triantafilli, Maria; Migdalis, Ilias; Papadavid, Evangelia; Mantzoros, Christos S

    2016-01-01

    There are limited data on fetuin-A, soluble leptin receptor (sOB-R) and free leptin index (FLI) in patients with chronic lymphocytic leukemia (CLL). The aim of this study was to compare circulating fetuin-A, sOB-R levels and FLI between 95 patients with CLL and 95 matched controls, as well as among different stages of CLL. Circulating fetuin-A was significantly lower in cases than controls (241.9 ± 99.2 vs. 288.8 ± 127.7 μg/mL; p = 0.005). Although circulating sOB-R levels were similar between groups, FLI was lower in cases than controls (0.45 ± 0.42 vs. 0.67 ± 0.57; p = 0.003). Furthermore, lower fetuin-A or FLI, but not sOB-R, were independently associated with CLL (p < 0.05), particularly among overweight/obese individuals. Fetuin-A, s-OB-R and FLI were similar between different stages of CLL severity, or between symptomatic and asymptomatic disease. In conclusion, circulating fetuin-A and FLI, but not sOB-R, were lower in patients with CLL than controls, a finding warranting further investigation.

  6. 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.

  7. Downregulation of Death-Associated Protein Kinase 1 (DAPK1) in Chronic Lymphocytic Leukemia

    PubMed Central

    Raval, Aparna; Tanner, Stephan M.; Byrd, John C.; Angerman, Elizabeth B.; Perko, James D.; Chen, Shih-Shih; Hackanson, Björn; Grever, Michael R.; Lucas, David M.; Matkovic, Jennifer J.; Lin, Thomas S.; Kipps, Thomas J.; Murray, Fiona; Weisenburger, Dennis; Sanger, Warren; Lynch, Jane; Watson, Patrice; Jansen, Mary; Yoshinaga, Yuko; Rosenquist, Richard; de Jong, Pieter J.; Coggill, Penny; Beck, Stephan; Lynch, Henry; de la Chapelle, Albert; Plass, Christoph

    2007-01-01

    Summary The heritability of B cell chronic lymphocytic leukemia (CLL) is relatively high; however, no predisposing mutation has been convincingly identified. We show that loss or reduced expression of death-associated protein kinase 1 (DAPK1) underlies cases of heritable predisposition to CLL and the majority of sporadic CLL. Epigenetic silencing of DAPK1 by promoter methylation occurs in almost all sporadic CLL cases. Furthermore, we defined a disease haplotype, which segregates with the CLL phenotype in a large family. DAPK1 expression of the CLL allele is downregulated by 75% in germline cells due to increased HOXB7 binding. In the blood cells from affected family members, promoter methylation results in additional loss of DAPK1 expression. Thus, reduced expression of DAPK1 can result from germline predisposition, as well as epigenetic or somatic events causing or contributing to the CLL phenotype. PMID:17540169

  8. Past, present and future role of chlorambucil in the treatment of chronic lymphocytic leukemia.

    PubMed

    Goede, Valentin; Eichhorst, Barbara; Fischer, Kirsten; Wendtner, Clemens-Martin; Hallek, Michael

    2015-06-01

    For many decades, chlorambucil was the standard of care for chronic lymphocytic leukemia (CLL), but meanwhile has been replaced by purine analog-based chemoimmunotherapy. Monotherapy with the alkylator only retained significance in the treatment of older patients unfit for standard treatment. After successful phase II studies, recent phase III trials established combinations of chlorambucil with anti-CD20 antibodies such as rituximab, ofatumumab and obinutuzumab as a valuable treatment option for these patients. Today, chlorambucil therefore should be used as a chemotherapy backbone for antibody-based chemoimmunotherapy in this patient population rather than as monotherapy. Starting from the past role of chlorambucil in CLL treatment, we here review the most recent efforts to elaborate chlorambucil-based chemoimmunotherapy in CLL and discuss clinically relevant questions that arise from this approach.

  9. 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.

  10. 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

  11. 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

  12. 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.

  13. The chronic lymphocytic leukemia microenvironment: Beyond the B-cell receptor.

    PubMed

    Choi, Michael Y; Kashyap, Manoj Kumar; Kumar, Deepak

    2016-03-01

    Malignant B cells accumulate in the peripheral blood, bone marrow, and lymphoid organs of patients with chronic lymphocytic leukemia (CLL). In the tissue compartments, CLL shape a protective microenvironment by coopting normal elements. The efficacy of drugs that target these interactions further underscores their importance in the pathogenesis of CLL. While the B cell receptor (BCR) pathway clearly plays a central role in the CLL microenvironment, there is also rationale to evaluate agents that inhibit other aspects or modulate the immune cells in the microenvironment. Here we review the main cellular components, soluble factors, and signaling pathways of the CLL microenvironment, and highlight recent clinical advances. As the BCR pathway is reviewed elsewhere, we focus on other aspects of the microenvironment. Copyright © 2016 Elsevier Ltd. All rights reserved.

  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. 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.

  16. 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.

  17. 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

  18. 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.

  19. 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.

  20. 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

  1. 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

  2. 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.

  3. 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

  4. 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 ...

  5. 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 ...

  6. The novel plant-derived agent silvestrol has B-cell selective activity in chronic lymphocytic leukemia and acute lymphoblastic leukemia in vitro and in vivo.

    PubMed

    Lucas, David M; Edwards, Ryan B; Lozanski, Gerard; West, Derek A; Shin, Jungook D; Vargo, Melissa A; Davis, Melanie E; Rozewski, Darlene M; Johnson, Amy J; Su, Bao-Ning; Goettl, Virginia M; Heerema, Nyla A; Lin, Thomas S; Lehman, Amy; Zhang, Xiaoli; Jarjoura, David; Newman, David J; Byrd, John C; Kinghorn, A Douglas; Grever, Michael R

    2009-05-07

    Therapeutic options for advanced B-cell acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL) are limited. Available treatments can also deplete T lymphocytes, leaving patients at risk of life-threatening infections. In the National Cancer Institute cell line screen, the structurally unique natural product silvestrol produces an unusual pattern of cytotoxicity that suggests activity in leukemia and selectivity for B cells. We investigated silvestrol efficacy using primary human B-leukemia cells, established B-leukemia cell lines, and animal models. In CLL cells, silvestrol LC(50) (concentration lethal to 50%) is 6.9 nM at 72 hours. At this concentration, there is no difference in sensitivity of cells from patients with or without the del(17p13.1) abnormality. In isolated cells and whole blood, silvestrol is more cytotoxic toward B cells than T cells. Silvestrol causes early reduction in Mcl-1 expression due to translational inhibition with subsequent mitochondrial damage, as evidenced by reactive oxygen species generation and membrane depolarization. In vivo, silvestrol causes significant B-cell reduction in Emu-Tcl-1 transgenic mice and significantly extends survival of 697 xenograft severe combined immunodeficient (SCID) mice without discernible toxicity. These data indicate silvestrol has efficacy against B cells in vitro and in vivo and identify translational inhibition as a potential therapeutic target in B-cell leukemias.

  7. 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

  8. 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

  9. Functional analysis of sucrase-isomaltase mutations from chronic lymphocytic leukemia patients.

    PubMed

    Rodríguez, David; Ramsay, Andrew J; Quesada, Víctor; Garabaya, Cecilia; Campo, Elías; Freije, José M P; López-Otín, Carlos

    2013-06-01

    Next-generation sequencing techniques have emerged as powerful tools for the understanding of cancer genomes. In recent years, whole-exome and whole-genome sequencing strategies have enabled the annotation of a comprehensive mutation landscape of chronic lymphocytic leukemia (CLL), the most frequent leukemia in western countries. Several recurrently mutated genes have been identified, with a subset being validated as neoplastic drivers. Still, a main challenge remains for the differentiation between driver and passenger mutations among candidates as well as for the functional description of the newly discovered leukemogenic genes that could be utilized for personalized anti-tumor strategies. In this scenario, we have identified the metabolic enzyme sucrase-isomaltase (SI) as one of the most frequently mutated genes in a cohort of 105 CLL patients. Here, we demonstrate that these SI mutations result in loss of enzyme function by preventing the biosynthesis of catalytically competent SI at the cell surface. Transcriptome analyses of RNA from CLL patients with SI loss-of-function mutations have uncovered gene expression patterns that depict ample metabolic reprogramming, pinpointing SI as a putative player in the cancer-associated metabolic switch. These results highlight SI as a relevant target for clinical evaluation in future CLL studies.

  10. Skin cancer surveillance and malignancies of the skin in a community-dwelling cohort of patients with newly diagnosed chronic lymphocytic leukemia.

    PubMed

    Mansfield, Aaron S; Rabe, Kari G; Slager, Susan L; Schwager, Susan M; Call, Timothy G; Brewer, Jerry D; Shanafelt, Tait D

    2014-01-01

    Assess compliance with skin cancer screening guidelines in a community-dwelling cohort of patients with newly diagnosed chronic lymphocytic leukemia (CLL) and evaluate the clinical utility of such screening. We identified patients diagnosed at Mayo Clinic with CLL between January 1, 2004, and June 1, 2012, who resided within 30 miles of Mayo Clinic. We evaluated adherence to skin cancer screening and identified the prevalence of skin malignancies during follow-up. Medical records were reviewed to document skin cancer screening and diagnosis of a skin malignancy. Collectively, 113 individuals who met criteria were diagnosed with CLL during the study interval. Forty-one patients (36%) had a whole body skin examination by either a dermatologist or primary care provider documented within 6 months of diagnosis; of these; nine (8% of overall cohort; 22% of examined patients) had a skin malignancy identified. Fifteen additional skin malignancies were diagnosed during follow-up. There were a total of 24 skin malignancies (21% of cohort) diagnosed, including basal cell carcinoma (n = 10), squamous cell carcinoma (n = 11), sebaceous carcinomas (n = 2), and melanoma (n = 1). We documented a low compliance with guidelines to screen for skin malignancy in a community-dwelling cohort of patients with newly diagnosed CLL. Standardized and systems-based approaches are likely to increase compliance with skin cancer screening guidelines in patients with CLL.

  11. Plasma alemtuzumab levels in patients with chronic lymphocytic leukemia treated with alemtuzumab combined with chemotherapy reflect the efficacy of the treatment: a hypothesis.

    PubMed

    Vojdeman, Fie Juhl; Jurlander, Jesper; van't Veer, Mars; Itälä-Remes, Maija; Kimby, Eva; Tjønnfjord, Geir Erland; Walewski, Jan; Kozák, Tomas; Polliack, Aaron; Montagna, Michela; Regazzi, Mario; Kirkby, Nikolai; van Oers, Marinus; Geisler, Christian Hartmann

    2013-04-01

    In the HOVON68 trial comparing subcutaneous low-dose alemtuzumab (LD-A) used together with fludarabine (F) and cyclophosphamide (C) with FC alone in high-risk chronic lymphocytic leukemia (CLL), LD-AFC resulted in significantly more clinical and molecular responses than FC, but also in more opportunistic infections. In a subgroup analysis of alemtuzumab trough levels during treatment by a sensitive enzyme-linked immunosorbent assay (ELISA) method, detectable levels were found in 4/6 complete and 0/3 partial responders. A relationship between alemtuzumab plasma levels, response and duration of lymphocytopenia was evident. We hypothesize that following combination therapy, the response may not be a function of the alemtuzumab levels, but the opposite, that plasma alemtuzumab levels are a function of the efficacy of the entire treatment, and the fewer leukemic target cells that are remaining, the higher are the levels of plasma alemtuzumab. This concept may well provide a guide for alemtuzumab dosage in future trials.

  12. The novel receptor tyrosine kinase Axl is constitutively active in B-cell chronic lymphocytic leukemia and acts as a docking site of nonreceptor kinases: implications for therapy

    PubMed Central

    Secreto, Charla; Boysen, Justin; Sassoon, Traci; Shanafelt, Tait D.; Mukhopadhyay, Debabrata; Kay, Neil E.

    2011-01-01

    Recently, we detected that chronic lymphocytic leukemia (CLL) B-cell–derived microvesicles in CLL plasma carry a constitutively phosphorylated novel receptor tyrosine kinase (RTK), Axl, indicating that Axl was acquired from the leukemic B cells. To examine Axl status in CLL, we determined the expression of phosphorylated-Axl (P-Axl) in freshly isolated CLL B cells by Western blot analysis. We detected differential levels of P-Axl in CLL B cells, and further analysis showed that expression of P-Axl was correlated with the other constitutively phosphorylated kinases, including Lyn, phosphoinositide-3 kinase, SyK/ζ-associated protein of 70 kDa, phospholipase C γ2 in CLL B cells. We found that these intracellular signaling molecules were complexed with P-Axl in primary CLL B cells. When Axl and Src kinases were targeted by a Src/Abl kinase inhibitor, bosutinib (SKI-606), or a specific-inhibitor of Axl (R428), robust induction of CLL B-cell apoptosis was observed in both a dose- and time-dependent manner. Therefore, we have identified a novel RTK in CLL B cells which appears to work as a docking site for multiple non-RTKs and drives leukemic cell survival signals. These findings highlight a unique target for CLL treatment. PMID:21135257

  13. Therapeutic inhibition of USP7-PTEN network in chronic lymphocytic leukemia: a strategy to overcome TP53 mutated/deleted clones

    PubMed Central

    Carrà, Giovanna; Panuzzo, Cristina; Torti, Davide; Parvis, Guido; Crivellaro, Sabrina; Familiari, Ubaldo; Volante, Marco; Morena, Deborah; Lingua, Marcello Francesco; Brancaccio, Mara; Guerrasio, Angelo; Pandolfi, Pier Paolo; Saglio, Giuseppe; Taulli, Riccardo; Morotti, Alessandro

    2017-01-01

    Chronic Lymphocytic Leukemia (CLL) is a lymphoproliferative disorder with either indolent or aggressive clinical course. Current treatment regiments have significantly improved the overall outcomes even if higher risk subgroups - those harboring TP53 mutations or deletions of the short arm of chromosome 17 (del17p) - remain highly challenging. In the present work, we identified USP7, a known de-ubiquitinase with multiple roles in cellular homeostasis, as a potential therapeutic target in CLL. We demonstrated that in primary CLL samples and in CLL cell lines USP7 is: i) over-expressed through a mechanism involving miR-338-3p and miR-181b deregulation; ii) functionally activated by Casein Kinase 2 (CK2), an upstream interactor known to be deregulated in CLL; iii) effectively targeted by the USP7 inhibitor P5091. Treatment of primary CLL samples and cell lines with P5091 induces cell growth arrest and apoptosis, through the restoration of PTEN nuclear pool, both in TP53-wild type and -null environment. Importantly, PTEN acts as the main tumor suppressive mediator along the USP7-PTEN axis in a p53 dispensable manner. In conclusion, we propose USP7 as a new druggable target in CLL. PMID:28418900

  14. Therapeutic inhibition of USP7-PTEN network in chronic lymphocytic leukemia: a strategy to overcome TP53 mutated/deleted clones.

    PubMed

    Carrà, Giovanna; Panuzzo, Cristina; Torti, Davide; Parvis, Guido; Crivellaro, Sabrina; Familiari, Ubaldo; Volante, Marco; Morena, Deborah; Lingua, Marcello Francesco; Brancaccio, Mara; Guerrasio, Angelo; Pandolfi, Pier Paolo; Saglio, Giuseppe; Taulli, Riccardo; Morotti, Alessandro

    2017-05-30

    Chronic Lymphocytic Leukemia (CLL) is a lymphoproliferative disorder with either indolent or aggressive clinical course. Current treatment regiments have significantly improved the overall outcomes even if higher risk subgroups - those harboring TP53 mutations or deletions of the short arm of chromosome 17 (del17p) - remain highly challenging. In the present work, we identified USP7, a known de-ubiquitinase with multiple roles in cellular homeostasis, as a potential therapeutic target in CLL. We demonstrated that in primary CLL samples and in CLL cell lines USP7 is: i) over-expressed through a mechanism involving miR-338-3p and miR-181b deregulation; ii) functionally activated by Casein Kinase 2 (CK2), an upstream interactor known to be deregulated in CLL; iii) effectively targeted by the USP7 inhibitor P5091. Treatment of primary CLL samples and cell lines with P5091 induces cell growth arrest and apoptosis, through the restoration of PTEN nuclear pool, both in TP53-wild type and -null environment. Importantly, PTEN acts as the main tumor suppressive mediator along the USP7-PTEN axis in a p53 dispensable manner. In conclusion, we propose USP7 as a new druggable target in CLL.

  15. 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.

  16. 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.

  17. First-line therapy with fludarabine compared with chlorambucil does not result in a major benefit for elderly patients with advanced chronic lymphocytic leukemia.

    PubMed

    Eichhorst, Barbara F; Busch, Raymonde; Stilgenbauer, Stephan; Stauch, Martina; Bergmann, Manuela A; Ritgen, Matthias; Kranzhöfer, Nicole; Rohrberg, Robert; Söling, Ulrike; Burkhard, Oswald; Westermann, Anne; Goede, Valentin; Schweighofer, Carmen D; Fischer, Kirsten; Fink, Anna-Maria; Wendtner, Clemens M; Brittinger, Günter; Döhner, Hartmut; Emmerich, Bertold; Hallek, Michael

    2009-10-15

    Although chronic lymphocytic leukemia (CLL) is a disease of elderly patients, subjects older than 65 years are heavily underrepresented in clinical trials. The German CLL study group (GCLLSG) initiated a multicenter phase III trial for CLL patients older than 65 years comparing first-line therapy with fludarabine with chlorambucil. A total of 193 patients with a median age of 70 years were randomized to receive fludarabine (25 mg/m(2) for 5 days intravenously, every 28 days, for 6 courses) or chlorambucil (0.4 mg/kg body weight [BW] with an increase to 0.8 mg/kg, every 15 days, for 12 months). Fludarabine resulted in a significantly higher overall and complete remission rate (72% vs 51%, P = .003; 7% vs 0%, P = .011). Time to treatment failure was significantly shorter in the chlorambucil arm (11 vs 18 months; P = .004), but no difference in progression-free survival time was observed (19 months with fludarabine, 18 months with chlorambucil; P = .7). Moreover, fludarabine did not increase the overall survival time (46 months in the fludarabine vs 64 months in the chlorambucil arm; P = .15). Taken together, the results suggest that in elderly CLL patients the first-line therapy with fludarabine alone does not result in a major clinical benefit compared with chlorambucil. This trial is registered with www.isrctn.org under identifier ISRCTN 36294212.

  18. CCI-779 in Treating Patients With Recurrent or Refractory B-Cell Non-Hodgkin's Lymphoma or Chronic Lymphocytic Leukemia

    ClinicalTrials.gov

    2014-05-07

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

  19. 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

  20. 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.

  1. The Relation of Illness Perceptions to Stress, Depression, and Fatigue in Patients with Chronic Lymphocytic Leukemia

    PubMed Central

    Maddocks, Kami; Andersen, Barbara L.

    2016-01-01

    Objective Chronic lymphocytic leukemia (CLL) is the most prevalent adult leukemia and is incurable. The course and treatment of CLL is unique and characterized by repeated cycles of treatment, stable disease, and relapse. Utilizing a Self-Regulatory Model framework (Leventhal et al., 1980), we examined the relationship between patients’ illness perceptions and cancer-specific stress, depression, and fatigue. Our aim was to test illness perceptions as predictors of these outcomes when variance due to disease and treatment variables was controlled. Design Data were collected on 147 patients with relapsed/refractory CLL as they entered a phase-II clinical trial of an investigational medication at a university affiliated, National Cancer Institute designated comprehensive cancer center. Main outcome measures Cancer-specific stress, depressive symptoms, and fatigue interference. Results Hierarchical multiple regression was used. Consequences and emotional representation were related to all outcomes (ps <.01). Illness concern was related to cancer-specific stress (p <.01), and identity was related to fatigue interference (p <.01). All relationships were observed while controlling for number of previous CLL therapies received. Conclusion Illness perceptions are related to cancer-specific stress, depressive symptoms, and fatigue interference in relapsed/refractory CLL. Interventions targeted at restructuring maladaptive illness perceptions may have clinical benefit in this population. PMID:26982998

  2. 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.

  3. The impact of race, ethnicity, age and sex on clinical outcome in chronic lymphocytic leukemia: a comprehensive Surveillance, Epidemiology, and End Results analysis in the modern era.

    PubMed

    Nabhan, Chadi; Aschebrook-Kilfoy, Briseis; Chiu, Brian C-H; Smith, Sonali M; Shanafelt, Tait D; Evens, Andrew M; Kay, Neil E

    2014-12-01

    To analyze racial, ethnic, sex and age disparities in chronic lymphocytic leukemia (CLL), we examined population-based overall survival (OS) data from Surveillance, Epidemiology, and End Results (SEER)-13 (1992-2009) across various races/ethnicities over two consecutive 9-year periods: era 1 (1992-2000) and era 2 (2001-2009). We analyzed 28 590 patients (whites: 24 438, blacks: 1954, Hispanics: 1389 and Asians/Pacific Islanders [A/PI]: 809). A higher proportion of whites were aged > 80 years (22% vs. 17% [Hispanics], 16% [blacks], 16% [A/PI]; p < 0.001). Higher socioeconomic status (SES) was also identified for A/PI and whites compared with blacks and Hispanics (p < 0.001). OS for all patients improved at 5 years (66% vs. 60%, p < 0.0001) and was significant in all races/ethnicities except A/PI. Patients of higher SES had better outcomes than others independent of era, but both SES classes experienced relative improvement in their OS across eras. The OS of patients with CLL has improved in the modern era but racial/ethnic, gender and SES differences persist, warranting further investigation.

  4. Flow cytometric analysis of CD5+ B cells: a frame of reference for minimal residual disease analysis in chronic lymphocytic leukemia.

    PubMed

    Gupta, Ritu; Jain, Paresh; Deo, S V S; Sharma, Atul

    2004-03-01

    Recent reports suggest that CD5+ B cells constitute up to 47% of the total B cells in normal peripheral blood (PB), a finding that would restrict the sensitivity of the CD5/CD19 flow cytometric assay for minimal residual disease (MRD) analysis in chronic lymphocytic leukemia (CLL). We studied 40 normal samples (PB, 20; bone marrow [BM], 20) using CD5-fluorescein isothiocyanate (FITC)/CD19-phycoerythrin (PE) immunostaining to evaluate the reference range of CD5+ B cells. The mean percentage of CD5+ B cells per total number of B cells was 12.2% (range, 3.6%-23.9%) in PB and 11.7% (range, 4.4%-19.5%) in BM. On serial dilution, this assay could detect 1 CLL cell in 1,000 leukocytes (sensitivity, 0. 1%). A distinct "bright" CD5+ B-cell subpopulation, consistent with a CLL-like-phenotype, was observed in 3 samples. Our results suggest that the CD5-FITC/CD19-PE assay has a clinically useful sensitivity for MRD analysis in CLL. The usefulness of this assay as a screening tool to identify the earliest stage of indolent CLL needs further study.

  5. 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.

  6. 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

  7. 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.

  8. Impact of bone marrow stromal cells on Bcl-2 family members in chronic lymphocytic leukemia

    PubMed Central

    Patel, Viralkumar; Balakrishnan, Kumudha; Wierda, William G.; Gandhi, Varsha

    2014-01-01

    Chronic lymphocytic leukemia (CLL) is the most common form of adult leukemia in the western world. High levels of Bcl-2 family anti-apoptotic proteins are responsible for apoptotic-resistance. Besides anti-apoptotic proteins, microenvironment provides substantial surviving signals to CLL leukemic cells. However, the in-depth-knowledge on the role of individual Bcl-2 family members in the context of microenvironment is still limited. We performed a comprehensive analysis of transcripts and proteins of 18 Bcl-2 family members using “apoptosis array micro fluidic card” in primary cells before and after stromal co-cultures. Our data showed that, 5 of 6 anti-apoptotic members (excluding Bcl-b), 2 of 3 pro-apoptotic members (excluding Bok) and 6 of 9 BH3-only members were present at detectable mRNA levels in CLL cells. Importantly, stromal mediated extended survival of CLL cells was in strong association with elevated global transcription. Upon co-culturing with stromal cells, there was early response of increase in anti- (2/5) and pro-apoptotic protein (3/8) transcripts on day 1, while increase in anti-apoptotic proteins were observed on day 3, with no significant change in pro-apoptotic proteins. Our study revealed a differential pattern of expression of both transcripts and proteins following stromal co-cultures, proposing significance of Bcl-2 family members in stromal microenvironment. PMID:23837491

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

    PubMed

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

    2016-08-23

    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.

  10. 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

  11. 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.

  12. 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.

  13. 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

  14. 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.

  15. 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

  16. A Phase 2 Trial of Fludarabine Combined With Subcutaneous Alemtuzumab for the Treatment of Relapsed/Refractory B-Cell Chronic Lymphocytic Leukemia.

    PubMed

    Flowers, Christopher R; Brown, Jennifer R; Rosenthal, Hilary; Stock, Wendy; Katzen, Harvey I; Cohen, Jonathon B; Sinha, Rajni; Lakhanpal, Shailendra; Leis, Jose F; Waller, Edmund K; Jaye, David L

    2015-11-01

    Alemtuzumab is effective in fludarabine-refractory patients with chronic lymphocytic leukemia. We performed a phase 2 study of alemtuzumab in combination with fludarabine in patients with relapsed disease. Patients received alemtuzumab and fludarabine daily on days 1 to 5 of a 28-day cycle for up to 6 cycles with the primary objective of determining the rate of complete response. Of 60 enrolled patients, 51 had previously received fludarabine, and 60% had received 3 or more prior therapies. Five patients experienced complete response (8.3%) and 12 experienced partial response, yielding an overall response rate of 28.3% for the intention-to-treat population. Among the 41 patients who completed at least 4 cycles of therapy, the complete response rate was 20%. Median progression-free survival was 211 days. Forty-seven percent of patients experienced cytomegalovirus viremia, including 4 patients with symptomatic cytomegalovirus disease. All patients responded to antiviral therapy. Despite some evidence of efficacy in this setting, the primary end point for the study was not met. In the era of targeted agents that are well tolerated, the combination of fludarabine and alemtuzumab should be used rarely for a select group of fit patients who are refractory to standard therapies. Copyright © 2015 Elsevier Inc. All rights reserved.

  17. 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

  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

    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.

  19. 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.

  20. 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

  1. 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.

  2. 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

  3. 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

  4. 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.

  5. 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

  6. 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.

  7. 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.

  8. 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

  9. 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.

  10. 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.

  11. 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

  12. 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.

  13. 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.

  14. Salinomycin inhibits Wnt signaling and selectively induces apoptosis in chronic lymphocytic leukemia cells

    PubMed Central

    Lu, Desheng; Choi, Michael Y.; Yu, Jian; Castro, Januario E.; Kipps, Thomas J.; Carson, Dennis A.

    2011-01-01

    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. PMID:21788521

  15. 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.

  16. Lack of TIR8/SIGIRR triggers progression of chronic lymphocytic leukemia in mouse models.

    PubMed

    Bertilaccio, Maria Teresa Sabrina; Simonetti, Giorgia; Dagklis, Antonis; Rocchi, Martina; Rodriguez, Tania Veliz; Apollonio, Benedetta; Mantovani, Alberto; Ponzoni, Maurilio; Ghia, Paolo; Garlanda, Cecilia; Caligaris-Cappio, Federico; Muzio, Marta

    2011-07-21

    Inflammation is involved in the initiation and progression of several chronic lymphoid malignancies of B-cell type. Toll-like receptors (TLR) are transmembrane inflammatory receptors that on recognition of pathogen-associated molecular patterns trigger an innate immune response and bridge the innate and adaptive immune response by acting as costimulatory signals for B cells. Fine tuning of TLR and IL-1R-like (ILR) activity is regulated by TIR8 (SIGIRR), a transmembrane receptor of the TLR/ILR family which inhibits other family members. To test the hypothesis that TLR and/or ILR may play a role in the natural history of chronic B-cell tumors, we crossed Eμ-TCL1 transgenic mice, a well established model of chronic lymphocytic leukemia (CLL), with mice lacking the inhibitory receptor TIR8 that allow an unabated TLR-mediated stimulation. We here report that in the absence of TIR8 the appearance of monoclonal B-cell expansions is accelerated and mouse life span is shortened. The morphology and phenotype of the mouse leukemic expansions reproduce the progression of human CLL into an aggressive and frequently terminal phase characterized by the appearance of prolymphocytes. This study reveals an important pathogenetic implication of TLR in CLL development and progression.

  17. Early prediction of outcome and response to alemtuzumab therapy in chronic lymphocytic leukemia.

    PubMed

    Rawstron, Andy C; Kennedy, Ben; Moreton, Paul; Dickinson, Anita J; Cullen, Matthew J; Richards, Stephen J; Jack, Andrew S; Hillmen, Peter

    2004-03-15

    Alemtuzumab therapy is effective for some refractory chronic lymphocytic leukemia (CLL), but identifying responders requires at least 8 weeks of therapy. Early identification of nonresponders would minimize toxicity and/or facilitate more effective strategies. The aim of this study was to identify a minimally invasive method for early prediction of response and relapse. Flow cytometric monitoring was performed in 887 blood samples and 201 marrow samples from 43 patients undergoing intravenous alemtuzumab therapy. Although the absolute lymphocytosis was resolved in all patients by week 4, significant depletion of bone marrow tumor only occurred if circulating B-lymphocyte counts were persistently less than 0.001 x 10(9)/L, which was rare in nonresponders. The majority of patients (16/28) who did not benefit from a full course of therapy were identified with 100% positive predictive value using the following algorithm: peripheral B-cell count greater than 0.001 x 10(9)/L at week 2 with less than 1 log depletion of circulating B cells between weeks 2 and 4. Monitoring CLL levels after treatment identified patients at risk of early disease progression and could potentially improve patient management. During alemtuzumab therapy, bone marrow CLL depletion only occurs after abrogation of circulating tumor, requiring close monitoring of circulating B-cell levels. If validated in prospective studies, blood monitoring at 2 and 4 weeks may be used to optimize therapy.

  18. B-Cell Chronic Lymphocytic Leukemia with 11q22.3 Rearrangement in Patient with Chronic Myeloid Leukemia Treated with Imatinib

    PubMed Central

    Gniot, Michał; Lewandowska, Maria; Wache, Anna; Czyż, Anna; Jarmuż-Szymczak, Małgorzata; Komarnicki, Mieczysław

    2016-01-01

    The coexistence of two diseases chronic myeloid leukemia (CML) and B-cell chronic lymphocytic leukemia (B-CLL) is a rare phenomenon. Both neoplastic disorders have several common epidemiological denominators (they occur more often in men over 50 years of age) but different origin and long term prognosis. In this paper we described the clinical and pathological findings in patient with CML in major molecular response who developed B-CLL with 11q22.3 rearrangement and Coombs positive hemolytic anemia during the imatinib treatment. Due to the presence of the symptoms of autoimmune hemolytic anemia and optimal CML response to the imatinib treatment, the decision about combined therapy with prednisone and imatinib was made. During the follow-up, the normalization of complete blood count and resolution of peripheral lymphadenopathy were noted. The hematologic response of B-CLL was diagnosed. The repeated FISH analysis of cultured peripheral blood lymphocytes showed 2% of cells carrying 11q22.3 rearrangement. At the same time, molecular monitoring confirmed the deep molecular response of CML. The effectiveness of such combination in the described case raises the question about the best therapeutic option in such situation, especially in patients with good imatinib tolerance and optimal response. PMID:27034682

  19. 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

  20. Feasibility of Lenalidomide Therapy for Persistent Chronic Lymphocytic Leukemia after Allogeneic Transplantation.

    PubMed

    Khouri, Maria R; Jabbour, Elias J; Gulbis, Alison M; Turturro, Francesco; Ledesma, Celina; Korbling, Martin; Samuels, Barry I; Ahmed, Sairah; Alousi, Amin M; Ciurea, Stefan O; Marin, David; Patel, Krina K; Popat, Uday R; Bueso-Ramos, Carlos E; Bassett, Roland L; Khouri, Issa F

    2017-08-01

    In patients with chronic lymphocytic leukemia (CLL), persistence of disease after allogeneic stem cell transplantation (alloSCT) can result in poor outcomes. In an effort to improve these outcomes, patients with persistent CLL who were 90 to 100 days beyond alloSCT with no evidence of graft-versus-host-disease (GVHD) were randomized to receive lenalidomide or standard care (withdrawal of immunosuppression followed by donor lymphocyte infusion). Lenalidomide was initiated at 5 mg every other day and increased to 10 mg daily, if tolerated, in each patient. Of 38 patients enrolled, 17 (45%) met the eligibility criteria for randomization. Of these 17 patients, 8 were randomized to undergo lenalidomide therapy. Five (62%) patients had to stop taking the drug because of toxicity. The main reason for drug discontinuation was acute GVHD in 43% of patients. This incidence was 11% in the patients who were randomized to not receive lenalidomide. With a median follow-up of 2.6 years, the median survival was 3.4 years for those receiving lenalidomide. This was not reached in patients randomized to not receive lenalidomide and in patients in complete remission who were not randomized. These results suggested that treatments other than lenalidomide are needed for persistent CLL after alloSCT. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

  1. 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.

  2. Inhibitors of XIAP sensitize CD40-activated chronic lymphocytic leukemia cells to CD95-mediated apoptosis

    PubMed Central

    Kater, Arnon P.; Dicker, Frank; Mangiola, Massimo; Welsh, Kate; Houghten, Richard; Ostresh, John; Nefzi, Adel; Reed, John C.; Pinilla, Clemencia; Kipps, Thomas J.

    2005-01-01

    Patients with chronic lymphocytic leukemia (CLL) treated with adenovirus CD154 (Ad-CD154, CD40 ligand [CD40L]) gene therapy experienced rapid reductions in leukemia cell counts and lymph node size associated with the induced expression of Fas (CD95). However, CLL cells initially resist CD95-mediated apoptosis within the first 3 days after CD40 ligation in vitro. Thereafter, they become sensitive, which is associated with the CD40-induced expression of the proapoptotic protein B-cell leukemia 2 homology 3 (BH3) interacting domain death agonist (Bid). We hypothesized that the initial resistance to CD95-mediated apoptosis may be due to the high-level expression of X-linked inhibitor of apoptosis protein (XIAP) by CLL cells. Consistent with this, CLL cells from patients 1 day after treatment with autologous Ad-CD154-transduced CLL cells became sensitive to CD95-mediated apoptosis following treatment with a novel XIAP inhibitor, 1540-14. Similarly, 1540-14 specifically enhanced CD95-mediated apoptosis of CLL cells following CD40 ligation in vitro. Immunoblot analyses demonstrated that treatment with 1540-14 allowed CD40-stimulated CLL cells to experience high-level activation of caspases-8 and -3 and cleavage of poly(adenosine diphosphate [ADP]-ribose) polymerase following CD95 ligation. This study demonstrates that distal apoptosis regulators contribute to the initial resistance of CD40-activated CLL cells to CD95-mediated apoptosis and suggests that XIAP inhibitors might enhance the effectiveness of immune-based treatment strategies that target CD40, such as CD154 gene therapy. (Blood. 2005;106:1742-1748) PMID:15914559

  3. Safety and efficacy of abexinostat, a pan-histone deacetylase inhibitor, in non-Hodgkin lymphoma and chronic lymphocytic leukemia: results of a phase II study.

    PubMed

    Ribrag, Vincent; Kim, Won Seog; Bouabdallah, Reda; Lim, Soon Thye; Coiffier, Bertrand; Illes, Arpad; Lemieux, Bernard; Dyer, Martin J S; Offner, Fritz; Felloussi, Zakia; Kloos, Ioana; Luan, Ying; Vezan, Remus; Graef, Thorsten; Morschhauser, Franck

    2017-05-01

    Histone deacetylase inhibitors are members of a class of epigenetic drugs that have proven activity in T-cell malignancies, but little is known about their efficacy in B-cell lymphomas. Abexinostat is an orally available hydroxamate-containing histone deacetylase inhibitor that differs from approved inhibitors; its unique pharmacokinetic profile and oral dosing schedule, twice daily four hours apart, allows for continuous exposure at concentrations required to efficiently kill tumor cells. In this phase II study, patients with relapsed/refractory non-Hodgkin lymphoma or chronic lymphocytic leukemia received oral abexinostat at 80 mg BID for 14 days of a 21-day cycle and continued until progressive disease or unacceptable toxicity. A total of 100 patients with B-cell malignancies and T-cell lymphomas were enrolled between October 2011 and July 2014. All patients received at least one dose of study drug. Primary reasons for discontinuation included progressive disease (56%) and adverse events (25%). Grade 3 or over adverse events and any serious adverse events were reported in 88% and 73% of patients, respectively. The most frequently reported grade 3 or over treatment-emergent related adverse events were thrombocytopenia (80%), neutropenia (27%), and anemia (12%). Among the 87 patients evaluable for efficacy, overall response rate was 28% (complete response 5%), with highest responses observed in patients with follicular lymphoma (overall response rate 56%), T-cell lymphoma (overall response rate 40%), and diffuse large B-cell lymphoma (overall response rate 31%). Further investigation of the safety and efficacy of abexinostat in follicular lymphoma, T-cell lymphoma, and diffuse large B-cell lymphoma implementing a less dose-intense week-on-week-off schedule is warranted. (Trial registered at: EudraCT-2009-013691-47). Copyright© Ferrata Storti Foundation.

  4. 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