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Sample records for advanced chronic lymphocytic

  1. Approach to Chronic Lymphocytic Meningitis.

    PubMed

    Khadilkar, Satish V; Nadkarni, Nilesh

    2015-09-01

    Chronic meningitis is a common clinical problem. Early diagnosis and appropriate therapy is important in improving the overall outcome and to prevent long-lasting sequels. As many etiological agents lead to the development of chronic lymphocytic meningitis, it is important to develop a systematic approach to the diagnosis; taking clues from history, examination and laboratory tests, to make an accurate diagnosis and institute appropriate therapy. This review focuses on the diagnostic approach towards the commonly encountered situation of chronic lymphocytic meningitis. Chronic meningitis is defined as meningeal inflammation that persists for more than 4 weeks. Chronic meningitis accounts for less than 10% of all the cases of meningitis.1 Causes of chronic lymphocytic meningitis are mainly divided into infectious and non-infectious listed in Table 1.2 Due to advancement in investigations, diseases causing chronic meningitis may be diagnosed earlier than 4 weeks and hence the definition should be considered as a rough guideline. PMID:27608867

  2. 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

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

    ClinicalTrials.gov

    2016-03-16

    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

  4. 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

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

    ClinicalTrials.gov

    2016-10-07

    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

  6. What Is Chronic Lymphocytic Leukemia?

    MedlinePlus

    ... blood, and lymphoid tissue 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 ...

  7. 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

  8. Management of chronic lymphocytic leukemia

    PubMed Central

    Ghia, Paolo; Hallek, Michael

    2014-01-01

    In the last decade, the management of chronic lymphocytic leukemia has undergone profound changes that have been driven by an improved understanding of the biology of the disease and the approval of several new drugs. Moreover, many novel drugs are currently under evaluation for rapid approval or have been approved by regulatory agencies, further broadening the available therapeutic armamentarium for patients with chronic lymphocytic leukemia. The use of novel biological and genetic parameters combined with a careful clinical evaluation allows us to dissect some of the heterogeneity of the disease and to distinguish patients with a very mild onset and course, who often will not need any treatment, from those with an intermediate prognosis and a third group with a very aggressive course (high-risk leukemia). On this background, it becomes increasingly challenging to select the right treatment strategy. In this paper, we describe our own approach to the management of different patients with chronic lymphocytic leukemia. PMID:24881042

  9. 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

  10. Leukemia -- Chronic T-Cell Lymphocytic

    MedlinePlus

    ... Chronic T-Cell Lymphocytic: Overview Print to PDF Leukemia - Chronic T-Cell Lymphocytic: Overview Approved by the ... Platelets that help the blood to clot About leukemia Types of leukemia are named after the specific ...

  11. 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

  12. 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

  13. 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

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

    ClinicalTrials.gov

    2016-05-04

    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

  15. 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

    2016-10-10

    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

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

    MedlinePlus

    ... Topic Additional resources for 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. 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.

  18. Anti-lymphocyte antibody levels in chronic lymphocytic leukaemia.

    PubMed

    Lewis, C M; Pegrum, G D

    1979-01-01

    A radioimmunoassay for measuring levels of lymphocyte autoantibody in chronic lymphocytic leukaemia (CLL) has been developed. Antibody in the form of crude IgG was extracted from patients' sera and iodinated. The assay utilizes its cross-reactivity with other CLL cells. Levels were measured in 23 patients. The results show that an inverse relationship exists between the quantity of circulating CLL autoantibodies and the number of mouse red blood cell rosetting lymphocytes (M cells). The preliminary findings do not correlate with disease activity although it is our impression that patients who are maintaining higher levels of autoantibody and fewer M-rosetting cells have nonprogressive disease.

  19. Elevated Neutrophil-to-Lymphocyte Ratio Predicts Intermediate-Term Outcomes in Patients Who Have Advanced Chronic Kidney Disease with Peripheral Artery Disease Receiving Percutaneous Transluminal Angioplasty

    PubMed Central

    Chen, I-Chih; Yu, Chao-Chin; Wu, Yi-Hsuan; Chao, Ting-Hsing

    2016-01-01

    Background Inflammation plays an important role in the pathogenesis of cardiovascular disease in patients with advanced chronic kidney disease (CKD). Neutrophil-to-lymphocyte ratio (NLR), an inflammatory biomarker, has not been evaluated in patients who have advanced CKD with peripheral artery disease (PAD) undergoing percutaneous transluminal angioplasty (PTA), especially in Taiwan. Methods We retrospectively evaluated 148 advanced CKD (creatinine clearance rate ≤ 30 mL/min/1.73 m2) identified from a prospective registry in our hospital (303 PTA cases in total). Kaplan-Meier analysis with log-rank test was used to study event-free survival, and all univariables (p value < 0.1) were put into multivariate Cox regression analysis. Results During the mean follow-up time of 8.6 ± 7.8 months, 35.1% of the cases achieved primary composite endpoint (all-cause mortality or major amputation), 25.5% underwent death from any cause, and 14.9% underwent major or minor amputation. Rutherford grade 6, either NLR or NLR ≥ 3.76, and a history of hypertension had a positively prognostic impact on the occurrence of primary composite endpoint, whereas higher albumin level (≥ 3.0 mg/dL) and technical success had a significantly protective effect. History of hypertension, either NLR or NLR ≥ 3.76, and age were associated with all-cause mortality. In addition, Rutherford 6, higher albumin level (≥ 3.0 mg/dL), technical success, NLR, and age could predict the occurrence of major amputation. Conclusions NLR, but not C-reactive protein or platelet-lymphocyte ratio, is an important prognostic predictor of all major clinical outcomes in patients with advanced CKD and PAD receiving PTA. Further studies are warranted to establish a better strategy and healthcare program in this clinical setting. PMID:27713601

  20. 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

  1. 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

  2. Chronic lymphocytic leukemia: case-based session.

    PubMed

    Rai, K R; Döhner, H; Keating, M J; Montserrat, E

    2001-01-01

    Drs. Hartmut Döhner, Michael J. Keating, Kanti R. Rai and Emili Montserrat form the panel to review chronic lymphocytic leukemia (CLL) while focusing on the clinical features of a particular patient. The pace of progress in CLL has accelerated in the past decade. The pathophysiological nature of this disease, as had been known in the past, was based largely on the intuitive and empiric notions of two leaders in hematology, William Dameshek and David Galton. Now the works of a new generation of leaders are providing us with the scientific explanations of why CLL is a heterogeneous disease, perhaps consisting of at least two separate entities. In one form of CLL, the leukemic lymphocytes have a surface immunoglobulin (Ig) variable region gene that has undergone somatic mutations, with tell-tale markers suggesting that these cells had previously traversed the germinal centers. Such patients have a distinctly superior prognosis than their counterparts whose leukemic lymphocytes IgV genes have no mutations (these are indeed immunologically naive cells), who have a worse prognosis. The introduction of fluorescence in situ hybridization (FISH) technique has provided us with new insights into the diverse chromosomal abnormalities that can occur in CLL, and which have significant impact on the clinical behavior and prognosis of patients with this disease. Major advances in therapeutics of CLL also have occurred during the past decade. Two monoclonal antibodies, Campath-1H (anti-CD52) and rituximab (anti-CD20), and one nucleoside analogue, fludarabine, have emerged as three agents of most promise in the front-line treatment of this disease. Studies currently in progress reflect our attempts to find the most effective manner of combining these agents to improve the overall survival statistics for CLL patients. As in many other hematological malignancies, high dose chemotherapy followed by autologous or HLA-compatible allogeneic stem cells rescue strategies are under study as

  3. Five-Year Follow-Up of Patients With Advanced Chronic Lymphocytic Leukemia Treated With Allogeneic Hematopoietic Cell Transplantation After Nonmyeloablative Conditioning

    PubMed Central

    Sorror, Mohamed L.; Storer, Barry E.; Sandmaier, Brenda M.; Maris, Michael; Shizuru, Judith; Maziarz, Richard; Agura, Edward; Chauncey, Thomas R.; Pulsipher, Michael A.; McSweeney, Peter A.; Wade, James C.; Bruno, Benedetto; Langston, Amelia; Radich, Jerald; Niederwieser, Dietger; Blume, Karl G.; Storb, Rainer; Maloney, David G.

    2008-01-01

    Purpose We reported encouraging early results of allogeneic hematopoietic cell transplantation (HCT) after nonmyeloablative conditioning in 64 patients who had advanced chronic lymphocytic leukemia (CLL). Here, we have extended the follow-up to a median of 5 years and have included data on an additional 18 patients. Patients and Methods Eighty-two patients, age 42 to 72 years, who had fludarabine-refractory CLL were conditioned with 2 Gy total-body irradiation alone or combined with fludarabine followed by HCT from related (n = 52) or unrelated (n = 30) donors. Results Complete remission (CR) and partial remission were achieved in 55% and 15% of patients, respectively. Higher CR rates were noted after unrelated HCT (67% v 48%). The 5-year incidences of nonrelapse mortality (NRM), progression/relapse, overall survival, and progression-free survival were 23%, 38%, 50%, and 39%, respectively. Among 25 patients initially reported in CR, 8% relapsed and 8% died as a result of NRM, whereas 84% have remained alive and in CR. Among 14 responding patients who were tested and who had molecular eradication of their disease, two died as a result of NRM, two relapsed, and 10 have remained negative. At 5 years, 76% of living patients were entirely well, whereas 24% continued to receive immunosuppression for chronic graft-versus-host disease; the median performance status in each group was 100% and 90%, respectively. Lymphadenopathy ≥ 5 cm, but not cytogenetic abnormalities at HCT, predicted relapse. In a risk-stratification model, patients who had lymphadenopathy less than 5 cm and no comorbidities had a 5-year OS of 71%. Conclusion Nonmyeloablative HCT resulted in a median survival of 5 years for patients who had fludarabine-refractory CLL with sustained remissions and in the continued resolution of chronic graft-versus-host disease in surviving patients. PMID:18794548

  4. Rituximab, fludarabine, and total body irradiation as conditioning regimen before allogeneic hematopoietic stem cell transplantation for advanced chronic lymphocytic leukemia: long-term prospective multicenter study.

    PubMed

    Michallet, Mauricette; Socié, Gerard; Mohty, Mohamad; Sobh, Mohamad; Bay, Jacques-O; Morisset, Stéphane; Labussière-Wallet, Hélène; Tabrizi, Reza; Milpied, Noel; Bordigoni, Pierre; El-Cheikh, Jean; Blaise, Didier

    2013-02-01

    To evaluate the efficacy and toxicity of reduced-intensity conditioning (RIC) combining fludarabine, low-dose total body irradiation (TBI) and rituximab before allogeneic hematopoietic stem cell transplantation (allo-HSCT) from human leucocyte antigen (HLA) identical siblings, we conducted a prospective study in patients ≤65 years old with advanced chronic lymphocytic leukemia (CLL) stage B or C in response after a salvage treatment. Conditioning included rituximab (375 mg/m² on day 5), fludarabine (30 mg/m² from day 4 to day 2), TBI (2 Gy on day 0), and rituximab (500 mg/m² on days 1 and 8). Forty patients were included, 34 (85%) were male with a median age of 54 years (range, 35-65 years), 38 (95%) were in B stage, and 2 were in stage C; only 7 patients (17%) were in complete response. Seven (17%) patients did not receive rituximab. Thirty-nine (98%) patients engrafted, 17 patients developed acute graft-versus-host disease (GVHD) grade ≥II with a cumulative incidence at 3 months of 44% (36-52) with a significant protective effect of rituximab (p = 0.02). The cumulative incidence of chronic GVHD was 29% (21-36) at 12 months for both limited and extensive forms. The median overall survival was not reached with 5-years probability of 55% (41-74). The multivariate analysis showed a positive effect of rituximab on overall survival and event-free survival (hazard ratio [HR] = 0.1 [0-0.6], p = 0.02; and HR = 0.1 [0-0.4], p = 0.035, respectively). The association of fludarabine, TBI, and rituximab is feasible, well tolerated, and allows better outcomes in advanced CLL.

  5. The Pathogenesis of Chronic Lymphocytic Leukemia

    PubMed Central

    Galton, D. A. G.

    1966-01-01

    The pathogenesis of chronic lymphocytic leukemia was examined in a series of 88 cases observed during a 15-year period. In untreated cases the trend of the absolute lymphocyte counts followed two main patterns. In the type I trend, the counts rose throughout the observation period; in the type II trend, the tendency to rise ceased and the counts stabilized above and below a mean value, the stationary trend being maintained for months or years. The type II trend was associated with relatively benign disease. The development of lymphocytosis was correlated with the progression of lymphadenopathy. It is suggested that lymphocytosis may result from the physiological process of recirculation and that the accumulation of lymphocytes may result from the proliferation of a single slightly abnormal cell-line. The abnormal cells might survive an unusually long time because they are unable to respond to stimuli which cause normal lymphocytes to transform. PMID:4952384

  6. 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

    2016-03-28

    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

  7. 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. PMID:26830086

  8. Novel agents for chronic lymphocytic leukemia

    PubMed Central

    2013-01-01

    Chronic lymphocytic leukemia (CLL) is a heterogeneous group of B-cell neoplasm. CLL is typically sensitive to a variety of cytotoxic agents, but relapse frequently occurs with conventional approaches. The treatment of CLL is evolving rapidly with the introduction of novel drugs, such as bendamustine, ofatumumab, lenalidomide, ibrutinib, idelalisib, veltuzumab, XmAb5574, navitoclax, dasatinib, alvespimycin, and TRU-016. This review summarizes the most current clinical experiences with these agents in the treatment of CLL. PMID:23680477

  9. Ibrutinib and Rituximab Compared With Fludarabine Phosphate, Cyclophosphamide, and Rituximab in Treating Patients With Untreated Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

    ClinicalTrials.gov

    2016-11-04

    Anemia; Fever, Sweat, and Hot Flashes; 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; Weight Change

  10. The lymph node in chronic lymphocytic leukemia.

    PubMed

    Dick, F R; Maca, R D

    1978-01-01

    Lymph nodes were examined from 41 cases of typical chronic lymphocytic leukemia (CLL). Degree of immaturity was graded as absent to minimal (Grade I), moderate (Grade II) and marked (Grade III). A moderate degree of immaturity was found in the lymph node in 14 of 41 cases even though the cells seen on the initial bone marrow and peripheral blood smears obtained from these patients were essentially all mature. The morphology of these nodes could be confused with poorly differentiated lymphocytic or mixed lymphocytic-histiocytic lymphoma in terms of the degree of immaturity present. A marked degree of immaturity present. A marked degree of immaturity was found in 5 cases; the morphology of these cases resembled histiocytic lymphoma. In the remaining 22 cases immaturity was essentially absent. The morphology of these cases was similar to that of diffuse well differentiated lymphocytic lymphoma. Our studies suggest that a moderate degree of immaturity in the lymph node of patients with CLL does not indicate that these patients will have a marked shortening of their survival. PMID:580071

  11. [Ultrastructure of blood lymphocytes in dairy cows with chronic lymphocytic leukemia].

    PubMed

    Cerný, L; Hajdu, I

    1982-03-01

    The morphology of blood lymphocytes was studied ultrastructurally in cows with chronical lymphocytic leucosis (CLL) and in healthy controls. A significantly higher occurrence of the so-called nuclear pockets in the leucaemic lymphocytes was found (13.8% v. 0.83% in healthy animals). The surfaces of lymphocytes were stained with ruthenium red; this showed the possibility of differentiating two distinct populations of lymphocytes in peripheral blood. In this way, a prevalence of B-lymphocytes, constituting 89.7% of all lymphocytes, was demonstrated in animals suffering from CLL. PMID:6179285

  12. [Treatment of patients with chronic lymphocytic leukemia].

    PubMed

    Mucsi, Orsolya

    2016-06-01

    Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western countries. The abnormal B lymphocytes progress into the blood and infiltrate the bone marrow, liver, spleen and lymph nodes. CLL is a disease of the adults and older individuals who often have coexisting conditions. It usually progresses slowly, but in patients who need treatment, CLL eventually returns. For relapsed, refractory patients treatment options are limited. The only curative treatment is bone marrow transplantation. However, the new, alternative therapeutics show superior efficacy in CLL than standard regimens. The aim of this review is to summarize the most important therapeutic aspects of CLL and to give an insight into the novel treatment options. PMID:27275639

  13. Predicting survival in chronic lymphocytic leukemia.

    PubMed

    Bazargan, Ali; Tam, Constantine S; Keating, Michael J

    2012-03-01

    There is increasing interest in the use of prognostic markers that may predict survival and guide management in patients diagnosed with the early stages of chronic lymphocytic leukemia (CLL). Currently, the most important traditional prognostic factors include clinical staging, lymphocyte doubling time and β2-microglobulin/thymidine kinase; and the most important novel markers include karyotypic aberrations (typically assessed by FISH probes or CpG oligonucleotide karyotyping) and IgVH mutation status. Although each of these factors have individually shown significant correlations with survival, there is increasing appreciation that the most complete information may be obtained by using a combination of several factors in prognostic normograms or models. In this article, we review the current state-of-the-art with regards to CLL prognostic factors and discuss how they can be applied in the clinic. PMID:22369330

  14. Secondary autoimmune cytopenias in chronic lymphocytic leukemia.

    PubMed

    Rogers, Kerry A; Woyach, Jennifer A

    2016-04-01

    Secondary autoimmune cytopenias in chronic lymphocytic leukemia are distinct clinical entities that require specific management. These autoimmune disorders have a complex pathogenesis that involves both the leukemic cells and the immune environment in which they exist. The mechanism is not the same in all cases, and to varying degrees involves the chronic lymphocytic leukemia (CLL) cells in antibody production, antigen presentation, and stimulation of T cells and bystander polyclonal B cells. Diagnosis of autoimmune cytopenias can be challenging as it is difficult to differentiate between autoimmunity and bone marrow failure due to disease progression. There is a need to distinguish these causes, as prognosis and treatment are not the same. Evidence regarding treatment of secondary autoimmune cytopenias is limited, but many effective options exist and treatment can be selected with severity of disease and patient factors in mind. With new agents to treat CLL coming into widespread clinical use, it will be important to understand how these will change the natural history and treatment of autoimmune cytopenias.

  15. 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

  16. Human lymphocyte surface immunoglobulin capping. Normal characteristics and anomalous behavior of chronic lymphocytic leukemic lymphocytes.

    PubMed Central

    Cohen, H J

    1975-01-01

    The phenomenon of redistribution of surface membrane immunoglobulin (Ig) components (capping) has been well described in mouse lymphoid cells. The characteristics of this process in human lymphocytes are less clear. This study characterizes the phenomenon of surface membrane Ig redistribution of normal and chronic lymphocytic leukemia (CLL) lymphocytes with the use of fluoroscein-labeled anti-Ig sera. Normal lymphocytes underwent rapid cap formation after incubation with anti-Ig serum in the cold and subsequent rewarming. The morphology was characteristic with aggregation over the pole of the cell opposite the nucleus and over the uropod when present. The process was energy dependent but independent of protein synthesis, and could be inhibited by vincristine, vinblastine, and colchicine but not by cytochalasin B. CLL cells, on the other hand, though showing fluorescent complex aggregation on the surface, rarely demonstrated unidirectional movement of these aggregates to form a cap. Cap formation in these cells could not be stimulated by supplementing the energy source or protein concentration of the medium nor by adding glutamic acid which could partially reverse the vincristine and vinblastine inhibition of normal capping. The failure of agents which inhibit motility to inhibit capping of the normal lymphocytes suggests that active locomotion is not a direct prerequisite for capping. The results also suggest the involvement of microtubules in normal capping and the possibility that abnormal membrane structure or microtubular function could explain the failure of CLL cells to behave normally in this regard. The role of this cellular defect in the immune deficiencies exhibited by many patients with CLL, however, is not established. Images PMID:1088910

  17. Serum gastrin in canine chronic lymphocytic-plasmacytic enteritis

    PubMed Central

    2005-01-01

    Abstract This study evaluates serum gastrin concentrations in dogs with chronic lymphocytic-plasmacytic enteritis, as well as its possible relationship with the severity of lesions present in the stomach. To achieve this aim, 5 dogs without gastrointestinal disease and 15 dogs with chronic lymphocytic-plasmacytic enteritis were included. Serum gastrin concentrations were significantly increased in dogs with chronic lymphocytic-plasmacytic enteritis compared with those in dogs without gastrointestinal disease. Also, there was a positive correlation between the severity of the gastric lesion and the serum gastrin concentration. Our findings indicate the possibility that gastrin plays a role in the etiology of an accompanying chronic antral gastritis in canine chronic lymphocytic-plasmacytic enteritis. PMID:16152719

  18. 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. PMID:27040699

  19. Ibrutinib (PCI-32765) in Chronic Lymphocytic Leukemia

    PubMed Central

    Jain, Nitin; O’Brien, Susan

    2015-01-01

    SYNOPSIS B-cell receptor (BCR) signaling is essential for chronic lymphocytic leukemia (CLL) cell survival. Many kinases in the BCR signaling pathway are currently being studied as potential therapeutic targets. These include Lyn, Syk, PI3 and Bruton tyrosine (BTK). Ibrutinib (PCI-32765) is a novel first-in-class selective inhibitor of BTK. Preclinical evidence suggests that ibrutinib inhibits CLL cell survival and proliferation. In addition, it also affects CLL cell migration and homing. Early clinical data in CLL and non-Hodgkin’s lymphoma patients is very encouraging. In relapsed-refractory patients with CLL, a 67% response rate was observed (420mg dose cohort) with single-agent ibrutinib. Long-term follow-up of these studies and other ongoing/planned studies of ibrutinib either as single-agent or in combination with monoclonal antibodies and chemoimmunotherapy is eagerly awaited. It is likely that ibrutinib and other drugs targeting the BCR pathway will become an integral component of CLL therapy. PMID:23915749

  20. Genomic and epigenomic heterogeneity in chronic lymphocytic leukemia

    PubMed Central

    Guièze, Romain

    2015-01-01

    Defining features of chronic lymphocytic leukemia (CLL) are not only its immunophenotype of CD19+CD5+CD23+sIgdim expressing clonal mature B cells but also its highly variable clinical course. In recent years, advances in massively parallel sequencing technologies have led to rapid progress in our understanding of the CLL genome and epigenome. Overall, these studies have clearly demarcated not only the vast degree of genetic and epigenetic heterogeneity among individuals with CLL but also even within individual patient leukemias. We herein review the rapidly growing series of studies assessing the genetic and epigenetic features of CLL within clinically defined periods of its growth. These studies strongly suggest an evolving spectrum of lesions over time and that these features may have clinical impact. PMID:26065654

  1. Chronic Lymphocytic Leukemia in Chornobyl Cleanup Workers.

    PubMed

    Bazyka, Dimitry; Gudzenko, Natalya; Dyagil, Iryna; Goroh, Eugeny; Polyschuk, Oksana; Trotsuk, Natalya; Babkina, Nataly; Romanenko, Anatoly

    2016-08-01

    This paper describes the chronic lymphocytic leukemia (CLL) incidence in a cohort of 110,645 (enlarged later to 152,520) male Ukrainian cleanup workers of the Chornobyl (Chernobyl) accident who were exposed to a range of radiation doses over the 1986-1990 time period. The standardized incidence rates are presented for a 27-y period after the exposure. For 2007-2012 period, the authors have identified the incident CLL cases in an enlarged cohort of 152,520 persons by linkage of the cohort file with the Ukrainian National Cancer Registry (NCRU). CLL data for the previous period (1987-2006) were identified in a frame of the Ukrainian-American leukemia study in the original cohort of 110,645 male clean-up workers. A significant CLL incidence excess was shown for the entire study period 1987-2012, with more prominent levels for the earliest years (1987-1996) when the standardized incidence rate (SIR) value was estimated to be 3.61 with 95% confidence interval from 2.32 to 4.91. In 2007-2012, the CLL incidence decreased substantially but still exceeded the national level although not significantly. In parallel, the several studies were performed at the National Research Center for Radiation Medicine (NRCRM) to explore if any clinical and cytogenetic features of CLL existed in the clean-up workers. The clinical study included 80 exposed and 70 unexposed CLL cases. Among the major clinical differences of the CLL course in the clean-up workers were a shorter period of white blood cells (WBC) doubling (10.7 vs. 18.0; p<0.001), frequent infectious episodes, lymphoadenopathy and hepatosplenomegaly (37 vs. 16), higher expression for CD38, and lower expression for ZAP-70 antigen. PMID:27356063

  2. Management of Chronic Lymphocytic Leukemia in the Elderly

    PubMed Central

    Barrientos, Jacqueline C.

    2016-01-01

    Background Because chronic lymphocytic leukemia (CLL) typically follows an indolent course, many patients do not need to initiate therapy until they reach a relatively advanced age, when frailty and reduced organ function can make some of the standard treatments difficult to tolerate and less effective. However, recent advances in the understanding of CLL biology and the approval of agents in novel treatment classes have offered significant advances in the management of the disease. Methods The author reviewed current treatment goals in CLL management, including issues surrounding complete remission (CR) and minimal residual disease (MRD); the findings of trials of treatments from novel drug classes, primarily kinase inhibitors and monoclonal antibodies; and current strategies for use of standard and novel therapies for treatment of individuals diagnosed with CLL, particularly elderly patients. Results Several agents and regimens featuring improved clinical outcomes and tolerability are now available or in advanced development for the management of CLL patients, including the elderly and those with high-risk disease. These include ibrutinib, idelalisib plus rituximab, and obinutuzumab plus chlorambucil. Conclusion The availability of Bruton’s tyrosine kinase inhibitors and phosphatidylinositol 3-kinase inhibitors and other novel therapies will allow elderly CLL patients to receive more efficacious treatment with greater tolerability than available with traditional approaches for management of the disease. PMID:26618342

  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. [Significance of Minimal Residual Disease in Chronic Lymphocytic Leukemia].

    PubMed

    Doubek, M

    2015-01-01

    Newly introduced highly effective treatment options increase the importance of minimal residual disease measurement in chronic lymphocytic leukemia. Minimal residual disease is gaining interest mainly as a predictive marker; however, clinical significance of minimal residual dis-ease in chronic lymphocytic leukemia in many different situations remains unresolved. Factors with a possible impact on the clinical significance of minimal residual disease are as follows: technique for minimal residual disease quantification, treatment regimen, peripheral blood vs. bone marrow analysis or time -point for sampling. Highly sensitive methods now available to evaluate minimal residual disease can detect a single chronic lymphocytic leukemia cell in 10(-4)- 10(-5) leukocytes using either allele -specific oligonucleotide polymerase chain reaction or multicolor flow cytometry. Minimal residual disease quantification as a surrogate marker to assess treatment efficacy in routine hematological practice has to be further evaluated.

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

    ClinicalTrials.gov

    2016-04-26

    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

  6. 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

    2016-08-31

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

  7. Bacillary angiomatosis in a patient with chronic lymphocytic leukemia.

    PubMed

    Petersen, K; Earhart, K C; Wallace, M R

    2008-10-01

    Bacillary angiomatosis is a cutaneous or visceral infection with Bartonella henselae or Bartonella quintana. Cases usually occur in HIV infected individuals. We present a 60-year-old man with chronic lymphocytic leukemia and neutropenic fever caused by bacillary angiomatosis. The nine BA cases in oncology patients are reviewed.

  8. [Determination of kinetic parameters lymphocyte populations in cows with chronic lymphocytic leukemia].

    PubMed

    Kuznetsov, V A; Feofanova, T V; Busol, V A; Nikolaeva, N V

    1995-01-01

    We analyzed changes in the number of lymphocytes in the blood of cows with chronic lymphoid leukemia using the Gomperts equation of population dynamics. The parameters of this equation were determined. Coefficients beta and gamma proved to be the most variable. The former reflects the delay and the latter characterizes the maximum rate of growth of the lymphocyte population. According to these parameters, three groups of animals were distinguished with different kinetics of leucosis and different correlations between immuno-hematological indices. PMID:7670356

  9. The changing paradigm of chronic lymphocytic leukemia management.

    PubMed

    Lobetti-Bodoni, Chiara; Bertoni, Francesco; Stussi, Georg; Cavalli, Franco; Zucca, Emanuele

    2013-07-01

    B cell-chronic lymphocytic leukemia (CLL), the commonest adult leukemia in western world, is today most often diagnosed at early-stage, following the accidental detection of lymphocytosis during a routine blood analysis. Moreover, the expectations of CLL patients have dramatically changed in the past decade and for the first time a significant overall survival improvement has been demonstrated in the disease--at least in the younger and fit patients--with the use of the FCR regimen, which combines rituximab fludarabine and cyclophosphamide. New drugs and new regimens are currently being developed for the relapsed patients and for those too old or too frail to receive aggressive treatments. Some of these promising compounds will likely be part of the future front-line treatments. Additionally, the increasing knowledge on the molecular features that predict the clinical outcome may soon result in a molecular classification of the disease. These acquisitions are producing a migration from palliative care to a curative and individually-tailored approach. In this review we tried to summarize the advances achieved in the past decade and help the specialists in internal medicine and the general practitioners to understand the completely changed scenario in which the disease should nowadays be managed.

  10. 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. PMID:22160019

  11. The clinical implications of gene mutations in chronic lymphocytic leukaemia.

    PubMed

    Rossi, Davide; Gaidano, Gianluca

    2016-04-12

    Chronic lymphocytic leukaemia (CLL) is a molecularly heterogeneous disease as revealed by recent genomic studies. Among genetic lesions that are recurrent in CLL, few clinically validated prognostic markers, such as TP53 mutations and 17p deletion, are available for the use in clinical practice to guide treatment decisions. Recently, several novel molecular markers have been identified in CLL. Though these mutations have not yet gained the qualification of predictive factors for treatment tailoring, they have shown to be promising to refine the prognostic stratification of patients. The introduction of targeted drugs is changing the genetics of CLL, and has disclosed the acquisition of previously unexpected drug resistant mutations in signalling pathway genes. Ultra-deep next generation sequencing has allowed to reach deep levels of resolution of the genetic portrait of CLL providing a precise definition of its subclonal genetic architecture. This approach has shown that small subclones harbouring drug resistant mutations anticipate the development of a chemorefractory phenotype. Here we review the recent advances in the definition of the genomic landscape of CLL and the ongoing research to characterise the clinical implications of old and new molecular lesions in the setting of both conventional chemo-immunotherapy and targeted drugs. PMID:27031852

  12. 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

  13. 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

  14. Significance of mouse red cell rosette-forming lymphocytes in chronic lymphocytic leukaemia.

    PubMed

    Pegrum, G D; Evans, C A

    1978-01-01

    Increased mouse red cell (M) rosetting lymphocytes were demonstrated in the peripheral blood of patients with chronic lymphatic leukaemia. The range was wide, and patients showed considerable variation not only in the number of M cells but also in T and B rosetting lymphocytes. Treatment reduced M rosette lymphocytes proportionately as the total white count fell, and differential removal occurred only when the patients became leucopaenic. If we assume the M rosetting cells are the abnormal 'leukaemic' cells, treatment does not preferentially remove these. The M rosetting capacity appeared to be related to the presence of an immunoglobulin factor previously demonstrated on the cells and in the serum of patients with CLL which enhances in vitro viability of the leukaemic cells.

  15. Idelalisib for the treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma.

    PubMed

    Barrientos, Jacqueline C

    2016-09-01

    Idelalisib is a first-in-class selective oral PI3Kδ inhibitor for the treatment of patients with relapsed chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma, a predominantly elderly population with high comorbidity. The drug promotes apoptosis in primary CLL cells ex vivo, independent of common prognostic markers and inhibits CLL cell homing, migration and adhesion to cells in the microenvironment. Idelalisib has shown efficacy with acceptable safety as monotherapy and combination therapy in relapsed/refractory CLL. Idelalisib has clinical activity in patients with CLL with del(17p). The development of other novel B-cell-targeted agents provides the opportunity to evaluate additional idelalisib treatment combinations for their potential to further improve outcomes in CLL/small lymphocytic lymphoma.

  16. Giant Pyogenic Granuloma in a Patient with Chronic Lymphocytic Leukemia

    PubMed Central

    Plovanich, Molly; Tsibris, Hillary C.; Lian, Christine G.; Mostaghimi, Arash

    2014-01-01

    Pyogenic granuloma, also known as lobular capillary hemangioma, is a common benign vascular proliferative lesion that can present at any age on the skin or mucous membranes. Most lesions do not exceed 2 cm, but there are a handful of giant cutaneous pyogenic granulomas that have been reported, often in individuals with underlying immune dysfunction. Here, we report the first giant pyogenic granuloma in a patient with a hematological malignancy, chronic lymphocytic leukemia. PMID:25408651

  17. Mutational landscape and underlying mutational processes in chronic lymphocytic leukemia.

    PubMed

    Kasar, S; Brown, J R

    2016-07-01

    Sequencing studies have been instrumental in understanding the genetic basis of chronic lymphocytic leukemia (CLL). Our recent whole-genome sequencing study focusing on lower cytogenetic risk CLL demonstrated that CLL mutations can be attributed to 3 key mutational processes-2 types of activation induced-cytidine deaminase (AID) signatures and an aging signature-that operate at different times throughout CLL evolution. PMID:27652313

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

    PubMed

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

    2016-09-01

    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

  19. Synthesis of DNA and Poly(Adenosine Diphosphate Ribose) in Normal and Chronic Lymphocytic Leukemia Lymphocytes

    PubMed Central

    Berger, Nathan A.; Adams, Jessie W.; Sikorski, Georgina W.; Petzold, Shirley J.; Shearer, William T.

    1978-01-01

    Peripheral blood lymphocytes were isolated from 9 patients with chronic lymphocytic leukemia (CLL) and 12 normal control donors. The cells were assayed for synthesis of DNA and poly-(adenosine diphosphate ribose) (poly[ADPR]) immediately after isolation and on successive days following their treatment with phytohemagglutinin (PHA). Two different techniques were used to measure DNA synthesis. In the standard technique, DNA synthesis was measured by incubating intact cells with [3H]deoxythymidine. In the new technique, the lymphocytes were first rendered permeable to nucleotides, then DNA synthesis was measured by incubating them with [3H]deoxythymidine triphosphate in the presence of deoxyATP, deoxyGTP, deoxyCTP, ATP, and Mg++. Both assays showed the anticipated rise in DNA synthesis after PHA stimulation of normal cells. PHA-stimulated lymphocytes from patients with CLL demonstrated low levels of DNA synthesis in both assay systems. The initial levels of poly(ADPR) synthesis were greater in CLL lymphocytes than in normal cells. Studies with a T-cell-depleted population of normal cells showed the same activity for poly(ADPR) synthesis that was demonstrated by the original population of normal cells. PHA stimulation produced an increase in poly(ADPR) synthesis in both the normal and CLL cells. The increase in poly(ADPR) synthesis in normal cells was coincident with the increase in DNA synthesis. The increase in poly(ADPR) synthesis in the CLL cells was dissociated from the delayed and diminished increase in DNA synthesis. Thus, CLL cells have higher than normal initial levels of poly(ADPR) synthesis. Poly(ADPR) synthesis is dissociated from DNA synthesis in CLL cells whereas it varies directly with DNA synthesis in normal lymphocytes. PMID:659624

  20. 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

  1. 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).

  2. Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Version 1.2015

    PubMed Central

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

    2016-01-01

    Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are different manifestations of the same disease, which are managed in the same way. The advent of novel monoclonal antibodies (ofatumumab and obinutuzumab) led to the development of effective chemoimmunotherapy regimens. The recently approved small molecule kinase inhibitors (ibrutinib and idelalisib) are effective treatment options for CLL in elderly patients with decreased tolerance for aggressive regimens and in patients with poor prognostic features who do not benefit from conventional chemoimmunotherapy regimens. This portion of the NCCN Guidelines for Non-Hodgkin’s Lymphomas describes the recent specific to the incorporation of recently approved targeted therapies for the management of patients with newly diagnosed and relapsed or refractory CLL/SLL. PMID:25736010

  3. Hypercalcaemia associated with chronic lymphocytic leukaemia in a Giant Schnauzer.

    PubMed

    Kleiter, M; Hirt, R; Kirtz, G; Day, M J

    2001-05-01

    A 7-year-old male Giant Schnauzer was referred with a history of severe vomiting, lethargy, weight loss, polydipsia and polyuria. Detailed investigations revealed leucocytosis with a marked lymphocytosis, mild non-regenerative anaemia, thrombocytopenia, hypercalcaemia and azotaemia. Circulating lymphocytes were small and well-differentiated, and the same lymphoid population was present in bone marrow. Chronic lymphocyctic leukaemia with associated paraneoplastic hypercalcaemia was diagnosed. Immunohistochemical staining of a bone marrow biopsy revealed a neoplastic B-cell line expressing CD79. The dog responded to therapy with prednisolone and chlorambucil for a period of 8 months.

  4. Acquired factor XI inhibitor in chronic lymphocytic leukaemia.

    PubMed Central

    Goodrick, M. J.; Prentice, A. G.; Copplestone, J. A.; Pamphilon, D. H.; Boon, R. J.

    1992-01-01

    A 71 year old man with chronic lymphocytic leukaemia (CLL) experienced excessive bleeding following transurethral resection of the prostate. Investigations showed a prolonged kaolin cephalin clotting time (KCCT) with low concentrations of factor XI. The prolonged KCCT was largely corrected by mixing with normal plasma but this correction was lost on incubation, confirming the presence of an inhibitor. He was treated with pulsed methylprednisolone and chlorambucil which resulted in the resolution of the bleeding problem and the loss of detectable circulating inhibitor. PMID:1577975

  5. Lymphocyte dysfunction in chronic graft-versus-host disease

    SciTech Connect

    Saxon, A.; McIntyre, R.E.; Stevens, R.H.; Gale, R.P.

    1981-10-01

    Three recipients of HLA-identical bone marrow transplants developed chronic graft-versus-host disease (cGVHD) and hypergammaglobulinemia. All three had evidence of abnormal B-lymphocyte function, including a polyclonal increase in immunoglobulins (Ig), antinuclear antibodies, rheumatoid factor, lymphocytotoxins, and increased immune complexes. T-lymphocyte function was also abnormal, including decreased mitogen reactivity and delayed cutaneous hypersensitivity. The cellular basis of these immune abnormalities was studied in an in vitro system in which we analyzed spontaneous pokeweed mitogen (PWM) driven Ig synthesis. Multiple defects in both T- and B-lymphocyte function were detected. In contrast to normal B cells, circulating B cells from all three patients with cGVHD spontaneously synthesized in vitro greater than 200 ng of IgG and in two of the three greater than 175 ng of IgM. This increase in spontaneous Ig synthesis was not due to a deficiency of regulatory cells, since T cells from the three patients suppressed spontaneous Ig synthesis in a normal fashion. In contrast to this increased spontaneous Ig synthesis, the response of the patients' B cells to PWM-driven Ig synthesis was normal. Using the PWM system we demonstrated several defects in these patients' T cells, including increased suppressor activity and decreased helper cell activity. These data indicate that some patients with cGVHD have multiple defects in both T- and B-cell function that may contribute to their profound immune deficiency.

  6. A case of chronic lymphocytic leukemia with massive ascites

    PubMed Central

    Yonal, Ipek; Nazlıgul, Esra; Tas, Gulsum; Agan, Mehmet Ramazan; Yenerel, Mustafa Nuri; Nalcaci, Meliha

    2012-01-01

    An 81-year old woman with a history of chronic lymphocytic leukemia (CLL) was admitted with night sweats and abdominal distension. A complete blood count showed hemoglobin 5 g/dL, white blood cell (WBC) count 28.5×109/L and platelets 38.4×109/L. Peripheral blood smear examination showed a large number of smudge cells and lymphocytosis composed of mature-looking lymphocytes with clumped nuclear chromatin. Computed tomography scan demonstrated enlarged cervical, axillary, paraaortic, retroperitoneal and mesenteric lymph nodes with concomitant omental thickening and ascites. Also, the liver and the spleen were enlarged in the presence of multiple ill-defined hypoechoic areas in the latter. Histopathological analysis of the cervical lymph node biopsy was consistent with CLL. Bone marrow examination showed diffuse infiltration of the marrow with small lymphocytes. Analysis of the ascitic fluid revealed an exudate with WBC 1220 cells/mL. Cytocentrifuge preparation of the ascitic fluid showed small mature lymphoid cells containing hyperchromatic nuclei with coarsely granular chromatin. On flow cytometric analysis of the ascitic fluid, expression of CD5, CD19, CD20, CD22, CD23, CD45 and HLA-DR was compatible with a diagnosis of CLL, in accordance with the results of the peripheral blood analysis. The patient was treated with chemotherapy consisting of cyclophosphamide, vincristine and prednisolone but died within one month after development of non-chylous ascites. PMID:23372915

  7. Chronic Lymphocytic Inflammation Specifies the Organ Tropism of Prions

    NASA Astrophysics Data System (ADS)

    Heikenwalder, Mathias; Zeller, Nicolas; Seeger, Harald; Prinz, Marco; Klöhn, Peter-Christian; Schwarz, Petra; Ruddle, Nancy H.; Weissmann, Charles; Aguzzi, Adriano

    2005-02-01

    Prions typically accumulate in nervous and lymphoid tissues. Because proinflammatory cytokines and immune cells are required for lymphoid prion replication, we tested whether inflammatory conditions affect prion pathogenesis. We administered prions to mice with five inflammatory diseases of the kidney, pancreas, or liver. In all cases, chronic lymphocytic inflammation enabled prion accumulation in otherwise prion-free organs. Inflammatory foci consistently correlated with lymphotoxin up-regulation and ectopic induction of FDC-M1+ cells expressing the normal cellular prion protein PrPC. By contrast, inflamed organs of mice lacking lymphotoxin-α or its receptor did not accumulate the abnormal isoform PrPSc, nor did they display infectivity upon prion inoculation. By expanding the tissue distribution of prions, chronic inflammatory conditions may act as modifiers of natural and iatrogenic prion transmission.

  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

    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

    2015-04-01

    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.

  9. 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

  10. [Latest advances in chronic pancreatitis].

    PubMed

    Domínguez-Muñoz, J Enrique

    2014-09-01

    This article summarizes some of the recent and clinically relevant advances in chronic pancreatitis. These advances mainly concern the early diagnosis of the disease, the prediction of the fibrosis degree of the gland, the evaluation of patients with asymptomatic hyperenzimemia, the medical and surgical treatment of abdominal pain and the knowledge of the natural history of the autoimmune pancreatitis. In patients with indetermined EUS findings of chronic pancreatitis, a new endoscopic ultrasound examination in the follow-up is of help to confirm or to exclude the disease. Smoking, number of relapses, results of pancreatic function tests and EUS findings allow predicting the degree of pancreatic fibrosis in patients with chronic pancreatitis. Antioxidant therapy has shown to be effective in reducing pain secondary to chronic pancreatitis, although the type and optimal dose of antioxidants remains to be elucidated. Development of intestinal bacterial overgrowth is frequent in patients with chronic pancreatitis, but its impact on symptoms is unknown and deserves further investigations. Finally, autoimmune pancreatitis relapses in about half of the patients with either type 1 or type 2 disease; relapses frequently occur within the first two years of follow-up.

  11. [Latest advances in chronic pancreatitis].

    PubMed

    Domínguez-Muñoz, J Enrique

    2013-10-01

    This article summarizes some of the recent and clinically relevant advances in chronic pancreatitis. These advances mainly concern knowledge of the etiopathogenesis of the disease, the pharmacological treatment of pain, and knowledge of the natural history of autoimmune pancreatitis. New evidence supports the relatively low prevalence of chronic alcoholic pancreatitis, and the role of tobacco in triggering the etiopathogenic mechanisms of chronic pancreatitis is better understood. Some studies have identified certain factors that are associated with having a positive genetic test in adults with chronic idiopathic pancreatitis, which should help to select those patients who should undergo genetic studies. Antioxidant therapy has been shown to be effective in reducing pain secondary to chronic pancreatitis, although the type and optimal dose of antioxidants remains to be elucidated. Finally, the development of exocrine and endocrine pancreatic insufficiency is a very common finding during the long-term follow-up of patients with autoimmune pancreatitis. Smoking also seems to play a role in this type of pancreatitis.

  12. 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

  13. [Latest advances in chronic pancreatitis].

    PubMed

    Domínguez Muñoz, J Enrique

    2015-09-01

    This article summarizes some of the recent and clinically relevant advances in chronic pancreatitis. These advances mainly concern the early diagnosis of the disease, the treatment of symptoms and complications, mainly pain and pancreatic exocrine insufficiency, and the diagnosis and therapy of autoimmune pancreatitis. The multimodal dynamic endoscopic ultrasound-guided secretin-stimulated evaluation of the pancreas provides relevant morphological and functional information for the diagnosis of chronic pancreatitis at early stages. Extracorporeal shock wave lithotripsy in patients with calcifying pancreatitis and endoscopic pancreatic stent placement are effective alternatives for pain therapy in patients with chronic pancreatitis. Presence of pancreatic exocrine insufficiency in patients with chronic pancreatitis is associated with a significantly increase of mortality rate. Despite that, pancreatic enzyme replacement therapy is not prescribed in the majority of patients with pancreatic exocrine insufficiency, or it is prescribed at a low dose. The newly developed and commercialized needles for endoscopic ultrasound-guided pancreatic biopsy are effective in retrieving appropriate tissue samples for the histological diagnosis of autoimmune pancreatitis. Maintenance therapy with azathioprine is effective and safe to prevent relapses in patients with autoimmune pancreatitis. PMID:26520201

  14. [Latest advances in chronic pancreatitis].

    PubMed

    Domínguez Muñoz, J Enrique

    2015-09-01

    This article summarizes some of the recent and clinically relevant advances in chronic pancreatitis. These advances mainly concern the early diagnosis of the disease, the treatment of symptoms and complications, mainly pain and pancreatic exocrine insufficiency, and the diagnosis and therapy of autoimmune pancreatitis. The multimodal dynamic endoscopic ultrasound-guided secretin-stimulated evaluation of the pancreas provides relevant morphological and functional information for the diagnosis of chronic pancreatitis at early stages. Extracorporeal shock wave lithotripsy in patients with calcifying pancreatitis and endoscopic pancreatic stent placement are effective alternatives for pain therapy in patients with chronic pancreatitis. Presence of pancreatic exocrine insufficiency in patients with chronic pancreatitis is associated with a significantly increase of mortality rate. Despite that, pancreatic enzyme replacement therapy is not prescribed in the majority of patients with pancreatic exocrine insufficiency, or it is prescribed at a low dose. The newly developed and commercialized needles for endoscopic ultrasound-guided pancreatic biopsy are effective in retrieving appropriate tissue samples for the histological diagnosis of autoimmune pancreatitis. Maintenance therapy with azathioprine is effective and safe to prevent relapses in patients with autoimmune pancreatitis.

  15. Triple cancer: chronic lymphocytic leukemia with bladder and prostate carcinoma.

    PubMed

    Gajendra, Smeeta; Sharma, Rashi; Sahoo, Manas Kumar

    2015-08-01

    B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is a common lymphoproliferative disorder with an increased risk of developing subsequent neoplasms of epithelial and mesenchymal origin. The decreased immunity and B-cell dysfunction in CLL probably accounts for this emergence of second malignancies. We report a case of synchronous bladder transitional cell carcinoma (TCC) and prostatic carcinoma with CLL. A 74-year-old male who underwent transurethral resection of the prostate (TURP) for benign prostatic hyperplasia 2 years before, presented with recurrent urinary tract infection. Peripheral blood smear revealed leukocytosis with absolute lymphocytosis (absolute lymphocyte count: 37870 cells/mm³). Flow cytometric immunophenotyping revealed 75% abnormal lymphoid cells which were positive for CD 19, CD5, CD23, CD22, CD200, CD20 (moderate) with lambda light chain restriction and negative for CD3, CD10, FMC7, CD38, CD138, IgM, CD103, CD123. F Fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) showed increased metabolic activity of the left lateral wall of the urinary bladder extending to the left UV junction, adjacent part of trigone and bladder neck region along with multiple heterogeneous enhancing areas with increased FDG avidity within the prostate. Transurethral resection of the bladder tumour by cystoscopy was performed. Histopathology showed high grade, muscle invasive urothelial carcinoma. Due to presence of uptake in the prostate, transurethral resection of the prostate was done and histopathology revealed adenocarcinoma of prostate (prostate specific antigen- positive), Gleason grade III+III and Gleason score 6. A high index of suspicion is required to detect synchronous and metachronous malignancies. Ancillary studies such as immunohistochemistry, flow cytometry and PET/CT are often essential for detection and an accurate diagnosis.

  16. Unusual intracytoplasmic immunoglobulin inclusions in chronic lymphocytic leukaemia.

    PubMed

    Guglielmi, P; Preud'Homme, J L; Gourdin, M F; Reyes, F; Daniel, M T

    1982-01-01

    Unusual intracytoplasmic immunoglobulin inclusions were found by immunofluorescence in three patients with chronic lymphocytic leukaemia. The inclusions contained the same immunoglobulin chains as those detected on the plasma membrane, except for delta chains which were expressed on the cell surface and not in the cytoplasmic inclusions. The cytoplasmic staining persisted throughout culture for 8 or more days. An initial study of patients 1's cells showed that the inclusions contained only mu chains, and kappa chains gradually became apparent after in vitro culture. In a second study, the fresh lymphocytes contained both mu and and kappa chains. Initially, biosynthetic experiments showed production of mu chains which polymerized in the cytoplasm and were not secreted. Subsequently there was synthesis of heavy and light chains which assembled into monomeric subunits that were retained and secretion of free light chains. The apparent molecular weight of these immunoglobulin chains was larger than that of their secretory counterparts. Immunoelectronmicroscopy revealed cytoplasmic mu chains in strands of endoplasmic reticulum. In the two other patients, immunofluorescence displayed unusual staining patterns of bright networks in perinuclear areas. PMID:6275878

  17. 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

  18. Antigen stimulation in the development of chronic lymphocytic leukemia.

    PubMed

    Karp, Marta; Giannopoulos, Krzysztof

    2013-12-05

    Chronic lymphocytic leukemia (CLL) is the most common leukemia in the western world. The mechanism the mechanism of the disease development still remains unrevealed. In recent years new unique molecular and clinical features of CLL have emerged leading to a unified hypothesis of CLL origin. Major progress in understanding CLL biology was made after identification of mutational status of immunoglobulin variable heavy chain (IGHV) genes, which also improved prediction of patients' clinical outcome. Preferential usage of IGHV genes has led to recognition of CLL-specific B cell receptors (BCRs), called stereotyped BCRs. Taken together, these data point to antigen stimulation of CLL progenitor cells. Studies on CLL antibody reactivity have shown affinity to molecular motifs on apoptotic cells and bacterial cell structures, supporting the current hypothesis of the CLL pathomechanism. In this paper we have summarized information available to date regarding current theory of cellular origin and pathology of CLL.

  19. 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

  20. CARs in Chronic Lymphocytic Leukemia – Ready to Drive

    PubMed Central

    Wierda, William; Jena, Bipulendu; Cooper, Laurence J. N.; Shpall, Elizabeth

    2013-01-01

    Adoptive transfer of antigen-specific T cells has been adapted by investigators for treatment of chronic lymphocytic leukemia (CLL). To overcome issues of immune tolerance which limits the endogenous adaptive immune response to tumor-associated antigens (TAAs), robust systems for the genetic modification and characterization of T cells expressing chimeric antigen receptors (CARs) to redirect specificity have been produced. Refinements with regards to persistence and trafficking of the genetically modified T cells are underway to help improve potency. Clinical trials utilizing this technology demonstrate feasibility, and increasingly, these early-phase trials are demonstrating impressive anti-tumor effects, particularly for CLL patients, paving the way for multi-center trials to establish the efficacy of CAR+ T cell therapy. PMID:23225251

  1. 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

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

    PubMed

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

    2015-02-01

    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

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

    PubMed

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

    2015-02-01

    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.

  4. 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

  5. Longterm decrease in the CD57 lymphocyte subset in a patient with chronic Lyme disease.

    PubMed

    Stricker, Raphael B; Burrascano, Joseph; Winger, Edward

    2002-01-01

    Lyme disease is a tickborne illness caused by the spirochete Borrelia burgdorferi. In a previous report we described a decrease in the CD57 lymphocyte subset in patients with chronic Lyme disease. We have now identified a patient with chronic relapsing and remitting symptoms of Lyme disease who had decreased levels of CD57 lymphocytes over 10 years. This observation represents the longest duration of an immunologic abnormality ever documented in chronic Lyme disease. The CD57 lymphocyte subset appears to be a useful marker of longterm infection with the Lyme disease spirochete.

  6. Non-coding recurrent mutations in chronic lymphocytic leukaemia.

    PubMed

    Puente, Xose S; Beà, Silvia; Valdés-Mas, Rafael; Villamor, Neus; Gutiérrez-Abril, Jesús; Martín-Subero, José I; Munar, Marta; Rubio-Pérez, Carlota; Jares, Pedro; Aymerich, Marta; Baumann, Tycho; Beekman, Renée; Belver, Laura; Carrio, Anna; Castellano, Giancarlo; Clot, Guillem; Colado, Enrique; Colomer, Dolors; Costa, Dolors; Delgado, Julio; Enjuanes, Anna; Estivill, Xavier; Ferrando, Adolfo A; Gelpí, Josep L; González, Blanca; González, Santiago; González, Marcos; Gut, Marta; Hernández-Rivas, Jesús M; López-Guerra, Mónica; Martín-García, David; Navarro, Alba; Nicolás, Pilar; Orozco, Modesto; Payer, Ángel R; Pinyol, Magda; Pisano, David G; Puente, Diana A; Queirós, Ana C; Quesada, Víctor; Romeo-Casabona, Carlos M; Royo, Cristina; Royo, Romina; Rozman, María; Russiñol, Nuria; Salaverría, Itziar; Stamatopoulos, Kostas; Stunnenberg, Hendrik G; Tamborero, David; Terol, María J; Valencia, Alfonso; López-Bigas, Nuria; Torrents, David; Gut, Ivo; López-Guillermo, Armando; López-Otín, Carlos; Campo, Elías

    2015-10-22

    Chronic lymphocytic leukaemia (CLL) is a frequent disease in which the genetic alterations determining the clinicobiological behaviour are not fully understood. Here we describe a comprehensive evaluation of the genomic landscape of 452 CLL cases and 54 patients with monoclonal B-lymphocytosis, a precursor disorder. We extend the number of CLL driver alterations, including changes in ZNF292, ZMYM3, ARID1A and PTPN11. We also identify novel recurrent mutations in non-coding regions, including the 3' region of NOTCH1, which cause aberrant splicing events, increase NOTCH1 activity and result in a more aggressive disease. In addition, mutations in an enhancer located on chromosome 9p13 result in reduced expression of the B-cell-specific transcription factor PAX5. The accumulative number of driver alterations (0 to ≥4) discriminated between patients with differences in clinical behaviour. This study provides an integrated portrait of the CLL genomic landscape, identifies new recurrent driver mutations of the disease, and suggests clinical interventions that may improve the management of this neoplasia. PMID:26200345

  7. Adenosine Deaminase Activity in Chronic Lymphocytic Leukemia and Healthy Subjects

    PubMed Central

    Ghaderi, Bayazid; Amini, Sabrieh; Maroofi, Farzad; Jalali, Chiya; Javanmardi, Mitra; Roshani, Daem; Abdi, Mohammad

    2016-01-01

    Background B cell chronic lymphocytic leukemia is one of the most frequent hematologic malignancies in the world. Cellular surface CD markers and serum Beta-2-microglobulin may be used as a prognostic tool in CLL patients. Objectives In the present study we introduce serum adenosine deaminase as a diagnostic marker in CLL. Materials and Methods Blood samples were collected from B-CLL and healthy subjects. White blood cell, red blood cell and platelet count and blood Erythrocyte sedimentation rate was recorded and serum Beta-2-microglobulin, Lactate dehydrogenase and total ADA enzyme activity were determined. Results Serum ADA activity was significantly higher in patients group than that of controls. ADA had a significant and direct correlation with B2M, WBC, LDH and ESR. However, there was not any relation between ADA and the stages of disease. Diagnostic cut-off, sensitivity and specificity of the serum ADA test were 27.97 U/L, 91% and 94%, respectively. Conclusions A higher ADA activity in patients group and its correlation with CLL markers were seen in our study. High diagnostic value of serum ADA in our study suggests that it might be considered as a useful screening tool among the other markers in CLL. PMID:27703646

  8. 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.

  9. 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.

  10. Prognostic factors and risk stratification in chronic lymphocytic leukemia.

    PubMed

    Parikh, Sameer A; Shanafelt, Tait D

    2016-04-01

    There is considerable heterogeneity in the clinical outcome of patients with chronic lymphocytic leukemia (CLL). While some patients live for decades without any therapy, others die within years of diagnosis despite multiple treatments. To better counsel newly diagnosed CLL patients about their disease course, the Rai and Binet staging systems were developed four decades ago. A deeper understanding of the biologic and molecular aberrations contributing to the pathogenesis of CLL led to identification of novel prognostic markers such as immunoglobulin heavy-chain variable gene (IGHV) mutation status, leukemia-cell expression of CD38, ZAP-70, and CD49d, and cytogenetic abnormalities detected by fluorescent in situ hybridization (FISH). The advent of next-generation sequencing has provided unprecedented insights into the subclonal architecture of CLL and its impact on disease progression and survival. More recently, integrated prognostic scoring systems that incorporate clinical, biologic and genetic characteristics into a single risk score have been developed and appear to improve the accuracy of prognostication for individual patients. This review summarizes the state-of-the-art prognostic factors and will guide the practicing clinician in their care of patients with CLL. PMID:27040701

  11. TACI Expression and Signaling in Chronic Lymphocytic Leukemia

    PubMed Central

    Mamara, Antigoni; Germenis, Anastasios E.; Kompoti, Maria; Palassopoulou, Maria; Mandala, Eudokia; Banti, Anastasia; Giannakoulas, Nikolaos

    2015-01-01

    TACI is a membrane receptor of BAFF and APRIL, contributing to the differentiation and survival of normal B cells. Although malignant B cells are also subjected on TACI signaling, there is a remarkable intradisease and interindividual variability of TACI expression in B-cell malignancies. The aim of our study was to explore the possible role of TACI signaling in the biology of chronic lymphocytic leukemia (CLL), including its phenotypic and clinical characteristics and prognosis. Ninety-four patients and 19 healthy controls were studied. CLL patients exhibited variable TACI expression, with the majority of cases displaying low to undetectable TACI, along with low to undetectable BAFF and increased APRIL serum levels compared to healthy controls. CLL cells with high TACI expression displayed a better survival capacity in vitro, when cultured with BAFF and/or APRIL. Moreover, TACI expression was positively correlated with the presence of monoclonal gammopathy and inversely with CD11c expression. Therefore, our study provides further evidence for the contribution of BAFF/APRIL signaling to CLL biology, suggesting also that TACI detection might be useful in the selection of patients for novel targeting therapeutic approaches. PMID:25950010

  12. Potential new agents for chronic lymphocytic leukemia treatment.

    PubMed

    Kiliańska, Zofia M; Rogalińska, Małgorzata

    2010-11-01

    Chronic lymphocytic leukemia (CLL) is the most frequent type of hematological cancer in the Western World. An accumulation of leukemic cells in peripheral blood of patients is a result of apoptosis disturbances as well as an increase in germinal centers CLL cell proliferation. The differences between CLL patients in the course and response to therapy reflects personal variability between patients in their genetic material. It was documented that many sufferers from CLL are over 60 years old, and because of many countries' population obsolescence this type of leukemia could become more frequent in the future. CLL remains incurable, and the therapy regimens available at present could induce even complete remissions, but finally a relapse of the disease. The etiology of this disease is still not known, but our understanding of the processes running in CLL cells has significantly increased. A number of new agents with potential of CLL cell elimination by apoptosis or autophagy were characterized. Some of them reflect potential in cell sensitization to standard therapy. The major challenge for the future is to develop targeted anti-cancer therapy and design the optimal personalized manner of CLL treatment. A special interest is focused on anti-cancer agents - natural substances of plant origin. This paper reviews chosen new anti-leukemic agents belonging to different drug-classes (new monoclonal antibodies or apoptosis-, BCR signaling- and cell cycle-related inhibitors, substances of plant origin) which are under intense investigation in preclinical studies and early clinical trials. PMID:21235440

  13. 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

  14. The significance of spliceosome mutations in chronic lymphocytic leukemia.

    PubMed

    Rozovski, Uri; Keating, Michael; Estrov, Zeev

    2013-07-01

    Cellular proteins produced via alternative splicing provide neoplastic cells with survival advantage and/or promote neoplastic cell proliferation. Pre-mRNA is spliced by the spliceosome consisting of large complexes of small nuclear RNA (snRNA) and protein subunits. Spliceosome gene mutations were detected in 40-80% of patients with myelodysplastic syndrome (MDS), particularly in those with ringed sideroblasts. Recently, two large whole-genome sequencing studies identified mutations in the spliceosome gene SF3B1 in approximately 10% of patients with chronic lymphocytic leukemia (CLL). Intrigued by these findings, we performed a pathway enrichment analysis and found that, unlike in MDS, in CLL spliceosome mutations exist almost exclusively in SF3B1. Patients with CLL with an SF3B1 gene mutation are characterized by a short progression-free survival and a low 10-year survival rate. Furthermore, the frequency of SF3B1 mutations is significantly higher in chemotherapy treated than in untreated patients with CLL, suggesting that chemotherapy induces SF3B1 gene mutations or selects a population of mutated cells. Whether SF3B1 gene mutations have a role in leukemogenesis, either because of altered splicing or other splicing-unrelated functions such as ectopic expression of Homeobox (Hox) genes previously reported in SF3B1+(/-) mice, remains to be determined.

  15. The immunoglobulin genes: structure and specificity in chronic lymphocytic leukemia.

    PubMed

    Tobin, Gerard

    2007-06-01

    The rearrangement of the immunoglobulin genes (IG) provides a large diversity of B-cell receptors conformations and allows the immune system to respond differently to foreign antigens. In chronic lymphocytic leukemia (CLL), there are a restricted number of stereotyped B-cell receptors rearranged by the tumor B-cells between CLL patients. These subsets with stereotyped receptors appear to have clinical implications, for example cases that rearrange the IGHV3-21 gene display poor clinical prognosis. The number of subsets with stereotyped receptors has been reported at a frequency of over 20% of CLL cases; however, the specificities of these receptors are still not clearly defined. Reactivity to epitopes from bacterial antigen, cytoskeleton components such as vimentin, and antigens on viable and apoptotic T-cell have been proposed. The role of antigen in CLL development is currently being more clearly defined with identification of stereotyped receptors, and their antigen specificity and the continued role antigen stimulation plays in CLL disease will be an important question in the future.

  16. Non-coding recurrent mutations in chronic lymphocytic leukaemia.

    PubMed

    Puente, Xose S; Beà, Silvia; Valdés-Mas, Rafael; Villamor, Neus; Gutiérrez-Abril, Jesús; Martín-Subero, José I; Munar, Marta; Rubio-Pérez, Carlota; Jares, Pedro; Aymerich, Marta; Baumann, Tycho; Beekman, Renée; Belver, Laura; Carrio, Anna; Castellano, Giancarlo; Clot, Guillem; Colado, Enrique; Colomer, Dolors; Costa, Dolors; Delgado, Julio; Enjuanes, Anna; Estivill, Xavier; Ferrando, Adolfo A; Gelpí, Josep L; González, Blanca; González, Santiago; González, Marcos; Gut, Marta; Hernández-Rivas, Jesús M; López-Guerra, Mónica; Martín-García, David; Navarro, Alba; Nicolás, Pilar; Orozco, Modesto; Payer, Ángel R; Pinyol, Magda; Pisano, David G; Puente, Diana A; Queirós, Ana C; Quesada, Víctor; Romeo-Casabona, Carlos M; Royo, Cristina; Royo, Romina; Rozman, María; Russiñol, Nuria; Salaverría, Itziar; Stamatopoulos, Kostas; Stunnenberg, Hendrik G; Tamborero, David; Terol, María J; Valencia, Alfonso; López-Bigas, Nuria; Torrents, David; Gut, Ivo; López-Guillermo, Armando; López-Otín, Carlos; Campo, Elías

    2015-10-22

    Chronic lymphocytic leukaemia (CLL) is a frequent disease in which the genetic alterations determining the clinicobiological behaviour are not fully understood. Here we describe a comprehensive evaluation of the genomic landscape of 452 CLL cases and 54 patients with monoclonal B-lymphocytosis, a precursor disorder. We extend the number of CLL driver alterations, including changes in ZNF292, ZMYM3, ARID1A and PTPN11. We also identify novel recurrent mutations in non-coding regions, including the 3' region of NOTCH1, which cause aberrant splicing events, increase NOTCH1 activity and result in a more aggressive disease. In addition, mutations in an enhancer located on chromosome 9p13 result in reduced expression of the B-cell-specific transcription factor PAX5. The accumulative number of driver alterations (0 to ≥4) discriminated between patients with differences in clinical behaviour. This study provides an integrated portrait of the CLL genomic landscape, identifies new recurrent driver mutations of the disease, and suggests clinical interventions that may improve the management of this neoplasia.

  17. [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.

  18. 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

  19. The Fahr syndrome and the chronic lymphocytic thyroiditis.

    PubMed

    Sava, Anca; Dumitrescu, Gabriela; Haba, Danisia; Hodorog, Diana; Mihailov, Claudia; Şapte, Elena

    2013-01-01

    Fahr syndrome (FS) refers to basal ganglia calcification that is associated with many neurological and psychiatric abnormalities and appears as secondary to other diseases. We described a case of FS patient who was admitted in the Department of Neurology of "Prof. Dr. Nicolae Oblu" Clinical Emergency Hospital, Iassy, Romania, with seizure and mood disorders. On CT, the cause of seizure was found to be the bilateral calcifications of cerebellum, basal ganglia, thalamus and internal capsule. As the patient died after 15 days of hospitalization due to new seizures and gastrointestinal infection, an autopsy was made. Grossly, there were bilateral symmetrically gritty yellow areas in basal ganglia, thalami, internal capsule, cerebral cortex, cerebellar folia, dentate nucleus, and brain stem. A detailed histopathological examination revealed five types of calcium deposits within the walls of capillaries, small and medium-sized arteries from the intracerebral affected areas, chronic lymphocytic thyroiditis and fibro-adipose tissue instead of parathyroids. We consider that intracerebral symmetrical calcifications were the results of the hypoparathyroidism determined by an ancient autoimmune parathyroiditis that evolved to fibrosis as at microscopy we found an autoimmune thyroiditis.

  20. 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

  1. 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

  2. Increased mitogenic response in lymphocytes from chronically centrifuged mice

    NASA Technical Reports Server (NTRS)

    Mueller, Otfried; Hunzinger, E.; Cogoli, Augusto; Bechler, B.; Lee, J.; Moore, J.; Duke, J.

    1990-01-01

    The effects upon the mitogenic response of splenic lymphocytes when exposing mice to prolonged hypergravity conditions (3.5 G for 1 year) were studied. Cultures of splenic lymphocytes isolated from both centrifuged and control (1 G) animals were stimulated with Concanavalin A and the response measured using both morphological and biochemical means. Lymphocytes obtained from centrifuged mice exhibited much higher activation rates (as measured by the incorporation of H-3 thymidine) and larger cell aggregates consisting of more lymphoblasts and mitotic figures than those observed in non centrifuged control animals. Isolated splenic lymphocytes thus appear to have been conditioned by hypergravity state.

  3. Bacillary Angiomatosis and Bacteremia due to Bartonella quintana in a Patient with Chronic Lymphocytic Leukemia.

    PubMed

    Fulchini, Rosamaria; Bloemberg, Guido; Boggian, Katia

    2013-01-01

    We present a 63-year-old man treated with alemtuzumab for chronic lymphocytic leukemia who developed multiple angiomatous papules and fever. Real-time polymerase chain reaction (RT-PCR) from a skin lesion and blood sample revealed Bartonella quintana as causative agent confirming the diagnosis of bacillary angiomatosis with bacteremia. Treatment with doxycycline, initially in combination with gentamicin, led to complete resolution of the lesions. This case shows the importance of considering bacillary angiomatosis as a rare differential diagnosis of angiomatous lesions in the immunocompromised patient, particularly in chronic lymphocytic leukemia and following lymphocyte depleting treatments as alemtuzumab.

  4. The chronic lymphocytic leukemia clone disrupts the bone marrow microenvironment.

    PubMed

    Janel, Alexandre; Dubois-Galopin, Frédérique; Bourgne, Céline; Berger, Juliette; Tarte, Karin; Boiret-Dupré, Nathalie; Boisgard, Stéphane; Verrelle, Pierre; Déchelotte, Pierre; Tournilhac, Olivier; Berger, Marc G

    2014-12-15

    The systematic localization of chronic lymphocytic leukemia (CLL) B-cells in the bone marrow (BM), together with the ex vivo protective effect of stromal cells on their spontaneous apoptosis, both indicate a specific role of the BM microenvironment. In vivo, the impact of CLL cells on mesenchymal stromal cells (MSCs) remains a source of debate. Here, we quantified and expanded colony forming unit-fibroblasts (CFU-Fs) from CLL-BM under standard conditions, analyzed the expression of selected genes, and studied secretion profiles. We observed failing of CLL-BM cultures in standard conditions (45.5% vs. <0.1%), and even after adding basic fibroblast growth factor (bFGF), there were fewer CFU-F than from normal BM (1.3 vs. 40/10(6) cells respectively; P<0.01). Furthermore, their polygonal aspect and low proliferative capacity, together with the expression of 384 selected genes and a secreted set of molecules related to senescence-associated secretory phenotype indicated a state of senescence, further confirmed by the higher proportion of senescence-associated β-galactosidase (SA-βGAL)-positive cells and p16INK4a overexpression. In our hands, hypoxic conditions (5% O2) did not rescue CFU-Fs. Given the role of MSC in BM tissue organization, we studied hematons that are generally considered to be elementary BM units. These structures were rare or had even disappeared completely. When hematons were present, we systematically observed nodular B-CLL cell invasion only. These data confirm that the B-CLL clone has a marked impact on MSC and disrupts BM organization in vivo, raising new questions about in vivo pathophysiology.

  5. Spotlight on chronic lymphocytic leukemia: a Pharma Matters report.

    PubMed

    D'Souza, P; Walker, G

    2014-07-01

    A paradigm shift in the treatment of chronic lymphocytic leukemia (CLL) has taken place over the past decade, as therapies have progressed from providing palliative relief to inducing complete remission, eradicating minimal disease and improving survival. The development of Rituxan® (rituximab) and its use in immunochemotherapy regimens has transformed the treatment of CLL and is the current gold standard in physically fit individuals aged < 65 years. Despite this therapeutic development, Rituxan-based immunochemotherapy is limited in the two CLL groups that form the majority of CLL cases-the elderly and patients with comorbidities and high risk factors. Moreover, within 2 years of first- and second-line therapy, around 25% and 50% of patients relapse, respectively, and patients who experience remission for several years exhibit poor responses to subsequent therapies. Therefore, there still remains a significant unmet need in CLL. The rapid development of small-molecule agents targeting the B-cell receptor signaling pathway has been stimulated both by the association of this pathway with the initiation and progression of CLL as well as the high response rates and durable remissions reported in early-stage trials. Imbruvica (ibrutinib), an oral first-in-class Bruton's tyrosine kinase inhibitor, recently entered the market following accelerated approval in the relapsed/refractory setting, but long-term survival data are currently immature. New therapies face several significant challenges: to provide even greater response rates, particularly in the elderly and in patients with comorbidities and high risk factors, and to overcome resistance to current treatments. Currently, the only curative treatment for CLL, allogeneic hematopoietic stem cell transplantation, is not an option for the majority of CLL patients. The ultimate question is whether small-molecule therapeutics can achieve a cure for CLL. It is hoped that developments in identifying the cytogenetic and

  6. Recent advancements of bortezomib in acute lymphocytic leukemia treatment.

    PubMed

    Du, Xiao-Li; Chen, Qi

    2013-01-01

    Although survival rates for acute lymphocytic leukemia (ALL), especially in children, have shown dramatic improvement over time, poor outcomes are still observed in patients who have refractory or relapsed disease after conventional chemotherapy. New therapeutic options are urgently needed. Bortezomib (Velcade, formerly PS-341) is the first proteasome inhibitor approved by the US FDA for the treatment of newly diagnosed multiple myeloma and relapsed/refractory multiple myeloma and mantle cell lymphoma. Although the mechanisms of bortezomib anticancer activity are still not completely understood, it is a new treatment option for patients with refractory or relapsed ALL, particularly when used in combination with conventional chemotherapy or targeted agents. This review summarizes recent advancements in the understanding of the bortezomib molecular mechanism of action in ALL. Understanding of the molecular approaches might help customize cancer chemotherapy for each individual patient, directing the field towards rational therapeutics.

  7. Richter syndrome in chronic lymphocytic leukemia: updates on biology, clinical features and therapy.

    PubMed

    Jamroziak, Krzysztof; Tadmor, Tamar; Robak, Tadeusz; Polliack, Aaron

    2015-07-01

    Richter syndrome (RS) or Richter transformation is the development of secondary aggressive lymphoma in the setting of underlying chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Most frequently CLL transforms into diffuse large B-cell lymphoma (DLBCL) (90%) and rarely (10%) into Hodgkin lymphoma, termed Hodgkin variant of Richter syndrome (HvRS). RS is generally characterized by an aggressive clinical course and poor prognosis. In recent years, major advances have been made in understanding genetic events which relate to the progression of CLL or transformation into RS. Better understanding of the molecular pathways has revealed that RS is not a single homogeneous entity. The majority of cases are clonally related to the original CLL clone, while a minority develop from an unrelated clone. This review summarizes new data relating to the molecular biology and the genetic/epigenetic changes occurring during Richter transformation, and also considers the clinical features and therapy for both DLBCL-RS and Hodgkin variant-RS.

  8. Generation of a poor prognostic chronic lymphocytic leukemia-like disease model: PKCα subversion induces up-regulation of PKCβII expression in B lymphocytes

    PubMed Central

    Nakagawa, Rinako; Vukovic, Milica; Tarafdar, Anuradha; Cosimo, Emilio; Dunn, Karen; McCaig, Alison M.; Holroyd, Ailsa; McClanahan, Fabienne; Ramsay, Alan G.; Gribben, John G.; Michie, Alison M.

    2015-01-01

    Overwhelming evidence identifies the microenvironment as a critical factor in the development and progression of chronic lymphocytic leukemia, underlining the importance of developing suitable translational models to study the pathogenesis of the disease. We previously established that stable expression of kinase dead protein kinase C alpha in hematopoietic progenitor cells resulted in the development of a chronic lymphocytic leukemia-like disease in mice. Here we demonstrate that this chronic lymphocytic leukemia model resembles the more aggressive subset of chronic lymphocytic leukemia, expressing predominantly unmutated immunoglobulin heavy chain genes, with upregulated tyrosine kinase ZAP-70 expression and elevated ERK-MAPK-mTor signaling, resulting in enhanced proliferation and increased tumor load in lymphoid organs. Reduced function of PKCα leads to an up-regulation of PKCβII expression, which is also associated with a poor prognostic subset of human chronic lymphocytic leukemia samples. Treatment of chronic lymphocytic leukemia-like cells with the selective PKCβ inhibitor enzastaurin caused cell cycle arrest and apoptosis both in vitro and in vivo, and a reduction in the leukemic burden in vivo. These results demonstrate the importance of PKCβII in chronic lymphocytic leukemia-like disease progression and suggest a role for PKCα subversion in creating permissive conditions for leukemogenesis. PMID:25616575

  9. Hypogammaglobulinaemia associated with abnormalities of both B and T lymphocytes in patients with chronic lymphatic leukaemia.

    PubMed Central

    Hersey, P; Wotherspoon, J; Reid, G; Gunz, F W

    1980-01-01

    The underlying basis for hypogammaglobulinaemia in patients with chronic lymphatic leukaemia (CLL) was investigated by measurement if immunoglobulin produced in vitro in cultures of pokeweek mitogen-stimulated B and T lymphocytes. B and T cells were separated by sheep red blood cell rosette techniques and, by culture of these cells from CLL patients in various combinations with B or T cells from normal subjects, it was possible to measure independently the function of B lymphocytes and the helper or suppressor function of T lymphocytes. By these methods it was found that the B lymphocytes of six of eight patients failed to produce immunoglobulins in vitro. B lymphocytes from two patients appeared to produce immunoglobulins in vitro. T lymphocytes from five of the eight patients had low or undetectable helper T cell function and in six patients their T lymphocytes had excessive suppressor activity in comparison to T lymphocyte populations from normal subjects. Whether the primary abnormality in the CLL T cell populations was a deficiency of helper T cells or excess of suppressor T cells was uncertain from these studies. These results suggest that immunoglobulin production by B lymphocytes from most patients with CLL was abnormal but also that T cells from CLL patients may be abnormal in respect to their role in immunoglobulin production at an early stage of the disease. These findings may assist in understanding the pathogenesis of this disease and lead to new approaches in treatment. PMID:6445798

  10. Identification of cellular immunoglobulins in chronic lymphocytic leukaemia by immunoperoxidase staining.

    PubMed Central

    Markey, G M; McConnell, R E; Alexander, H D; Morris, T C; Robertson, J H

    1983-01-01

    An indirect immunoperoxidase technique has been used for visualisation of cellular immunoglobulins in chronic lymphocytic leukaemia. Baker's formol calcium was used as fixative. Monoclonal light and heavy chain patterns were demonstrated in 24 out of 27 cases. Only one case did not have any demonstrable immunoglobulins. The presence of alpha or gamma heavy chain immunoglobulin isotypes in leukaemic lymphocytes was found to be related to low mouse rosetting capacity (p less than 0.05). Images PMID:6418770

  11. FCRL6 distinguishes mature cytotoxic lymphocytes and is upregulated in patients with B cell chronic lymphocytic leukemia

    PubMed Central

    Schreeder, Daniel M.; Pan, Jicun; Li, Fu Jun; Vivier, Eric; Davis, Randall S.

    2009-01-01

    Fc receptor-like 6 (FCRL6), the most recently characterized member of the FCRL family, is a cell surface glycoprotein with tyrosine-based regulatory potential. An extensive survey of human hematopoietic tissues disclosed that FCRL6 expression by NK and T cell subpopulations increases as a function of differentiation and is remarkably restricted to mature lymphocytes with cytotoxic capability. In particular, FCRL6 distinguishes perforin-expressing CD56dim NK cells, Vδ1+ and Vδ2+ γδ T cells, effector and effector memory CD8+ T cells, and rare cytotoxic CD4+ T cells in adult tissues. Analysis of this receptor in B cell chronic lymphocytic leukemia (CLL) was also performed. FCRL6 was found to mark significantly expanded populations of cytotoxic CD8+ T, CD4+ T, and NK cells in patients with CLL. Despite sequence homology with the known Fc receptors for IgG and IgE, FCRL6 did not bind immunoglobulin. Although FCRL6 can be tyrosine-phosphorylated, its antibody-mediated ligation was unable to influence cellular activation. Collectively these results demonstrate that FCRL6 is a distinct indicator of cytotoxic effector lymphocytes that is upregulated in diseases characterized by chronic immune stimulation. PMID:18991291

  12. Neutrophil/Lymphocyte Ratio Can Predict Postoperative Mortality in Patients with Chronic Thromboembolic Pulmonary Hypertension

    PubMed Central

    Emin Kalkan, Mehmet; Arslan, Akin; Gezer Tas, Serpil; Koksal, Cengiz; Bekiroglu, Nural; Yildizeli, Bedrettin

    2015-01-01

    Objective: The aim of our study was to investigate clinical importance of neutrophil/ lymphocyte ratio in patients with Chronic thromboembolic pulmonary hypertension. Methods: 125 consecutive patients with a diagnosis of Chronic thromboembolic pulmonary hypertension were operated pulmonary thromboendarterectomy in our center between February 2011 and August 2013. 106 patients included into the study due to limitations. The patients were classified into two groups as patients discharged alive (Group 1) and those dying in the hospital (Group 2). Baseline neutrophil/lymphocyte ratio level was measured by dividing neutrophil count to lymphocyte count. Results: 84 patients (79%) were in Group 1, 22 patients (21%) were in Group 2. Patients with higher neutrophil/lymphocyte ratio in admission have a significantly higher mortality rate and postoperative pulmonary vascular resistance was found statistically significant variable to predict the mortality. Receiver operator characteristic (ROC) analysis revealed that using a cut-off point of 2.54, admission neutrophil/lymphocyte ratio predicts mortality. Also, correlation analysis showed a significant correlation between preoperative pulmonary vascular resistance and neutrophil/lymphocyte ratio. Conclusion: The neutrophil/lymphocyte ratio level may be a useful and noninvasive biomarker for operative risk stratification for mortality after pulmonary thromboendarterectomy. PMID:25753325

  13. 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

  14. [Human chronic chagasic myocarditis: quantitative study of CD4+ and CD8+ lymphocytes in inflammatory exudates].

    PubMed

    Tostes Júnior, S; Lopes, E R; Pereira, F E; Chapadeiro, E

    1994-01-01

    Myocardial exsudate CD4+ and CD8+ lymphocytes were counted in transmural left ventricular free wall frozen sections taken from 10 necropsied chronic cardiac chagasic patients. The cells were labeled with monoclonal antibodies using a streptavidin-biotin technique. We counted: 1) lymphocytes in the total exsudate (LTE) and, separately, 2) the lymphocytes touching or very near to myocells (LTVNM). Lymphocytes were considered very near whenever their own nuclear shortest nuclear diameter was larger than their distance from myocells. CD8+ lymphocytes were more numerous than CD4+ lymphocytes, especially among the LTVNM. The LTE CD4/CD8 ratio was 0.37 +/- 0.20, but the LTVNM CD4/CD8 ratio was smaller (0.23 +/- 0.11). Among the LTE, 34 +/- 11% of CD8+ (against 24 +/- 12% of CD4+) were LTVNM. All these differences were statistically significant. Both subtypes of T-lymphocytes were found to have an intimate relationship with both ruptured and unruptured myocells, and parasites were not seen. These findings are in accordance with the idea that the myocardial cell lesions in the cardiac form of human Chagas' disease are mediated mainly by T-cytotoxic lymphocytes.

  15. Progressive trichodysplasia spinulosa in a patient with chronic lymphocytic leukaemia in remission.

    PubMed

    Lee, Joyce S-S; Frederiksen, Peter; Kossard, Steven

    2008-02-01

    A 70-year old Caucasian man with chronic lymphocytic leukaemia developed trichodysplasia spinulosa 2 months after ceasing chemotherapy. Histological features characteristic to this condition include dilated and enlarged hair follicles, hyperplastic hair bulbs, hyperplasia of inner root sheath cells with numerous large, eosinophilic, trichohyaline granules, and hypercornification. Although he was in remission for chronic lymphocytic leukaemia, lesions were slowly progressive 15 months after cessation of chemotherapy. We also describe a painless pull-test where spicules can be easily plucked and assessed microscopically for inner root sheath keratinization, or observed with surface microscopy in a clinic setting.

  16. 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.

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

    ClinicalTrials.gov

    2016-08-16

    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

  18. Lymphocyte cytosolic protein 1 is a chronic lymphocytic leukemia membrane-associated antigen critical to niche homing

    PubMed Central

    Dubovsky, Jason A.; Chappell, Danielle L.; Harrington, Bonnie K.; Agrawal, Kitty; Andritsos, Leslie A.; Flynn, Joseph M.; Jones, Jeffrey A.; Paulaitis, Michael E.; Bolon, Brad; Johnson, Amy J.

    2013-01-01

    Membrane antigens are critical to the pathogenesis of chronic lymphocytic leukemia (CLL) as they facilitate microenvironment homing, proliferation, and survival. Targeting the CLL membrane and associated signaling patterns is a current focus of therapeutic development. Many tumor membrane targets are simultaneously targeted by humoral immunity, thus forming recognizable immunoglobulin responses. We sought to use this immune response to identify novel membrane-associated targets for CLL. Using a novel strategy, we interrogated CLL membrane-specific autologous immunoglobulin G reactivity. Our analysis unveiled lymphocyte cytosolic protein 1 (LCP1), a lymphocyte-specific target that is highly expressed in CLL. LCP1 plays a critical role in B-cell biology by crosslinking F-actin filaments, thereby solidifying cytoskeletal structures and providing a scaffold for critical signaling pathways. Small interfering RNA knockdown of LCP1 blocked migration toward CXCL12 in transwell assays and to bone marrow in an in vivo xenotransplant model, confirming a role for LCP1 in leukemia migration. Furthermore, we demonstrate that the Bruton’s tyrosine kinase inhibitor ibrutinib or the PI3K inhibitor idelalisib block B-cell receptor induced activation of LCP1. Our data demonstrate a novel strategy to identify cancer membrane target antigens using humoral anti-tumor immunity. In addition, we identify LCP1 as a membrane-associated target in CLL with confirmed pathogenic significance. This clinical trial was registered at clinicaltrials.gov; study ID number: OSU-0025 OSU-0156. PMID:24009233

  19. 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

  20. Acute blast crisis in a patient with chronic lymphocytic leukemia. Immunoperoxidase study.

    PubMed

    Laurent, G; Gourdin, M F; Flandrin, G; Kuhlein, E; Pris, J; Reyes, F

    1981-01-01

    Using a case study of a blastic crisis supervening on chronic lymphocytic leukemia, we were able to determine that the cells in question were B cells derived from the same clone by using immunofluorescence and immunoperoxidase techniques. The immunoperoxidase technique provided excellent morphological details and enhanced the phenotype study. PMID:6791439

  1. Refractory Bartonella quintana bacillary angiomatosis following chemotherapy for chronic lymphocytic leukaemia.

    PubMed

    Holmes, Natasha E; Opat, Stephen; Kelman, Anthony; Korman, Tony M

    2011-01-01

    Bacillary angiomatosis is a well-recognized infection with cutaneous and systemic manifestations caused by Bartonella henselae or Bartonella quintana and occurs in immunocompromised patients. We report a case of B. quintana bacillary angiomatosis following fludarabine-based chemotherapy for chronic lymphocytic leukaemia that was refractory to standard treatment and was complicated by lymphadenopathy and osteomyelitis.

  2. Aberrant TIRAP and MyD88 expression in B-cell chronic lymphocytic leukemia.

    PubMed

    Antosz, Halina; Sajewicz, Joanna; Marzec-Kotarska, Barbara; Dmoszyńska, Anna; Baszak, Jacek; Jargiełło-Baszak, Małgorzata

    2013-06-01

    TIRAP and Myd88 are adaptor proteins for Toll-like receptors-2 and -4 (TLR2/4) which are engaged in transducing the signal to downstream molecules. Several studies have shown the increased role of infection factors in pathogenesis of B cell chronic lymphocytic leukemia (B-CLL). This prompted us to test whether there is a correlation between MyD88-TIRAP dynamics before and after inflammatory stimuli. We determined the mRNA and protein expression of TIRAP and MyD88 in CD5(+)CD19(+) B-CLL cells and in a subpopulation of normal B CD19(+) lymphocytes. Additionally we determined the influence of lipopolysaccharide Escherichia coli - TLR4-ligand (LPS) and Staphylococcus aureus strain Cowan I - TLR2-ligand (SAC) on TIR-domain-containing adaptor protein, also called MyD88 adaptor-like (TIRAP) and myeloid differentiation primary response protein 88 (MyD88) expression. We have found that the mRNA and protein expression of TIRAP and MyD88 in B-CLL lymphocytes is lower compared with that in normal B lymphocytes. LPS and SAC stimulation in normal lymphocytes significantly altered neither TIRAP nor MyD88 mRNA expression, whereas TIRAP protein level substantially decreased after TLR agonist treatment. We did not observe any changes in MyD88 protein level after B lymphocyte stimulation. There was a significant increase in TIRAP mRNA expression after LPS and SAC stimulation of B-CLL cells. MyD88 mRNA expression levels in B-CLL lymphocytes slightly decreased upon treatment with either stimulator. Stimulation with TLR agonists did not cause changes in TIRAP and MyD88 expression at the protein level in B-CLL lymphocytes. The results of our study suggest that there may exist a, yet unknown, defect of TIRAP and MyD88 proteins in B-CLL lymphocytes. PMID:23419703

  3. Molecular bases of chronic lymphocytic leukemia in light of new treatments.

    PubMed

    Rossi, Davide; Ciardullo, Carmela; Spina, Valeria; Gaidano, Gianluca

    2013-01-01

    The human genome era heralded a fundamental progress in the field of cancer genetics that shifted from a candidate gene approach toward global views of genomes and transcriptomes. Whole genome/exome sequencing has disclosed the genetic landscape of several hematologic tumors, providing comprehensive catalogs of somatic mutations and new insights into the genes that contribute to cellular transformation. Thanks to these technical progresses, research on the molecular pathogenesis of chronic lymphocytic leukemia (CLL) has also advanced at a sustained pace in recent times revealing NOTCH1, SF3B1, BIRC3, and MYD88 as the most recurrently (>5%) mutated genes that have been identified in CLL. Beside mutations of cancer related genes, another mechanism involved in disease initiation and progression of mature B-cell tumors, including CLL, is represented by B cell receptor (BCR) signaling. The BCR plays a central role in disease pathogenesis and, consequently, BCR signaling might represent a suitable target for therapy in many patients. Currently, the Bruton tyrosine kinase (BTK) inhibitor ibrutinib, which acts downstream the BCR signaling pathway, appears to be particularly promising and shows important clinical activity in CLL.

  4. Bayesian clustering of flow cytometry data for the diagnosis of B-chronic lymphocytic leukemia.

    PubMed

    Lakoumentas, John; Drakos, John; Karakantza, Marina; Nikiforidis, George C; Sakellaropoulos, George C

    2009-04-01

    In the rapidly advancing field of flow cytometry, methodologies facilitating automated clinical decision support are increasingly needed. In the case of B-chronic lymphocytic leukemia (B-CLL), discrimination of the various subpopulations of blood cells is an important task. In this work, our objective is to provide a useful paradigm of computer-based assistance in the domain of flow-cytometric data analysis by proposing a Bayesian methodology for flow cytometry clustering. Using Bayesian clustering, we replicate a series of (unsupervised) data clustering tasks, usually performed manually by the expert. The proposed methodology is able to incorporate the expert's knowledge, as prior information to data-driven statistical learning methods, in a simple and efficient way. We observe almost optimal clustering results, with respect to the expert's gold standard. The model is flexible enough to identify correctly non canonical clustering structures, despite the presence of various abnormalities and heterogeneities in data; it offers an advantage over other types of approaches that apply hierarchical or distance-based concepts.

  5. Genetic Counseling for DAPK1 Mutation in a Chronic Lymphocytic Leukemia Family

    PubMed Central

    Lynch, Henry T.; Ferrara, Kelly; Weisenburger, Dennis; Sanger, Warren; Lynch, Jane F.; Thomé, Stephan

    2008-01-01

    Genetic counseling has become the clinical bedrock of hereditary cancer. Countless advances in molecular genetics contributing to the identification of cancer-causing germline mutations have increased its importance. We report perhaps the world’s first genetic counseling experience involving a family with hereditary chronic lymphocytic leukemia and the cancer-causing mutation in the death-associated protein kinase 1 (DAPK1) gene. This hereditary disorder currently lacks any preventive or curative interventions for mutation carriers. This family has been under our investigation for a decade, during which time genealogy, cancer of all anatomic sites, medical and pathology records, and, whenever possible, slides and tissue blocks were reviewed. Family attendance at three Family Information Services provided intensive education about this disease. Blood and skin fibroblasts were obtained for molecular genetic studies of DNA leading to the discovery of the DAPK1 mutation in the family. Their intellectual and emotional reaction to its presence or absence in them was assessed. This family serves as a model for genetic counseling in disorders where life-saving intervention is not yet possible. PMID:18940472

  6. Assessment of red blood cell distribution width as a prognostic marker in chronic lymphocytic leukemia

    PubMed Central

    Podhorecka, Monika; Halicka, Dorota; Szymczyk, Agnieszka; Macheta, Arkadiusz; Chocholska, Sylwia; Hus, Marek; Darzynkiewicz, Zbigniew

    2016-01-01

    Red blood cell distribution width (RDW) is a quantitative measure of the variability in size of circulating erythrocytes. It was recently reported that RDW is a prognostic factor for infection diseases, cardiovascular and pulmonary diseases, as well as some neoplasms. Moreover, RDW is remarkably strong predictor of longevity, including all causes of death, for adults aged 45 years and older. To explain this occurrence it was proposed that persistent IGFs/mTOR signaling is one of the factors that play a role in affecting the RDW and mortality. The above observations induced us to analyze the prognostic role of RDW in chronic lymphocytic leukemia (CLL) being the most frequent type of adult leukemia in Western countries. The obtained results have shown that RDW may be considered as a potential CLL prognostic marker. Elevated RDW level at the moment of diagnosis was associated with advanced disease and presence of other poor prognostic factors. It is also connected with overall survival indicating shorter time in patients with elevated RDW. It is possible that the presently observed correlation between mortality and RDW of the CLL patients is affected by their metabolic (IGF-1/mTOR driven)- rather than chronological- aging. The patients with high level of RDW are expected to have an increased persistent level of IGF-1/mTOR signaling. Within the framework of personalized therapy, these CLL patients therefore would be expected to be more sensitive to the treatment with mTOR inhibitors. PMID:27147570

  7. Specialization of Hepatitis C Virus Envelope Glycoproteins for B Lymphocytes in Chronically Infected Patients

    PubMed Central

    Douam, Florian; Bobay, Louis-Marie; Maurin, Guillemette; Fresquet, Judith; Calland, Noémie; Maisse, Carine; Durand, Tony; Cosset, François-Loïc; Féray, Cyrille

    2015-01-01

    ABSTRACT Hepatitis C virus (HCV) productively infects hepatocytes. Virion surface glycoproteins E1 and E2 play a major role in this restricted cell tropism by mediating virus entry into particular cell types. However, several pieces of evidence have suggested the ability of patient-derived HCV particles to infect peripheral blood mononuclear cells. The viral determinants and mechanisms mediating such events remain poorly understood. Here, we aimed at isolating viral determinants of HCV entry into B lymphocytes. For this purpose, we constructed a library of full E1E2 sequences isolated from serum and B lymphocytes of four chronically infected patients. We observed a strong phylogenetic compartmentalization of E1E2 sequences isolated from B lymphocytes in one patient, indicating that E1E2 glycoproteins can represent important mediators of the strong segregation of two specialized populations in some patients. Most of the E1E2 envelope glycoproteins were functional and allowed transduction of hepatocyte cell lines using HCV-derived pseudoparticles. Strikingly, introduction of envelope glycoproteins isolated from B lymphocytes into the HCV JFH-1 replicating virus switched the entry tropism of this nonlymphotropic virus from hepatotropism to lymphotropism. Significant detection of viral RNA and viral proteins within B cells was restricted to infections with JFH-1 harboring E1E2 from lymphocytes and depended on an endocytic, pH-dependent entry pathway. Here, we achieved for the first time the isolation of HCV viral proteins carrying entry-related lymphotropism determinants. The identification of genetic determinants within E1E2 represents a first step for a better understanding of the complex relationship between HCV infection, viral persistence, and extrahepatic disorders. IMPORTANCE Hepatitis C virus (HCV) mainly replicates within the liver. However, it has been shown that patient-derived HCV particles can slightly infect lymphocytes in vitro and in vivo, highlighting

  8. 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.

  9. 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.

  10. Phenotype study with monoclonal antibodies of T lymphocyte colonies in normal individuals and in patients with chronic OKT8+ lymphocytic leukaemia.

    PubMed

    Andre, C; Farcet, J P; Oudhriri, N; Gourdin, M F; Bouguet, J; Reyes, F

    1983-11-01

    The lymphocyte colony forming capacity of peripheral blood mononuclear cells from normal controls and from two patients with chronic OKT8+ lymphocytic leukaemia was determined in agar culture under PHA stimulation. The number and size of the colonies in patients were reduced compared to normal. The lymphocytic phenotype of colony cells was studied with monoclonal antibodies in colonies harvested from agar culture and in colonies expanded in liquid culture in the presence of TCGF. This study was performed in individual colonies and in pooled colonies. Colonies from normal controls contained a mixture of the OKT4+ and OKT8+ lymphocyte subsets. In contrast, colonies from the two patients contained essentially OKT4+ lymphocytes. The data indicate that, in the patients, progenitors of the OKT8+ subset are unresponsive to normal proliferative and/or differentiative stimuli under the present culture conditions. PMID:6606509

  11. Phenotype study with monoclonal antibodies of T lymphocyte colonies in normal individuals and in patients with chronic OKT8+ lymphocytic leukaemia.

    PubMed Central

    Andre, C; Farcet, J P; Oudhriri, N; Gourdin, M F; Bouguet, J; Reyes, F

    1983-01-01

    The lymphocyte colony forming capacity of peripheral blood mononuclear cells from normal controls and from two patients with chronic OKT8+ lymphocytic leukaemia was determined in agar culture under PHA stimulation. The number and size of the colonies in patients were reduced compared to normal. The lymphocytic phenotype of colony cells was studied with monoclonal antibodies in colonies harvested from agar culture and in colonies expanded in liquid culture in the presence of TCGF. This study was performed in individual colonies and in pooled colonies. Colonies from normal controls contained a mixture of the OKT4+ and OKT8+ lymphocyte subsets. In contrast, colonies from the two patients contained essentially OKT4+ lymphocytes. The data indicate that, in the patients, progenitors of the OKT8+ subset are unresponsive to normal proliferative and/or differentiative stimuli under the present culture conditions. PMID:6606509

  12. Composite mantle cell lymphoma and chronic lymphocytic leukemia/small lymphocytic lymphoma: a clinicopathologic and molecular study.

    PubMed

    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; Wang, Michael; 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 more aggressive neoplasm. Rarely, cases of 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 2 lymphomas. Eleven composite MCL and CLL/SLL cases were identified. The clinical, morphologic and immunophenotypic features of the MCL and CLL/SLL were characterized. IGH (immunoglobulin heavy chain) 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 MCLs had blastoid or pleomorphic and 5 small lymphocytic features. The CLL/SLL component was nodular (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 MCL and CLL/SLL components represent distinct disease processes and do not share a common progenitor B-cell.

  13. 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

  14. Immune and hormonal changes in early-stage chronic lymphocytic leukemia patients.

    PubMed

    Everaus, H; Lehtmaa, J; Luik, E; Kŏdar, H

    1992-11-01

    Fifty-six previously untreated stage-I (according to Rai) chronic lymphocytic leukemia (CLL) patients were examined for their clinical data, immunological characteristics, and hormonal values. Dysfunction of T and B lymphocytes was demonstrated by changed lymphocyte blastogenic response to stimulation with phytohemagglutinin (PHA), concanavalin A (ConA), pisum sativatum agglutinin (PSA), wheat germ agglutinin (WGA), recombinant interleukin 2 (IL 2), and dextran sulfate (DxS); also by decreased immunoglobulin levels (IgG, IgA, IgE) and increased beta 2-microglobulin (beta 2-M) values. Simultaneously, dysregulation of the hypothalamic-pituitary-adrenal axis, immune system integration, imbalance of sex hormones, and changes in thyroid hormones were observed in the same group of patients. Disturbed immunohormonal interactions in early-stage CLL may be responsible for the pathogenetic mechanisms in this lymphoproliferative malignancy.

  15. Immune and hormonal changes in early-stage chronic lymphocytic leukemia patients.

    PubMed

    Everaus, H; Lehtmaa, J; Luik, E; Kŏdar, H

    1992-11-01

    Fifty-six previously untreated stage-I (according to Rai) chronic lymphocytic leukemia (CLL) patients were examined for their clinical data, immunological characteristics, and hormonal values. Dysfunction of T and B lymphocytes was demonstrated by changed lymphocyte blastogenic response to stimulation with phytohemagglutinin (PHA), concanavalin A (ConA), pisum sativatum agglutinin (PSA), wheat germ agglutinin (WGA), recombinant interleukin 2 (IL 2), and dextran sulfate (DxS); also by decreased immunoglobulin levels (IgG, IgA, IgE) and increased beta 2-microglobulin (beta 2-M) values. Simultaneously, dysregulation of the hypothalamic-pituitary-adrenal axis, immune system integration, imbalance of sex hormones, and changes in thyroid hormones were observed in the same group of patients. Disturbed immunohormonal interactions in early-stage CLL may be responsible for the pathogenetic mechanisms in this lymphoproliferative malignancy. PMID:1457579

  16. Leukemia cutis in B-cell chronic lymphocytic leukemia presenting as an episodic papulovesicular eruption.

    PubMed

    Rosman, Ilana S; Nunley, Kara S; Lu, Dongsi

    2011-01-01

    A 53-year-old man presented with a recurrent pruritic eruption accompanied by oral sores. His past medical history was significant for subclinical B-cell chronic lymphocytic leukemia (CLL), which had never been treated. On exam, there were erythematous papules and plaques studded with vesicles on the neck, trunk, and upper extremities. Two skin biopsies showed common features of a perivascular and periadnexal lymphocytic infiltrate in the superficial to mid-dermis. Immunohistochemical staining of the lymphocytes showed co-expression of CD20, CD23, CD5, and CD43, consistent with a diagnosis of cutaneous involvement by the patient's CLL. This case highlights the importance of considering leukemia cutis in patients with underlying CLL presenting with unusual clinical features. PMID:21971272

  17. [The role of genetic polymorphisms of interleukins in chronic lymphocytic leukemia in patients of different ages].

    PubMed

    Sirotina, S S; Tikunova, T S; Proshchaev, K I; Efremova, O A; Batlutskaia, I V; Iakunchenko, T I; Sobianin, F I; Churnosov, M I; Alekseev, S M

    2014-01-01

    Chronic lymphocytic leukemia (CLL) is a multifactorial disease, in which development the important role played the cytokine genes, in particular interleukins. This type of leukemia is more common in the elderly. The purpose of the study was to evaluate the association of genetic polymorphisms of interleukin with the development of chronic lymphocytic leukemia among residents of the Central Chernozem region of Russia. Genotyping of the -889C/T IL-1A, -590C/T IL-4 and VNTR IL-1 Ra was conducted in 206 patients with CLL and 307 individuals of the control group. The study found that the genetic risk factor for the development of CLL is allele -590T IL-4 (OR=-1,45). The development of thrombocytopenia in patients with CLL is associated with genetic variants -889T IL-1A (OR=1,95), -889TT IL-1A (OR=6,2) and IL-1Ra*1 (OR=-2,32).

  18. Case report: Concomitant Chronic Lymphocytic Leukaemia and Cytogenetically Normal de novo Acute Leukaemia in a Patient.

    PubMed

    Kajtár, Béla; Rajnics, Péter; Egyed, Miklós; Alizadeh, Hussain

    2015-01-01

    The simultaneous occurrence of acute myeloid leukaemia with untreated chronic lymphocytic leukemia is extremely rare. We report a case of a 74-year-old man who was evaluated for macrocytic anaemia. Based on the morphology and immunophenotyping analysis of peripheral blood, a diagnosis of chronic lymphocytic leukemia was established. Subsequently, the bone marrow examination revealed the presence of two distinct, coexisting CLL and AML clones. Cytogenetic and molecular genetic analysis detected deletion 13q14.3 and unmutated immunoglobulin variable heavy-chain in the CLL clone, only. The AML and CLL clones did not share clonality, and the AML did not involve the peripheral blood. A diagnosis of cytogenetically normal de novo AML occurring concurrently with untreated CLL has not been reported previously in English literature.

  19. Romidepsin in Treating Patients With Lymphoma, Chronic Lymphocytic Leukemia, or Solid Tumors With Liver Dysfunction

    ClinicalTrials.gov

    2016-09-26

    Adult Mixed Glioma; Adult Pineal Gland Astrocytoma; Adult Solid Neoplasm; AIDS Related Immunoblastic Lymphoma; AIDS-Related Burkitt Lymphoma; AIDS-Related Diffuse Large Cell Lymphoma; AIDS-Related Diffuse Mixed Cell Lymphoma; AIDS-Related Diffuse Small Cleaved Cell Lymphoma; AIDS-Related Hodgkin Lymphoma; AIDS-Related Lymphoblastic Lymphoma; AIDS-Related Lymphoma; AIDS-Related Primary Central Nervous System Lymphoma; Glioma; Lymphoma; Recurrent Adult Brain Neoplasm; Recurrent Adult Soft Tissue Sarcoma; Recurrent Bladder Carcinoma; Recurrent Breast Carcinoma; Recurrent Chronic Lymphocytic Leukemia; Recurrent Colorectal Carcinoma; Recurrent Cutaneous T-Cell Non-Hodgkin Lymphoma; Recurrent Head and Neck Carcinoma; Recurrent Lung Carcinoma; Recurrent Mature T- and NK-Cell Non-Hodgkin Lymphoma; Recurrent Melanoma; Recurrent Pancreatic Carcinoma; Recurrent Prostate Carcinoma; Recurrent Renal Cell Carcinoma; Recurrent Thyroid Gland Carcinoma; Refractory Chronic Lymphocytic Leukemia; Refractory Cutaneous T-Cell Non-Hodgkin Lymphoma; Refractory Mature T-Cell and NK-Cell Non-Hodgkin Lymphoma

  20. Advances in Understanding and Managing Chronic Urticaria.

    PubMed

    Moolani, Yasmin; Lynde, Charles; Sussman, Gordon

    2016-01-01

    There have been recent advances in the classification and management of chronic urticaria. The new term chronic spontaneous urticaria (CSU) has replaced chronic idiopathic urticaria and chronic autoimmune urticaria. In addition, chronic inducible urticaria (CINDU) has replaced physical urticaria and includes other forms of inducible urticaria, such as cholinergic and aquagenic urticaria. Furthermore, novel research has resulted in a new understanding with guidelines being revised in the past year by both the American Academy of Allergy, Asthma, and Immunology (AAAAI) and the European Academy of Allergy and Clinical Immunology (EAACI)/Global Allergy and Asthma European Network (GA (2)LEN)/European Dermatology Forum (EDF)/World Allergy Organization (WAO). There are some differences in the recommendations, which will be discussed, but the core updates are common to both groups. The basic treatment for chronic urticaria involves second-generation non-sedating non-impairing H 1 antihistamines as first-line treatment. This is followed by up to a 4-fold increase in the licensed dose of these H 1 antihistamines. The major therapeutic advance in recent years has been in third-line treatment with omalizumab, a humanized monoclonal anti-immunoglobulin E (anti-IgE) antibody that prevents binding of IgE to the high-affinity IgE receptor. Several multicenter randomized controlled trials have shown safety and efficacy of omalizumab for CSU. There are also some small studies showing efficacy of omalizumab in CINDU. While there were previously many treatment options which were lacking in strong evidence, we are moving into an era where the treatment algorithm for chronic urticaria is simplified and contains more evidence-based, effective, and less toxic treatment options.

  1. 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

  2. Tumour lysis syndrome after treatment of chronic lymphocytic leukaemia with fludarabine.

    PubMed Central

    Montalban, C.; Liaño, F.; Aguilera, A.

    1994-01-01

    Fludarabine is one of the most recent and promising therapeutic agents for chronic lymphocytic leukaemia. We describe a patient who developed tumour lysis syndrome after the first course of treatment with fludarabine and call attention to this uncommon but potentially lethal complication that has not been previously taken into account in this neoplasia. It should always be anticipated when patients are treated with new and effective drugs. PMID:7971632

  3. 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

  4. Rare association of chronic lymphocytic thyroiditis with dermatomyositis.

    PubMed

    Charalabopoulos, Konstantinos; Mittari, Evanthia; Peschos, Dimitrios; Golias, Christos; Charalabopoulos, Alexander; Tsanou, Eleni; Batistatou, Anna

    2006-05-01

    Autoimmune thyroid disease (AITD) has been associated with other autoimmune diseases such as chronic urticaria, insulin-dependent diabetes mellitus, Sjøgren's syndrome, inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, psoriasis, ankylosing spondylitis, and dermatomyositis (DM). AITD is a common disorder affecting primarily women, and both genetic and environmental factors are included in its pathogenesis. DM is considered an autoimmune disease of the muscles and skin. Although AITD is the most common cause of hypothyroidism, to the best of our knowledge, only three cases of DM and AITD in the same patient have been reported in the last 40 years. We consider that both are developed from the same autoimmune background. Herein, we present a case of a 30-year-old man with a 4-year history of AITD who was diagnosed as suffering as well from DM.

  5. Advances in therapeutics for chronic hepatitis B.

    PubMed

    Yang, Ninghan; Bertoletti, Antonio

    2016-03-01

    Chronic hepatitis B infection remains a major disease burden globally, and leads to high risk of hepatocellular carcinoma development. Current therapies of nucleot(s)ide analogues and interferon alpha treatment remain limited in their efficacy. Several key findings in the hepatitis B virus (HBV) life cycle have led to the development of novel antiviral drugs to inhibit viral replication and persistence. In addition, recent studies on HBV-specific innate and adaptive immune responses have advanced development of immunotherapy to restore immune mediated virus control in chronic hepatitis B patients. In this review, we discuss potential new therapeutic strategies targeting HBV or the host immune system that might lead to a sustained cure for chronic hepatitis B. PMID:26363922

  6. 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

  7. 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

  8. Recognition of antigen-specific B-cell receptors from chronic lymphocytic leukemia patients by synthetic antigen surrogates.

    PubMed

    Sarkar, Mohosin; Liu, Yun; Morimoto, Jumpei; Peng, Haiyong; Aquino, Claudio; Rader, Christoph; Chiorazzi, Nicholas; Kodadek, Thomas

    2014-12-18

    In patients with chronic lymphocytic leukemia (CLL), a single neoplastic antigen-specific B cell accumulates and overgrows other B cells, leading to immune deficiency. CLL is often treated with drugs that ablate all B cells, leading to further weakening of humoral immunity, and a more focused therapeutic strategy capable of targeting only the pathogenic B cells would represent a significant advance. One approach to this would be to develop synthetic surrogates of the CLL antigens allowing differentiation of the CLL cells and healthy B cells in a patient. Here, we describe nonpeptidic molecules capable of targeting antigen-specific B cell receptors with good affinity and selectivity using a combinatorial library screen. We demonstrate that our hit compounds act as synthetic antigen surrogates and recognize CLL cells and not healthy B cells. Additionally, we argue that the technology we developed can be used to identify other classes of antigen surrogates.

  9. Synthesis of antibodies to hepatitis B virus by cultured lymphocytes from chronic hepatitis B surface antigen carriers

    SciTech Connect

    Dusheiko, G.M.; Hoofnagle, J.H.; Cooksley, W.G.; James, S.P.; Jones, E.A.

    1983-05-01

    It has been postulated that host immune defects are responsible for the development and persistence of the hepatitis B surface antigen (HBsAg) carrier state. The synthesis of both anti-HBs and antibody to hepatitis B core antigen (anti-HBc) in cultures containing peripheral blood mononuclear cells from chronic HBsAg carriers and from control (antibody-positive) patients was measured in the presence of pokeweed mitogen. Similar amounts of polyclonal IgG and IgM were synthesized by cultures containing lymphocytes from chronic carriers and controls. Anti-HBc was detectable in lymphocyte supernatants from 2 of 20 controls and from 21 of 29 carriers. The presence of anti-HBc synthesis in vitro correlated with high serum titers of anti-HBc. In contrast, anti-HBs was detected in lymphocyte supernatants from 6 of 20 controls (predominantly in those who had high serum titers of anti-HBs) but in none of the supernatants from 29 HBsAg carriers. Co-culture experiments were performed using T and B lymphocyte fractions that had been purified by affinity chromatography. B lymphocytes from carriers co-cultured with allogeneic irradiated (''helper'') T lymphocytes from controls synthesized normal amounts of IgG, IgM, and anti-HBc but still did not synthesize detectable amounts of anti-HBs. In the converse experiments, B lymphocytes from controls were co-cultured with irradiated T lymphocytes from carriers. The T lymphocytes from 16 of 24 carriers augmented anti-HBs production by control B cells normally, the remaining eight did not. Finally, mixtures of control B cells and control irradiated T lymphocytes were co-cultured with T lymphocytes from chronic HBsAg carriers. 5 of 12 carriers demonstrated active suppression of anti-HBs production, and in three this suppression was specific, as IgG and IgM production remained normal.

  10. 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.

  11. Targeting the spliceosome in chronic lymphocytic leukemia with the macrolides FD-895 and pladienolide-B.

    PubMed

    Kashyap, Manoj K; Kumar, Deepak; Villa, Reymundo; La Clair, James J; Benner, Chris; Sasik, Roman; Jones, Harrison; Ghia, Emanuela M; Rassenti, Laura Z; Kipps, Thomas J; Burkart, Michael D; Castro, Januario E

    2015-07-01

    RNA splicing plays a fundamental role in human biology. Its relevance in cancer is rapidly emerging as demonstrated by spliceosome mutations that determine the prognosis of patients with hematologic malignancies. We report studies using FD-895 and pladienolide-B in primary leukemia cells derived from patients with chronic lymphocytic leukemia and leukemia-lymphoma cell lines. We found that FD-895 and pladienolide-B induce an early pattern of mRNA intron retention - spliceosome modulation. This process was associated with apoptosis preferentially in cancer cells as compared to normal lymphocytes. The pro-apoptotic activity of these compounds was observed regardless of poor prognostic factors such as Del(17p), TP53 or SF3B1 mutations and was able to overcome the protective effect of culture conditions that resemble the tumor microenvironment. In addition, the activity of these compounds was observed not only in vitro but also in vivo using the A20 lymphoma murine model. Overall, these findings give evidence for the first time that spliceosome modulation is a valid target in chronic lymphocytic leukemia and provide an additional rationale for the development of spliceosome modulators for cancer therapy.

  12. 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

  13. Therapeutic effects of stress-programmed lymphocytes transferred to chronically stressed mice.

    PubMed

    Scheinert, Rachel B; Haeri, Mitra H; Lehmann, Michael L; Herkenham, Miles

    2016-10-01

    Our group has recently provided novel insights into a poorly understood component of intercommunication between the brain and the immune system by showing that psychological stress can modify lymphocytes in a manner that may boost resilience to psychological stress. To demonstrate the influence of the adaptive immune system on mood states, we previously showed that cells from lymph nodes of socially defeated mice, but not from unstressed mice, conferred anxiolytic and antidepressant-like effects and elevated hippocampal cell proliferation when transferred into naïve lymphopenic Rag2(-/-) mice. In the present study, we asked whether similar transfer could be anxiolytic and antidepressant when done in animals that had been rendered anxious and depressed by chronic psychological stress. First, we demonstrated that lymphopenic Rag2(-/-) mice and their wild-type C57BL/6 mouse counterparts had similar levels of affect normally. Second, we found that following chronic (14days) restraint stress, both groups displayed an anxious and depressive-like phenotype and decreased hippocampal cell proliferation. Third, we showed that behavior in the open field test and light/dark box was normalized in the restraint-stressed Rag2(-/-) mice following adoptive transfer of lymph node cells from green fluorescent protein (GFP) expressing donor mice previously exposed to chronic (14days) of social defeat stress. Cells transferred from unstressed donor mice had no effect on behavior. Immunolabeling of GFP+ cells confirmed that tissue engraftment had occurred at 14days after transfer. We found GFP+ lymphocytes in the spleen, lymph nodes, blood, choroid plexus, and meninges of the recipient Rag2(-/-) mice. The findings suggest that the adaptive immune system may play a key role in promoting recovery from chronic stress. The data support using lymphocytes as a novel therapeutic target for anxiety states. PMID:27109071

  14. Improving therapy of chronic lymphocytic leukemia with chimeric antigen receptor T cells.

    PubMed

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

    2016-04-01

    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 redirecting 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.

  15. Rituximab plus fludarabine and cyclophosphamide or other agents in chronic lymphocytic leukemia.

    PubMed

    Robak, Tadeusz; Lech-Maranda, Ewa; Robak, Pawel

    2010-10-01

    Over the last few years, several monoclonal antibodies have been investigated in patients with B-cell lymphoid malignancies. Rituximab is the most important monoclonal antibody of clinical value in these disorders. Rituximab is an IgG1 chimeric antibody containing murine light- and heavy-chain variable region sequences and human constant region sequences. Since approval in 1997, rituximab has become the standard of care in follicular B-cell lymphoma, chronic lymphocytic leukemia (CLL) and aggressive lymphoma when combined with chemotherapy. Higher clinical benefits of rituximab can be seen in patients with CLL when it is added to other chemotherapeutic agents. Several recent reports have suggested that in patients with CLL, rituximab combined with purine nucleoside analogs (PNAs) or PNAs and cyclophosphamide may improve the results with acceptable toxicity, both in previously untreated and refractory/relapsed patients. The randomized, multinational Phase III study (REACH trial) has shown that rituximab combined with fludarabine and cyclophosphamide (R-FC regimen) results in 10 months longer progression-free survival, and higher overall response and complete response rates than fludarabine and cyclophosphamide (FC regimen) in previously treated patients. The German CLL study group initiated a multicenter, multinational Phase III trial, CLL8, to evaluate the efficacy and tolerability of R-FC versus FC for the first-line treatment of patients with advanced CLL. The overall response rate was significantly higher in the R-FC arm (95%) compared with FC (88%). The complete response rate in the R-FC arm was 44% compared with 27% in the FC arm. The recently updated analysis has demonstrated longer overall survival in the R-FC group. Recent clinical observations have revealed that combinations of rituximab with pentostatin and cyclophosphamide, or cladribine and cyclophosphamide are also highly active regimens in previously untreated CLL. In addition, the results of

  16. Impaired catecholaminergic signalling of B lymphocytes in patients with chronic rheumatic diseases

    PubMed Central

    Wahle, M; Kolker, S; Krause, A; Burmester, G; Baerwald, C

    2001-01-01

    OBJECTIVE—To investigate further the influence of the autonomic nervous system on chronic rheumatic diseases.
METHODS—The density and affinity of β2 adrenergic receptors (β2R) on CD19+ lymphocytes in patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and systemic sclerosis (SSc), as well as intracellular cAMP levels in patients with RA and SLE, were determined. Human peripheral blood mononuclear cells were separated from venous blood of patients and healthy controls by Ficoll-Hypaque density centrifugation. CD19+ lymphocytes were purified by magnetic cell sorting, and β2R were determined by a radioligand binding assay with [125I]iodocyanopindolol. Intracellular cAMP levels and β2R agonist induced cell death were measured by a radioimmunoassay and flow cytometry using annexin-V binding, respectively. Systemic disease activity of the patients was evaluated using multifactorial scoring systems.
RESULTS—The density of β2R on peripheral CD19+ lymphocytes was significantly decreased in patients with RA, SLE, and SSc compared with healthy controls. In patients with RA and SSc β2R density was negatively correlated with systemic disease activity. Furthermore, although basal intracellular cAMP levels were raised in patients with RA and SLE, the increase of cAMP upon stimulation of β2R was significantly reduced in these patients compared with control subjects. Preliminary data suggest that β2R agonist induced cell death is diminished in patients with RA exhibiting decreased β2R densities.
CONCLUSIONS—The results of this study show a reduction of β2R densities on B lymphocytes mirrored by an impaired intracellular cAMP generation in patients with chronic rheumatic diseases, indicating a decreased influence of the autonomic nervous system on B cells in these conditions.

 PMID:11302874

  17. 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

  18. Expansion of NK Cells and Reduction of NKG2D Expression in Chronic Lymphocytic Leukemia. Correlation with Progressive Disease

    PubMed Central

    Huergo-Zapico, Leticia; Acebes-Huerta, Andrea; Gonzalez-Rodriguez, Ana Pilar; Contesti, Juan; Gonzalez-García, Esther; Payer, Angel R.; Villa-Alvarez, Monica; Fernández-Guizán, Azahara; López-Soto, Alejandro; Gonzalez, Segundo

    2014-01-01

    The immune system may mediate anti-tumor responses in chronic lymphocytic leukemia (CLL) which may affect disease progression and survival. In this study, we analyzed the immune characteristics of 99 consecutive previously diagnosed CLL patients and 50 healthy controls. The distribution of lymphocyte subsets at diagnosis was retrospectively analyzed. Compared with controls, leukemia patients showed an expansion of NK and CD8 T cells at diagnosis. The relative number of CD8 T cells at diagnosis was associated with time to treatment, suggesting that CD8 T cells may modify disease progression. The distribution of lymphocyte subsets was analyzed again when patients were enrolled in this study. The median time since these patients were diagnosed was 277 weeks. Compared with diagnosis, the absolute number of CD8 T cells significantly decreased in these patients, reaching similar values to healthy controls; however NK cells kept significantly elevated overtime. Nevertheless, NK cells showed an impaired expression of NKG2D receptor and a defective cytotoxic activity. This down-regulation of NKG2D expression was further enhanced in patients with advanced and progressive disease. Additionally, membrane NKG2D levels significantly decreased on CD8 T cells, but a significant increase of NKG2D+CD4+ T cells was observed in CLL patients. The cytotoxic activity of NK cells was diminished in CLL patients; however the treatments with IL-2, IL-15, IL-21 and lenalidomide were able to restore their activity. The effect of IL-2 and IL-15 was associated with the increase of NKG2D expression on immune cells, but the effect of IL-21 and lenalidomide was not due to NKG2D up-regulation. The expansion of NK cells and the reversibility of NK cell defects provide new opportunities for the immunotherapeutic intervention in CLL. PMID:25286418

  19. [Palliative care needs in advanced chronic illness].

    PubMed

    Tripodoro, Vilma A; Rynkiewicz, María C; Llanos, Victoria; Padova, Susana; De Lellis, Silvina; De Simone, Gustavo

    2016-01-01

    About 75% of population will die from one or more chronic progressive diseases. From this projection WHO urged countries to devise strategies for strengthening palliative treatment as part of comprehensive care. In Catalonia, Spain, direct measurement of the prevalence of these patients with NECPAL CCOMS-ICO© tool was 1.5% of the population. This tool is an indicative, not dichotomous, quali-quantitative multifactorial evaluation to be completed by the treating physician. In Argentina there is no information on these patients. Our goal was to explore and characterize the proportion of chronically ill patients in palliative care needs, by NECPAL CCOMS-ICO© tool, in an accessible population of the City of Buenos Aires. General hospitals of the Health Region 2 (Piñero, álvarez and Santojanni) and its program areas were surveyed. In Health Region 1, we surveyed the Udaondo gastroenterology hospital. A total of 53 physicians (704 patients) were interviewed. It was identified that 29.5% of these patients were affected by advanced chronic diseases; 72.1% of them were NECPAL positive, younger (median 64) than in others studies, and more than 98% presented high levels of comorbidity. Palliative care demand (31.4%) and needs (52.7%) were recorded. Specific indicators of fragility, progression, severity and kind of chronic disease were described. The main finding was to identify, with an instrument not based on mortality that, in Buenos Aires City, 1 in 3 patients with chronic diseases could die in the next year and had palliative care needs. PMID:27295702

  20. Primary hyperparathyroidism due to an intrathyroidal parathyroid adenoma associated with chronic lymphocytic thyroiditis.

    PubMed

    Cating-Cabral, Monica Therese; Cabungcal, Arsenio Claro; Villafuerte, Cesar Vincent; Añel-Quimpo, Joselynna

    2012-06-08

    This is a case of a 44-year-old woman with an anterior neck mass and hypothyroidism who presented with an incidental finding of an elevated serum calcium level and was found to have primary hyperparathyroidism and osteoporosis. During surgical exploration no parathyroid adenoma was found, although a nodule was palpated within the right thyroid lobe. Examination of the excised right thyroid lobe revealed an intrathyroidal parathyroid adenoma and chronic lymphocytic thyroiditis. After surgery, she did not develop severe hypocalcaemia and this was attributed to preoperative treatment with pamidronate. In the months following surgery, parathyroid hormone remained undetectable.

  1. A case of chronic lymphocytic leukemia still taking etanercept for ankylosing spondylitis.

    PubMed

    Kuşkonmaz, Ş M; Mercan, R; Ozturk, M A

    2016-01-01

    The possible risk of hematologic malignancies in anti TNF users is a matter of debate. Whether associated with the drug or not, how to behave when a hematologic malignancy is discovered in the course of anti TNF treatment remains unanswered. Here we present a 66 year old male patient who had AS for 30 years and had been on etanercept for the last two years and who is diagnosed with B cell chronic lymphocytic leukemia (CLL) stage 1. The patient is still on etanercept for 5 years after the diagnosis without any progression in CLL. PMID:27115116

  2. Fludarabine phosphate for the first-line treatment of chronic lymphocytic leukaemia.

    PubMed

    Walker, S; Palmer, S; Erhorn, S; Brent, S; Dyker, A; Ferrie, L; Horsley, W; Macfarlane, K; White, S; Thomas, S

    2009-06-01

    This paper presents a summary of the evidence review group (ERG) report into the clinical and cost-effectiveness of fludarabine phosphate or fludarabine plus cyclophosphamide for the first-line treatment of chronic lymphocytic leukaemia,based upon the evidence submission from Schering Health Care (SHC) to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal (STA) process.The submission was of good quality with no major errors or omissions in the clinical evidence.Two published studies and seven abstracts were included in the company submission, which showed improvements in overall response and progression-free survival (PFS) and a higher complete response rate in the fludarabine containing arms; however, until the complete data are made available for evaluation these results must be interpreted with caution. The manufacturer's decision-analytic Markov model to estimate the cost-effectiveness of treatment with fludarabine monotherapy, fludarabine plus cyclophosphamide and chlorambucil was considered to be the most relevant source for informing this STA;it was appropriate for the decision problem and the data sources used to inform the model were appropriate from a UK NHS perspective.The incremental cost-effectiveness ratio of fludarabine plus cyclophosphamide compared with chlorambucil from the revised model presented in the manufacturer's addendum was pounds 3244 per additional quality-adjusted life-year.The results were robust to a range of subgroup and sensitivity analyses. Additional sensitivity and survival analyses were carried by the ERG to investigate possible bias in the results. This brought into question the validity of the assumptions underpinning the extrapolation of data over a lifetime time horizon and showed that the ICER estimates submitted by the manufacturer were notcalculated correctly and uncertainty surrounding the decision problems was not expressed fully.Based on these analyses the ERG

  3. Endobronchial deposits of chronic lymphocytic leukemia - an unusual cause of central airway obstruction.

    PubMed

    Maw, Miranda; Harvey, Michael; Harrington, Zinta; Baraket, Melissa; Montgomery, Renn; Williamson, Jonathan

    2015-06-01

    A 66-year-old woman with a background of chronic lymphocytic leukemia (CLL) was admitted to the hospital on several occasions with recurrent episodes of community-acquired pneumonia. Computed tomography and bronchoscopy revealed multiple obstructing endobronchial polyps. Post-obstructive pneumonia together with immunoglobulin G deficiency was considered the most likely cause of these recurrent infections. Bronchoscopy was performed for removal of the critically obstructing lesions. Histopathology revealed replacement of bronchial mucosa with CLL deposits. Despite a brief window of infection-free survival following therapy, she remained susceptible to pneumonia with further hospital admissions and eventually died from her disease. PMID:26090107

  4. Regulatory T-cells in chronic lymphocytic leukemia: actor or innocent bystander?

    PubMed Central

    D’Arena, Giovanni; Simeon, Vittorio; D’Auria, Fiorella; Statuto, Teodora; Sanzo, Paola Di; Martino, Laura De; Marandino, Aurelio; Sangiorgio, Michele; Musto, Pellegrino; Feo, Vincenzo De

    2013-01-01

    Regulatory T (Treg) cells are now under extensive investigation in chronic lymphocytic leukemia (CLL). This small subset of T-cells has been, in fact, considered to be involved in the pathogenesis and progression of CLL. However, whether Treg dysregulation in CLL plays a key role or it rather represents a simple epiphenomenon is still matter of debate. In the former case, Treg cells could be appealing for targeting therapies. Finally, Treg cells have also been proposed as a prognostic indicator of the disease clinical course. PMID:23358515

  5. Aggressive squamous cell carcinoma of the skin after chronic lymphocytic leukemia.

    PubMed

    Bridges, N; Steinberg, J J

    1986-09-01

    We report two cases of squamous cell carcinoma (SCC) of the skin subsequent to chronic lymphocytic leukemia (CLL). Both cases had an unusually aggressive course for a nonmelanoma skin malignancy with extensive metastases in both, resulting in death in one patient. A literature review supports the likelihood of an increased incidence of SCC in patients with CLL. Though the mechanism is unknown, immunosuppression may play a central role. We urge patients with CLL to avoid exposure to direct sun. Any questionable skin lesion should be biopsied early, and completely excised if it is a tumor. The patient should also be examined thoroughly for metastatic disease via subsequent follow-up visits.

  6. Metformin inhibits cell cycle progression of B-cell chronic lymphocytic leukemia cells.

    PubMed

    Bruno, Silvia; Ledda, Bernardetta; Tenca, Claudya; Ravera, Silvia; Orengo, Anna Maria; Mazzarello, Andrea Nicola; Pesenti, Elisa; Casciaro, Salvatore; Racchi, Omar; Ghiotto, Fabio; Marini, Cecilia; Sambuceti, Gianmario; DeCensi, Andrea; Fais, Franco

    2015-09-01

    B-cell chronic lymphocytic leukemia (CLL) was believed to result from clonal accumulation of resting apoptosis-resistant malignant B lymphocytes. However, it became increasingly clear that CLL cells undergo, during their life, iterative cycles of re-activation and subsequent clonal expansion. Drugs interfering with CLL cell cycle entry would be greatly beneficial in the treatment of this disease. 1, 1-Dimethylbiguanide hydrochloride (metformin), the most widely prescribed oral hypoglycemic agent, inexpensive and well tolerated, has recently received increased attention for its potential antitumor activity. We wondered whether metformin has apoptotic and anti-proliferative activity on leukemic cells derived from CLL patients. Metformin was administered in vitro either to quiescent cells or during CLL cell activation stimuli, provided by classical co-culturing with CD40L-expressing fibroblasts. At doses that were totally ineffective on normal lymphocytes, metformin induced apoptosis of quiescent CLL cells and inhibition of cell cycle entry when CLL were stimulated by CD40-CD40L ligation. This cytostatic effect was accompanied by decreased expression of survival- and proliferation-associated proteins, inhibition of signaling pathways involved in CLL disease progression and decreased intracellular glucose available for glycolysis. In drug combination experiments, metformin lowered the apoptotic threshold and potentiated the cytotoxic effects of classical and novel antitumor molecules. Our results indicate that, while CLL cells after stimulation are in the process of building their full survival and cycling armamentarium, the presence of metformin affects this process.

  7. The VEGF receptor, neuropilin-1, represents a promising novel target for chronic lymphocytic leukemia patients.

    PubMed

    Piechnik, Agnieszka; Dmoszynska, Anna; Omiotek, Marcin; Mlak, Radosław; Kowal, Małgorzata; Stilgenbauer, Stephan; Bullinger, Lars; Giannopoulos, Krzysztof

    2013-09-15

    Angiogenesis has been shown to substantially contribute to the progression of chronic lymphocytic leukemia (CLL). Neuropilin-1 (NRP1) represents a receptor for vascular endothelial growth factor (VEGF), which has been reported to be overexpressed in several malignancies. In our study, we characterized mRNA levels of VEGF receptors including NRP1 in a large cohort of CLL patients (n = 114), additionally we performed a detailed characterization of NRP1 expression on B cells, plasmacytoid dendritic cells (PDCs) and regulatory T cells (Tregs). The expression of NRP1 was significantly higher on leukemic lymphocytes compared to control B lymphocytes on mRNA and protein levels (22.72% vs. 0.2%, p = 0.0003, respectively), Tregs (42.6% vs. 16.05%, p = 0.0003) and PDCs (100% vs. 98% p < 0.0001). In functional studies, we found higher NRP1 expression on CLL cells after stimulation with VEGF. The correlation between expression of VEGF receptors: FLT1, NRP1 and FOXP3 expression (r(2) = 0.53, p < 0.0001 and r(2) = 0.49, p < 0.0001, respectively) was observed. Earlier we described the specific Treg reduction during the therapy with thalidomide in vivo. Now we observe the reduction of the NRP1 expression on Tregs in vitro, thereby suggesting a possible target of thalidomide action. In conclusion, NRP1 might represent an interesting link between angiogenesis and tolerance mechanisms and represents interesting target for therapy.

  8. Mycobacterium genavense infection in a patient with long-standing chronic lymphocytic leukaemia.

    PubMed

    Krebs, T; Zimmerli, S; Bodmer, T; Lämmle, B

    2000-10-01

    We describe the first case of disseminated infection with Mycobacterium genavense in an HIV-seronegative patient with a chronic haematological disorder. Our patient, an 80-year-old woman, had been under long-term treatment with chlorambucil (partially in combination with prednisone) for B-cell chronic lymphocytic leukaemia (B-CLL). When she developed general fatigue and progressive anaemia, as well as progressive lymphadenopathy and splenomegaly, bone marrow biopsy revealed granulomas with acid-fast bacilli, and cultures of both bone marrow and blood grew M. genavense. The patient's CD4+ cell count was approximately 100 microL(-1). Treatment with clarithromycin, ethambutol and rifabutin resulted in improvement of anaemia and general health as well as in regression of lymphadenopathy and splenomegaly. PMID:11086646

  9. Accelerated growth of skin carcinoma following fludarabine therapy for chronic lymphocytic leukemia.

    PubMed

    Rashid, Kamran; Ng, Richard; Mastan, Alina; Sager, Dianne; Hirschman, Richard

    2005-07-01

    We present four patients with chronic lymphocytic leukemia treated with fludarabine, who developed aggressive skin cancer after years of quiescence, a short time after institution of treatment. Their leukemias responded well to therapy with fludarabine with initial treatment as well as relapse. Three patients had recurrence with basal cell carcinomas with multiple, rapidly growing tumors and one had recurrence of both basal and squamous cancers and eventually died of metastatic squamous cell carcinoma. Fludarabine induces prolonged period of lymphopenia, affecting especially the T cell population, which is crucial in the defense against skin cancers. There appears to be a direct association between fludarabine and the flare up of skin cancers in these patients, possibly analogous to the increased incidence of these malignancies in patients on chronic cyclosporine immunosuppression.

  10. AgNOR clusters as a parameter of cell kinetics in chronic lymphocytic leukaemia

    PubMed Central

    Lorand-Metze, Irene; Metze, Konradin

    1996-01-01

    Aims—To study correlations between the pattern of silver stained nucleolar organiser regions (AgNORs) in chronic lymphocytic leukaemia (CLL) and parameters of tumour kinetics. To investigate whether quantitation of the AgNOR pattern can be used to discriminate between patients with stable and progressive disease. Methods—Peripheral blood smears from 48 patients with CLL, classified as having either stable or progressive disease (Rai stage III or IV; bulky lymph nodes or massive splenomegaly; or peripheral lymphocytes >100 × 109/1), were studied. For each patient, total tumour mass (TTM) and for patients undergoing a period of observation without treatment, the TTM duplication time (DT) and the lymphocyte doubling time (LDT) were calculated. Results—Four cell types could be distinguished according to their AgNOR pattern: (1) cells with a single cluster; (2) cells with a single compact nucleolus; (3) cells with two compact nucleoli; and (4) cells with several scattered dots. The percentage of cells with clusters was the AgNOR parameter which correlated best with TTM and LDT. Correlations were also seen between the proportion of cells with clusters and age and haemoglobin concentration. A significant correlation with DT could be detected only when age was kept constant. Linear discriminant analysis revealed that the percentage of cells with clusters was the most important prognostic factor. This alone classified 94% of the patients correctly (jackknive procedure) as either stable or progressive CLL. Conclusions—The percentage of circulating lymphocytes with clusters of AgNORs can be used as a parameter of tumour kinetics in CLL and helps to discriminate between patients with stable and progressive disease. For practical purposes, a value of more than 13% of cells with clusters is suggestive of progressive disease. Images PMID:16696103

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

    PubMed Central

    Del Principe, Maria Ilaria; Bo, Michele Dal; 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. PMID:26565002

  12. Atypical Lymphocytes and Cellular Cannibalism: A Phenomenon, First of its Kind to be Discovered in Chronic Periapical Lesions

    PubMed Central

    Patil, Kaustubh P.; Nayyar, Abhishek Singh; Sasane, Rutuparna S

    2016-01-01

    Introduction Lymphocytes are often termed to be isomorphic, having a monotonous light microscopic appearance. Morphological aspects of lymphocytes in tissue sections thereby are not routinely taken notice of as their morphology seems to vary only in case of lymphoid malignancies, hematological malignancies apart from certain viral infections. Atypical lymphocytes are the lymphocytes with unusual shape, size or overall structure. These are more commonly known as reactive lymphocytes. The unusual histomorphological feature of these cells include larger size than normal lymphocytes; in some cells the size exceeds even 30 microns. The large size is the result of antigenic stimulation of the cell. Alongwith these, the other rare feature which is recently coming under light is “Cellular Cannibalism” which is defined as a large cell enclosing a slightly smaller one within its cytoplasm. Previously, this feature was noted only in cases of malignant tumors. Aim The objectives of this study were to determine the proportion of atypical lymphocytes in chronic periapical granulomas and cysts; to determine the proportionate cellular cannibalism in these periapical lesions. Materials and Methods This was a descriptive, observational study conducted in the Department of Oral Medicine and Radiology and Oral Pathology and Microbiology. Haematoxylin and eosin stained 30 slides of chronic periapical granulomas and 20 slides of cysts reported in the year 2014-15 and the clinical proformas of the patients were retrieved from the files of the Department of Oral Medicine and Radiology and Oral Pathology and Microbiology. These slides were evaluated by 3 experts from the specialization of Oral Pathology and Microbiology to determine the presence of atypical lymphocytes and cellular cannibalism under high power magnification (400X). Results Out of the 30 slides of chronic periapical granulomas, about 12 slides (40%) revealed presence of atypical lymphocytes. In case of slides of chronic

  13. Lymphocytes from Chronically Stressed Mice Confer Antidepressant-Like Effects to Naive Mice

    PubMed Central

    Brachman, Rebecca A.; Lehmann, Michael L.; Maric, Dragan

    2015-01-01

    We examined whether cells of the adaptive immune system retain the memory of psychosocial stress and thereby alter mood states and CNS function in the host. Lymphocytes from mice undergoing chronic social defeat stress or from unstressed control mice were isolated and adoptively transferred into naive lymphopenic Rag2−/− mice. Changes in affective behavior, hippocampal cell proliferation, microglial activation states, and blood cytokine levels were examined in reconstituted stress-naive mice. The mice receiving lymphocytes from defeated donors showed less anxiety, more social behavior, and increased hippocampal cell proliferation compared with those receiving no cells or cells from unstressed donors. Mice receiving stressed immune cells had reduced pro-inflammatory cytokine levels in the blood relative to the other groups, an effect opposite to the elevated donor pro-inflammatory cytokine profile. Furthermore, mice receiving stressed immune cells had microglia skewed toward an anti-inflammatory, neuroprotective M2-like phenotype, an effect opposite the stressed donors' M1-like pro-inflammatory profile. However, stress had no effect on lymphocyte surface marker profiles in both donor and recipient mice. The data suggest that chronic stress-induced changes in the adaptive immune system, contrary to conferring anxiety and depressive behavior, protect against the deleterious effects of stress. Improvement in affective behavior is potentially mediated by reduced peripheral pro-inflammatory cytokine load, protective microglial activity, and increased hippocampal cell proliferation. The data identify the peripheral adaptive immune system as putatively involved in the mechanisms underlying stress resilience and a potential basis for developing novel rapid-acting antidepressant therapies. PMID:25632130

  14. [Apoptosis of Peripheral Blood Lymphocytes in the Members of the Techa River Cohort Chronically Exposed to Radiation].

    PubMed

    Blinova, E A; Akleyev, A V

    2016-01-01

    The purpose of the present research was to estimate the intensity of the apoptotic death of lymphocytes during the period of carcinogenic effect realization in the residents of the Techa riverside villages. The investigation included analyses of the frequency of lymphocytes at the early and late stages of apoptosis and necrosis of peripheral blood lymphocytes using the method of FITC Annexin V, lymphocyte counts at the stage of DNA fragmentation using the TUNEL method, and the number of CD95(+)-lymphocytes. In the capacity of additional tests, loading tests involving in vitro irradiation at the dose of 1 Gy of a suspension of lymphocytes and incubations for 5 and 24 hours were used. Activation of the initial apoptotic and necrotic death of peripheral blood lymphocytes was revealed in the persons chronically exposed to low-intensity radiation within the range from 0.01 to 4.23 Gy. Exposed patients demonstrated a decrease in the number of CD95(+)-cells as compared to unexposed patients. The results of the cell death studies in the persons residing in the Techa riverside villages testify indirectly to the genomic instability of the peripheral blood lymphocytes. PMID:27245002

  15. Multiple productive immunoglobulin heavy chain gene rearrangements in chronic lymphocytic leukemia are mostly derived from independent clones

    PubMed Central

    Plevova, Karla; Francova, Hana Skuhrova; Burckova, Katerina; Brychtova, Yvona; Doubek, Michael; Pavlova, Sarka; Malcikova, Jitka; Mayer, Jiri; Tichy, Boris; Pospisilova, Sarka

    2014-01-01

    In chronic lymphocytic leukemia, usually a monoclonal disease, multiple productive immunoglobulin heavy chain gene rearrangements are identified sporadically. Prognostication of such cases based on immunoglobulin heavy variable gene mutational status can be problematic, especially if the different rearrangements have discordant mutational status. To gain insight into the possible biological mechanisms underlying the origin of the multiple rearrangements, we performed a comprehensive immunogenetic and immunophenotypic characterization of 31 cases with the multiple rearrangements identified in a cohort of 1147 patients with chronic lymphocytic leukemia. For the majority of cases (25/31), we provide evidence of the co-existence of at least two B lymphocyte clones with a chronic lymphocytic leukemia phenotype. We also identified clonal drifts in serial samples, likely driven by selection forces. More specifically, higher immunoglobulin variable gene identity to germline and longer complementarity determining region 3 were preferred in persistent or newly appearing clones, a phenomenon more pronounced in patients with stereotyped B-cell receptors. Finally, we report that other factors, such as TP53 gene defects and therapy administration, influence clonal selection. Our findings are relevant to clonal evolution in the context of antigen stimulation and transition of monoclonal B-cell lymphocytosis to chronic lymphocytic leukemia. PMID:24038023

  16. 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

  17. The use of rituximab and bendamustine in treating chronic lymphocytic leukaemia (CLL) in end-stage renal disease (ESRD).

    PubMed

    Shoji, Jun; Lew, Susie Q

    2013-05-02

    A patient with a history of type 2 diabetes mellitus and chronic lymphocytic leukaemia has renal failure with large kidneys. The patient refused kidney biopsy to determine the aetiology of her renal failure. She uses peritoneal dialysis to treat renal failure. She received rituximab and bendamustine to treat chronic lymphocytic leukaemia. Adenopathy resolves with treatment and she does not experience any electrolyte disturbances or decrease in urine output as a result of chemotherapy in the setting of renal failure. Renal function did not recover with chemotherapy.

  18. Recent advances and novel treatment paradigms in acute lymphocytic leukemia

    PubMed Central

    Papadantonakis, Nikolaos; Advani, Anjali S.

    2016-01-01

    This is an exciting time in the treatment of acute lymphoblastic leukemia (ALL) given the advances in the relapsed/refractory setting. The development of antibody treatments (including antibody drug conjugates with toxins) offers a different treatment approach compared with conventional chemotherapy regimens. Moreover, the use of bispecific T-cell-engager antibodies (BiTEs) such as blinatumomab harness the cytotoxic activity of T cells against CD19-positive lymphoblasts. Another strategy involves the use of chimeric antigen receptor (CAR) T cells. CAR T cells have demonstrated promising results in the relapsed/refractory setting. However, the use of BiTEs and CAR T cells is also associated with a distinct set of adverse reactions that must be taken into account by the treating physician. Apart from the above strategies, the use of other targeted therapies has attracted interest. Namely, the discovery of the Philadelphia (Ph)-like signature in children and young adults with ALL has led to the use of tyrosine kinase inhibitors (TKI) in these patients. The different drugs and strategies that are being tested in the relapsed/refractory ALL setting pose a unique challenge in identifying the optimum sequence of treatment and determining which approaches should be considered for frontline treatment.

  19. Pre-malignant lymphoid cells arise from hematopoietic stem/progenitor cells in chronic lymphocytic leukemia.

    PubMed

    Kikushige, Yoshikane; Miyamoto, Toshihiro

    2015-11-01

    Human malignancies progress through a multistep process that includes the development of critical somatic mutations over the clinical course. Recent novel findings have indicated that hematopoietic stem cells (HSCs), which have the potential to self-renew and differentiate into multilineage hematopoietic cells, are an important cellular target for the accumulation of critical somatic mutations in hematological malignancies and play a central role in myeloid malignancy development. In contrast to myeloid malignancies, mature lymphoid malignancies, such as chronic lymphocytic leukemia (CLL), are thought to originate directly from differentiated mature lymphocytes; however, recent compelling data have shown that primitive HSCs and hematopoietic progenitor cells contribute to the pathogenesis of mature lymphoid malignancies. Several representative mutations of hematological malignancies have been identified within the HSCs of CLL and lymphoma patients, indicating that the self-renewing long-lived fraction of HSCs can serve as a reservoir for the development of oncogenic events. Novel mice models have been established as human mature lymphoma models, in which specific oncogenic events target the HSCs and immature progenitor cells. These data collectively suggest that HSCs can be the cellular target involved in the accumulation of oncogenic events in the pathogenesis of mature lymphoid and myeloid malignancies.

  20. 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.

  1. The impact of Agent Orange exposure on presentation and prognosis of patients with chronic lymphocytic leukemia.

    PubMed

    Baumann Kreuziger, Lisa M; Tarchand, Gobind; Morrison, Vicki A

    2014-01-01

    Exposure to Agent Orange (AO) and the contaminating chemical 2,3,7,8-tetrachlorodibenzodioxin (TCDD) has been associated with the development of chronic lymphocytic leukemia (CLL). Of the 195 veterans diagnosed with CLL from 2001 to 2010 in a retrospective cohort from the Minneapolis Veterans Affairs Medical Center, 33 (17%) were exposed to AO. Prognostic factors including Rai stage, lymphocyte doubling time and cytogenetics did not differ between exposed and unexposed patients. Exposed patients were younger at diagnosis (61 vs. 72 years, p < 0.0001) and time to CLL treatment was shorter (9.6 vs. 30.2 months, p = 0.02). Overall survival did not differ between exposed and unexposed patients on Kaplan-Meier analysis, but when adjusted for age, AO exposure had a hazard ratio of death of 1.8 compared to non-exposure (95% confidence interval 0.7-4.5, p = 0.24). The high estimate of the mortality hazard combined with the relatively low numbers in the exposure group suggests that further examination in a larger patient population is warranted. PMID:23573826

  2. Serum copper is a simple but valuable prognostic marker in B-cell chronic lymphocytic leukemia.

    PubMed

    Labib, Hany A; Hassanein, Mona; Etewa, Rasha L

    2014-12-01

    We investigated the relationship between serum copper and various prognostic factors, time to start treatment, and treatment response in patients with B-cell chronic lymphocytic leukemia (B-CLL) and related disorders. Fifty newly diagnosed CLL patients aged 36-70 years were included. Patients were studied for serum lactate dehydrogenase (LDH), serum copper, direct Coombs' test, serum β(2) microglobulin (β(2)M), immunophenotyping for diagnosis of B-CLL, evaluation of CD38 and zeta-associated protein (ZAP-70) expression, and fluorescence in situ hybridization technique for cytogenetic analysis. Fourteen of 50 patients had high serum copper level; they had a significant increase in LDH, serum β(2)M, incidence of positive Coombs' test, CD38 and ZAP-70, incidence of 17p del, and a decrease in hemoglobin concentration, lymphocyte doubling time and time to start treatment with a lower treatment response rate. No significant difference was found with regard to Rai staging for CLL. These results indicate that serum copper level, a cheap and simple laboratory test, is of great value in CLL patients as it showed a significant association with some important adverse prognostic markers such as increased expression of ZAP-70 and CD38, shorter time to start treatment and poor response to treatment.

  3. The impact of Agent Orange exposure on presentation and prognosis of patients with chronic lymphocytic leukemia.

    PubMed

    Baumann Kreuziger, Lisa M; Tarchand, Gobind; Morrison, Vicki A

    2014-01-01

    Exposure to Agent Orange (AO) and the contaminating chemical 2,3,7,8-tetrachlorodibenzodioxin (TCDD) has been associated with the development of chronic lymphocytic leukemia (CLL). Of the 195 veterans diagnosed with CLL from 2001 to 2010 in a retrospective cohort from the Minneapolis Veterans Affairs Medical Center, 33 (17%) were exposed to AO. Prognostic factors including Rai stage, lymphocyte doubling time and cytogenetics did not differ between exposed and unexposed patients. Exposed patients were younger at diagnosis (61 vs. 72 years, p < 0.0001) and time to CLL treatment was shorter (9.6 vs. 30.2 months, p = 0.02). Overall survival did not differ between exposed and unexposed patients on Kaplan-Meier analysis, but when adjusted for age, AO exposure had a hazard ratio of death of 1.8 compared to non-exposure (95% confidence interval 0.7-4.5, p = 0.24). The high estimate of the mortality hazard combined with the relatively low numbers in the exposure group suggests that further examination in a larger patient population is warranted.

  4. 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.

  5. Advanced chronic lymphoid leukemia with severe bronchopneumonia: an Autopsy Case Report.

    PubMed

    Amaral, Felipe Gomes Campos; Lima, Luiz Guilherme Cernaglia Aureliano; Hatanaka, Veruska Menegatti Anastacio; Siqueira, Sheila Aparecida Coelho; Duarte-Neto, Amaro Nunes

    2016-01-01

    Chronic lymphocytic leukemia (CLL) is a lymphoid neoplasia with the B immunophenotype, which corresponds to the leukemic form of lymphocytic lymphoma. This entity is characterized, in most cases, by immunosuppression due to impaired function of immune cells, hypogammaglobulinemia, bone marrow infiltration, and immune dysfunction due to the neoplasia and the chemotherapy, when prescribed. We describe the case of a 63-year-old woman with a previous diagnosis of advanced CLL, refractory to treatment, who presented respiratory failure at the emergency department and died soon after hospital admission. The autopsy examination showed a large retroperitoneal mass compressing large vessels and abdominal and pelvic organs; generalized lymphadenopathy; and liver, spleen, bone marrow, heart and kidney infiltration. A Gram-negative bacilli bronchopneumonia with diffuse alveolar damage was detected, which was likely to be the immediate cause of death. PMID:27284536

  6. Advanced chronic lymphoid leukemia with severe bronchopneumonia: an Autopsy Case Report

    PubMed Central

    Amaral, Felipe Gomes Campos; Lima, Luiz Guilherme Cernaglia Aureliano; Hatanaka, Veruska Menegatti Anastacio; Siqueira, Sheila Aparecida Coelho

    2016-01-01

    Chronic lymphocytic leukemia (CLL) is a lymphoid neoplasia with the B immunophenotype, which corresponds to the leukemic form of lymphocytic lymphoma. This entity is characterized, in most cases, by immunosuppression due to impaired function of immune cells, hypogammaglobulinemia, bone marrow infiltration, and immune dysfunction due to the neoplasia and the chemotherapy, when prescribed. We describe the case of a 63-year-old woman with a previous diagnosis of advanced CLL, refractory to treatment, who presented respiratory failure at the emergency department and died soon after hospital admission. The autopsy examination showed a large retroperitoneal mass compressing large vessels and abdominal and pelvic organs; generalized lymphadenopathy; and liver, spleen, bone marrow, heart and kidney infiltration. A Gram-negative bacilli bronchopneumonia with diffuse alveolar damage was detected, which was likely to be the immediate cause of death. PMID:27284536

  7. Complementary and alternative medicine use in patients with chronic lymphocytic leukemia: an Italian multicentric survey.

    PubMed

    D'Arena, Giovanni; Laurenti, Luca; Coscia, Marta; Cortelezzi, Agostino; Chiarenza, Annalisa; Pozzato, Gabriele; Vigliotti, Maria Luigia; Nunziata, Giuseppe; Fragasso, Alberto; Villa, Maria Rosaria; Grossi, Alberto; Selleri, Carmine; Deaglio, Silvia; La Sala, Antonio; Del Poeta, Giovanni; Simeon, Vittorio; Aliberti, Luig; De Martino, Laura; Giudice, Aldo; Musto, Pellegrino; De Feo, Vincenzo

    2014-04-01

    Complementary and alternative medicine (CAM) is common in patients with cancer and its use is steadily increasing over time. We performed a multicenter survey in which the use of CAM in 442 Italian patients with chronic lymphocytic leukemia (CLL), the commonest form of leukemia in Western countries, was assessed. Data were collected by means of a face-to-face standardized questionnaire with several items. Mean age was 69 years; 258 patients (58%) were male and 184 (42%) female. Seventy-three patients (16.5%) were found to be CAM users. The most common CAM therapies were green tea, aloe formulations and high dose vitamins. Predictors of CAM use were female gender, younger age, higher education level, internet availability and newspaper reading. The reasons for CAM popularity among these patients are complex. Given the number of patients combining therapy with CAM and its possible drug interactions, doctor interest as well as patient education about CAM should be improved. PMID:23829282

  8. Chronic lymphocytic thyroiditis, thyrotoxicosis, and low radioactive iodine uptake. Report of four cases.

    PubMed

    Gluck, F B; Nusynowitz, M L; Plymate, S

    1975-09-25

    To characterize four patients with thyrotoxicosis and a low radioactive iodine uptake, thyroid biopsies were performed, and iodine metabolism was studied. Histologic examination showed the presence of chronic lymphocytic thyroiditis, with no features of Graves's disease, in all. Detailed studies in one patient revealed insufficient metabolism of iodine to account for the clinical and chemical features of thyrotoxicosis, which implies that release of stored hormone by the inflammatory process causes the thyrotoxic state. The thyrotoxicosis in this entity subsides spontaneously. Thus, this form of thyrotoxicosis differs from the usual form found in Graves's disease in that histologie features of Graves's disease are absent, the radioactive iodine uptake is low, and specific antithyroid therapy is contraindicated. The observations further demonstrate that the radioactive iodine uptake remains a valuable tool in the diagnosis of thyrotoxicosis and the differentiation of its various forms.

  9. Temporal bone metastasis as a sign of relapsing chronic lymphocytic leukemia

    PubMed Central

    Aljafar, Hadeel M.; Alsuhibani, Sari S.; Alahmari, Mohammad S.; Alzahrani, Musaed A.

    2015-01-01

    Otologic manifestations in chronic lymphocytic leukemia (CLL) are common presentations. However, temporal bone metastasis is rarely described as a sign of relapsing CLL. A 65-year-old male diabetic patient known to have CLL on remission presented to the outpatient otolaryngology clinic with a one month history of progressive bilateral otalgia and right otorrhea, despite multiple courses of antibiotics. He was admitted with suspicion of malignant otitis externa. Left ear showed large hemorrhagic bullae on the posterior segment of tympanic membrane. Left sided facial paralysis developed on the third day of admission. Full recovery of facial paralysis is achieved by 10 days course of corticotherapy. Histological examination of middle ear tissue biopsy showed infiltration by monotonous small lymphoid cells, showing round nuclei, condensed chromatin suggestive of CLL. Although rare, unusual otologic manifestations should raise the suspicion of a temporal bone metastasis as a sign of relapsing CLL. PMID:26446337

  10. Acute sinusitis and blindness as the first presentation of chronic lymphocytic leukaemia.

    PubMed

    Lim, K H; Thomas, G; van Beers, E J; Hosman, A E; Mourits, M P; van Noesel, C J M; Kater, A P; Reinartz, S M

    2014-12-01

    Chronic lymphocytic leukaemia (CLL) is the most frequent form of leukaemia among adults in the Western world, presenting at a median age of 65 years. The diagnosis is usually made incidentally during routine blood examination while the disease is still in its early phase. We report a case of blindness of 24 hours due to acute sinusitis based on CLL localisation in a patient with undiagnosed CLL. Emergency endoscopic sinus surgery and intra- and extra-ocular orbital decompression were performed. The sinusitis resolved after surgery and intravenous antibiotics. Her vision improved within 24 hours and eventually recovered completely after six months. Her CLL remained in an indolent state, needing no active treatment. This case illustrates that blindness from a lymphoproliferative disorder may be treated with emergency endoscopic sinus surgery instead of conventional chemotherapy in order to salvage the vision first, even if the vision is lost for more than 24 hours.

  11. Increased oxidative damage associated with unfavorable cytogenetic subgroups in chronic lymphocytic leukemia.

    PubMed

    Collado, Rosa; Ivars, David; Oliver, Isabel; Tormos, Carmen; Egea, Mercedes; Miguel, Amparo; Sáez, Guillermo T; Carbonell, Félix

    2014-01-01

    Oxidative stress contributes to genomic instability in chronic lymphocytic leukemia (CLL), but its relationship with the acquisition of specific chromosomal abnormalities is unknown. We recruited 55 untreated CLL patients and assessed 8-oxo-2'-deoxyguanosine (8-oxo-dG), glutathione, and malondialdehyde (MDA) levels, and we compared them among the cytogenetic subgroups established using fluorescence in situ hybridization (FISH). Significant increases in 8-oxo-dG and/or MDA were observed in patients with unfavorable cytogenetic aberrations (17p and 11q deletions) compared to the 13q deletion group. TP53 deletion patients exhibited a diminished DNA repair efficiency. Finally, cases with normal FISH also showed enhanced 8-oxo-dG, which could result in adverse outcomes.

  12. Increased Oxidative Damage Associated with Unfavorable Cytogenetic Subgroups in Chronic Lymphocytic Leukemia

    PubMed Central

    Tormos, Carmen; Sáez, Guillermo T.; Carbonell, Félix

    2014-01-01

    Oxidative stress contributes to genomic instability in chronic lymphocytic leukemia (CLL), but its relationship with the acquisition of specific chromosomal abnormalities is unknown. We recruited 55 untreated CLL patients and assessed 8-oxo-2′-deoxyguanosine (8-oxo-dG), glutathione, and malondialdehyde (MDA) levels, and we compared them among the cytogenetic subgroups established using fluorescence in situ hybridization (FISH). Significant increases in 8-oxo-dG and/or MDA were observed in patients with unfavorable cytogenetic aberrations (17p and 11q deletions) compared to the 13q deletion group. TP53 deletion patients exhibited a diminished DNA repair efficiency. Finally, cases with normal FISH also showed enhanced 8-oxo-dG, which could result in adverse outcomes. PMID:25054143

  13. Chronic lymphocytic leukemia of the bladder: an atypical etiology of gross hematuria

    PubMed Central

    Isharwal, Sudhir; Pooli, Aydin; Lele, Subodh; Feloney, Michael

    2014-01-01

    Chronic lymphocytic leukemia (CLL) is a rare hematologic disorder with affected patients having complications of frequent infections and possible transformation to a more aggressive malignancy. The occurrence of CLL in the bladder is a rare event, with few reported cases. As a result, its aggressiveness and the optimal course for treatment are unknown. Despite this, its presence in the bladder warrants continued surveillance, as recurrence and progression to other bladder malignancies are possible. We present a 71-year-old woman initially diagnosed with CLL who was plagued by recurrent hematuria and dysuria for over a decade, which lead to multiple negative urologic workups. However, these continued workups eventually lead to her diagnosis of bladder CLL with a subsequent finding of carcinoma in situ that was prompted by a suspicious surveillance cystoscopy performed 4 months after her initial bladder diagnosis. Hence, infiltration of CLL in the urinary bladder merits close follow up, including additional urologic procedures. PMID:25276230

  14. Rho and Rap guanosine triphosphatase signaling in B cells and chronic lymphocytic leukemia.

    PubMed

    Mele, Silvia; Devereux, Stephen; Ridley, Anne J

    2014-09-01

    Chronic lymphocytic leukemia (CLL) cells proliferate predominantly in niches in the lymph nodes, where signaling from the B cell receptor (BCR) and the surrounding microenvironment are critical for disease progression. In addition, leukemic cells traffic constantly from the bloodstream into the lymph nodes, migrate within lymphatic tissues and egress back to the bloodstream. These processes are driven by chemokines and their receptors, and depend on changes in cell migration and integrin-mediated adhesion. Here we describe how Rho and Rap guanosine triphosphatases (GTPases) contribute to both BCR signaling and chemokine receptor signaling, particularly by regulating cytoskeletal dynamics and integrin activity. We propose that new inhibitors of BCR-activated kinases are likely to affect CLL cell trafficking via Rho and Rap GTPases, and that upstream regulators or downstream effectors could be good targets for therapeutic intervention in CLL.

  15. Complementary and alternative medicine use in patients with chronic lymphocytic leukemia: an Italian multicentric survey.

    PubMed

    D'Arena, Giovanni; Laurenti, Luca; Coscia, Marta; Cortelezzi, Agostino; Chiarenza, Annalisa; Pozzato, Gabriele; Vigliotti, Maria Luigia; Nunziata, Giuseppe; Fragasso, Alberto; Villa, Maria Rosaria; Grossi, Alberto; Selleri, Carmine; Deaglio, Silvia; La Sala, Antonio; Del Poeta, Giovanni; Simeon, Vittorio; Aliberti, Luig; De Martino, Laura; Giudice, Aldo; Musto, Pellegrino; De Feo, Vincenzo

    2014-04-01

    Complementary and alternative medicine (CAM) is common in patients with cancer and its use is steadily increasing over time. We performed a multicenter survey in which the use of CAM in 442 Italian patients with chronic lymphocytic leukemia (CLL), the commonest form of leukemia in Western countries, was assessed. Data were collected by means of a face-to-face standardized questionnaire with several items. Mean age was 69 years; 258 patients (58%) were male and 184 (42%) female. Seventy-three patients (16.5%) were found to be CAM users. The most common CAM therapies were green tea, aloe formulations and high dose vitamins. Predictors of CAM use were female gender, younger age, higher education level, internet availability and newspaper reading. The reasons for CAM popularity among these patients are complex. Given the number of patients combining therapy with CAM and its possible drug interactions, doctor interest as well as patient education about CAM should be improved.

  16. Regulatory T-Cells in Chronic Lymphocytic Leukemia and Autoimmune Diseases

    PubMed Central

    D’Arena, Giovanni; Rossi, Giovanni; Vannata, Barbara; Deaglio, Silvia; Mansueto, Giovanna; D’Auria, Fiorella; Statuto, Teodora; Simeon, Vittorio; De Martino, Laura; Marandino, Aurelio; Del Poeta8, Giovanni; De Feo, Vincenzo; Musto, Pellegrino

    2012-01-01

    Regulatory T-cells (Tregs) constitute a small subset of cells that are actively involved in maintaining self-tolerance, in immune homeostasis and in antitumor immunity. They are thought to play a significant role in the progression of cancer and are generally increased in patient with chronic lymphocytic leukemia (CLL). Their number correlates with more aggressive disease status and is predictive of the time to treatment, as well. Moreover, it is now clear that dysregulation in Tregs cell frequency and/or function may result in a plethora of autoimmune diseases, including multiple sclerosis, type 1 diabetes mellitus, myasthenia gravis, systemic lupus erythematosus, autoimmune lymphoproliferative disorders, rheumatoid arthritis, and psoriasis. Efforts are made aiming to develop approaches to deplete Tregs or inhibit their function in cancer and autoimmune disorders, as well. PMID:22973497

  17. Anti-CD20 monoclonal antibodies in chronic lymphocytic leukemia: from uncertainties to promises.

    PubMed

    Bagacean, Cristina; Zdrenghea, Mihnea; Tempescul, Adrian; Cristea, Victor; Renaudineau, Yves

    2016-05-01

    Over the last two decades, anti-CD20 monoclonal antibody (mAb) therapy has improved patient outcome in B-cell malignancies, and confirmed CD20 as an important target in chronic lymphocytic leukemia (CLL). Until recently, the gold standard was based on the utilization of rituximab combined with chemotherapy (fludarabine and cyclophosphamide), but patients often relapse. Next, with our better understanding of mAb engineering, anti-CD20 mAb therapy has evolved with the development of new mAb permitting significant clinical responses by improving pharmacokinetics, safety, activity and immunogenicity. Last but not least, the development of key tumoral tyrosine kinase inhibitors and their association with anti-CD20 mAb is a work in progress with promising results. PMID:27140410

  18. Genetic modification of primary chronic lymphocytic leukemia cells with a lentivirus expressing CD38

    PubMed Central

    Pearce, Laurence; Morgan, Liam; Lin, Thet Thet; Hewamana, Saman; Matthews, R. James; Deaglio, Silvia; Rowntree, Clare; Fegan, Christopher; Pepper, Christopher; Brennan, Paul

    2010-01-01

    Studies of the role of individual genes in chronic lymphocytic leukemia (CLL) have been hampered by the inability to consistently transfect primary tumor cells. Here, we describe a highly efficient method of genetically modifying primary CLL cells using a VSVG pseudotyped lentiviral vector. We transduced CD38 negative CLL cells with a lentiviral vector encoding CD38 which caused increased surface CD38 expression in all the samples tested (n=17) with no evidence of plasmacytoid differentiation. The mean percentage of positive cells expressing CD38 was 87%±8.5% and the mean cell viability 74%±17%. This high level of transduction of all the CLL cell samples tested demonstrates the utility of this technique which should prove applicable for the introduction and analysis of other genes in these non-dividing cells. PMID:20207849

  19. Progress in BCL2 inhibition for patients with chronic lymphocytic leukemia.

    PubMed

    Tam, Constantine S; Seymour, John F; Roberts, Andrew W

    2016-04-01

    The prosurvival protein BCL2 is uniformly expressed in chronic lymphocytic leukemia (CLL), and enables leukemia cell survival in the face of cytotoxic treatment and increasing genomic, metabolic, and oxidative stresses. The therapeutic potential of BCL2 inhibition was first observed in the clinic following BCL2 antisense therapy. Subsequently, a number of small molecule inhibitors were developed to mimic the function of the pro-apoptotic BH3-only proteins (BH3-mimetics). These molecules are now in late-phase clinical trials and demonstrate potent activity, including the occurrence of acute tumor lysis syndrome in subjects with multiply relapsed, chemorefractory CLL. In this review, we discuss the history and summarize current knowledge regarding BCL2 inhibition as therapy of CLL. PMID:27040706

  20. Ibrutinib: a novel Bruton's tyrosine kinase inhibitor with outstanding responses in patients with chronic lymphocytic leukemia.

    PubMed

    Barrientos, Jacqueline; Rai, Kanti

    2013-08-01

    New treatment options are urgently needed for patients with relapsed chronic lymphocytic leukemia (CLL) who fail to respond to currently available therapies or cannot achieve a sustained response. Moreover, targeted agents with less myelotoxicity are necessary to treat patients with multiple comorbidities who would otherwise be unable to tolerate standard regimens. Ibrutinib, a Bruton's tyrosine kinase inhibitor, has shown highly encouraging results in phase I/II trials in patients with treatment-naive, relapsed and refractory CLL even in the presence of high risk disease or poor prognostic markers. In phase I/II trials, ibrutinib 420 mg or 840 mg - given continuously as single agent or at a dose of 420 mg daily in combination with a monoclonal antibody or chemoimmunotherapy - has been associated with high response rates and durable clinical remissions. Phase II and III trials are currently under way for treatment-naive patients, relapsed/refractory patients, and for those patients harboring a 17p deletion.

  1. Preclinical modeling of novel therapeutics in chronic lymphocytic leukemia: the tools of the trade.

    PubMed

    Herman, Sarah E M; Wiestner, Adrian

    2016-04-01

    In the last decade our understanding of chronic lymphocytic leukemia (CLL) biology and pathogenesis has increased substantially. These insights have led to the development of several new agents with novel mechanisms of action prompting a change in therapeutic approaches from chemotherapy-based treatments to targeted therapies. Multiple preclinical models for drug development in CLL are available; however, with the advent of these targeted agents, it is becoming clear that not all models and surrogate readouts of efficacy are appropriate for all drugs. In this review we discuss in vitro and in vivo preclinical models, with a particular focus on the benefits and possible pitfalls of different model systems in the evaluation of novel therapeutics for the treatment of CLL. PMID:27040700

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

    PubMed

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

    2006-02-01

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

  3. 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.

  4. 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.

  5. 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. PMID:27489195

  6. Genetic characterization of the paraimmunoblastic variant of small lymphocytic lymphoma/chronic lymphocytic leukemia: A case report and review of the literature.

    PubMed

    Espinet, Blanca; Larriba, Itziar; Salido, Marta; Florensa, Lourdes; Woessner, Soledad; Sans-Sabrafen, Jordi; Barranco, Carles; Serrano, Sergi; Solé, Francesc

    2002-11-01

    Paraimmunoblastic variant of small lymphocytic lymphoma/chronic lymphocytic leukemia (SLL/CLL) is characterized by a diffuse proliferation of cells, called paraimmunoblasts, normally located on the pseudoproliferation centers. Patients usually present with multiple lymphadenopathies and a rapid and aggressive progression of the disease. We report a case with paraimmunoblastic variant of SLL/CLL genetically well-characterized by conventional cytogenetics, comparative genomic hybridization (CGH), IgH/BCL-1, IgH/BCL-2, and p53 fluorescent in situ hybridization (FISH) probes and polymerase chain reaction (PCR) for detection of IgH/BCL-2 translocation. A complex karyotype was found, with p53 deletion confirmed by CGH and FISH; however, no translocations involving either BCL-2 or BCL-1 and the immunoglobulin heavy chain gene were identified. A literature review shows only 20 previously reported cases, 6 of which involve genetic studies. PMID:12454822

  7. The prognostic impact of minimal residual disease in patients with chronic lymphocytic leukemia requiring first-line therapy.

    PubMed

    Santacruz, Rodrigo; Villamor, Neus; Aymerich, Marta; Martínez-Trillos, Alejandra; López, Cristina; Navarro, Alba; Rozman, María; Beà, Sílvia; Royo, Cristina; Cazorla, Maite; Colomer, Dolors; Giné, Eva; Pinyol, Magda; Puente, Xose S; López-Otín, Carlos; Campo, Elías; López-Guillermo, Armando; Delgado, Julio

    2014-05-01

    A proportion of patients with chronic lymphocytic leukemia achieve a minimal residual disease negative status after therapy. We retrospectively evaluated the impact of minimal residual disease on the outcome of 255 consecutive patients receiving any front-line therapy in the context of a detailed prognostic evaluation, including assessment of IGHV, TP53, NOTCH1 and SF3B1 mutations. The median follow-up was 73 months (range, 2-202) from disease evaluation. The median treatment-free survival durations for patients achieving a complete response without or with minimal residual disease, a partial response and no response were 76, 40, 11 and 11 months, respectively (P<0.001). Multivariate analysis revealed that three variables had a significant impact on treatment-free survival: minimal residual disease (P<0.001), IGHV status (P<0.001) and β2-microglobulin levels (P=0.012). With regards to overall survival, factors predictive of an unfavorable outcome were minimal residual disease positivity (P=0.014), together with advanced age (P<0.001), unmutated IGHV status (P=0.001), TP53 mutations (P<0.001) and elevated levels of β2-microglobulin (P=0.003). In conclusion, for patients requiring front-line therapy, achievement of minimal residual disease negativity is associated with significantly prolonged treatment-free and overall survival irrespective of other prognostic markers or treatment administered.

  8. Low expression of CD200 predicts shorter time-to-treatment in chronic lymphocytic leukemia.

    PubMed

    Miao, Yi; Fan, Lei; Wu, Yu-Jie; Xia, Yi; Qiao, Chun; Wang, Yan; Wang, Li; Hong, Min; Zhu, Hua-Yuan; Xu, Wei; Li, Jian-Yong

    2016-03-22

    CD200, formerly known as OX-2, is a type I glycoprotein that is expressed on a variety of cell types. CD200 has been shown to be overexpressed in chronic lymphocytic leukemia (CLL). Although previous studies have confirmed the diagnostic value of CD200 in differentiating CLL from to other B-cell chronic lymphoproliferative disorders especially mantle cell lymphoma, whether CD200 has prognostic significance in CLL remains to be determined. We evaluated the mean fluorescence intensity (MFI) of CD200 in 307 consecutive, untreated patients with CLL in our center using flow cytometry. Using a CD200 MFI cutoff of 189.5, these cases could be divided into two groups. Patients with lower CD200 MFI (< 189.5) had a significantly shorter time-to-treatment (TTT) than those with higher CD200 MFI (≥ 189.5) (median TTT: 2 months vs 28 months, p = 0.0008). However, the effect of CD200 MFI on overall survival was not significant (CD200 MFI < 189.5: undefined vs CD200 MFI ≥ 189.5: undefined, P = 0.2379). In subgroup analysis, CD200 MFI retained its prognostic value in patients with favourable characteristics such as Binet stage A disease, mutated IGHV status, normal TP53 or negative CD38 expression. In conclusion, our study identified CD200 MFI as a potential prognostic factor in CLL. PMID:26910908

  9. The monocytic population in chronic lymphocytic leukemia shows altered composition and deregulation of genes involved in phagocytosis and inflammation

    PubMed Central

    Maffei, Rossana; Bulgarelli, Jenny; Fiorcari, Stefania; Bertoncelli, Linda; Martinelli, Silvia; Guarnotta, Carla; Castelli, Ilaria; Deaglio, Silvia; Debbia, Giulia; De Biasi, Sara; Bonacorsi, Goretta; Zucchini, Patrizia; Narni, Franco; Tripodo, Claudio; Luppi, Mario; Cossarizza, Andrea; Marasca, Roberto

    2013-01-01

    Macrophages reside in tissues infiltrated by chronic lymphocytic leukemia B cells and the extent of infiltration is associated with adverse prognostic factors. We studied blood monocyte population by flow cytometry and whole-genome microarrays. A mixed lymphocyte reaction was performed to evaluate proliferation of T cells in contact with monocytes from patients and normal donors. Migration and gene modulation in normal monocytes cultured with CLL cells were also evaluated. The absolute number of monocytes increased in chronic lymphocytic leukemia patients compared to the number in normal controls (792±86 cells/μL versus 485±46 cells/μL, P=0.003). Higher numbers of non-classical CD14+CD16++ and Tie-2-expressing monocytes were also detected in patients. Furthermore, we performed a gene expression analysis of monocytes in chronic lymphocytic leukemia patients, showing up-regulation of RAP1GAP and down-regulation of tubulins and CDC42EP3, which would be expected to result in impairment of phagocytosis. We also detected gene alterations such as down-regulation of PTGR2, a reductase able to inactivate prostaglandin E2, indicating immunosuppressive activity. Accordingly, the proliferation of T cells in contact with monocytes from patients was inhibited compared to that of cells in contact with monocytes from normal controls. Finally, normal monocytes in vitro increased migration and up-regulated CD16, RAP1GAP, IL-10, IL-8, MMP9 and down-regulated PTGR2 in response to leukemic cells or conditioned media. In conclusion, altered composition and deregulation of genes involved in phagocytosis and inflammation were found in blood monocytes obtained from chronic lymphocytic leukemia patients, suggesting that leukemia-mediated “education” of immune elements may also include the establishment of a skewed phenotype in the monocyte/macrophage population. PMID:23349302

  10. Novel Biomarker Proteins in Chronic Lymphocytic Leukemia: Impact on Diagnosis, Prognosis and Treatment

    PubMed Central

    Admoni-Elisha, Lee; Nakdimon, Itay; Shteinfer, Anna; Prezma, Tal; Arif, Tasleem; Arbel, Nir; Melkov, Anna; Zelichov, Ori; Levi, Itai; Shoshan-Barmatz, Varda

    2016-01-01

    In many cancers, cells undergo re-programming of metabolism, cell survival and anti-apoptotic defense strategies, with the proteins mediating this reprogramming representing potential biomarkers. Here, we searched for novel biomarker proteins in chronic lymphocytic leukemia (CLL) that can impact diagnosis, treatment and prognosis by comparing the protein expression profiles of peripheral blood mononuclear cells from CLL patients and healthy donors using specific antibodies, mass spectrometry and binary logistic regression analyses and other bioinformatics tools. Mass spectrometry (LC-HR-MS/MS) analysis identified 1,360 proteins whose expression levels were modified in CLL-derived lymphocytes. Some of these proteins were previously connected to different cancer types, including CLL, while four other highly expressed proteins were not previously reported to be associated with cancer, and here, for the first time, DDX46 and AK3 are linked to CLL. Down-regulation expression of two of these proteins resulted in cell growth inhibition. High DDX46 expression levels were associated with shorter survival of CLL patients and thus can serve as a prognosis marker. The proteins with modified expression include proteins involved in RNA splicing and translation and particularly mitochondrial proteins involved in apoptosis and metabolism. Thus, we focused on several metabolism- and apoptosis-modulating proteins, particularly on the voltage-dependent anion channel 1 (VDAC1), regulating both metabolism and apoptosis. Expression levels of Bcl-2, VDAC1, MAVS, AIF and SMAC/Diablo were markedly increased in CLL-derived lymphocytes. VDAC1 levels were highly correlated with the amount of CLL-cancerous CD19+/CD5+ cells and with the levels of all other apoptosis-modulating proteins tested. Binary logistic regression analysis demonstrated the ability to predict probability of disease with over 90% accuracy. Finally, based on the changes in the levels of several proteins in CLL patients, as

  11. Elevated neutrophil to lymphocyte ratio predicts mortality in medical inpatients with multiple chronic conditions

    PubMed Central

    Isaac, Vivian; Wu, Chia-Yi; Huang, Chun-Ta; Baune, Bernhard T.; Tseng, Chia-Lin; McLachlan, Craig S.

    2016-01-01

    Abstract Neutrophil to lymphocyte ratio (NLR) is an easy measurable laboratory marker used to evaluate systemic inflammation. Elevated NLR is associated with poor survival and increased morbidity in cancer and cardiovascular disease. However, the usefulness of NLR to predict morbidity and mortality in a hospital setting for patients with multiple chronic conditions has not been previously examined. In this study, we investigate the association between NLR and mortality in multimorbid medical inpatients. Two hundred thirty medical in-patients with chronic conditions were selected from a single academic medical center in Taiwan. Retrospective NLRs were calculated from routine full blood counts previously obtained during the initial hospital admission and at the time of discharge. Self-rated health (using a single-item question), medical disorders, depressive symptoms, and medical service utilization over a 1-year period were included in the analyses. Mortality outcomes were ascertained by reviewing electronic medical records and follow-up. The mortality rate at 2-year follow-up was 23%. Depression (odds ratio [OR] 1.9 [95% CI 1.0–3.7]), poor self-rated health (OR 2.1 [95% CI 1.1–3.9]), being hospitalized 2 or more times in the previous year (OR 2.3 [95% CI 1.2–4.6]), metastatic cancer (OR 4.7 [95% CI 2.3–9.7]), and chronic liver disease (OR 4.3 [95% CI 1.5–12.1]) were associated with 2-year mortality. The median (interquartile range) NLR at admission and discharge were 4.47 (2.4–8.7) and 3.65 (2.1–6.5), respectively. Two-year mortality rates were higher in patients with an elevated NLR at admission (NLR <3 = 15.5%, NLR >3 = 27.6%) and discharge (NLR < 3 = 14.7%, NLR >3 = 29.1%). Multivariate logistic regression demonstrated that an elevated NLR >3.0 at admission (OR 2.3 [95% CI 1.0–5.2]) and discharge (OR 2.3 [95% CI 1.1–5.0]) were associated with mortality independent of baseline age, sex, education, metastatic cancer, liver disease

  12. Elevated neutrophil to lymphocyte ratio predicts mortality in medical inpatients with multiple chronic conditions.

    PubMed

    Isaac, Vivian; Wu, Chia-Yi; Huang, Chun-Ta; Baune, Bernhard T; Tseng, Chia-Lin; McLachlan, Craig S

    2016-06-01

    Neutrophil to lymphocyte ratio (NLR) is an easy measurable laboratory marker used to evaluate systemic inflammation. Elevated NLR is associated with poor survival and increased morbidity in cancer and cardiovascular disease. However, the usefulness of NLR to predict morbidity and mortality in a hospital setting for patients with multiple chronic conditions has not been previously examined. In this study, we investigate the association between NLR and mortality in multimorbid medical inpatients. Two hundred thirty medical in-patients with chronic conditions were selected from a single academic medical center in Taiwan. Retrospective NLRs were calculated from routine full blood counts previously obtained during the initial hospital admission and at the time of discharge. Self-rated health (using a single-item question), medical disorders, depressive symptoms, and medical service utilization over a 1-year period were included in the analyses. Mortality outcomes were ascertained by reviewing electronic medical records and follow-up. The mortality rate at 2-year follow-up was 23%. Depression (odds ratio [OR] 1.9 [95% CI 1.0-3.7]), poor self-rated health (OR 2.1 [95% CI 1.1-3.9]), being hospitalized 2 or more times in the previous year (OR 2.3 [95% CI 1.2-4.6]), metastatic cancer (OR 4.7 [95% CI 2.3-9.7]), and chronic liver disease (OR 4.3 [95% CI 1.5-12.1]) were associated with 2-year mortality. The median (interquartile range) NLR at admission and discharge were 4.47 (2.4-8.7) and 3.65 (2.1-6.5), respectively. Two-year mortality rates were higher in patients with an elevated NLR at admission (NLR <3 = 15.5%, NLR >3 = 27.6%) and discharge (NLR < 3 = 14.7%, NLR >3 = 29.1%). Multivariate logistic regression demonstrated that an elevated NLR >3.0 at admission (OR 2.3 [95% CI 1.0-5.2]) and discharge (OR 2.3 [95% CI 1.1-5.0]) were associated with mortality independent of baseline age, sex, education, metastatic cancer, liver disease, depression, and previous

  13. Excess mortality after treatment with fludarabine and cyclophosphamide in combination with alemtuzumab in previously untreated patients with chronic lymphocytic leukemia in a randomized phase 3 trial.

    PubMed

    Lepretre, Stephane; Aurran, Therese; Mahé, Beatrice; Cazin, Bruno; Tournilhac, Olivier; Maisonneuve, Herve; Casasnovas, Olivier; Delmer, Alain; Leblond, Veronique; Royer, Bruno; Corront, Bernadette; Chevret, Sylvie; Delépine, Roselyne; Vaudaux, Sandrine; Van Den Neste, Eric; Béné, Marie Christine; Letestu, Remi; Cymbalista, Florence; Feugier, Pierre

    2012-05-31

    A French and Belgian multicenter phase 3 trial was conducted in medically fit patients with untreated chronic lymphocytic leukemia. Of 178 patients enrolled in the study, 165 were randomly assigned to receive 6 courses of oral fludarabine and cyclophosphamide (FC) in combination with rituximab (FCR; 375 mg/m(2) in cycle one, 500 mg/m(2) in all subsequent cycles) or alemtuzumab (FCCam; 30 mg subcutaneously injected on cycle days 1-3); each cycle was 28 days. Recruitment was halted prematurely because of excess toxicity; 8 patients died in the FCCam group, 3 from lymphoma and 5 from in-fection. Overall response rates were 91% with FCR and 90% with FCCam (P = .79). Complete remission rates were 33.75% with FCR and 19.2% with FCCam (P = .04). Three-year progression-free survival was 82.6% with FCR and 72.5% with FCCam (P = .21). Three-year overall survival was similar between the 2 arms at 90.1% in the FCR arm and 86.4% in the FCCam arm (P = .27). These results indicate that the FCCam regimen for the treatment of advanced chronic lymphocytic leukemia was not more effective than the FCR regimen and was associated with an unfavorable safety profile, representing a significant limitation of its use. This study is registered with www.clinicaltrials.gov as number NCT00564512. PMID:22337714

  14. A targeted therapy for protein and lipid kinases in chronic lymphocytic leukemia.

    PubMed

    Robak, P; Robak, T

    2012-01-01

    Protein kinases (PKs) and lipid kinases (LKs) are good choices for targets of signal transduction therapy as these enzymes are involved in signaling pathways, and are often related to the pathogenesis of lymphoid malignancies. The attractiveness of PKs and LKs as drug able targets is enhanced by the fact that they are enzymes whose biological activity can be turned off by drugs that block their catalytic site. In the last few years small molecular kinase inhibitors (KIs) have been synthesized and become available for preclinical studies and clinical trials. The first KI, introduced into clinical practice in 1998, was imatinib mesylate, which became the first choice drug in chronic myeloid leukemia. More recently, several KIs have been developed to target the proximal B-cell receptor (BCR) signaling pathway including spleen tyrosine kinase inhibitor (Fostamatinib) and Bruton's tyrosine kinase inhibitors (Ibrutinib, AVL-263). These agents are currently evaluated in early clinical trials in chronic lymphocytic leukemia (CLL) and other diseases. Cyclin-dependent kinase (Cdk) inhibitors, flavopiridol (alvocidib), BMS-387032 (SNS-032), sunitinib and sorafenib are currently under evaluation in clinical trials for relapsed/refractory CLL. Multi-tyrosine kinase inhibitors including vandetanib (ZD6474) bosutinib (SKI-606), TKI258 (CHIR-258), pazopanib (GW786034) and axitinib (AG013736) have been also developed for the treatment of lymphoid malignancies. Phosphatidylinositol 3-kinases (PI3K ) are a family of lipid kinases that mediate signals from cell surface receptors. CAL-101 (GS-1101) is an oral PI3Kδ-specific inhibitor which has shown preclinical and clinical activity against CLL. This article summarizes recent achievements in the mechanism of action, pharmacological properties and clinical activity and toxicity of PK and LK inhibitors in CLL.

  15. Chronic lymphocytic leukaemia with 17p deletion: a retrospective analysis of prognostic factors and therapy results.

    PubMed

    Delgado, Julio; Espinet, Blanca; Oliveira, Ana C; Abrisqueta, Pau; de la Serna, Javier; Collado, Rosa; Loscertales, Javier; Lopez, Montserrat; Hernandez-Rivas, Jose A; Ferra, Christelle; Ramirez, Angel; Roncero, Josep M; Lopez, Cristina; Aventin, Anna; Puiggros, Anna; Abella, Eugenia; Carbonell, Felix; Costa, Dolors; Carrio, Anna; Gonzalez, Marcos

    2012-04-01

    Patients with chronic lymphocytic leukaemia (CLL) whose tumour cells harbour a 17p deletion (17p-) are universally considered to have a poor prognosis. The deletion can be detected at diagnosis or during the evolution of the disease, particularly in patients who have received chemotherapy. We sought to evaluate the natural history of patients with 17p- CLL, identify predictive factors within this prognostic subgroup, and evaluate the results of different therapeutic approaches. Data from 294 patients with 17p- CLL followed up at 20 different institutions was retrospectively collected and analysed. Median age was 68 (range 27-98) years at the time of fluorescence in situ hybridization analysis. After 17p- documentation, 52% received treatment, achieving an overall response rate of 50%. Median overall survival was 41 months, and was significantly shorter in patients with elevated beta(2)-microglobulin concentration (P < 0·001), B symptoms (P = 0·016), higher percentage of cells with deletion (P < 0·001), and acquired deletions (P = 0·012). These findings suggest that patients with 17p- CLL have a variable prognosis that can be refined using simple clinical and laboratory features, including 17p- clone size, beta2-microglobulin concentration, presence of B symptoms and type of deletion (de novo versus acquired).

  16. AID induces intraclonal diversity and genomic damage in CD86(+) chronic lymphocytic leukemia cells.

    PubMed

    Huemer, Michael; Rebhandl, Stefan; Zaborsky, Nadja; Gassner, Franz J; Hainzl, Stefan; Weiss, Lukas; Hebenstreit, Daniel; Greil, Richard; Geisberger, Roland

    2014-12-01

    The activation-induced cytidine deaminase (AID) mediates somatic hypermutation and class switch recombination of the Ig genes by directly deaminating cytosines to uracils. As AID causes a substantial amount of off-target mutations, its activity has been associated with lymphomagenesis and clonal evolution of B-cell malignancies. Although it has been shown that AID is expressed in B-cell chronic lymphocytic leukemia (CLL), a clear analysis of in vivo AID activity in this B-cell malignancy remained elusive. In this study performed on primary human CLL samples, we report that, despite the presence of a dominant VDJ heavy chain region, a substantial intraclonal diversity was observed at VDJ as well as at IgM switch regions (Sμ), showing ongoing AID activity in vivo during disease progression. This AID-mediated heterogeneity was higher in CLL subclones expressing CD86, which we identified as the proliferative CLL fraction. Finally, CD86 expression correlated with shortened time to first treatment and increased γ-H2AX focus formation. Our data demonstrate that AID is active in CLL in vivo and thus, AID likely contributes to clonal evolution of CLL.

  17. 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.

  18. The novel NF-κB inhibitor IMD-0354 induces apoptosis in chronic lymphocytic leukemia.

    PubMed

    Kanduri, M; Tobin, G; Aleskog, A; Nilsson, K; Rosenquist, R

    2011-03-01

    Nuclear factor-κB (NF-κB) is an important regulator of cell survival and has been shown to be constitutively active in chronic lymphocytic leukemia (CLL) cells. Recently, a novel NF-κB inhibitor, IMD-0354 (N-(3, 5-bis-trifluoromethyl-phenyl)-5-chloro-2-hydroxy-benzamide), was shown to specifically inhibit the phosphorylation of IκBα by IkB kinases, thus preventing NF-κB release. In this study, we investigated if IMD-0354 can inhibit NF-κB activation and induce apoptosis in CLL cells in vitro. The rate of increase in apoptosis, drug sensitivity and DNA-binding activity of NF-κB were studied using Annexin V stainings, the fluorometric microculture cytotoxicity assay and electrophoretic mobility shift assay, respectively. Finally, the impact of IMD-0354 treatment on the expression of a set of apoptosis-related genes was investigated. The results clearly show that IMD-0354 induced apoptosis (mean 26%, range 8-48%) in CLL cells, independent of immunoglobulin heavy variable (IGHV) gene mutational status, and showed a dose-dependent cytotoxic effect. IMD-0354 treatment also significantly lowered the DNA-binding activity of NF-κB in CLL cells. In addition, we identified differences in expression levels of pro- and antiapoptotic genes following IMD-0354 treatment. In summary, our novel findings show that IMD-0354 can induce apoptosis in CLL cells, and thus merits further investigation as an anticancer agent in vivo. PMID:22829125

  19. 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

  20. HIF-1α regulates the interaction of chronic lymphocytic leukemia cells with the tumor microenvironment

    PubMed Central

    Valsecchi, Roberta; Coltella, Nadia; Belloni, Daniela; Ponente, Manfredi; ten Hacken, Elisa; Scielzo, Cristina; Scarfò, Lydia; Bertilaccio, Maria Teresa Sabrina; Brambilla, Paola; Lenti, Elisa; Martinelli Boneschi, Filippo; Brendolan, Andrea; Ferrero, Elisabetta; Ferrarini, Marina; Ghia, Paolo; Tonon, Giovanni; Ponzoni, Maurilio; Caligaris-Cappio, Federico

    2016-01-01

    Hypoxia-inducible transcription factors (HIFs) regulate a wide array of adaptive responses to hypoxia and are often activated in solid tumors and hematologic malignancies due to intratumoral hypoxia and emerging new layers of regulation. We found that in chronic lymphocytic leukemia (CLL), HIF-1α is a novel regulator of the interaction of CLL cells with protective leukemia microenvironments and, in turn, is regulated by this interaction in a positive feedback loop that promotes leukemia survival and propagation. Through unbiased microarray analysis, we found that in CLL cells, HIF-1α regulates the expression of important chemokine receptors and cell adhesion molecules that control the interaction of leukemic cells with bone marrow and spleen microenvironments. Inactivation of HIF-1α impairs chemotaxis and cell adhesion to stroma, reduces bone marrow and spleen colonization in xenograft and allograft CLL mouse models, and prolongs survival in mice. Of interest, we found that in CLL cells, HIF-1α is transcriptionally regulated after coculture with stromal cells. Furthermore, HIF-1α messenger RNA levels vary significantly within CLL patients and correlate with the expression of HIF-1α target genes, including CXCR4, thus further emphasizing the relevance of HIF-1α expression to CLL pathogenesis. PMID:26825709

  1. Clustering of Expression Data in Chronic Lymphocytic Leukemia Reveals New Molecular Subdivisions

    PubMed Central

    Yepes, Sally; Torres, Maria Mercedes; Andrade, Rafael E.

    2015-01-01

    Although the identification of inherent structure in chronic lymphocytic leukemia (CLL) gene expression data using class discovery approaches has not been extensively explored, the natural clustering of patient samples can reveal molecular subdivisions that have biological and clinical implications. To explore this, we preprocessed raw gene expression data from two published studies, combined the data to increase the statistical power, and performed unsupervised clustering analysis. The clustering analysis was replicated in 4 independent cohorts. To assess the biological significance of the resultant clusters, we evaluated their prognostic value and identified cluster-specific markers. The clustering analysis revealed two robust and stable subgroups of CLL patients in the pooled dataset. The subgroups were confirmed by different methodological approaches (non-negative matrix factorization NMF clustering and hierarchical clustering) and validated in different cohorts. The subdivisions were related with differential clinical outcomes and markers associated with the microenvironment and the MAPK and BCR signaling pathways. It was also found that the cluster markers were independent of the immunoglobulin heavy chain variable (IGVH) genes mutational status. These findings suggest that the microenvironment can influence the clinical behavior of CLL, contributing to prognostic differences. The workflow followed here provides a new perspective on differences in prognosis and highlights new markers that should be explored in this context. PMID:26355846

  2. Modifying akt signaling in B-cell chronic lymphocytic leukemia cells.

    PubMed

    Hofbauer, Sebastian W; Piñón, Josefina D; Brachtl, Gabriele; Haginger, Lucia; Wang, Wei; Jöhrer, Karin; Tinhofer, Ingeborg; Hartmann, Tanja Nicole; Greil, Richard

    2010-09-15

    Emerging evidence suggests that the survival of B-cell chronic lymphocytic leukemia (CLL) cells is dependent on microenvironmental influences such as antigenic stimulation and support by stromal cells. Akt, also known as protein kinase B, is a central component in prosurvival signaling downstream of these events. We investigated the role of Akt and its modulation by the protooncogene T-cell leukemia 1a (Tcl1a) in the survival pathways of primary CLL samples and CLL-derived prolymphocytic cell lines MEC-1 and MEC-2. Akt activation was increased by the protective presence of human bone marrow stromal cells and B-cell receptor mimicking signals but antagonized by direct Akt blockade with the novel specific inhibitor AiX, with preferential apoptosis induction in CLL cells with an unmutated immunoglobulin status, which predicts poor clinical outcome. In addition, we found a direct interaction of Akt with Tcl1a in an endogenous coimmunoprecipitation assay. Confirming the critical role of Tcl1a in modulating Akt signaling, Akt activation was enhanced by overexpressing Tcl1a in CLL. In contrast, decreasing Tcl1a levels by small interfering RNA reduced Akt activation in the fludarabine-insensitive CLL cell line MEC-2 and sensitized the malignant cells to fludarabine treatment. In summary, our data reveal a significant role for the Akt-Tcl1a axis in CLL survival and propose a further evaluation of this interplay for targeting chemoresistance phenomena.

  3. Outcomes for patients with chronic lymphocytic leukemia and acute leukemia or myelodysplastic syndrome.

    PubMed

    Tambaro, F P; Garcia-Manero, G; O'Brien, S M; Faderl, S H; Ferrajoli, A; Burger, J A; Pierce, S; Wang, X; Do, K-A; Kantarjian, H M; Keating, M J; Wierda, W G

    2016-02-01

    Acute leukemia (AL) and myelodysplastic syndrome (MDS) are uncommon in chronic lymphocytic leukemia (CLL). We retrospectively identified 95 patients with CLL, also diagnosed with AL (n=38) or MDS (n=57), either concurrently (n=5) or subsequent (n=90) to CLL diagnosis and report their outcomes. Median number of CLL treatments prior to AL and MDS was 2 (0-9) and 1 (0-8), respectively; the most common regimen was purine analog combined with alkylating agent±CD20 monoclonal antibody. Twelve cases had no prior CLL treatment. Among 38 cases with AL, 33 had acute myelogenous leukemia (AML), 3 had acute lymphoid leukemia (ALL; 1 Philadelphia chromosome positive), 1 had biphenotypic and 1 had extramedullary (bladder) AML. Unfavorable AML karyotype was noted in 26, and intermediate risk in 7 patients. There was no association between survival from AL and number of prior CLL regimens or karyotype. Expression of CD7 on blasts was associated with shorter survival. Among MDS cases, all International Prognostic Scoring System (IPSS) were represented; karyotype was unfavorable in 36, intermediate in 6 and favorable in 12 patients; 10 experienced transformation to AML. Shorter survival from MDS correlated with higher risk IPSS, poor-risk karyotype and increased number of prior CLL treatments. Overall, outcomes for patients with CLL subsequently diagnosed with AL or MDS were very poor; AL/MDS occurred without prior CLL treatment. Effective therapies for these patients are desperately needed.

  4. Not all IGHV3-21 chronic lymphocytic leukemias are equal: prognostic considerations.

    PubMed

    Baliakas, Panagiotis; Agathangelidis, Andreas; Hadzidimitriou, Anastasia; Sutton, Lesley-Ann; Minga, Eva; Tsanousa, Athina; Scarfò, Lydia; Davis, Zadie; Yan, Xiao-Jie; Shanafelt, Tait; Plevova, Karla; Sandberg, Yorick; Vojdeman, Fie Juhl; Boudjogra, Myriam; Tzenou, Tatiana; Chatzouli, Maria; Chu, Charles C; Veronese, Silvio; Gardiner, Anne; Mansouri, Larry; Smedby, Karin E; Pedersen, Lone Bredo; Moreno, Denis; Van Lom, Kirsten; Giudicelli, Véronique; Francova, Hana Skuhrova; Nguyen-Khac, Florence; Panagiotidis, Panagiotis; Juliusson, Gunnar; Angelis, Lefteris; Anagnostopoulos, Achilles; Lefranc, Marie-Paule; Facco, Monica; Trentin, Livio; Catherwood, Mark; Montillo, Marco; Geisler, Christian H; Langerak, Anton W; Pospisilova, Sarka; Chiorazzi, Nicholas; Oscier, David; Jelinek, Diane F; Darzentas, Nikos; Belessi, Chrysoula; Davi, Frederic; Ghia, Paolo; Rosenquist, Richard; Stamatopoulos, Kostas

    2015-01-29

    An unresolved issue in chronic lymphocytic leukemia (CLL) is whether IGHV3-21 gene usage, in general, or the expression of stereotyped B-cell receptor immunoglobulin defining subset #2 (IGHV3-21/IGLV3-21), in particular, determines outcome for IGHV3-21-utilizing cases. We reappraised this issue in 8593 CLL patients of whom 437 (5%) used the IGHV3-21 gene with 254/437 (58%) classified as subset #2. Within subset #2, immunoglobulin heavy variable (IGHV)-mutated cases predominated, whereas non-subset #2/IGHV3-21 was enriched for IGHV-unmutated cases (P = .002). Subset #2 exhibited significantly shorter time-to-first-treatment (TTFT) compared with non-subset #2/IGHV3-21 (22 vs 60 months, P = .001). No such difference was observed between non-subset #2/IGHV3-21 vs the remaining CLL with similar IGHV mutational status. In conclusion, IGHV3-21 CLL should not be axiomatically considered a homogeneous entity with adverse prognosis, given that only subset #2 emerges as uniformly aggressive, contrasting non-subset #2/IGVH3-21 patients whose prognosis depends on IGHV mutational status as the remaining CLL.

  5. Pharmacological inhibitors of NF-kappaB accelerate apoptosis in chronic lymphocytic leukaemia cells.

    PubMed

    Pickering, B M; de Mel, S; Lee, M; Howell, M; Habens, F; Dallman, C L; Neville, L A; Potter, K N; Mann, J; Mann, D A; Johnson, P W M; Stevenson, F K; Packham, G

    2007-02-22

    Nuclear factor-kappaB (NF-kappaB) is a transcription factor that plays a critical role in the inappropriate survival of various types of malignant cells. Chronic lymphocytic leukaemia (CLL) is the most common B-cell malignancy in the Western world. Although overexpression and regulation of NF-kappaB has been described in CLL, its function remains unclear. Exposure of CLL cells to BAY117082 or Kamebakaurin, potent pharmacological inhibitors of the NF-kappaB pathway, accelerated apoptosis in approximately 70% of cases. Sensitivity to NF-kappaB pathway inhibitors was not related to the prognostic markers VH status, CD38 or Zap70 expression, or to the levels of nuclear NF-kappaB. Normal peripheral B cells were resistant to the apoptosis-inducing effects of these compounds. Cell death induced by the inhibitors was associated with activation of caspase-9 and -3, and loss of mitochondrial membrane polarization, but did not involve changes in the expression of Bcl-2 or Mcl-1. Inhibitors caused an increase in c-jun NH2-terminal kinase activity in CLL, but this did not appear to be important for apoptosis. Microarray analysis identified some potential novel NF-kappaB target genes, including interleukin-16- and the Bcl-2- related survival protein Bcl-w. These results demonstrate that a substantial proportion of CLL are dependent on NF-kappaB for enhanced survival and suggest that inhibition of NF-kappaB may have therapeutic potential.

  6. No evidence of transmission of chronic lymphocytic leukemia through blood transfusion.

    PubMed

    Hjalgrim, Henrik; Rostgaard, Klaus; Vasan, Senthil K; Ullum, Henrik; Erikstrup, Christian; Pedersen, Ole B V; Nielsen, Kaspar R; Titlestad, Kjell-Einar; Melbye, Mads; Nyrén, Olof; Edgren, Gustaf

    2015-10-22

    Monoclonal B-cell lymphocytosis (MBL) is a precursor of chronic lymphocytic leukemia (CLL). Observations of MBL in blood donors raise concern that transmitted MBL may cause recipient CLL. Using a database with health information on 1.5 million donors and 2.1 million recipients, we compared CLL occurrence among 7413 recipients of blood from 796 donors diagnosed with CLL after donation cessation, and among 80, 431 recipients of blood from 7477 matched CLL-free donors. During follow-up, 12 and 107 cases of CLL occurred among the exposed and unexposed recipients, respectively, yielding a relative risk of 0.94 (95% confidence interval, 0.52-1.71). Analyses using the entire database showed no evidence of CLL clustering among recipients of blood from individual donors. In conclusion, when donor MBL was approximated by subsequent donor CLL diagnosis, data from 2 countries' entire computerized transfusion experience over more than 30 years indicate that MBL/CLL transmission does not contribute importantly to recipient CLL risk.

  7. Oncolytic reovirus enhances rituximab-mediated antibody-dependent cellular cytotoxicity against chronic lymphocytic leukaemia.

    PubMed

    Parrish, C; Scott, G B; Migneco, G; Scott, K J; Steele, L P; Ilett, E; West, E J; Hall, K; Selby, P J; Buchanan, D; Varghese, A; Cragg, M S; Coffey, M; Hillmen, P; Melcher, A A; Errington-Mais, F

    2015-09-01

    The naturally occurring oncolytic virus (OV), reovirus, replicates in cancer cells causing direct cytotoxicity, and can activate innate and adaptive immune responses to facilitate tumour clearance. Reovirus is safe, well tolerated and currently in clinical testing for the treatment of multiple myeloma, in combination with dexamethasone/carfilzomib. Activation of natural killer (NK) cells has been observed after systemic delivery of reovirus to cancer patients; however, the ability of OV to potentiate NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC) is unexplored. This study elucidates the potential of oncolytic reovirus for the treatment of chronic lymphocytic leukaemia (CLL), both as a direct cytotoxic agent and as an immunomodulator. We demonstrate that reovirus: (i) is directly cytotoxic against CLL, which requires replication-competent virus; (ii) phenotypically and functionally activates patient NK cells via a monocyte-derived interferon-α (IFNα)-dependent mechanism; and (iii) enhances ADCC-mediated killing of CLL in combination with anti-CD20 antibodies. Our data provide strong preclinical evidence to support the use of reovirus in combination with anti-CD20 immunotherapy for the treatment of CLL.

  8. Clonal evolution in patients with chronic lymphocytic leukaemia developing resistance to BTK inhibition

    PubMed Central

    Burger, Jan A.; Landau, Dan A.; Taylor-Weiner, Amaro; Bozic, Ivana; Zhang, Huidan; Sarosiek, Kristopher; Wang, Lili; Stewart, Chip; Fan, Jean; Hoellenriegel, Julia; Sivina, Mariela; Dubuc, Adrian M.; Fraser, Cameron; Han, Yulong; Li, Shuqiang; Livak, Kenneth J.; Zou, Lihua; Wan, Youzhong; Konoplev, Sergej; Sougnez, Carrie; Brown, Jennifer R.; Abruzzo, Lynne V.; Carter, Scott L.; Keating, Michael J.; Davids, Matthew S.; Wierda, William G.; Cibulskis, Kristian; Zenz, Thorsten; Werner, Lillian; Cin, Paola Dal; Kharchencko, Peter; Neuberg, Donna; Kantarjian, Hagop; Lander, Eric; Gabriel, Stacey; O'Brien, Susan; Letai, Anthony; Weitz, David A.; Nowak, Martin A.; Getz, Gad; Wu, Catherine J.

    2016-01-01

    Resistance to the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib has been attributed solely to mutations in BTK and related pathway molecules. Using whole-exome and deep-targeted sequencing, we dissect evolution of ibrutinib resistance in serial samples from five chronic lymphocytic leukaemia patients. In two patients, we detect BTK-C481S mutation or multiple PLCG2 mutations. The other three patients exhibit an expansion of clones harbouring del(8p) with additional driver mutations (EP300, MLL2 and EIF2A), with one patient developing trans-differentiation into CD19-negative histiocytic sarcoma. Using droplet-microfluidic technology and growth kinetic analyses, we demonstrate the presence of ibrutinib-resistant subclones and estimate subclone size before treatment initiation. Haploinsufficiency of TRAIL-R, a consequence of del(8p), results in TRAIL insensitivity, which may contribute to ibrutinib resistance. These findings demonstrate that the ibrutinib therapy favours selection and expansion of rare subclones already present before ibrutinib treatment, and provide insight into the heterogeneity of genetic changes associated with ibrutinib resistance. PMID:27199251

  9. Targeting Stereotyped B Cell Receptors from Chronic Lymphocytic Leukemia Patients with Synthetic Antigen Surrogates.

    PubMed

    Sarkar, Mohosin; Liu, Yun; Qi, Junpeng; Peng, Haiyong; Morimoto, Jumpei; Rader, Christoph; Chiorazzi, Nicholas; Kodadek, Thomas

    2016-04-01

    Chronic lymphocytic leukemia (CLL) is a disease in which a single B-cell clone proliferates relentlessly in peripheral lymphoid organs, bone marrow, and blood. DNA sequencing experiments have shown that about 30% of CLL patients have stereotyped antigen-specific B-cell receptors (BCRs) with a high level of sequence homology in the variable domains of the heavy and light chains. These include many of the most aggressive cases that haveIGHV-unmutated BCRs whose sequences have not diverged significantly from the germ line. This suggests a personalized therapy strategy in which a toxin or immune effector function is delivered selectively to the pathogenic B-cells but not to healthy B-cells. To execute this strategy, serum-stable, drug-like compounds able to target the antigen-binding sites of most or all patients in a stereotyped subset are required. We demonstrate here the feasibility of this approach with the discovery of selective, high affinity ligands for CLL BCRs of the aggressive, stereotyped subset 7P that cross-react with the BCRs of several CLL patients in subset 7p, but not with BCRs from patients outside this subset.

  10. Mitochondrial metabolism contributes to oxidative stress and reveals therapeutic targets in chronic lymphocytic leukemia.

    PubMed

    Jitschin, Regina; Hofmann, Andreas D; Bruns, Heiko; Giessl, Andreas; Bricks, Juliane; Berger, Jana; Saul, Domenica; Eckart, Michael J; Mackensen, Andreas; Mougiakakos, Dimitrios

    2014-04-24

    Alterations of cellular metabolism represent a hallmark of cancer. Numerous metabolic changes are required for malignant transformation, and they render malignant cells more prone to disturbances in the metabolic framework. Despite the high incidence of chronic lymphocytic leukemia (CLL), metabolism of CLL cells remains a relatively unexplored area. The examined untreated CLL patients displayed a metabolic condition known as oxidative stress, which was linked to alterations in their lymphoid compartment. Our studies identified mitochondrial metabolism as the key source for abundant reactive oxygen species (ROS). Unlike in other malignant cells, we found increased oxidative phosphorylation in CLL cells but not increased aerobic glycolysis. Furthermore, CLL cells adapted to intrinsic oxidative stress by upregulating the stress-responsive heme-oxygenase-1 (HO-1). Our data implicate that HO-1 was, beyond its function as an antioxidant, involved in promoting mitochondrial biogenesis. Thus ROS, adaptation to ROS, and mitochondrial biogenesis appear to form a self-amplifying feedback loop in CLL cells. Taking advantage of the altered metabolic profile, we were able to selectively target CLL cells by PK11195. This benzodiazepine derivate blocks the mitochondrial F1F0-ATPase, leads to a surplus production of mitochondrial superoxide, and thereby induces cell death in CLL cells. Taken together, our findings depict how bioenergetics and redox characteristics could be therapeutically exploited in CLL.

  11. Trisomy 12 in chronic lymphocytic leukemia and hairy cell leukemia: a cytogenetic and interphase cytogenetic study.

    PubMed

    Cuneo, A; Bigoni, R; Balboni, M; Carli, M G; Piva, N; Fagioli, F; Latorraca, A; Wlodarska, I; van den Berghe, H; Castoldi, G

    1994-09-01

    Fluorescent in situ hybridization (FISH) with a chromosome 12-specific pericentromeric probe was performed in 42 patients with B-cell chronic lymphocytic leukemia (CLL) and in 10 patients with hairy cell leukemia (HCL). In all cases, a normal karyotype in more than 10 metaphase cells was obtained by conventional chromosome study. FISH documented that 6/42 patients with CLL in fact had trisomy 12 in 15-49% interphase cells. Sequential FISH studies were performed in 2 cases, showing an increase of percentage of trisomic cells over a 2-month to 4-year period. Two out of 10 patients with HCL, one of whom had morphologic features consistent with a diagnosis of HCL variant, showed 5.5 and 10% interphase nuclei with three fluorescent signals, a finding suggestive of the presence of trisomy 12. Combined immunophenotyping and FISH staining in these patients with HCL documented that trisomic cells were CD11c-positive, CD13-negative, and CD2-negative. We conclude that FISH is a sensitive technique allowing for the detection of trisomy 12 in a fraction of cytogenetically normal patients affected with CLL and HCL. PMID:7858495

  12. Chronic Lymphocytic Leukaemia: Census of Patients Treated in Italian Haematology Units

    PubMed Central

    Salvi, Gianfranco; Innocenti, Idanna; Autore, Francesco; Laurenti, Luca

    2015-01-01

    This study was conducted by contacting the population of the Italian haematology units and collecting from 68% of them data concerning the number of patients with chronic lymphocytic leukaemia visited over the previous 12 months, with the aim of obtaining an overview of the treatment of this disease and comparing the results with the prevalence estimates found in literature. The projection obtained (about 17,000 patients visited in the previous 12 months) is probably overestimated because of double-counting of patients who may have been treated at two different facilities during the year, although it is also underestimated since the internal medicine units were not involved. The balance of these two opposite factors is not known. It is important to bear in mind the approximation with which the count was performed in facilities for which no official data were available. Albeit with these limits, the results obtained are in line with some existing prevalence data and make it possible to determine the portion of patients at different Binet stages and in the various age ranges, identifying the corresponding therapeutic treatments. Use of the CIRS scale to classify patients as FIT and UNFIT was seen to be still somewhat limited. PMID:26543525

  13. Differential expression and function of CD27 in chronic lymphocytic leukemia cells expressing ZAP-70.

    PubMed

    Lafarge, Sandrine T; Hou, Sen; Pauls, Samantha D; Johnston, James B; Gibson, Spencer B; Marshall, Aaron J

    2015-07-01

    Chronic lymphocytic leukemia is a malignancy driven by abberant B cell signaling and survival. Leukemic B cells accumulate in the peripheral blood and the lymphoid organs where contact with stromal cells and T cells provide critical survival signals. Clinical severity of CLL is associated with several prognostic markers including expression of the kinase ZAP-70. ZAP-70 expression enhances signaling via the B cell antigen receptor and is associated with increased cell adhesion and migration capacity. Here we report that ZAP-70-positive CLL patients display significantly higher expression of the TNF superfamily receptor and memory marker CD27 than do ZAP-70 negative patients. CD27 expression by CLL was acutely elevated upon BCR cross-linking, or upon ectopic expression of ZAP-70. CD27 expression correlated with functional capacity to adhere to stromal cells and antibody blockade of CD27 impaired CLL binding to stroma. These results provide the first evidence for differential expression of CD27 among CLL prognostic groups, suggest a role for ZAP-70 dependent signaling in CD27 induction and implicate CD27 in cell-cell interactions with the lymphoid tissue microenvironment.

  14. Overexpression of IL-9 induced by STAT6 activation promotes the pathogenesis of chronic lymphocytic leukemia

    PubMed Central

    Chen, Na; Lu, Kang; Li, Peipei; Lv, Xiao; Wang, Xin

    2014-01-01

    Chronic lymphocytic leukemia (CLL) is a common leukemia in adults, but its pathogenesis is still poorly understood. Recently, extensive evidence suggests that the malignant cells of CLL patients secrete a range of cytoprotective cytokines including interleukin-4 (IL-4). IL-4 induced the rapid phosphorylation(p) and activation of the signal transducer and activator of transcription (STAT)-6 transcription factor in CLL cells in vitro. Interleukin-9 (IL-9) is not expressed by Th2 and Th9 cells in the absence of STAT6 expression. To elucidate whether there was a function link between IL-9 and STAT6 in CLL, MEC-1 cells were analyzed using RT-PCR, and western blot. Interestingly, when added with recombinant human IL-4 (rIL-4) in culturing MEC-1 cells, expressions of p-STAT6 and IL-9 in MEC-1 cells increased at a time-dependent manner and their expressions could be inhibited by STAT6 inhibitor. Our data indicated that the upregulation of IL-9 induced by pSTAT6 may be involved in the pathogenesis of CLL. PMID:24966942

  15. Progressive multifocal leukoencephalopathy following oral fludarabine treatment of chronic lymphocytic leukemia.

    PubMed

    Cid, J; Revilla, M; Cervera, A; Cervantes, F; Muñoz, E; Ferrer, I; Montserrat, E

    2000-07-01

    Progressive multifocal leukoencephalopathy (PML) is a subacute demyelinating disorder of the central nervous system usually affecting immunocompromised individuals and is due to infection of the oligodendrocytes by the JC virus. A case of PML in a chronic lymphocytic leukemia (CLL) patient treated with fludarabine is reported, representing the second such instance in which the diagnosis of the neurological disorder was established by brain biopsy. A 61-year-old man with a 14-year history of B-cell type CLL, for which he had received chlorambucil therapy 10 years earlier, developed progressive paresis of both left extremities at 7 months of receiving low doses of oral fludarabine, when his CD4 count has decreased to 0.08 x 10(9)/l. Cranial magnetic resonance imaging revealed a subcortical focal lesion at the right precentral gyrus and a focal lesion at the right thalamus, and a stereotactic brain biopsy showed pathological findings consistent with PML, namely severe myelin breakdown, reactive astrocytosis, and abnormal, huge glial cells with large bizarre nuclei showing granular basophilic inclusions, whereas the presence of the JC virus was demonstrated by in situ hybridization. The present case, in addition to a few previously reported, calls attention to the possibility that severe neurological side effects can be associated with the immunosuppression provoked by the use of fludarabine in CLL patients. PMID:10965788

  16. Minimal residual disease surveillance in chronic lymphocytic leukemia by fluorescence-activated cell sorting.

    PubMed

    Ringelstein-Harlev, Shimrit; Fineman, Riva

    2014-10-01

    Achievement of complete response (CR) to therapy in chronic lymphocytic leukemia (CLL) has become a feasible goal, directly correlating with prolonged survival. It has been established that the classic definition of CR actually encompasses a variety of disease loads, and more sensitive multiparameter flow cytometry and polymerase chain reaction methods can detect the disease burden with a much higher sensitivity. Detection of malignant cells with a sensitivity of 1 tumor cell in 10,000 cells (10(-4)), using the abovementioned sophisticated techniques, is the current cutoff for minimal residual disease (MRD). Tumor burdens lower than 10(-4) are defined as MRD-negative. Several studies in CLL have determined the achievement of MRD negativity as an independent favorable prognostic factor, leading to prolonged disease-free and overall survival, regardless of the treatment protocol or the presence of other pre-existing prognostic indicators. Minimal residual disease evaluation using flow cytometry is a sensitive and applicable approach which is expected to become an integral part of future prospective trials in CLL designed to assess the role of MRD surveillance in treatment tailoring.

  17. Immunoglobulin gene rearrangements in Chinese and Italian patients with chronic lymphocytic leukemia.

    PubMed

    Marinelli, Marilisa; Ilari, Caterina; Xia, Yi; Del Giudice, Ilaria; Cafforio, Luciana; Della Starza, Irene; Raponi, Sara; Mariglia, Paola; Bonina, Silvia; Yu, Zhen; Yang, Wenjuan; Qiu, Lugui; Chan, Thomas; Piciocchi, Alfonso; Kwong, Yok-Lam; Tse, Eric; Li, Jianyong; Guarini, Anna; Xu, Wei; Foà, Robin

    2016-04-12

    Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in the Western world, whereas in Asia the incidence is about 10 times lower. The basis for this ethnic and geographic variation is currently unknown. The aim of this study was to characterize IGHVDJ rearrangements and stereotype of the HCDR3 region in a series of 623 Chinese CLL, in order to identify possible differences in immunoglobulin gene usage and their potential pathogenetic implications. Chinese CLL were compared to 789 Italian CLL. Chinese patients showed a higher proportion of mutated IGHV and a more frequent usage of IGHV3-7, IGHV3-74, IGHV4-39 and IGHV4-59 genes. A significantly lower usage of IGHV1-69 and IGHV1-2 was documented, with comparable IGHV3-21 frequency (3% Chinese vs 3.8% Italian CLL). The proportion of known stereotyped receptors was significantly lower in Chinese (19.7%) than in Italian CLL (25.8%), despite a significantly higher frequency of subset #8 (p= 0.0001). Moreover, new paired clusters were identified among Chinese cases. Overall, these data support a potential different antigenic exposure between Eastern and Western CLL.

  18. BCL-2 Inhibitors Sensitize Therapy-resistant Chronic Lymphocytic Leukemia Cells to VSV Oncolysis

    PubMed Central

    Samuel, Sara; Beljanski, Vladimir; Van Grevenynghe, Julien; Richards, Stephanie; Ben Yebdri, Fethia; He, Zhong; Nichols, Carmen; Belgnaoui, S Mehdi; Steel, Courtney; Goulet, Marie-Line; Shamy, April; Brown, Dawn; Abesada, Guillermo; Haddad, Elias K; Hiscott, John

    2013-01-01

    Many primary cancers including chronic lymphocytic leukemia (CLL) are resistant to vesicular stomatitis virus (VSV)-induced oncolysis due to overexpression of the antiapoptotic and antiautophagic members of the B-cell lymphoma-2 (BCL-2) family. In the present study, we investigated the mechanisms of CLL cell death induced as a consequence of VSV infection in the presence of BCL-2 inhibitors, obatoclax, and ABT-737 in primary ex vivo CLL patient samples. Microarray analysis of primary CD19+ CD5+ CLL cells treated with obatoclax and VSV revealed changes in expression of genes regulating apoptosis, the mechanistic target of rapamycin (mTOR) pathway, and cellular metabolism. A combined therapeutic effect was observed for VSV and BCL-2 inhibitors in cells from untreated patients and from patients unresponsive to standard of care therapy. In addition, combination treatment induced several markers of autophagy—LC3-II accumulation, p62 degradation, and staining of autophagic vacuoles. Inhibition of early stage autophagy using 3-methyladenine (3-MA) led to increased apoptosis in CLL samples. Mechanistically, a combination of BCL-2 inhibitors and VSV disrupted inhibitory interactions of Beclin-1 with BCL-2 and myeloid cell leukemia-1 (MCL-1), thus biasing cells toward autophagy. We propose a mechanism in which changes in cellular metabolism, coupled with pharmacologic disruption of the BCL-2–Beclin-1 interactions, facilitate induction of apoptosis and autophagy to mediate the cytolytic effect of VSV. PMID:23689597

  19. Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia

    PubMed Central

    Puente, Xose S.; Pinyol, Magda; Quesada, Víctor; Conde, Laura; Ordóñez, Gonzalo R.; Villamor, Neus; Escaramis, Georgia; Jares, Pedro; Beà, Sílvia; González-Díaz, Marcos; Bassaganyas, Laia; Baumann, Tycho; Juan, Manel; López-Guerra, Mónica; Colomer, Dolors; Tubío, José M. C.; López, Cristina; Navarro, Alba; Tornador, Cristian; Aymerich, Marta; Rozman, María; Hernández, Jesús M.; Puente, Diana A.; Freije, José M. P.; Velasco, Gloria; Gutiérrez-Fernández, Ana; Costa, Dolors; Carrió, Anna; Guijarro, Sara; Enjuanes, Anna; Hernández, Lluís; Yagüe, Jordi; Nicolás, Pilar; Romeo-Casabona, Carlos M.; Himmelbauer, Heinz; Castillo, Ester; Dohm, Juliane C.; de Sanjosé, Silvia; Piris, Miguel A.; de Alava, Enrique; Miguel, Jesús San; Royo, Romina; Gelpí, Josep L.; Torrents, David; Orozco, Modesto; Pisano, David G.; Valencia, Alfonso; Guigó, Roderic; Bayés, Mónica; Heath, Simon; Gut, Marta; Klatt, Peter; Marshall, John; Raine, Keiran; Stebbings, Lucy A.; Futreal, P. Andrew; Stratton, Michael R.; Campbell, Peter J.; Gut, Ivo; López-Guillermo, Armando; Estivill, Xavier; Montserrat, Emili; López-Otín, Carlos; Campo, Elías

    2012-01-01

    Chronic lymphocytic leukaemia (CLL), the most frequent leukaemia in adults in Western countries, is a heterogeneous disease with variable clinical presentation and evolution1,2. Two major molecular subtypes can be distinguished, characterized respectively by a high or low number of somatic hypermutations in the variable region of immunoglobulin genes3,4. The molecular changes leading to the pathogenesis of the disease are still poorly understood. Here we performed whole-genome sequencing of four cases of CLL and identified 46 somatic mutations that potentially affect gene function. Further analysis of these mutations in 363 patients with CLL identified four genes that are recurrently mutated: notch 1 (NOTCH1), exportin 1 (XPO1), myeloid differentiation primary response gene 88 (MYD88) and kelch-like 6 (KLHL6). Mutations in MYD88 and KLHL6 are predominant in cases of CLL with mutated immunoglobulin genes, whereas NOTCH1 and XPO1 mutations are mainly detected in patients with unmutated immunoglobulins. The patterns of somatic mutation, supported by functional and clinical analyses, strongly indicate that the recurrent NOTCH1, MYD88 and XPO1 mutations are oncogenic changes that contribute to the clinical evolution of the disease. To our knowledge, this is the first comprehensive analysis of CLL combining whole-genome sequencing with clinical characteristics and clinical outcomes. It highlights the usefulness of this approach for the identification of clinically relevant mutations in cancer. PMID:21642962

  20. MicroRNA as biomarkers and regulators in B-cell chronic lymphocytic leukemia.

    PubMed

    Moussay, Etienne; Wang, Kai; Cho, Ji-Hoon; van Moer, Kris; Pierson, Sandrine; Paggetti, Jérôme; Nazarov, Petr V; Palissot, Valérie; Hood, Leroy E; Berchem, Guy; Galas, David J

    2011-04-19

    Early cancer detection and disease stratification or classification are critical to successful treatment. Accessible, reliable, and informative cancer biomarkers can be medically valuable and can provide some relevant insights into cancer biology. Recent studies have suggested improvements in detecting malignancies by the use of specific extracellular microRNAs (miRNAs) in plasma. In chronic lymphocytic leukemia (CLL), an incurable hematologic disorder, sensitive, early, and noninvasive diagnosis and better disease classification would be very useful for more effective therapies. We show here that circulating miRNAs can be sensitive biomarkers for CLL, because certain extracellular miRNAs are present in CLL patient plasma at levels significantly different from healthy controls and from patients affected by other hematologic malignancies. The levels of several of these circulating miRNAs also displayed significant differences between zeta-associated protein 70 (ZAP-70)(+) and ZAP-70(-) CLL. We also determined that the level of circulating miR-20a correlates reliably with diagnosis-to-treatment time. Network analysis of our data, suggests a regulatory network associated with BCL2 and ZAP-70 expression in CLL. This hypothesis suggests the possibility of using the levels of specific miRNAs in plasma to detect CLL and to determine the ZAP-70 status. PMID:21460253

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

    PubMed Central

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

    2015-01-01

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

  2. Chronic lymphocytic leukaemia: could immunological tolerance mechanisms be the origin of lymphoid neoplasms?

    PubMed Central

    García-Muñoz, Ricardo; Llorente, Luis

    2014-01-01

    Immunological tolerance theory in chronic lymphocytic leukaemia (CLL): we suggest that B cells that express B-cell receptors (BCR) that recognize their own BCR epitopes are viewed by immune system as ‘dangerous cells’. BCR autonomous signalling may induce constant receptor editing and mistakes in allelic exclusion. The fact that whole BCR recognizes a self-antigen or foreing antigen may be irrelevant in early B cell development. In early B cells, autonomous signalling induced by recognition of the BCR’s own epitopes simulates an antigen-antibody engagement. In the bone marrow this interaction is viewed as recognition of self-molecules and induces receptor editing. In mature B cells autonomous signalling by the BCR may promote ‘reversible anergy’ and also may correct self-reactivity induced by the somatic hypermutation mechanisms in mutated CLL B cells. However, in unmutated CLL B cells, BCR autonomous signalling in addition to self-antigen recognition augments B cell activation, proliferation and genomic instability. We suggest that CLL originates from a coordinated normal immunologic tolerance mechanism to destroy self-reactive B cells. Additional genetic damage induced by tolerance mechanisms may immortalize self-reactive B cells and transform them into a leukemia. PMID:24645778

  3. Clonal evolution in patients with chronic lymphocytic leukaemia developing resistance to BTK inhibition.

    PubMed

    Burger, Jan A; Landau, Dan A; Taylor-Weiner, Amaro; Bozic, Ivana; Zhang, Huidan; Sarosiek, Kristopher; Wang, Lili; Stewart, Chip; Fan, Jean; Hoellenriegel, Julia; Sivina, Mariela; Dubuc, Adrian M; Fraser, Cameron; Han, Yulong; Li, Shuqiang; Livak, Kenneth J; Zou, Lihua; Wan, Youzhong; Konoplev, Sergej; Sougnez, Carrie; Brown, Jennifer R; Abruzzo, Lynne V; Carter, Scott L; Keating, Michael J; Davids, Matthew S; Wierda, William G; Cibulskis, Kristian; Zenz, Thorsten; Werner, Lillian; Dal Cin, Paola; Kharchencko, Peter; Neuberg, Donna; Kantarjian, Hagop; Lander, Eric; Gabriel, Stacey; O'Brien, Susan; Letai, Anthony; Weitz, David A; Nowak, Martin A; Getz, Gad; Wu, Catherine J

    2016-05-20

    Resistance to the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib has been attributed solely to mutations in BTK and related pathway molecules. Using whole-exome and deep-targeted sequencing, we dissect evolution of ibrutinib resistance in serial samples from five chronic lymphocytic leukaemia patients. In two patients, we detect BTK-C481S mutation or multiple PLCG2 mutations. The other three patients exhibit an expansion of clones harbouring del(8p) with additional driver mutations (EP300, MLL2 and EIF2A), with one patient developing trans-differentiation into CD19-negative histiocytic sarcoma. Using droplet-microfluidic technology and growth kinetic analyses, we demonstrate the presence of ibrutinib-resistant subclones and estimate subclone size before treatment initiation. Haploinsufficiency of TRAIL-R, a consequence of del(8p), results in TRAIL insensitivity, which may contribute to ibrutinib resistance. These findings demonstrate that the ibrutinib therapy favours selection and expansion of rare subclones already present before ibrutinib treatment, and provide insight into the heterogeneity of genetic changes associated with ibrutinib resistance.

  4. Chronic lymphocytic leukemia: molecular heterogeneity revealed by high-throughput genomics

    PubMed Central

    2013-01-01

    Chronic lymphocytic leukemia (CLL) has been consistently at the forefront of genetic research owing to its prevalence and the accessibility of sample material. Recently, genome-wide technologies have been intensively applied to CLL genetics, with remarkable progress. Single nucleotide polymorphism arrays have identified recurring chromosomal aberrations, thereby focusing functional studies on discrete genomic lesions and leading to the first implication of somatic microRNA disruption in cancer. Next-generation sequencing (NGS) has further transformed our understanding of CLL by identifying novel recurrently mutated putative drivers, including the unexpected discovery of somatic mutations affecting spliceosome function. NGS has further enabled in-depth examination of the transcriptional and epigenetic changes in CLL that accompany genetic lesions, and has shed light on how different driver events appear at different stages of disease progression and clonally evolve with relapsed disease. In addition to providing important insights into disease biology, these discoveries have significant translational potential. They enhance prognosis by highlighting specific lesions associated with poor clinical outcomes (for example, driver events such as mutations in the splicing factor subunit gene SF3B1) or with increased clonal heterogeneity (for example, the presence of subclonal driver mutations). Here, we review new genomic discoveries in CLL and discuss their possible implications in the era of precision medicine. PMID:23731665

  5. Relationship of blood monocytes with chronic lymphocytic leukemia aggressiveness and outcomes: a multi-institutional study.

    PubMed

    Friedman, Daphne R; Sibley, Alexander B; Owzar, Kouros; Chaffee, Kari G; Slager, Susan; Kay, Neil E; Hanson, Curtis A; Ding, Wei; Shanafelt, Tait D; Weinberg, J Brice; Wilcox, Ryan A

    2016-07-01

    Monocyte-derived cells, constituents of the cancer microenvironment, support chronic lymphocytic leukemia (CLL) cell survival in vitro via direct cell-cell interaction and secreted factors. We hypothesized that circulating absolute monocyte count (AMC) reflects the monocyte-derived cells in the microenvironment, and that higher AMC is associated with increased CLL cell survival in vivo and thus inferior CLL patient outcomes. We assessed the extent to which AMC at diagnosis of CLL is correlated with clinical outcomes, and whether this information adds to currently used prognostic markers. We evaluated AMC, clinically used prognostic markers, and time to event data from 1,168 CLL patients followed at the Mayo Clinic, the Duke University Medical Center, and the Durham VA Medical Center. Elevated AMC was significantly associated with inferior clinical outcomes, including time to first therapy (TTT) and overall survival (OS). AMC combined with established clinical and molecular prognostic markers significantly improved risk-stratification of CLL patients for TTT. As an elevated AMC at diagnosis is associated with accelerated disease progression, and monocyte-derived cells in the CLL microenvironment promote CLL cell survival and proliferation, these findings suggest that monocytes and monocyte-derived cells are rational therapeutic targets in CLL. Am. J. Hematol. 91:687-691, 2016. © 2016 Wiley Periodicals, Inc.

  6. Chronic Lymphocytic Leukaemia: Census of Patients Treated in Italian Haematology Units.

    PubMed

    Salvi, Gianfranco; Innocenti, Idanna; Autore, Francesco; Laurenti, Luca

    2015-01-01

    This study was conducted by contacting the population of the Italian haematology units and collecting from 68% of them data concerning the number of patients with chronic lymphocytic leukaemia visited over the previous 12 months, with the aim of obtaining an overview of the treatment of this disease and comparing the results with the prevalence estimates found in literature. The projection obtained (about 17,000 patients visited in the previous 12 months) is probably overestimated because of double-counting of patients who may have been treated at two different facilities during the year, although it is also underestimated since the internal medicine units were not involved. The balance of these two opposite factors is not known. It is important to bear in mind the approximation with which the count was performed in facilities for which no official data were available. Albeit with these limits, the results obtained are in line with some existing prevalence data and make it possible to determine the portion of patients at different Binet stages and in the various age ranges, identifying the corresponding therapeutic treatments. Use of the CIRS scale to classify patients as FIT and UNFIT was seen to be still somewhat limited. PMID:26543525

  7. Clonal evolution in patients with chronic lymphocytic leukaemia developing resistance to BTK inhibition.

    PubMed

    Burger, Jan A; Landau, Dan A; Taylor-Weiner, Amaro; Bozic, Ivana; Zhang, Huidan; Sarosiek, Kristopher; Wang, Lili; Stewart, Chip; Fan, Jean; Hoellenriegel, Julia; Sivina, Mariela; Dubuc, Adrian M; Fraser, Cameron; Han, Yulong; Li, Shuqiang; Livak, Kenneth J; Zou, Lihua; Wan, Youzhong; Konoplev, Sergej; Sougnez, Carrie; Brown, Jennifer R; Abruzzo, Lynne V; Carter, Scott L; Keating, Michael J; Davids, Matthew S; Wierda, William G; Cibulskis, Kristian; Zenz, Thorsten; Werner, Lillian; Dal Cin, Paola; Kharchencko, Peter; Neuberg, Donna; Kantarjian, Hagop; Lander, Eric; Gabriel, Stacey; O'Brien, Susan; Letai, Anthony; Weitz, David A; Nowak, Martin A; Getz, Gad; Wu, Catherine J

    2016-01-01

    Resistance to the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib has been attributed solely to mutations in BTK and related pathway molecules. Using whole-exome and deep-targeted sequencing, we dissect evolution of ibrutinib resistance in serial samples from five chronic lymphocytic leukaemia patients. In two patients, we detect BTK-C481S mutation or multiple PLCG2 mutations. The other three patients exhibit an expansion of clones harbouring del(8p) with additional driver mutations (EP300, MLL2 and EIF2A), with one patient developing trans-differentiation into CD19-negative histiocytic sarcoma. Using droplet-microfluidic technology and growth kinetic analyses, we demonstrate the presence of ibrutinib-resistant subclones and estimate subclone size before treatment initiation. Haploinsufficiency of TRAIL-R, a consequence of del(8p), results in TRAIL insensitivity, which may contribute to ibrutinib resistance. These findings demonstrate that the ibrutinib therapy favours selection and expansion of rare subclones already present before ibrutinib treatment, and provide insight into the heterogeneity of genetic changes associated with ibrutinib resistance. PMID:27199251

  8. Syncytial giant cell hepatitis in a patient with chronic lymphocytic leukemia

    PubMed Central

    GUPTA, Neil; NJEI, Basile

    2016-01-01

    While it commonly occurs in the pediatric population, syncytial giant cell hepatitis is rare in adults, which is diagnosed histologically by the presence of multinucleated cells in the liver. The literature has recorded only approximately one hundred cases in adults during the past two decades in whom malignancy is rarely associated with giant cell hepatitis. Our patient is a 66-year-old woman who was diagnosed with chronic lymphocytic leukemia (CLL) and subsequently developed syncytial giant cell hepatitis. This disease is usually linked to virus infection, autoimmune diseases, and drug medications. The association between CLL and giant cell hepatitis is rare, with only three cases reported. In most cases viral particles on electron microscopy are reported and the patients usually have a history of chemotherapy and hypogammaglobulinemia. Unlike such cases, our patient developed giant cell hepatitis in the absence of such confounding variables. The treatment for our patient was a high-dose corticosteroid and rituxan, with improvement in liver enzymes. PMID:26147671

  9. Meta-analysis of genome-wide association studies discovers multiple loci for chronic lymphocytic leukemia

    PubMed Central

    Berndt, Sonja I.; Camp, Nicola J.; Skibola, Christine F.; Vijai, Joseph; Wang, Zhaoming; Gu, Jian; Nieters, Alexandra; Kelly, Rachel S.; Smedby, Karin E.; Monnereau, Alain; Cozen, Wendy; Cox, Angela; Wang, Sophia S.; Lan, Qing; Teras, Lauren R.; Machado, Moara; Yeager, Meredith; Brooks-Wilson, Angela R.; Hartge, Patricia; Purdue, Mark P.; Birmann, Brenda M.; Vajdic, Claire M.; Cocco, Pierluigi; Zhang, Yawei; Giles, Graham G.; Zeleniuch-Jacquotte, Anne; Lawrence, Charles; Montalvan, Rebecca; Burdett, Laurie; Hutchinson, Amy; Ye, Yuanqing; Call, Timothy G.; Shanafelt, Tait D.; Novak, Anne J.; Kay, Neil E.; Liebow, Mark; Cunningham, Julie M.; Allmer, Cristine; Hjalgrim, Henrik; Adami, Hans-Olov; Melbye, Mads; Glimelius, Bengt; Chang, Ellen T.; Glenn, Martha; Curtin, Karen; Cannon-Albright, Lisa A.; Diver, W Ryan; Link, Brian K.; Weiner, George J.; Conde, Lucia; Bracci, Paige M.; Riby, Jacques; Arnett, Donna K.; Zhi, Degui; Leach, Justin M.; Holly, Elizabeth A.; Jackson, Rebecca D.; Tinker, Lesley F.; Benavente, Yolanda; Sala, Núria; Casabonne, Delphine; Becker, Nikolaus; Boffetta, Paolo; Brennan, Paul; Foretova, Lenka; Maynadie, Marc; McKay, James; Staines, Anthony; Chaffee, Kari G.; Achenbach, Sara J.; Vachon, Celine M.; Goldin, Lynn R.; Strom, Sara S.; Leis, Jose F.; Weinberg, J. Brice; Caporaso, Neil E.; Norman, Aaron D.; De Roos, Anneclaire J.; Morton, Lindsay M.; Severson, Richard K.; Riboli, Elio; Vineis, Paolo; Kaaks, Rudolph; Masala, Giovanna; Weiderpass, Elisabete; Chirlaque, María- Dolores; Vermeulen, Roel C. H.; Travis, Ruth C.; Southey, Melissa C.; Milne, Roger L.; Albanes, Demetrius; Virtamo, Jarmo; Weinstein, Stephanie; Clavel, Jacqueline; Zheng, Tongzhang; Holford, Theodore R.; Villano, Danylo J.; Maria, Ann; Spinelli, John J.; Gascoyne, Randy D.; Connors, Joseph M.; Bertrand, Kimberly A.; Giovannucci, Edward; Kraft, Peter; Kricker, Anne; Turner, Jenny; Ennas, Maria Grazia; Ferri, Giovanni M.; Miligi, Lucia; Liang, Liming; Ma, Baoshan; Huang, Jinyan; Crouch, Simon; Park, Ju-Hyun; Chatterjee, Nilanjan; North, Kari E.; Snowden, John A.; Wright, Josh; Fraumeni, Joseph F.; Offit, Kenneth; Wu, Xifeng; de Sanjose, Silvia; Cerhan, James R.; Chanock, Stephen J.; Rothman, Nathaniel; Slager, Susan L.

    2016-01-01

    Chronic lymphocytic leukemia (CLL) is a common lymphoid malignancy with strong heritability. To further understand the genetic susceptibility for CLL and identify common loci associated with risk, we conducted a meta-analysis of four genome-wide association studies (GWAS) composed of 3,100 cases and 7,667 controls with follow-up replication in 1,958 cases and 5,530 controls. Here we report three new loci at 3p24.1 (rs9880772, EOMES, P=2.55 × 10−11), 6p25.2 (rs73718779, SERPINB6, P=1.97 × 10−8) and 3q28 (rs9815073, LPP, P=3.62 × 10−8), as well as a new independent SNP at the known 2q13 locus (rs9308731, BCL2L11, P=1.00 × 10−11) in the combined analysis. We find suggestive evidence (P<5 × 10−7) for two additional new loci at 4q24 (rs10028805, BANK1, P=7.19 × 10−8) and 3p22.2 (rs1274963, CSRNP1, P=2.12 × 10−7). Pathway analyses of new and known CLL loci consistently show a strong role for apoptosis, providing further evidence for the importance of this biological pathway in CLL susceptibility. PMID:26956414

  10. Microsatellite instability in patients with chronic B-cell lymphocytic leukaemia

    PubMed Central

    Niv, E; Bomstein, Y; Yuklea, M; Lishner, M

    2005-01-01

    The purpose of our study was to evaluate the microsatellite instability (MSI) at selected loci with known involvement in the oncogenesis of chronic B-cell lymphocytic leukaemia (B-CLL). DNA from B cells (tumour cells) and from T cells (normal controls) of 27 samples of 26 patients with previously untreated B-CLL was extracted. Microsatellite instability in six microsatellite markers was tested using GeneScan Analysis Software. The rate of replication errors positive phenotype (RER+) was determined (MSI in more than 30% of examined loci). RER+ was found in four out of 27 paients (14.8%). A larger proportion of patients with stage C B-CLL exhibited RER+ than those with stage A or B (P<0.05). A higher prevalence of RER+ was demonstrated in a subgroup of patients with additional malignancies (three out of eight patients) in comparison with patients with B-CLL alone (1/19) (P=0.031). In conclusion, our study demonstrated that MSI might have a more prominent role in pathogenesis of B-CLL than reported todate. This may result from a selection of microsatellite markers adjacent to chromosomal loci, which are involved in B-cell malignancies, and using GeneScan Analysis Software, which is most modern and precise method of microsatellite analysis. PMID:15812543

  11. Analysis of rearranged immunoglobulin genes indicating a process of clonal evolution in chronic lymphocytic leukaemia.

    PubMed

    Hakim, I; Rechavi, G; Brok-Simoni, F; Grossman, Z; Amariglio, N; Mandel, M; Ramot, B; Ben-Bassat, I; Katzir, N

    1993-07-01

    Chronic lymphocytic leukaemia (CLL) is known to be a stable monoclonal neoplasm. In contrast to early studies demonstrating no more than two hybridizing immunoglobulin heavy chain bands corresponding to the two expected alleles, we have demonstrated an unexpected multiband pattern when the HindIII-digested DNA samples from 38 CLL patients were analysed by Southern blot hybridization using JH and C mu gene probes. In order to characterize the genetic basis for the multiband pattern, we molecularly cloned the immunoglobulin heavy chain genes of one of the patients whose leukaemic DNA sample demonstrated three hybridizing JH bands and a loss of the germline band. The cloned rearranged immunoglobulin genes could be divided, based on the restriction mapping and the hybridization with the various probes, into two basic patterns representing two alleles. In one of the cloned rearranged immunoglobulin genes a secondary rearrangement occurred that resulted in the addition of 300 base-pair long sequence into the switch region, and the creation of a HindIII restriction site. The results of the study suggest that clonal evolution occurs in some CLL, and that many of these neoplasms are indeed oligoclonal due to the accumulation of secondary genetic changes.

  12. Automatic detection of axillary lymphadenopathy on CT scans of untreated chronic lymphocytic leukemia patients

    NASA Astrophysics Data System (ADS)

    Liu, Jiamin; Hua, Jeremy; Chellappa, Vivek; Petrick, Nicholas; Sahiner, Berkman; Farooqui, Mohammed; Marti, Gerald; Wiestner, Adrian; Summers, Ronald M.

    2012-03-01

    Patients with chronic lymphocytic leukemia (CLL) have an increased frequency of axillary lymphadenopathy. Pretreatment CT scans can be used to upstage patients at the time of presentation and post-treatment CT scans can reduce the number of complete responses. In the current clinical workflow, the detection and diagnosis of lymph nodes is usually performed manually by examining all slices of CT images, which can be time consuming and highly dependent on the observer's experience. A system for automatic lymph node detection and measurement is desired. We propose a computer aided detection (CAD) system for axillary lymph nodes on CT scans in CLL patients. The lung is first automatically segmented and the patient's body in lung region is extracted to set the search region for lymph nodes. Multi-scale Hessian based blob detection is then applied to detect potential lymph nodes within the search region. Next, the detected potential candidates are segmented by fast level set method. Finally, features are calculated from the segmented candidates and support vector machine (SVM) classification is utilized for false positive reduction. Two blobness features, Frangi's and Li's, are tested and their free-response receiver operating characteristic (FROC) curves are generated to assess system performance. We applied our detection system to 12 patients with 168 axillary lymph nodes measuring greater than 10 mm. All lymph nodes are manually labeled as ground truth. The system achieved sensitivities of 81% and 85% at 2 false positives per patient for Frangi's and Li's blobness, respectively.

  13. Protein expression analysis of chromosome 12 candidate genes in chronic lymphocytic leukemia (CLL).

    PubMed

    Winkler, D; Schneider, C; Kröber, A; Pasqualucci, L; Lichter, P; Döhner, H; Stilgenbauer, S

    2005-07-01

    The pathogenic role of trisomy 12 in chronic lymphocytic leukemia (CLL) remains unresolved, but recently an upregulated RNA expression level has been observed for chromosome 12 candidate genes. In the current study, the protein expression of chromosome 12 candidate genes was characterized by comparing CLL cases with (n=58) or without (n=16) trisomy 12, CD19+-B-cells and cell lines (JVM-2, EHEB, JURKAT). Immunoblotting was performed to quantify the levels of AID, APAF-1, ARF3, CCND2, CDK2, CKD4, GLI, MDM-2, p27, Smac/DIABLO and STAT6 (signal transducer and activator of transcription 6). The cell lines showed distinct expression patterns for CCND2, MDM-2, p27, Smac/DIABLO and STAT6, and displayed higher levels of CDK2 and CDK4 than the CLL cases. JURKAT and the CLL cases expressed uniformly high levels of p27, but low levels of CCND2. AID expression in the CLL cases was weak with slight variations regardless of the subgroup affiliation. The expression of the investigated proteins was independent of the trisomy 12 status as well as of the VH mutation status. The comparison of CD19+-B-cells with CLL revealed higher protein levels in CLL for CDK4, p27, Smac/DIABLO and STAT6. Further studies including protein expression experiments in genetic high-risk subgroups of CLL have to elucidate whether these proteins qualify as candidates for targeted CLL therapies. PMID:15902296

  14. Tumor evolutionary directed graphs and the history of chronic lymphocytic leukemia

    PubMed Central

    Wang, Jiguang; Khiabanian, Hossein; Rossi, Davide; Fabbri, Giulia; Gattei, Valter; Forconi, Francesco; Laurenti, Luca; Marasca, Roberto; Del Poeta, Giovanni; Foà, Robin; Pasqualucci, Laura; Gaidano, Gianluca; Rabadan, Raul

    2014-01-01

    Cancer is a clonal evolutionary process, caused by successive accumulation of genetic alterations providing milestones of tumor initiation, progression, dissemination, and/or resistance to certain therapeutic regimes. To unravel these milestones we propose a framework, tumor evolutionary directed graphs (TEDG), which is able to characterize the history of genetic alterations by integrating longitudinal and cross-sectional genomic data. We applied TEDG to a chronic lymphocytic leukemia (CLL) cohort of 70 patients spanning 12 years and show that: (a) the evolution of CLL follows a time-ordered process represented as a global flow in TEDG that proceeds from initiating events to late events; (b) there are two distinct and mutually exclusive evolutionary paths of CLL evolution; (c) higher fitness clones are present in later stages of the disease, indicating a progressive clonal replacement with more aggressive clones. Our results suggest that TEDG may constitute an effective framework to recapitulate the evolutionary history of tumors. DOI: http://dx.doi.org/10.7554/eLife.02869.001 PMID:25496728

  15. Meta-analysis of genome-wide association studies discovers multiple loci for chronic lymphocytic leukemia.

    PubMed

    Berndt, Sonja I; Camp, Nicola J; Skibola, Christine F; Vijai, Joseph; Wang, Zhaoming; Gu, Jian; Nieters, Alexandra; Kelly, Rachel S; Smedby, Karin E; Monnereau, Alain; Cozen, Wendy; Cox, Angela; Wang, Sophia S; Lan, Qing; Teras, Lauren R; Machado, Moara; Yeager, Meredith; Brooks-Wilson, Angela R; Hartge, Patricia; Purdue, Mark P; Birmann, Brenda M; Vajdic, Claire M; Cocco, Pierluigi; Zhang, Yawei; Giles, Graham G; Zeleniuch-Jacquotte, Anne; Lawrence, Charles; Montalvan, Rebecca; Burdett, Laurie; Hutchinson, Amy; Ye, Yuanqing; Call, Timothy G; Shanafelt, Tait D; Novak, Anne J; Kay, Neil E; Liebow, Mark; Cunningham, Julie M; Allmer, Cristine; Hjalgrim, Henrik; Adami, Hans-Olov; Melbye, Mads; Glimelius, Bengt; Chang, Ellen T; Glenn, Martha; Curtin, Karen; Cannon-Albright, Lisa A; Diver, W Ryan; Link, Brian K; Weiner, George J; Conde, Lucia; Bracci, Paige M; Riby, Jacques; Arnett, Donna K; Zhi, Degui; Leach, Justin M; Holly, Elizabeth A; Jackson, Rebecca D; Tinker, Lesley F; Benavente, Yolanda; Sala, Núria; Casabonne, Delphine; Becker, Nikolaus; Boffetta, Paolo; Brennan, Paul; Foretova, Lenka; Maynadie, Marc; McKay, James; Staines, Anthony; Chaffee, Kari G; Achenbach, Sara J; Vachon, Celine M; Goldin, Lynn R; Strom, Sara S; Leis, Jose F; Weinberg, J Brice; Caporaso, Neil E; Norman, Aaron D; De Roos, Anneclaire J; Morton, Lindsay M; Severson, Richard K; Riboli, Elio; Vineis, Paolo; Kaaks, Rudolph; Masala, Giovanna; Weiderpass, Elisabete; Chirlaque, María-Dolores; Vermeulen, Roel C H; Travis, Ruth C; Southey, Melissa C; Milne, Roger L; Albanes, Demetrius; Virtamo, Jarmo; Weinstein, Stephanie; Clavel, Jacqueline; Zheng, Tongzhang; Holford, Theodore R; Villano, Danylo J; Maria, Ann; Spinelli, John J; Gascoyne, Randy D; Connors, Joseph M; Bertrand, Kimberly A; Giovannucci, Edward; Kraft, Peter; Kricker, Anne; Turner, Jenny; Ennas, Maria Grazia; Ferri, Giovanni M; Miligi, Lucia; Liang, Liming; Ma, Baoshan; Huang, Jinyan; Crouch, Simon; Park, Ju-Hyun; Chatterjee, Nilanjan; North, Kari E; Snowden, John A; Wright, Josh; Fraumeni, Joseph F; Offit, Kenneth; Wu, Xifeng; de Sanjose, Silvia; Cerhan, James R; Chanock, Stephen J; Rothman, Nathaniel; Slager, Susan L

    2016-01-01

    Chronic lymphocytic leukemia (CLL) is a common lymphoid malignancy with strong heritability. To further understand the genetic susceptibility for CLL and identify common loci associated with risk, we conducted a meta-analysis of four genome-wide association studies (GWAS) composed of 3,100 cases and 7,667 controls with follow-up replication in 1,958 cases and 5,530 controls. Here we report three new loci at 3p24.1 (rs9880772, EOMES, P=2.55 × 10(-11)), 6p25.2 (rs73718779, SERPINB6, P=1.97 × 10(-8)) and 3q28 (rs9815073, LPP, P=3.62 × 10(-8)), as well as a new independent SNP at the known 2q13 locus (rs9308731, BCL2L11, P=1.00 × 10(-11)) in the combined analysis. We find suggestive evidence (P<5 × 10(-7)) for two additional new loci at 4q24 (rs10028805, BANK1, P=7.19 × 10(-8)) and 3p22.2 (rs1274963, CSRNP1, P=2.12 × 10(-7)). Pathway analyses of new and known CLL loci consistently show a strong role for apoptosis, providing further evidence for the importance of this biological pathway in CLL susceptibility. PMID:26956414

  16. Targeting Stereotyped B Cell Receptors from Chronic Lymphocytic Leukemia Patients with Synthetic Antigen Surrogates.

    PubMed

    Sarkar, Mohosin; Liu, Yun; Qi, Junpeng; Peng, Haiyong; Morimoto, Jumpei; Rader, Christoph; Chiorazzi, Nicholas; Kodadek, Thomas

    2016-04-01

    Chronic lymphocytic leukemia (CLL) is a disease in which a single B-cell clone proliferates relentlessly in peripheral lymphoid organs, bone marrow, and blood. DNA sequencing experiments have shown that about 30% of CLL patients have stereotyped antigen-specific B-cell receptors (BCRs) with a high level of sequence homology in the variable domains of the heavy and light chains. These include many of the most aggressive cases that haveIGHV-unmutated BCRs whose sequences have not diverged significantly from the germ line. This suggests a personalized therapy strategy in which a toxin or immune effector function is delivered selectively to the pathogenic B-cells but not to healthy B-cells. To execute this strategy, serum-stable, drug-like compounds able to target the antigen-binding sites of most or all patients in a stereotyped subset are required. We demonstrate here the feasibility of this approach with the discovery of selective, high affinity ligands for CLL BCRs of the aggressive, stereotyped subset 7P that cross-react with the BCRs of several CLL patients in subset 7p, but not with BCRs from patients outside this subset. PMID:26851280

  17. Total expression of HLA-G and TLR-9 in chronic lymphocytic leukemia patients.

    PubMed

    Własiuk, Paulina; Tomczak, Waldemar; Zając, Małgorzata; Dmoszyńska, Anna; Giannopoulos, Krzysztof

    2013-12-01

    Suppressed immune status facilitates immune escape mechanisms that allow chronic lymphocytic leukemia cells to proliferate and expand. The expression of HLA-G could effectively inhibit the immune response. In immune response inhibitory signals follow activation of immune system which might be occur during bacterial or viral infection in CLL patients. In the current study we characterized two components of immune system, inhibitory molecule HLA-G with its receptor - CD85j and Toll-like receptor 9. The material was obtained from 41 CLL patients and 41 HV with similar median age. In CLL patients expression of intracellular and surface HLA-G and soluble HLA-G levels were significantly higher than in HV. We found higher expression of CD85j compared to HV and the positive correlation between expression of HLA-G and CD85j. All the CLL cells expressed TLR-9, and the level of expression positively correlated with expression of HLA-G and CD85j. Patients with higher expression of intracellular expression of TLR-9 have significantly longer treatment-free survival than patients with low expression of TLR-9 (57 months vs. 8 months, respectively). Summarizing in CLL we characterized activatory and inhibitory components of immune system that might be connected functionally. Analysis of TLR-9 expression might have additional prognostic value for CLL patients.

  18. Specific cytotoxic T-cell immune responses against autoantigens recognized by chronic lymphocytic leukaemia cells.

    PubMed

    Zaleska, Joanna; Skorka, Katarzyna; Zajac, Malgorzata; Karczmarczyk, Agnieszka; Karp, Marta; Tomczak, Waldemar; Hus, Marek; Wlasiuk, Paulina; Giannopoulos, Krzysztof

    2016-08-01

    Mounting evidence suggests that autoreactivity and inflammatory processes are involved in the pathogenesis of chronic lymphocytic leukaemia (CLL). Cytoskeletal proteins, including non-muscle myosin heavy chain IIA (MYHIIA), vimentin (VIM) and cofilin-1 (CFL1), exposed on the surface of apoptotic cells have been identified as autoantigens that are recognized by the specific B-cell receptors of the CLL cells. In 212 CLL patients analysed with quantitative reverse transcriptase-polymerase chain reaction we found CFL1 overexpression and low expression of MYH9 in comparison with healthy volunteers. We detected specific cytotoxic immune responses for peptides derived from MYHIIA in 66·7%, VIM in 87·5% and CFL1 in 62·5% CLL patients in an Enzyme-Linked ImmunoSpot assay. Low frequencies of autoreactive peptide-specific T cells were detected against MYHIIA, VIM and CFL1 in CLL patients ex vivo; most of the detected cells had an effector-memory phenotype. Our findings support the existence of cytotoxic immune responses against three autoantigens that have been identified as targets of CLL clonotypic B-cell receptors. The presence of autoreactive CD8(+) T cells against MYHIIA, VIM and CFL1 in CLL patients indicates the involvement of antigen-specific autoreactive T cells in the pathogenesis of CLL.

  19. AID induces intraclonal diversity and genomic damage in CD86+ chronic lymphocytic leukemia cells

    PubMed Central

    Huemer, Michael; Rebhandl, Stefan; Zaborsky, Nadja; Gassner, Franz J; Hainzl, Stefan; Weiss, Lukas; Hebenstreit, Daniel; Greil, Richard; Geisberger, Roland

    2014-01-01

    The activation-induced cytidine deaminase (AID) mediates somatic hypermutation and class switch recombination of the Ig genes by directly deaminating cytosines to uracils. As AID causes a substantial amount of off-target mutations, its activity has been associated with lymphomagenesis and clonal evolution of B-cell malignancies. Although it has been shown that AID is expressed in B-cell chronic lymphocytic leukemia (CLL), a clear analysis of in vivo AID activity in this B-cell malignancy remained elusive. In this study performed on primary human CLL samples, we report that, despite the presence of a dominant VDJ heavy chain region, a substantial intraclonal diversity was observed at VDJ as well as at IgM switch regions (Sμ), showing ongoing AID activity in vivo during disease progression. This AID-mediated heterogeneity was higher in CLL subclones expressing CD86, which we identified as the proliferative CLL fraction. Finally, CD86 expression correlated with shortened time to first treatment and increased γ-H2AX focus formation. Our data demonstrate that AID is active in CLL in vivo and thus, AID likely contributes to clonal evolution of CLL. PMID:25179679

  20. Establishment and Characterization of PCL12, a Novel CD5+ Chronic Lymphocytic Leukaemia Cell Line

    PubMed Central

    Agathangelidis, Andreas; Scarfò, Lydia; Barbaglio, Federica; Apollonio, Benedetta; Bertilaccio, Maria Teresa Sabrina; Ranghetti, Pamela; Ponzoni, Maurilio; Leone, Gabriella; De Pascali, Valeria; Pecciarini, Lorenza; Ghia, Paolo

    2015-01-01

    Immortalized cell lines representative of chronic lymphocytic leukemia (CLL) can assist in understanding disease pathogenesis and testing new therapeutic agents. At present, very few representative cell lines are available. We here describe the characterization of a new cell line (PCL12) that grew spontaneously from the peripheral blood (PB) of a CLL patient with progressive disease and EBV infection. The CLL cell origin of PCL12 was confirmed after the alignment of its IGH sequence against the “original” clonotypic sequence. The IGH gene rearrangement was truly unmutated and no CLL-related cytogenetic or genetic lesions were detected. PCL12 cells express CD19, CD20, CD5, CD23, low levels of IgM and IgD and the poor-outcome-associated prognostic markers CD38, ZAP70 and TCL1. In accordance with its aggressive phenotype the cell line is inactive in terms of LYN and HS1 phosphorylation. BcR signalling pathway is constitutively active and anergic in terms of p-ERK and Calcium flux response to α-IgM stimulation. PCL12 cells strongly migrate in vitro in response to SDF-1 and form clusters. Finally, they grow rapidly and localize in all lymphoid organs when xenotrasplanted in Rag2-/-γc-/- mice. PCL12 represents a suitable preclinical model for testing pharmacological agents. PMID:26110819

  1. Macrophage-mediated chronic lymphocytic leukemia cell survival is independent of APRIL signaling.

    PubMed

    van Attekum, Mha; Terpstra, S; Reinen, E; Kater, A P; Eldering, E

    2016-01-01

    Survival of chronic lymphocytic leukemia (CLL) cells is mainly driven by interactions within the lymph node (LN) microenvironment with bystander cells such as T cells or cells from the monocytic lineage. Although the survival effect by T cells is largely governed by the TNFR ligand family member CD40L, the exact mechanism of monocyte-derived cell-induced survival is not known. An important role has been attributed to the TNFR ligand, a proliferation-inducing ligand (APRIL), although the exact mechanism remained unclear. Since we detected that APRIL was expressed by CD68+ cells in CLL LN, we addressed its relevance in various aspects of CLL biology, using a novel APRIL overexpressing co-culture system, recombinant APRIL, and APRIL reporter cells. Unexpectedly, we found, that in these various systems, APRIL had no effect on survival of CLL cells, and activation of NF-κB was not enhanced on APRIL stimulation. Moreover, APRIL stity mulation did not affect CLL proliferation, neither as single stimulus nor in combination with known CLL proliferation stimuli. Furthermore, the survival effect conveyed by macrophages to CLL cells was not affected by transmembrane activator and CAML interactor-Fc, an APRIL decoy receptor. We conclude that the direct role ascribed to APRIL in CLL cell survival might be overestimated due to application of supraphysiological levels of recombinant APRIL. PMID:27551513

  2. Immunoglobulin gene rearrangements in Chinese and Italian patients with chronic lymphocytic leukemia

    PubMed Central

    Giudice, Ilaria Del; Cafforio, Luciana; Starza, Irene Della; Raponi, Sara; Mariglia, Paola; Bonina, Silvia; Yu, Zhen; Yang, Wenjuan; Qiu, Lugui; Chan, Thomas; Piciocchi, Alfonso; Kwong, Yok-Lam; Tse, Eric; Li, Jianyong; Guarini, Anna; Xu, Wei; Foà, Robin

    2016-01-01

    Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in the Western world, whereas in Asia the incidence is about 10 times lower. The basis for this ethnic and geographic variation is currently unknown. The aim of this study was to characterize IGHVDJ rearrangements and stereotype of the HCDR3 region in a series of 623 Chinese CLL, in order to identify possible differences in immunoglobulin gene usage and their potential pathogenetic implications. Chinese CLL were compared to 789 Italian CLL. Chinese patients showed a higher proportion of mutated IGHV and a more frequent usage of IGHV3-7, IGHV3-74, IGHV4-39 and IGHV4-59 genes. A significantly lower usage of IGHV1-69 and IGHV1-2 was documented, with comparable IGHV3-21 frequency (3% Chinese vs 3.8% Italian CLL). The proportion of known stereotyped receptors was significantly lower in Chinese (19.7%) than in Italian CLL (25.8%), despite a significantly higher frequency of subset #8 (p= 0.0001). Moreover, new paired clusters were identified among Chinese cases. Overall, these data support a potential different antigenic exposure between Eastern and Western CLL. PMID:26943037

  3. Chronic lymphocytic leukaemia with 17p deletion: a retrospective analysis of prognostic factors and therapy results.

    PubMed

    Delgado, Julio; Espinet, Blanca; Oliveira, Ana C; Abrisqueta, Pau; de la Serna, Javier; Collado, Rosa; Loscertales, Javier; Lopez, Montserrat; Hernandez-Rivas, Jose A; Ferra, Christelle; Ramirez, Angel; Roncero, Josep M; Lopez, Cristina; Aventin, Anna; Puiggros, Anna; Abella, Eugenia; Carbonell, Felix; Costa, Dolors; Carrio, Anna; Gonzalez, Marcos

    2012-04-01

    Patients with chronic lymphocytic leukaemia (CLL) whose tumour cells harbour a 17p deletion (17p-) are universally considered to have a poor prognosis. The deletion can be detected at diagnosis or during the evolution of the disease, particularly in patients who have received chemotherapy. We sought to evaluate the natural history of patients with 17p- CLL, identify predictive factors within this prognostic subgroup, and evaluate the results of different therapeutic approaches. Data from 294 patients with 17p- CLL followed up at 20 different institutions was retrospectively collected and analysed. Median age was 68 (range 27-98) years at the time of fluorescence in situ hybridization analysis. After 17p- documentation, 52% received treatment, achieving an overall response rate of 50%. Median overall survival was 41 months, and was significantly shorter in patients with elevated beta(2)-microglobulin concentration (P < 0·001), B symptoms (P = 0·016), higher percentage of cells with deletion (P < 0·001), and acquired deletions (P = 0·012). These findings suggest that patients with 17p- CLL have a variable prognosis that can be refined using simple clinical and laboratory features, including 17p- clone size, beta2-microglobulin concentration, presence of B symptoms and type of deletion (de novo versus acquired). PMID:22224845

  4. Targeting cholesterol synthesis increases chemoimmuno-sensitivity in chronic lymphocytic leukemia cells

    PubMed Central

    2014-01-01

    Background Cholesterol plays an important role in cancer development, drug resistance and chemoimmuno-sensitivity. Statins, cholesterol lowering drugs, can induce apoptosis, but also negatively interfere with CD-20 and rituximab-mediated activity. Our goal is to identify the alternative targets that could reduce cholesterol levels but do not interfere with CD-20 in chemo immunotherapy of chronic lymphocytic leukemia (CLL). Methods MEC-2 cells, a CLL cell line, and the peripheral blood mononuclear cells (PBMCs) from CLL patients were treated with cholesterol lowering agents, and analyzed the effect of these agents on cholesterol levels, CD-20 expression and distribution, and cell viability in the presence or absence of fludarabine, rituximab or their combinations. Results We found that MEC-2 cells treated with cholesterol lowering agents (BIBB-515, YM-53601 or TAK-475) reduced 20% of total cellular cholesterol levels, but also significantly promoted CD-20 surface expression. Furthermore, treatment of cells with fludarabine, rituximab or their combinations in the presence of BIBB-515, YM-53601 or TAK-475 enhanced MEC-2 cell chemoimmuno-sensitivity measured by cell viability. More importantly, these cholesterol lowering agents also significantly enhanced chemoimmuno-sensitivity of the PBMCs from CLL patients. Conclusion Our data demonstrate that BIBB-515, YM53601 and TAK-475 render chemoimmuno-therapy resistant MEC-2 cells sensitive to chemoimmuno-therapy and enhance CLL cell chemoimmuno-sensitivity without CD-20 epitope presentation or its downstream signaling. These results provide a novel strategy which could be applied to CLL treatment. PMID:25401046

  5. CXCL12-induced chemotaxis is impaired in T cells from patients with ZAP-70-negative chronic lymphocytic leukemia

    PubMed Central

    Borge, Mercedes; Nannini, Paula Romina; Galletti, Jeremías Gastón; Morande, Pablo Elías; Ávalos, Julio Sánchez; Bezares, Raimundo Fernando; Giordano, Mirta; Gamberale, Romina

    2010-01-01

    Background T cells from patients with chronic lymphocytic leukemia may play an important role in contributing to the onset, sustenance, and exacerbation of the disease by providing survival and proliferative signals to the leukemic clone within lymph nodes and bone marrow. Design and Methods By performing chemotaxis assays towards CXCL12, CCL21 and CCL19, we sought to evaluate the migratory potential of T cells from chronic lymphocytic leukemia patients. We next analyzed the chemokine-induced migration of T cells, dividing the chronic lymphocytic leukemia samples according to their expression of the poor prognostic factors CD38 and ZAP-70 in leukemic cells determined by flow cytometry. Results We found that T cells from patients with chronic lymphocytic leukemia are less responsive to CXCL12, CCL21 and CCL19 than T cells from healthy adults despite similar CXCR4 and CCR7 expression. Following separation of the patients into two groups according to ZAP-70 expression, we found that T cells from ZAP-70-negative samples showed significantly less migration towards CXCL12 compared to T cells from ZAP-70-positive samples and that this was not due to defective CXCR4 down-regulation, F-actin polymerization or to a lesser expression of ZAP-70, CD3, CD45, CD38 or CXCR7 on these cells. Interestingly, we found that leukemic cells from ZAP-70-negative samples seem to be responsible for the defective CXCR4 migratory response observed in their T cells. Conclusions Impaired migration towards CXCL12 may reduce the access of T cells from ZAP-70-negative patients to lymphoid organs, creating a less favorable microenvironment for leukemic cell survival and proliferation. PMID:20145264

  6. Pneumocystis jerovecii pneumonia in a patient with untreated chronic lymphocytic leukaemia: a novel case and postulations concerning the mechanism.

    PubMed

    Kalkanis, Alexandros; Judson, Marc A; Napier, Mark B

    2013-11-28

    Chronic lymphocytic leukaemia (CLL), even when severe, is not directly associated with opportunistic infections. Opportunistic infections that occur with CLL are almost exclusively related to immunosuppression caused by chemotherapeutic drugs used to treat CLL. We report a case of Pneumocystis jirovecii (PJ) pneumonia that occurred in a patient with untreated CLL with pulmonary involvement. We suspect that PJ pneumonia resulted from an inadequate immune response in the lung parenchyma resulting from excessive local accumulation of CLL cells.

  7. 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

  8. Early stem cell transplantation for chronic lymphocytic leukaemia: a chance for cure?

    PubMed Central

    Dreger, P.; von Neuhoff, N.; Kuse, R.; Sonnen, R.; Glass, B.; Uharek, L.; Schoch, R.; Löffler, H.; Schmitz, N.

    1998-01-01

    B-cell chronic lymphocytic leukaemia (CLL) cannot be cured by conventional therapy. To improve the prognosis of patients with CLL, we have designed a sequential treatment strategy that comprises intensive chemotherapy for mobilization of peripheral blood progenitor cells (PBPCs) and induction of minimal disease, followed by high-dose radiochemotherapy with stem cell reinfusion and post-transplant molecular monitoring by polymerase chain reaction (PCR) amplification of the complementary determining region III (CDRIII) gene. In a prospective study, we have evaluated this protocol in 18 patients with CLL, also including early stages of the disease. The median age was 49 (29-61) years; Binet stages were A, six; B, nine; and C, three. Adverse prognostic factors [high lymphocyte count and/or diffuse bone marrow (BM) infiltration] were present in 16 out of 18 patients. All patients showed a clone-specific molecular marker as demonstrated by PCR amplification of CDRIII rearrangements. For stem cell mobilization and reduction of tumour load, one to two cycles of Dexa-BEAM chemotherapy were administered, resulting in minimal disease (circulating lymphoma cells <1 x 10(9) l(-1); BM infiltration <20%; lymphomas <2 cm) in 16 out of 18 patients, including four patients who already had minimal disease before Dexa-BEAM. Stem cell harvesting was successful in 14 patients. All grafts [three BM, 11 peripheral blood (PB)] were purged from leukaemic cells using immunomagnetic methods. Thirteen patients having achieved minimal disease were reinfused with purged autologous stem cells (ASC) after preparation with total body irradiation and cyclophosphamide. Engraftment was delayed in patients receiving BM (n = 3) but prompt [neutrophils >0.5 x 10(9) l(-1) after 10 (9-13) days, platelets >20 x 10(9) l(-1) after 11 (9-214) days] in patients restored with PBPCs (n = 10). Procedure-related deaths did not occur. Although the results of CDRIII PCR suggest persistence or recurrence of the

  9. The autocrine motility factor receptor is overexpressed on the surface of B cells in Binet C chronic lymphocytic leukemia.

    PubMed

    Grund, Sofia; Olsson, Bob; Jernås, Margareta; Jacobsson, Stefan; Swolin, Birgitta; Nabi, Ivan R; Carlsson, Lena; Wadenvik, Hans

    2011-12-01

    Chronic lymphocytic leukemia (CLL) is a heterogeneous disease with a clinical spectrum reaching from discrete lymphocytosis to extensive enlargement of lymph nodes, spleen and liver, and bone marrow failure. The aim of this study was to identify genes that differentiate between patients with disease stage A vs. C according to Binet in order to better understand the disease. To achieve this, we performed DNA microarray analysis on B cells from CLL patients with stage A and C according to Binet and matched controls. Between CLL patients and controls, there were 1,528 differentially expressed genes and 360 genes were differentially expressed between Binet A and C patients. Due to the sheer number of regulated genes, we focused on the autocrine motility factor receptor (AMFR). AMFR has not previously been investigated in hematological disorders, but high expression of AMFR correlates with a more advanced stage and invasive potential in several human tumors. AMFR mRNA expression was higher in Binet A compared with Binet C patients (P=0.0053) and healthy controls (P=0.0051). Total AMFR protein was higher in Binet A patients compared to Binet C as analyzed by intracellular flow cytometry. However, AMFR exist both in the ER involved in protein degradation and on the cell surface involved in metastasis and cell motility. Cell surface AMFR was increased in Binet C compared with Binet A+B (P=0.016). In conclusion, the mRNA levels reflect the total amount of AMFR, whereas cell surface expression is associated with progression in CLL.

  10. Induction of B-lymphocyte antigens on the chronic myeloid leukemic cell line K562 using sodium butyrate.

    PubMed

    Fraser, J K; Berridge, M V

    1987-05-01

    Chronic myeloid leukemia (CML) is a disorder arising from a defect in the hemopoietic stem cell. Consequently, the malignant clone can involve all cells within the stem cell's capacity for differentiation, including erythrocytes, granulocytes, monocytes, megakaryocytes, and lymphocytes. Similarly, the K562 cell line, which was derived from a patient with CML, has been shown to be capable of differentiation towards erythrocytes, granulocytes, monocytes, and megakaryocytes, and in this respect may represent a model of the hemopoietic stem cell. However, although K562 shows properties of a myeloid stem cell, no lymphocyte-specific features or differentiation have yet been described. In the present study, K562 cells have been induced to differentiate by culture in the presence of sodium butyrate. The direction and extent of induced differentiation over 12 days were determined with a panel of monoclonal antibodies and with cytochemical stains. This treatment consistently induced expression of pre-B-cell markers, including B-lymphocyte-specific B4 and B1, and of the common acute lymphoblastic leukemia antigen (CALLA), recognized by J5. In addition to the increased expression of B-lymphocyte markers, butyrate induction of K562 resulted in a decrease in granulocyte markers, increases in certain monocyte and platelet markers, and an increase in beta 2 microglobulin expression. Butyrate-induced expression of B-lymphocyte markers was not observed with the myelomonocytic cell line U937. The expression of B-lymphocyte-specific antigens on butyrate-induced K562 may result from the relaxed control of gene expression, but alternatively these observations may indicate the lymphoid-myeloid stem cell nature of K562.

  11. Increased frequency of micronuclei in the lymphocytes of patients chronically infected with hepatitis B or hepatitis C virus

    PubMed Central

    Leite, Samantha Therezinha Almeida Pereira; da Silva, Marilene Borges; Pepato, Marco Andrey; Souto, Francisco José Dutra; dos Santos, Raquel Alves; Bassi-Branco, Carmen Lucia

    2013-01-01

    In this study, we analysed the frequency of micronuclei (MN), nucleoplasmic bridges (NPBs) and nuclear buds (NBUDs) and evaluated mutagen-induced sensitivity in the lymphocytes of patients chronically infected with hepatitis B virus (HBV) or hepatitis C virus (HCV). In total, 49 patients with chronic viral hepatitis (28 HBV-infected and 21 HCV-infected patients) and 33 healthy, non-infected blood donor controls were investigated. The frequencies (‰) of MN, NPBs and NBUDs in the controls were 4.41 ± 2.15, 1.15 ± 0.97 and 2.98 ± 1.31, respectively. The frequencies of MN and NPBs were significantly increased (p < 0.0001) in the patient group (7.01 ± 3.23 and 2.76 ± 2.08, respectively) compared with the control group. When considered separately, the HBV-infected patients (7.18 ± 3.57) and HCV-infected patients (3.27 ± 2.40) each had greater numbers of MN than did the controls (p < 0.0001). The HCV-infected patients displayed high numbers of NPBs (2.09 ± 1.33) and NBUDs (4.38 ± 3.28), but only the HBV-infected patients exhibited a significant difference (NPBs = 3.27 ± 2.40, p < 0.0001 and NBUDs = 4.71 ± 2.79, p = 0.03) in comparison with the controls. Similar results were obtained for males, but not for females, when all patients or the HBV-infected group was compared with the controls. The lymphocytes of the infected patients did not exhibit sensitivity to mutagen in comparison with the lymphocytes of the controls (p = 0.06). These results showed that the lymphocytes of patients who were chronically infected with HBV or HCV presented greater chromosomal instability. PMID:24626305

  12. Regulatory T-cell modulation by green tea in chronic lymphocytic leukemia.

    PubMed

    D'Arena, G; Simeon, V; De Martino, L; Statuto, T; D'Auria, F; Volpe, S; Deaglio, S; Maidecchi, A; Mattoli, L; Mercati, V; Musto, P; De Feo, V

    2013-01-01

    Regulatory T cells (Tregs) are considered to be key immunomodulatory cells of the immune system and are increased in chronic lymphocytic leukemia (CLL). Rai stage 0 identifies patients with early stage CLL for which there is no effective intervention at the present time and a "wait and see" policy is usually adopted. Some biological and clinical studies have reported that green tea constituents, such as epigallocatechin-gallate (EGCG), have antitumor effects on hematologic malignancies including CLL. We report data on a clinical trial in which green tea extracts were given orally to 12 patients with stage 0 CLL and 12 healthy subjects. Ten patients and 10 controls completed the 6-month scheduled therapy. Two patients and 2 controls stopped therapy within 1 month because of tachycardia and epigastralgia. Eight out 10 evaluable patients (80 percent) showed a reduction of lymphocytosis and absolute number of circulating Tregs, as well. One patient (10 percent) had a stabilization of lymphocytosis and a reduction of Tregs, and 1 patient (10 percent) showed an increase of both lymphocytosis and Tregs. Only the non-responding patient progressed after 5 months from the end of green tea administration and chemotherapy was given. Interestingly, both IL-10 and TGF-beta serum levels declined throughout the green tea intake period, in both patients and controls. These data seem to indicate that green tea is able to modulate circulating Tregs in CLL patients with early stage of the disease. This can result in the control of lymphocytosis as well as in the prevention of disease progression.

  13. 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

  14. A novel diagnostic biosensor for distinguishing immunoglobulin mutated and unmutated types of chronic lymphocytic leukemia.

    PubMed

    Ensafi, Ali A; Amini, Maryam; Rezaei, Behzad; Talebi, Majid

    2016-03-15

    In chronic lymphocytic leukemia (CLL), the immunoglobulin heavy-chain variable (IgVH) region may be mutated (Ig-mutated CLL) or unmutated (Ig-unmutated CLL); and the presence or absence of mutations in this region of CLL cells distinguishes two clinically distinct forms. It is important for physicians to distinguish between patients with Ig-unmutated CLL, where typically have more indolent disease with median survivals close to 25 years, and Ig-mutated CLL, where have more aggressive disease with median survivals around eight years. In this work, a biosensor capable of diagnosis and distinguishing between these two types of CLL was reported. The biosensor was fabricated by modifying a gold electrode with gold nanoparticles (AuNPS) followed by coating of ZAP70 oligonucleotide probe on the surface to detect specific sequence of ZAP70 gene. ZAP70 could predict the IgVH mutation status and is a good marker for differentiating Ig-mutated and Ig-unmutated CLL and serve as prognostic marker. First, we focused on achieving hybridization between probe and its complementary sequence. Hybridization between probe and target was determined with electrochemical impedance spectroscopy (EIS). Then, our efforts turned to optimize the conditions for the detection of any point mutation and also to maximize the selectivity. Under optimal conditions, the biosensor has a good calibration range between 2.0 × 10(-14) and 1.0 × 10(-9)molL(-1), with ZAP70 DNA sequence detection limit of 4.0 × 10(-15)molL(-1). We successfully detect hybridization first in synthetic samples, and ultimately in blood samples from patients. Experimental results illustrated that the nanostructured biosensor clearly discriminates between mutated and non-mutated CLL and predict the IgVH mutation status, which it has been considered as the single most informative stage independent prognostic factor in CLL.

  15. Randomized phase 2 study of obinutuzumab monotherapy in symptomatic, previously untreated chronic lymphocytic leukemia

    PubMed Central

    Flynn, Joseph M.; Kipps, Thomas J.; Boxer, Michael; Kolibaba, Kathryn S.; Carlile, David J.; Fingerle-Rowson, Guenter; Tyson, Nicola; Hirata, Jamie; Sharman, Jeff P.

    2016-01-01

    Obinutuzumab is a glycoengineered, type 2 anti-CD20 humanized antibody with single-agent activity in relapsed chronic lymphocytic leukemia (CLL). With other CD20 antibodies, a dose-response relationship has been shown. We therefore performed a randomized phase 2 study in symptomatic, untreated CLL patients to evaluate if an obinutuzumab dose response exists. Obinutuzumab was given at a dose of 1000 mg (100 mg IV day 1, 900 mg day 2, 1000 mg day 8 and day 15 of cycle 1; 1000 mg day 1 of cycles 2-8) or 2000 mg (100 mg IV day 1, 900 mg day 2, 1000 mg day 3, 2000 mg day 8 and day 15 of cycle 1; 2000 mg day 1 of cycles 2-8). The primary end point was overall response rate (ORR). Eighty patients were enrolled with similar demographics: median age 67 years, 41% high-risk Rai disease, and 10% del(17p)(13.1). ORR (67% vs 49%, P = .08) and complete response (CR) or CR with incomplete cytopenia response (20% vs 5%) favored 2000 mg obinutuzumab. Overall, therapy was well tolerated, and infusion events were manageable. This study demonstrates significant efficacy of obinutuzumab monotherapy, for 1000 mg as well as for 2000 mg, in untreated CLL patients with acceptable toxicity. Although exploratory, a dose-response relationship may exist, but its relevance to improving progression-free survival is uncertain and will require further follow-up. This trial was registered at www.clinicaltrials.gov as #NCT01414205. PMID:26472752

  16. Telomere shortening associated with increased genomic complexity in chronic lymphocytic leukemia.

    PubMed

    Dos Santos, Patricia; Panero, Julieta; Palau Nagore, Virginia; Stanganelli, Carmen; Bezares, Raimundo F; Slavutsky, Irma

    2015-11-01

    Telomeric dysfunction has been proposed as an emerging prognostic factor in chronic lymphocytic leukemia (CLL). We have explored the relationship between telomere length (TL) and chromosome alterations studied by fluorescence in situ hybridization (FISH) and conventional cytogenetics in 107 newly diagnosed CLL patients; 61 normal controls were also evaluated. Results were correlated with clinical parameters and outcome. Absolute TL measurement was carried out on DNA samples by real-time quantitative PCR. A significant telomere shortening in patients compared to controls was observed (p = 0.0001). The analysis taking into account FISH risk groups showed shorter TLs in cases with del11q/17p compared to patients with 13q14 deletion as a single alteration (p = 0.0037), no alterations (NA) (p = 0.028), and cases with abnormal karyotypes (p = 0.014). In addition, a significant TL reduction in cases with two or more anomalies with respect to those with NA (p = 0.033) and with one alteration (p = 0.045), and no differences compared to cases with deletions 11q/17p were observed. Patients with only one anomaly did not show statistical differences with respect to controls; meanwhile, a significant TL reduction in cases with two or more aberrations was observed (p = 0.025). The shortest telomeres were associated to 11q/17p deletion with significant differences compared to the remaining groups (p ≤ 0.045). Significantly shorter treatment free survival in patients with two or more alterations compared to those with NA plus one abnormality was observed (p = 0.0006). Our findings support the association between short TL and chromosome alterations in CLL and indicate the importance of telomere dysfunction in driving genomic instability in this pathology.

  17. Whole-exome sequencing in relapsing chronic lymphocytic leukemia: clinical impact of recurrent RPS15 mutations

    PubMed Central

    Ljungström, Viktor; Cortese, Diego; Young, Emma; Pandzic, Tatjana; Mansouri, Larry; Plevova, Karla; Ntoufa, Stavroula; Baliakas, Panagiotis; Clifford, Ruth; Sutton, Lesley-Ann; Blakemore, Stuart J.; Stavroyianni, Niki; Agathangelidis, Andreas; Rossi, Davide; Höglund, Martin; Kotaskova, Jana; Juliusson, Gunnar; Belessi, Chrysoula; Chiorazzi, Nicholas; Panagiotidis, Panagiotis; Langerak, Anton W.; Smedby, Karin E.; Oscier, David; Gaidano, Gianluca; Schuh, Anna; Davi, Frederic; Pott, Christiane; Strefford, Jonathan C.; Trentin, Livio; Pospisilova, Sarka; Ghia, Paolo; Stamatopoulos, Kostas; Sjöblom, Tobias

    2016-01-01

    Fludarabine, cyclophosphamide, and rituximab (FCR) is first-line treatment of medically fit chronic lymphocytic leukemia (CLL) patients; however, despite good response rates, many patients eventually relapse. Although recent high-throughput studies have identified novel recurrent genetic lesions in adverse prognostic CLL, the mechanisms leading to relapse after FCR therapy are not completely understood. To gain insight into this issue, we performed whole-exome sequencing of sequential samples from 41 CLL patients who were uniformly treated with FCR but relapsed after a median of 2 years. In addition to mutations with known adverse-prognostic impact (TP53, NOTCH1, ATM, SF3B1, NFKBIE, and BIRC3), a large proportion of cases (19.5%) harbored mutations in RPS15, a gene encoding a component of the 40S ribosomal subunit. Extended screening, totaling 1119 patients, supported a role for RPS15 mutations in aggressive CLL, with one-third of RPS15-mutant cases also carrying TP53 aberrations. In most cases, selection of dominant, relapse-specific subclones was observed over time. However, RPS15 mutations were clonal before treatment and remained stable at relapse. Notably, all RPS15 mutations represented somatic missense variants and resided within a 7 amino-acid, evolutionarily conserved region. We confirmed the recently postulated direct interaction between RPS15 and MDM2/MDMX and transient expression of mutant RPS15 revealed defective regulation of endogenous p53 compared with wild-type RPS15. In summary, we provide novel insights into the heterogeneous genetic landscape of CLL relapsing after FCR treatment and highlight a novel mechanism underlying clinical aggressiveness involving a mutated ribosomal protein, potentially representing an early genetic lesion in CLL pathobiology. PMID:26675346

  18. Sex chromosome loss may represent a disease-associated clonal population in chronic lymphocytic leukemia.

    PubMed

    Chapiro, Elise; Antony-Debre, Ileana; Marchay, Nathalie; Parizot, Christophe; Lesty, Claude; Cung, Hong-Anh; Mathis, Stephanie; Grelier, Aurore; Maloum, Karim; Choquet, Sylvain; Azgui, Zahia; Uzunov, Madalina; Leblond, Veronique; Merle-Beral, Helene; Sutton, Laurent; Davi, Frederic; Nguyen-Khac, Florence

    2014-03-01

    Whether sex chromosome loss (SCL) is an age-related phenomenon or a cytogenetic marker of hematological disease is unclear. To address this issue in chronic lymphocytic leukemia (CLL), we investigated 20 cases with X or Y chromosome loss detected by conventional cytogenetics (CC). The frequency of SCL was low in CLL (2.3%). It was the sole abnormality, as detected by CC, in 10/20 (50%) patients. Fluorescence in situ hybridization (FISH) analyses confirmed SCL in all patients tested, present in 5-88% of cells (median: 68%). Deletions of 13q were observed by FISH in 16/20 (80%) patients. Compared with CLL without SCL, SCL was significantly associated with 13q deletion, especially when bi-allelic (P = 0.04). Co-hybridization analyses showed that SCL could be a concomitant, primary or secondary change, or be present in an independent clone. FISH analyses were performed on blood sub-populations isolated by Ficoll or flow cytometry. Comparing mononuclear cells (including CLL cells) and polynuclear cells separated by Ficoll, a maximum of 2% of polynuclear cells were found with SCL, whereas mononuclear cells exhibited a significantly higher loss frequency (range: 6-87%) (P = 0.03). Comparing B-cells (including CLL cells) and T-cells sorted by flow cytometry, the proportion of B-CD19+ cells with SCL was significantly higher (range: 88-96%) than that observed in T-CD3+ cells (range: 2-6%) (P = 0.008). We conclude that SCL has to be considered as a clonal aberration in CLL that may participate in the oncogenic process.

  19. Potential therapeutic application of gold nanoparticles in B-chronic lymphocytic leukemia (BCLL): enhancing apoptosis

    PubMed Central

    Mukherjee, Priyabrata; Bhattacharya, Resham; Bone, Nancy; Lee, Yean K; Patra, Chitta Ranjan; Wang, Shanfeng; Lu, Lichun; Secreto, Charla; Banerjee, Pataki C; Yaszemski, Michael J; Kay, Neil E; Mukhopadhyay, Debabrata

    2007-01-01

    B-Chronic Lymphocytic Leukemia (CLL) is an incurable disease predominantly characterized by apoptosis resistance. We have previously described a VEGF signaling pathway that generates apoptosis resistance in CLL B cells. We found induction of significantly more apoptosis in CLL B cells by co-culture with an anti-VEGF antibody. To increase the efficacy of these agents in CLL therapy we have focused on the use of gold nanoparticles (GNP). Gold nanoparticles were chosen based on their biocompatibility, very high surface area, ease of characterization and surface functionalization. We attached VEGF antibody (AbVF) to the gold nanoparticles and determined their ability to kill CLL B cells. Gold nanoparticles and their nanoconjugates were characterized using UV-Visible spectroscopy (UV-Vis), transmission electron microscopy (TEM), thermogravimetric analysis (TGA) and X-ray photoelectron spectroscopy (XPS). All the patient samples studied (N = 7) responded to the gold-AbVF treatment with a dose dependent apoptosis of CLL B cells. The induction of apoptosis with gold-AbVF was significantly higher than the CLL cells exposed to only AbVF or GNP. The gold-AbVF treated cells showed significant down regulation of anti-apoptotic proteins and exhibited PARP cleavage. Gold-AbVF treated and GNP treated cells showed internalization of the nanoparticles in early and late endosomes and in multivesicular bodies. Non-coated gold nanoparticles alone were able to induce some levels of apoptosis in CLL B cells. This paper opens up new opportunities in the treatment of CLL-B using gold nanoparticles and integrates nanoscience with therapy in CLL. In future, potential opportunities exist to harness the optoelectronic properties of gold nanoparticles in the treatment of CLL. PMID:17488514

  20. 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.

  1. p53-dependent non-coding RNA networks in chronic lymphocytic leukemia.

    PubMed

    Blume, C J; Hotz-Wagenblatt, A; Hüllein, J; Sellner, L; Jethwa, A; Stolz, T; Slabicki, M; Lee, K; Sharathchandra, A; Benner, A; Dietrich, S; Oakes, C C; Dreger, P; te Raa, D; Kater, A P; Jauch, A; Merkel, O; Oren, M; Hielscher, T; Zenz, T

    2015-10-01

    Mutations of the tumor suppressor p53 lead to chemotherapy resistance and a dismal prognosis in chronic lymphocytic leukemia (CLL). Whereas p53 targets are used to identify patient subgroups with impaired p53 function, a comprehensive assessment of non-coding RNA targets of p53 in CLL is missing. We exploited the impaired transcriptional activity of mutant p53 to map out p53 targets in CLL by small RNA sequencing. We describe the landscape of p53-dependent microRNA/non-coding RNA induced in response to DNA damage in CLL. Besides the key p53 target miR-34a, we identify a set of p53-dependent microRNAs (miRNAs; miR-182-5p, miR-7-5p and miR-320c/d). In addition to miRNAs, the long non-coding RNAs (lncRNAs) nuclear enriched abundant transcript 1 (NEAT1) and long intergenic non-coding RNA p21 (lincRNA-p21) are induced in response to DNA damage in the presence of functional p53 but not in CLL with p53 mutation. Induction of NEAT1 and lincRNA-p21 are closely correlated to the induction of cell death after DNA damage. We used isogenic lymphoma cell line models to prove p53 dependence of NEAT1 and lincRNA-p21. The current work describes the p53-dependent miRNome and identifies lncRNAs NEAT1 and lincRNA-p21 as novel elements of the p53-dependent DNA damage response machinery in CLL and lymphoma.

  2. Night shift work and chronic lymphocytic leukemia in the MCC-Spain case-control study.

    PubMed

    Costas, Laura; Benavente, Yolanda; Olmedo-Requena, Rocío; Casabonne, Delphine; Robles, Claudia; Gonzalez-Barca, Eva-Maria; de la Banda, Esmeralda; Alonso, Esther; Aymerich, Marta; Tardón, Adonina; Marcos-Gragera, Rafael; Gimeno-Vázquez, Eva; Gómez-Acebo, Inés; Papantoniou, Kyriaki; Castaño-Vinyals, Gemma; Aragonés, Nuria; Pollán, Marina; Kogevinas, Manolis; de Sanjosé, Silvia

    2016-11-01

    Chronic lymphocytic leukemia (CLL) has few known modifiable risk factors. Recently, circadian disruption has been proposed as a potential contributor to lymphoid neoplasms' etiology. Serum melatonin levels have been found to be significantly lower in CLL subjects compared with healthy controls, and also, CLL prognosis has been related to alterations in the circadian molecular signaling. We performed the first investigation of an association between night shift work and CLL in 321 incident CLL cases and 1728 population-based controls in five areas of Spain. Participants were interviewed face-to-face by trained interviewers to collect information on sociodemographic factors, familial, medical and occupational history, including work shifts and other lifestyle factors. We used logistic regression models adjusted for potential confounders to estimate odds ratios (OR) and 95% confidence intervals (CI). Seventy-nine cases (25%) and 339 controls (20%) had performed night work. Overall, working in night shifts was not associated with CLL (OR = 1.06; 95% CI = 0.78-1.45, compared with day work). However, long-term night shift (>20 years) was positively associated with CLL (OR(tertile 3 vs . day-work)  = 1.77; 95% = 1.14-2.74), although no linear trend was observed (P trend = 0.18). This association was observed among those with rotating (OR(tertile 3 vs . day-work)  = 2.29; 95% CI = 1.33-3.92; P trend = 0.07), but not permanent night shifts (OR(tertile 3 vs . day-work) = 1.16; 95% CI = 0.60-2.25; P trend = 0.86). The association between CLL and long-term rotating night shift warrants further investigation.

  3. Modern treatment in chronic lymphocytic leukemia: impact on survival and efficacy in high-risk subgroups

    PubMed Central

    Cuneo, Antonio; Cavazzini, Francesco; Ciccone, Maria; Daghia, Giulia; Sofritti, Olga; Saccenti, Elena; Negrini, Massimo; Rigolin, Gian Matteo

    2014-01-01

    Treatment of chronic lymphocytic leukemia (CLL) has dramatically changed over the last years, with significant improvement in overall survival (OS) and increased efficacy in genetically defined “high-risk” disease. Besides prospective clinical trials usually enrolling young and fit patients, retrospective studies were performed comparing the outcome of patients belonging to different age groups and showing longer survival in patients diagnosed in the most recent periods. In patients younger than 70 years the 10-year relative survival was 43–53% in the 1980s as compared with 59–63% in the 2000s. Likewise, the 10-year relative survival in patients >70 years was 22–42% in the 1980s and 46–55% in the 2000s. Improved outcome derived in part by the introduction of effective regimens in genetically defined “high-risk” disease (i.e., 17p−, 11q−, TP53, NOTCH1, SF3B1 mutations), especially in the younger and/or fit patients. The unfavorable prognostic significance of 11q− was overcome by chemoimmunotherapy. High-dose steroids with anti-CD52 appeared to improve the response rate in 17p-/TP53 mutated cases and allogeneic transplantation achieved prolonged disease control irrespective of high-risk disease. Further improvement is being generated by the new anti-CD20 obinutuzumab in the elderly and by mechanism-based treatment using kinase-targeting agents or anti-BCL2 molecules yielding high-response rate and impressive progression-free survival in the chemorefractory setting as well as in previously untreated patients. PMID:24648042

  4. Validation of ZAP-70 methylation and its relative significance in predicting outcome in chronic lymphocytic leukemia

    PubMed Central

    Claus, Rainer; Lucas, David M.; Ruppert, Amy S.; Williams, Katie E.; Weng, Daniel; Patterson, Kara; Zucknick, Manuela; Oakes, Christopher C.; Rassenti, Laura Z.; Greaves, Andrew W.; Geyer, Susan; Wierda, William G.; Brown, Jennifer R.; Gribben, John G.; Barrientos, Jacqueline C.; Rai, Kanti R.; Kay, Neil E.; Kipps, Thomas J.; Shields, Peter; Zhao, Weiqiang; Grever, Michael R.; Plass, Christoph

    2014-01-01

    ZAP-70 methylation 223 nucleotides downstream of transcription start (CpG+223) predicts outcome in chronic lymphocytic leukemia (CLL), but its impact relative to CD38 and ZAP-70 expression or immunoglobulin heavy chain variable region (IGHV) status is uncertain. Additionally, standardizing ZAP-70 expression analysis has been unsuccessful. CpG+223 methylation was quantitatively determined in 295 untreated CLL cases using MassARRAY. Impact on clinical outcome vs CD38 and ZAP-70 expression and IGHV status was evaluated. Cases with low methylation (<20%) had significantly shortened time to first treatment (TT) and overall survival (OS) (P < .0001). For TT, low methylation defined a large subset of ZAP-70 protein-negative cases with significantly shortened TT (median, 8.0 vs 3.9 years for high vs low methylation; hazard ratio [HR] = 0.43; 95% confidence interval [CI], 0.25-0.74). Conversely, 16 ZAP-70 protein-positive cases with high methylation had poor outcome (median, 1.1 vs 2.3 years for high vs low methylation; HR = 1.62; 95% CI, 0.87-3.03). For OS, ZAP-70 methylation was the strongest risk factor; CD38 and ZAP-70 expression or IGHV status did not significantly improve OS prediction. A pyrosequencing assay was established that reproduced the MassARRAY data (κ coefficient > 0.90). Thus, ZAP-70 CpG+223 methylation represents a superior biomarker for TT and OS that can be feasibly measured, supporting its use in risk-stratifying CLL. PMID:24868078

  5. Endothelin-1 Promotes Survival and Chemoresistance in Chronic Lymphocytic Leukemia B Cells through ETA Receptor

    PubMed Central

    Martinelli, Silvia; Castelli, Ilaria; Valenti, Vanessa; Rossi, Davide; Bonacorsi, Goretta; Zucchini, Patrizia; Potenza, Leonardo; Vallisa, Daniele; Gattei, Valter; Poeta, Giovanni Del; Forconi, Francesco; Gaidano, Gianluca; Narni, Franco; Luppi, Mario; Marasca, Roberto

    2014-01-01

    The endothelin axis, comprising endothelins (ET-1, ET-2 and ET-3) and their receptors (ETAR and ETBR), has emerged as relevant player in tumor growth and metastasis. Here, we investigated the involvement of ET-1/ETAR axis in chronic lymphocytic leukemia (CLL). CLL cells expressed higher levels of ET-1 and ETA receptor as compared to normal B cells. ET-1 peptide stimulated phosphoinositide-3-kinase and mitogen-activated protein kinase signaling pathways, improved survival and promoted proliferation of leukemic cells throughout ETAR triggering. Moreover, the blockade of ETAR by the selective antagonist BQ-123 inhibited the survival advantage acquired by CLL cells in contact with endothelial layers. We also found that blocking ETAR via BQ-123 interferes with ERK phosphorylation and CLL pro-survival effect mediated by B-cell receptor (BCR) activation. The pro-apoptotic effect of phosphoinositide-3-kinase δ inhibitor idelalisib and mitogen-activated protein kinase inhibitor PD98059 was decreased by the addition of ET-1 peptide. Then, ET-1 also reduced the cytotoxic effect of fludarabine on CLL cells cultured alone or co-cultured on endothelial layers. ETAR blockade by BQ-123 inhibited the ET-1-mediated protection against drug-induced apoptosis. Lastly, higher plasma levels of big ET-1 were detected in patients (n = 151) with unfavourable prognostic factors and shorter time to first treatment. In conclusion, our data describe for the first time a role of ET-1/ETAR signaling in CLL pathobiology. ET-1 mediates survival, drug-resistance, and growth signals in CLL cells that can be blocked by ETAR inhibition. PMID:24901342

  6. Selective Bcl-2 inhibition to treat chronic lymphocytic leukemia and non-Hodgkin lymphoma.

    PubMed

    Ng, Samuel Y; Davids, Matthew S

    2014-04-01

    ABT-199, a second-generation BH3 mimetic, is an orally bioavailable, small molecule inhibitor that selectively targets B-cell lymphoma/leukemia 2 (Bcl-2). Bcl-2 is a key protein that inhibits the intrinsic mitochondrial pathway of apoptosis. First-generation BH3 mimetics such as navitoclax (ABT-263) had a broad range of inhibitory activity against Bcl-2 family members, including Bcl-2, Bcl-XL, and Bcl-w. This drug demonstrated antitumor activity in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL); however, on-target Bcl-XL inhibition led to dose-dependent thrombocytopenia and posed a barrier to maximizing the activity of this agent. Through an elegant reengineering of navitoclax, ABT-199 was developed as a Bcl-2-selective small molecule inhibitor. In preclinical studies, ABT-199 was shown to have greater than 100-fold selectivity for Bcl-2 over Bcl-XL. This selectivity has been consistent with the early results of the ongoing phase 1 clinical trial of ABT-199 in which the drug has demonstrated high rates of activity in relapsed/refractory CLL and NHL without dose-dependent thrombocytopenia. On-target tumor lysis syndrome (TLS) has been observed in a subset of patients treated with ABT-199, but changes in initial dosing and stepwise dose escalation have now been implemented to mitigate this risk. Ongoing correlative studies are being performed to help identify patients with the highest chance of response and the greatest risk for TLS. PMID:25003352

  7. Ongoing in vivo immunoglobulin class switch DNA recombination in chronic lymphocytic leukemia B cells.

    PubMed

    Cerutti, Andrea; Zan, Hong; Kim, Edmund C; Shah, Shefali; Schattner, Elaine J; Schaffer, András; Casali, Paolo

    2002-12-01

    Chronic lymphocytic leukemia (CLL) results from the expansion of malignant CD5(+) B cells that usually express IgD and IgM. These leukemic cells can give rise in vivo to clonally related IgG(+) or IgA(+) elements. The requirements and modalities of this process remain elusive. Here we show that leukemic B cells from 14 of 20 CLLs contain the hallmarks of ongoing Ig class switch DNA recombination (CSR), including extrachromosomal switch circular DNAs and circle transcripts generated by direct S micro -->Sgamma, S micro -->Salpha, and S micro -->Sepsilon as well as sequential Sgamma-->Salpha and Sgamma-->Sepsilon CSR. Similar CLL B cells express transcripts for activation-induced cytidine deaminase, a critical component of the CSR machinery, and contain germline I(H)-C(H) and mature V(H)DJ(H)-C(H) transcripts encoded by multiple Cgamma, Calpha, and Cepsilon genes. Ongoing CSR occurs in only a fraction of the CLL clone, as only small proportions of CD5(+)CD19(+) cells express surface IgG or IgA and lack IgM and IgD. In vivo class-switching CLL B cells down-regulate switch circles and circle transcripts in vitro unless exposed to exogenous CD40 ligand and IL-4. In addition, CLL B cells that do not class switch in vivo activate the CSR machinery and secrete IgG, IgA, or IgE upon in vitro exposure to CD40 ligand and IL-4. These findings indicate that in CLL at least some members of the malignant clone actively differentiate in vivo along a pathway that induces CSR. They also suggest that this process is elicited by external stimuli, including CD40 ligand and IL-4, provided by bystander immune cells.

  8. 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. PMID:27118540

  9. Spontaneous Immunity Against the Receptor Tyrosine Kinase ROR1 in Patients with Chronic Lymphocytic Leukemia

    PubMed Central

    Hojjat-Farsangi, Mohammad; Jeddi-Tehrani, Mahmood; Daneshmanesh, Amir Hossein; Mozaffari, Fariba; Moshfegh, Ali; Hansson, Lotta; Razavi, Seyed Mohsen; Sharifian, Ramazan Ali; Rabbani, Hodjattallah; Österborg, Anders; Mellstedt, Håkan; Shokri, Fazel

    2015-01-01

    Background ROR1 is a receptor tyrosine kinase expressed in chronic lymphocytic leukemia (CLL) and several other malignancies but absent in most adult normal tissues. ROR1 is considered an onco-fetal antigen. In the present study we analysed spontaneous humoral and cellular immunity against ROR1 in CLL patients. Materials and Methods Antibodies against ROR1 were analysed in 23 patients and 20 healthy donors by ELISA and Western blot. Purified serum IgG from patients was tested for cytotoxicity against CLL cells using the MTT viability assay. A cellular immune response against ROR1 derived HLA-A2 restricted 9 aa and 16 aa long peptides were analysed using peptide loaded dendritic cells co-cultured with autologous T cells from CLL patients (n = 9) and healthy donors (n = 6). IFN-γ, IL-5 and IL-17A-secreting T cells were assessed by ELISPOT and a proliferative response using a H3-thymidine incorporation assay. Results The majority of CLL patients had antibodies against ROR1. Significantly higher titers of anti-ROR1 antibodies were noted in patients with non-progressive as compared to progressive disease. The extracellular membrane-close ROR1 KNG domain seemed to be an immunodominant epitope. Ten patients with high titers of anti-ROR1 binding antibodies were tested for cytotoxicity. Five of those had cytotoxic anti-ROR1 antibodies against CLL cells. ROR1-specific IFN-γ and IL-17A producing T cells could be detected in CLL patients, preferentially in non-progressive as compared to patients with progressive disease (p<0.05). Conclusion ROR1 seemed to spontaneously induce a humoral as well as a T cell response in CLL patients. The data support the notion that ROR1 might be a specific neo-antigen and may serve as a target for immunotherapy. PMID:26562161

  10. Autologous Peripheral Blood Stem Cell Transplant Followed by Donor Bone Marrow Transplant in Treating Patients With High-Risk Hodgkin Lymphoma, Non-Hodgkin Lymphoma, Multiple Myeloma, or Chronic Lymphocytic Leukemia

    ClinicalTrials.gov

    2016-06-17

    B-Cell Prolymphocytic Leukemia; Plasma Cell Leukemia; Progression of Multiple Myeloma or Plasma Cell Leukemia; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Non-Hodgkin Lymphoma; Recurrent Childhood Hodgkin Lymphoma; Recurrent Childhood Non-Hodgkin Lymphoma; Recurrent Chronic Lymphocytic Leukemia; Recurrent Plasma Cell Myeloma; Recurrent Small Lymphocytic Lymphoma; Refractory Childhood Hodgkin Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Non-Hodgkin Lymphoma; Refractory Plasma Cell Myeloma; Refractory Small Lymphocytic Lymphoma; T-Cell Prolymphocytic Leukemia; Waldenstrom Macroglobulinemia

  11. Advances in the etiology of chronic pancreatitis.

    PubMed

    Lerch, Markus M; Mayerle, Julia; Aghdassi, Ali A; Budde, Christoph; Nitsche, Claudia; Sauter, Gabriele; Persike, Maria; Günther, Annett; Simon, Peter; Weiss, F Ulrich

    2010-01-01

    In the past, chronic pancreatitis has been regarded as a fairly uniform and largely untreatable disorder that most commonly affects patients who both lack gainful employment or adequate insurance coverage and have a tendency to smoke and drink. Large clinical trials suggest that this perception is not only misguided and discriminatory but also not based on facts. We forgot that the perception of chronic liver disease was similar before World War II, and just like liver cirrhosis the fibrosis and cirrhosis of the pancreas--i.e. chronic pancreatitis--is the end result of a range of environmental, inflammatory, infectious and genetic disorders. A growing number of these have only recently been recognized as a distinct entity and several of which are becoming truly treatable. A large proportion of the risk for developing pancreatitis is conveyed by genetic risk factors, and we estimate that less than half of those have been identified so far. The same holds true for protective factors that can prevent pancreatitis, even in the face of excessive alcohol abuse. Various gene mutations and polymorphisms appear to determine an individual's susceptibility for developing pancreatic disease, for the severity of the disease, and for the disease progression. The spectrum of genotype/phenotype associations ranges from straightforward autosomal dominant traits with near-complete penetrance, as for the most common mutations in the cationic trypsinogen gene (PRSS1), to moderate risks factors without mendelian inheritance patterns, as for SPINK1 and CFTR mutations, to very subtle risk associations and disease modifiers that can only be identified in large cohort studies, as for the chymotrypsin C, calcium-sensing receptor and the anionic trypsin (PRSS2) mutations. Only a better understanding of the disease mechanisms that underlie these changes will make an individualized therapy of pancreatic disorders a realistic option.

  12. Concomitant Presence of Two Distinct Clones of Chronic Lymphocytic Leukemia and Plasma Cell Myeloma in a Patient.

    PubMed

    Langer, Sabina; Mehta, Meenal; Saraf, Amrita; Gupta, Aastha; Pipliya, Keyur; Kakar, Atul; Bhargava, Manorama

    2016-06-01

    A 74 years old male patient, presented with history of generalized weakness, fatigue, loss of appetite and breathlessness on exertion for past one and a half months. On examination, he was found to have significant pallor and generalized lymphadenopathy (cervical, axillary and inguinal). The skeletal survey showed punched out lytic lesions in skull and pelvic bones. The peripheral smear examination showed lymphocytosis with absolute lymphocyte count of 25,000/μL. The bone marrow aspirates revealed a hypercellular marrow with 74 % lymphocytes & 14 % plasma cells, suggestive of chronic lymphoplasmacytic disorder. The bone marrow biopsy had two morphologically distinct populations of lymphocytes & plasma cells. The immunohistochemical markers on bone marrow biopsy showed hat plasma cells were positive for CD138 with kappa light chain restriction. Flow cytometry showed B cell population with CD19/CD5 co expression, CD5/CD23 coexpression, were positive for CD22, CD20 and negative for FMC-7 and lambda light chain. In addition, plasma cells were also identified as CD45 negative cells and showed CD38/CD138 co-expression with variable CD19 and CD56 positivity. Serum protein electrophoresis revealed M band, serum immunofixation electrophoresis corresponded to IgA -Kappa. The final diagnosis of chronic lymphocytic leukemia with concomittant presence of plasma cell myeloma was concluded. This case imparts an important message to look for presence of coexisting entities in a single specimen and highlights the benefits of testing both plasma cell and B-cell compartments when the clinical features are not entirely consistent Flow cytometry together with protein electrophoresis can help to clinch difficult and rare dual diagnosis. These cases are rare and pose therapeutic challenge. PMID:27408384

  13. Diagnosing and managing advanced chronic myeloid leukemia.

    PubMed

    Deininger, Michael W

    2015-01-01

    Clinical staging of chronic myeloid leukemia (CML) distinguishes between chronic phase (CP-CML), accelerated phase (AP-CML), and blastic phase (BP-CML), reflecting its natural history in the absence of effective therapy. Morphologically, transformation from CP-CML to AP/BP-CML is characterized by a progressive or sudden loss of differentiation. Multiple different somatic mutations have been implicated in transformation from CP-CML to AP/BC-CML, but no characteristic mutation or combination of mutations have emerged. Gene expression profiles of AP-CML and BP-CML are similar, consistent with biphasic evolution at the molecular level. Gene expression of tyrosine kinase inhibitor (TKI)-resistant CP-CML and second CP-CML resemble AP/BP-CML, suggesting that morphology alone is a poor predictor of biologic behavior. At the clinical level, progression to AP/BP-CML or resistance to first-line TKI therapy distinguishes a good risk condition with survival close to the general population from a disease likely to reduce survival. Progression while receiving TKI therapy is frequently caused by mutations in the target kinase BCR-ABL1, but progression may occur in the absence of explanatory BCR-ABL1 mutations, suggesting involvement of alternative pathways. Identifying patients in whom milestones of TKI response fail to occur or whose disease progress while receiving therapy requires appropriate molecular monitoring. Selection of salvage TKI depends on prior TKI history, comorbidities, and BCR-ABL1 mutation status. Despite the introduction of novel TKIs, therapy of AP/BP-CML remains challenging and requires accepting modalities with substantial toxicity, such as hematopoietic stem cell transplantation (HSCT). PMID:25993200

  14. 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

  15. Incidence and risk factors of bleeding-related adverse events in patients with chronic lymphocytic leukemia treated with ibrutinib

    PubMed Central

    Lipsky, Andrew H.; Farooqui, Mohammed Z.H.; Tian, Xin; Martyr, Sabrina; Cullinane, Ann M.; Nghiem, Khanh; Sun, Clare; Valdez, Janet; Niemann, Carsten U.; Herman, Sarah E. M.; Saba, Nakhle; Soto, Susan; Marti, Gerald; Uzel, Gulbu; Holland, Steve M.; Lozier, Jay N.; Wiestner, Adrian

    2015-01-01

    Ibrutinib is associated with bleeding-related adverse events of grade ≤2 in severity, and infrequently with grade ≥3 events. To investigate the mechanisms of bleeding and identify patients at risk, we prospectively assessed platelet function and coagulation factors in our investigator-initiated trial of single-agent ibrutinib for chronic lymphocytic leukemia. At a median follow-up of 24 months we recorded grade ≤2 bleeding-related adverse events in 55% of 85 patients. No grade ≥3 events occurred. Median time to event was 49 days. The cumulative incidence of an event plateaued by 6 months, suggesting that the risk of bleeding decreases with continued therapy. At baseline, von Willebrand factor and factor VIII levels were often high and normalized on treatment. Platelet function measured via the platelet function analyzer (PFA-100™) was impaired in 22 patients at baseline and in an additional 19 patients on ibrutinib (often transiently). Collagen and adenosine diphosphate induced platelet aggregation was tested using whole blood aggregometry. Compared to normal controls, response to both agonists was decreased in all patients with chronic lymphocytic leukemia, whether on ibrutinib or not. Compared to untreated chronic lymphocytic leukemia patients, response to collagen showed a mild further decrement on ibrutinib, while response to adenosine diphosphate improved. All parameters associated with a significantly increased risk of bleeding-related events were present at baseline, including prolonged epinephrine closure time (HR 2.74, P=0.012), lower levels of von Willebrand factor activity (HR 2.73, P=0.009) and factor VIII (HR 3.73, P=0.0004). In conclusion, both disease and treatment-related factors influence the risk of bleeding. Patients at greater risk for bleeding of grade ≤2 can be identified by clinical laboratory tests and counseled to avoid aspirin, non-steroidal anti-inflammatory drugs and fish oils. ClinicalTrials.gov identifier NCT01500733 PMID

  16. Incidence and risk factors of bleeding-related adverse events in patients with chronic lymphocytic leukemia treated with ibrutinib.

    PubMed

    Lipsky, Andrew H; Farooqui, Mohammed Z H; Tian, Xin; Martyr, Sabrina; Cullinane, Ann M; Nghiem, Khanh; Sun, Clare; Valdez, Janet; Niemann, Carsten U; Herman, Sarah E M; Saba, Nakhle; Soto, Susan; Marti, Gerald; Uzel, Gulbu; Holland, Steve M; Lozier, Jay N; Wiestner, Adrian

    2015-12-01

    Ibrutinib is associated with bleeding-related adverse events of grade ≤ 2 in severity, and infrequently with grade ≥ 3 events. To investigate the mechanisms of bleeding and identify patients at risk, we prospectively assessed platelet function and coagulation factors in our investigator-initiated trial of single-agent ibrutinib for chronic lymphocytic leukemia. At a median follow-up of 24 months we recorded grade ≤ 2 bleeding-related adverse events in 55% of 85 patients. No grade ≥ 3 events occurred. Median time to event was 49 days. The cumulative incidence of an event plateaued by 6 months, suggesting that the risk of bleeding decreases with continued therapy. At baseline, von Willebrand factor and factor VIII levels were often high and normalized on treatment. Platelet function measured via the platelet function analyzer (PFA-100™) was impaired in 22 patients at baseline and in an additional 19 patients on ibrutinib (often transiently). Collagen and adenosine diphosphate induced platelet aggregation was tested using whole blood aggregometry. Compared to normal controls, response to both agonists was decreased in all patients with chronic lymphocytic leukemia, whether on ibrutinib or not. Compared to untreated chronic lymphocytic leukemia patients, response to collagen showed a mild further decrement on ibrutinib, while response to adenosine diphosphate improved. All parameters associated with a significantly increased risk of bleeding-related events were present at baseline, including prolonged epinephrine closure time (HR 2.74, P=0.012), lower levels of von Willebrand factor activity (HR 2.73, P=0.009) and factor VIII (HR 3.73, P=0.0004). In conclusion, both disease and treatment-related factors influence the risk of bleeding. Patients at greater risk for bleeding of grade ≤ 2 can be identified by clinical laboratory tests and counseled to avoid aspirin, non-steroidal anti-inflammatory drugs and fish oils. ClinicalTrials.gov identifier NCT01500733.

  17. Telomere length and expression of human telomerase reverse transcriptase splice variants in chronic lymphocytic leukemia.

    PubMed

    Palma, Marzia; Parker, Anton; Hojjat-Farsangi, Mohammad; Forster, Jade; Kokhaei, Parviz; Hansson, Lotta; Osterborg, Anders; Mellstedt, Håkan

    2013-07-01

    Telomerase activity and telomere length (TL) are prognostic markers in chronic lymphocytic leukemia (CLL). The rate-limiting component of telomerase is human telomerase reverse transcriptase (hTERT), for which multiple transcripts exist. Two splicing sites, α and β, have been described that generate deleted transcripts. Only the full-length (FL; α⁺β⁺) transcript translates into a functional protein. The aim of this work was to characterize hTERT splice variants in CLL in relation to disease activity, clinical stage, immunoglobulin heavy chain variable (IGHV) genes mutational status, and TL. Real-time polymerase chain reaction assays were validated for quantification of the hTERT transcripts with either α deletion (del-α; α⁻β⁺)), β deletion (del-β; α⁺β⁻) or both α and β deletions (del-αβ; α⁻β⁻). The splice variant expression pattern was studied in 97 patients with CLL, 6 healthy control subjects, and one CD34 cell sample. TL was assessed with real-time polymerase chain reaction in 71 of 97 samples. Thirty-two percent of the cases did not express any of the splice variants. Average FL expression was 5.5-fold higher in IGHV-unmutated (n = 35) compared with mutated (n = 59) patients (p < 0.0001). FL levels correlated directly with the percentage of IGHV homology (r = 0.34; p = 0.0007) and inversely with TL (r = -0.44; p = 0.0001). Overall, FL expression correlated significantly with that of the other splice variants. All transcripts were more frequently expressed in progressive compared with nonprogressive patients (p < 0.0001 for FL and del-α; p = 0.01 for del-β; and p = 0.006 for del-αβ). This study provides a detailed insight into the hTERT transcript pattern in CLL, highlighting the necessity of subgrouping patients according to IGHV mutation status when analyzing hTERT expression.

  18. Chronic Lymphocytic Leukemia Patients Have a Preserved Cytomegalovirus-Specific Antibody Response despite Progressive Hypogammaglobulinemia

    PubMed Central

    Vanura, Katrina; Rieder, Franz; Kastner, Marie-Theres; Biebl, Julia; Sandhofer, Michael; Le, Trang; Strassl, Robert; Puchhammer-Stöckl, Elisabeth; Perkmann, Thomas; Steininger, Christoph F.; Stamatopoulos, Kostas; Graninger, Wolfgang; Jäger, Ulrich; Steininger, Christoph

    2013-01-01

    Chronic lymphocytic leukemia (CLL) is characterized by progressive hypogammaglobulinemia predisposing affected patients to a variety of infectious diseases but paradoxically not to cytomegalovirus (CMV) disease. Moreover, we found reactivity of a panel of CLL recombinant antibodies (CLL-rAbs) encoded by a germ-line allele with a single CMV protein, pUL32, despite differing antibody binding motifs. To put these findings into perspective, we studied prospectively relative frequency of viremia, kinetics of total and virus-specific IgG over time, and UL32 genetic variation in a cohort of therapy-naive patients (n=200). CMV-DNA was detected in 3% (6/200) of patients. The decay of total IgG was uniform (mean, 0.03; SD, 0.03) and correlated with that of IgG subclasses 1-4 in the paired samples available (n=64; p<0.001). Total CMV-specific IgG kinetics were more variable (mean, 0,02; SD, 0,06) and mean decay values differed significantly from those of total IgG (p=0.034). Boosts of CMV-specific antibody levels were observed in 49% (22/45) of CMV-seropositive patients. In contrast, VZV- and EBV-specific IgG levels decayed in parallel with total IgG levels (p=0.003 and p=0.001, respectively). VZV-specific IgG even became undetectable in 18% (9/50) of patients whereas CMV-specific ones remained detectable in all seropositive patients. The observed CMV-specific IgG kinetics were predicated upon the highly divergent kinetics of IgG specific for individual antigens - glycoprotein B-specific IgG were boosted in 51% and pUL32-specific IgG in 32% of patients. In conclusion, CLL patients have a preserved CMV-specific antibody response despite progressive decay of total IgG and IgG subclasses. CMV-specific IgG levels are frequently boosted in contrast to that of other herpesviruses indicative of a higher rate of CMV reactivation and antigen-presentation. In contrast to the reactivity of multiple different CLL-rAbs with pUL32, boosts of humoral immunity are triggered apparently by

  19. Chronic lymphocytic leukemia patients have a preserved cytomegalovirus-specific antibody response despite progressive hypogammaglobulinemia.

    PubMed

    Vanura, Katrina; Rieder, Franz; Kastner, Marie-Theres; Biebl, Julia; Sandhofer, Michael; Le, Trang; Strassl, Robert; Puchhammer-Stöckl, Elisabeth; Perkmann, Thomas; Steininger, Christoph F; Stamatopoulos, Kostas; Graninger, Wolfgang; Jäger, Ulrich; Steininger, Christoph

    2013-01-01

    Chronic lymphocytic leukemia (CLL) is characterized by progressive hypogammaglobulinemia predisposing affected patients to a variety of infectious diseases but paradoxically not to cytomegalovirus (CMV) disease. Moreover, we found reactivity of a panel of CLL recombinant antibodies (CLL-rAbs) encoded by a germ-line allele with a single CMV protein, pUL32, despite differing antibody binding motifs. To put these findings into perspective, we studied prospectively relative frequency of viremia, kinetics of total and virus-specific IgG over time, and UL32 genetic variation in a cohort of therapy-naive patients (n=200). CMV-DNA was detected in 3% (6/200) of patients. The decay of total IgG was uniform (mean, 0.03; SD, 0.03) and correlated with that of IgG subclasses 1-4 in the paired samples available (n=64; p<0.001). Total CMV-specific IgG kinetics were more variable (mean, 0,02; SD, 0,06) and mean decay values differed significantly from those of total IgG (p=0.034). Boosts of CMV-specific antibody levels were observed in 49% (22/45) of CMV-seropositive patients. In contrast, VZV- and EBV-specific IgG levels decayed in parallel with total IgG levels (p=0.003 and p=0.001, respectively). VZV-specific IgG even became undetectable in 18% (9/50) of patients whereas CMV-specific ones remained detectable in all seropositive patients. The observed CMV-specific IgG kinetics were predicated upon the highly divergent kinetics of IgG specific for individual antigens - glycoprotein B-specific IgG were boosted in 51% and pUL32-specific IgG in 32% of patients. In conclusion, CLL patients have a preserved CMV-specific antibody response despite progressive decay of total IgG and IgG subclasses. CMV-specific IgG levels are frequently boosted in contrast to that of other herpesviruses indicative of a higher rate of CMV reactivation and antigen-presentation. In contrast to the reactivity of multiple different CLL-rAbs with pUL32, boosts of humoral immunity are triggered apparently by

  20. Evidence for progenitors of chronic lymphocytic leukemia B cells that undergo intraclonal differentiation and diversification.

    PubMed

    Dono, M; Hashimoto, S; Fais, F; Trejo, V; Allen, S L; Lichtman, S M; Schulman, P; Vinciguerra, V P; Sellars, B; Gregersen, P K; Ferrarini, M; Chiorazzi, N

    1996-02-15

    Peripheral blood mononuclear cells from five patients with IgG+ B-type chronic lymphocytic leukemia (B-CLL) were analyzed for the presence of clone-specific Ig H chain variable region gene mRNA transcripts linked to C mu and/or C alpha. This was assessed by (1) comparing the lengths of portions of the VHDJH of the IgG+ CLL clones with those of the mu and alpha isotype-expressing B cells, (2) performing clone-specific endonuclease digestion studies, and (3) determining the DNA sequences of the mu and alpha isotype-expressing cDNA. Thus, when B-cell mRNA from these five patients were reverse transcribed with C gamma-specific primers and then amplified by polymerase chain reaction, dominant cDNA were found with lengths corresponding to those of the IgG+ CLL B cell. In addition, in four cases, cDNA of lengths identical to those of the CLL B cell were detected when mRNA was reverse transcribed and amplified using c mu- and/or C alpha-specific primers, strongly suggesting clonal relatedness. These CLL-related mu- and alpha-expressing cDNA were present in greater amounts that unrelated (non-CLL) mu- and alpha-expressing cDNA from normal B cells that used genes of the same VH family. When the sequences of these CLL-related C mu- and C alpha-expressing cDNA were compared with those of the IgG+ CLL clones, it was clear that they were derived from the same ancestral gene as the IgG-expressing CLL B cell, thus documenting their common origin. Finally, nucleotide point mutations were observed in the mu- and alpha-expressing cDNA of certain patients, indicating divergence with the CLL. These data suggest that IgM+ B cells, which are precursors of the leukemic B cells, exist in increased numbers in the blood of most patients with IgG+ B-CELL and that these cells may differentiate, accumulate V genes mutations, and undergo isotype switching in vivo. In addition, the data are consistent with a sequential-hit model for the evolution of CLL.

  1. Deregulated expression of circadian clock and clock-controlled cell cycle genes in chronic lymphocytic leukemia.

    PubMed

    Rana, Sobia; Munawar, Mustafa; Shahid, Adeela; Malik, Meera; Ullah, Hafeez; Fatima, Warda; Mohsin, Shahida; Mahmood, Saqib

    2014-01-01

    Circadian rhythms are endogenous and self-sustained oscillations of multiple biological processes with approximately 24-h rhythmicity. Circadian genes and their protein products constitute the molecular components of the circadian oscillator that form positive/negative feedback loops and generate circadian rhythms. The circadian regulation extends from core clock genes to various clock-controlled genes that include various cell cycle genes. Aberrant expression of circadian clock genes, therefore, may lead to genomic instability and accelerated cellular proliferation potentially promoting carcinogenesis. The current study encompasses the investigation of simultaneous expression of four circadian clock genes (Bmal1, Clock, Per1 and Per2) and three clock-controlled cell cycle genes (Myc, Cyclin D1 and Wee1) at mRNA level and determination of serum melatonin levels in peripheral blood samples of 37 CLL (chronic lymphocytic leukemia) patients and equal number of age- and sex-matched healthy controls in order to indicate association between deregulated circadian clock and manifestation of CLL. Results showed significantly down-regulated expression of Bmal1, Per1, Per2 and Wee1 and significantly up-regulated expression of Myc and Cyclin D1 (P < 0.0001) in CLL patients as compared to healthy controls. When expression of these genes was compared between shift-workers and non-shift-workers within the CLL group, the expression was found more aberrant in shift-workers as compared to non-shift-workers. However, this difference was found statistically significant for Myc and Cyclin D1 only (P < 0.05). Serum melatonin levels were found significantly low (P < 0.0001) in CLL subjects as compared to healthy controls whereas melatonin levels were found still lower in shift-workers as compared to non-shift-workers within CLL group (P < 0.01). Our results suggest that aberrant expression of circadian clock genes can lead to aberrant expression of their downstream targets that are

  2. Integration of Chinese Herbal Medicine Therapy Improves Survival of Patients With Chronic Lymphocytic Leukemia

    PubMed Central

    Fleischer, Tom; Chang, Tung-Ti; Chiang, Jen-Huai; Hsieh, Ching-Yun; Sun, Mao-Feng; Yen, Hung-Rong

    2016-01-01

    Abstract Utilization of Chinese Medicine (CM) is not uncommon in patients with chronic lymphocytic leukemia (CLL). However, the current knowledge of the usage and efficacy of CM among CLL patients is limited. The aim of this study was to determine the impact of integrative Chinese Herbal Medicine (CHM) on the disease course of CLL and ascertain the herbal products most commonly prescribed to patients with CLL. A Taiwanese nationwide population-based study involving the use of Western medicine and CM services provided by the National Health Insurance (NHI) was conducted. An NHI Research Database-based cohort study was performed; the timeframe of the study was January 2000 to December 2010. The end of the follow-up period was defined as December 31, 2011. A total of 808 patients were diagnosed with CLL in Taiwan within the defined study period. After randomly matching for age and sex and excluding patients younger than 18 years of age, data from 616 patients were analyzed. The 2 study groups both received standard of care treatment. In addition, 1 group also received CHM. Patients who were registered as receiving other forms of CM, such as acupuncture, were excluded. Hazard ratios of mortality were used to determine the influence of CHM and the therapeutic potential of herbal products. In total, 616 CLL patients were included in the analyses. We found that the HR associated with the adjunctive use of CHM was less than half when compared to the non-CHM group (0.43, 95% CI 0.33–0.55, P < 0.0001) and that treatment-naive patients who used CHM had the lowest HR. We also established that this association between reduction in HR and CHM was dose-dependent, and the longer CHM users received prescriptions, the lower the HR (P < 0.001). We supplied data from a relatively large population that spanned a significant amount of time. Our data suggests that the treatment of CLL with adjunctive CHM may have a substantial positive impact on mortality, especially for

  3. Monoclonal B lymphocytes with the characteristics of "indolent" chronic lymphocytic leukemia are present in 3.5% of adults with normal blood counts.

    PubMed

    Rawstron, Andy C; Green, Michael J; Kuzmicki, Anita; Kennedy, Ben; Fenton, James A L; Evans, Paul A S; O'Connor, Sheila J M; Richards, Stephen J; Morgan, Gareth J; Jack, Andrew S; Hillmen, Peter

    2002-07-15

    Molecular and cellular markers associated with malignant disease are frequently identified in healthy individuals. The relationship between these markers and clinical disease is not clear, except where a neoplastic cell population can be identified as in myeloma/monoclonal gammopathies of undetermined significance (MGUS). We have used the distinctive phenotype of chronic lymphocytic leukemia (CLL) cells to determine whether low levels of these cells can be identified in individuals with normal complete blood counts. CLL cells were identified by 4-color flow cytometric analysis of CD19/CD5/CD79b/CD20 expression in 910 outpatients over 40 years old. These outpatients were age- and sex-matched to the general population with normal hematologic parameters and no evident history of malignant disease. CLL phenotype cells were detectable in 3.5% of individuals at low level (median, 0.013; range, 0.002- 1.458 x 10(9) cells/L), and represented a minority of B lymphocytes (median, 11%; range, 3%-95%). Monoclonality was demonstrated by immunoglobulin light-chain restriction in all cases with CLL phenotype cells present and confirmed in a subset of cases by consensus-primer IgH-polymerase chain reaction. As in clinical disease, CLL phenotype cells were detected with a higher frequency in men (male-to-female ratio, 1.9:1) and elderly individuals (2.1% of 40- to 59-year-olds versus 5.0% of 60- to 89-year-olds, P =.01). The neoplastic cells were identical to good-prognosis CLL, being CD5+23+20(wk)79b(wk)11a(-)22(wk)sIg(wk)CD38-, and where assessed had a high degree (4.8%-6.6%) of IgH somatic hypermutation. The monoclonal CLL phenotype cells present in otherwise healthy individuals may represent a very early stage of indolent CLL and should be useful in elucidating the mechanisms of leukemogenesis.

  4. Chronic lymphocytic leukemia with a FGFR3 translocation: case report and literature review of an uncommon cytogenetic event.

    PubMed

    Geller, Matthew D; Pei, Ying; Spurgeon, Stephen E; Durum, Connie; Leeborg, Nicky J

    2014-01-01

    The t(4;14) (p16; q32) with fusion of the IGH (immunoglobulin heavy chain) and FGFR3 (fibroblast growth factor receptor 3) genes are rarely present in patients with chronic lymphocytic leukemia (CLL), with only two previously reported cases. We herein describe a unique case of CLL with the occurrence of a t(4;14) (p16;q32), trisomy 12, and deletion of 11q13-q23 in the same clonal cells. In contrast to myeloma, in which FGFR3 translocations are a common early cytogenetic hit, FGFR3 rearrangement in CLL appears to occur later in the disease course.

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

    ClinicalTrials.gov

    2013-09-27

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

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

    PubMed

    Lemanne, Dawn; 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.

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

    PubMed

    Lemanne, Dawn; 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

  8. 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

  9. 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

  10. Prospective study of prognostic factors in asymptomatic patients with B-cell chronic lymphocytic leukemia-like lymphocytosis: the cut-off of 11 × 10(9)/L monoclonal lymphocytes better identifies subgroups with different outcomes.

    PubMed

    Oliveira, A C; Fernández de Sevilla, A; Domingo, A; De La Banda, E; Domingo-Domènech, E; Mercadal, S; Ruiz-Xivillé, N; Alonso, E; Encuentra, M; González-Barca, E

    2015-04-01

    The arbitrary threshold of 5 × 10(9)/L chronic lymphocytic leukemia (CLL)-like lymphocytes differentiates monoclonal B lymphocytosis (MBL) from CLL. There are no prospective studies that search for the optimal cut-off of monoclonal lymphocytes able to predict outcome and simultaneously analyze the prognostic value of classic, immunophenotypic, and cytogenetic variables in patients with asymptomatic clonal CLL lymphocytosis (ACL), which includes MBL plus Rai 0 CLL patients. From 2003 to 2010, 231 ACL patients were enrolled in this study. Patients with 11q deletion and atypical lymphocyte morphology at diagnosis had shorter progression-free survival (PFS) (p = 0.007 and p = 0.015, respectively) and treatment-free survival (TFS) (p = 0.009 and p = 0.017, respectively). Elevated beta-2 microglobulin (B2M) also correlated with worse TFS (p = 0.002). The optimal threshold of monoclonal lymphocytes independently correlated with survival was 11 × 10(9)/L (p = 0.000 for PFS and p = 0.016 for TFS). As conclusion, monoclonal lymphocytosis higher than 11 × 10(9)/L better identifies two subgroups of patients with different outcomes than the standard cut-off value of 5 × 10(9)/L. Atypical lymphocyte morphology, 11q deletion and elevated B2M had a negative impact on the survival in ACL patients.

  11. Diagnosis of chronic myeloid and acute lymphocytic leukemias by detection of leukemia-specific mRNA sequences amplified in vitro.

    PubMed Central

    Kawasaki, E S; Clark, S S; Coyne, M Y; Smith, S D; Champlin, R; Witte, O N; McCormick, F P

    1988-01-01

    The Philadelphia chromosome is present in more than 95% of chronic myeloid leukemia patients and 13% of acute lymphocytic leukemia patients. The Philadelphia translocation, t(9;22), fuses the BCR and ABL genes resulting in the expression of leukemia-specific, chimeric BCR-ABL messenger RNAs. To facilitate diagnosis of these leukemias, we have developed a method of amplifying and detecting only the unique mRNA sequences, using an extension of the polymerase chain reaction technique. Diagnosis of chronic myeloid and acute lymphocytic leukemias by this procedure is rapid, much more sensitive than existing protocols, and independent of the presence or absence of an identifiable Philadelphia chromosome. Images PMID:3165197

  12. Management of Advanced-Phase Chronic Myelogenous Leukemia.

    PubMed

    Radich, Jerald P

    2016-05-01

    Chronic myelogenous leukemia represents the poster child of successful precision medicine in cancer, with amazing survival results achieved with targeted tyrosine kinase inhibitors (TKIs) in many patients with chronic-phase disease. Unfortunately, however, this good news has not extended to patients in blast crisis, for whom survival has not clearly been improved with TKIs. During his presentation at the NCCN 21st Annual Conference, Jerald P. Radich, MD, briefly explored the biology behind advanced-stage disease and several of the molecular findings in disease progression. He also reviewed some of the therapeutic options in advanced disease, emphasizing that transplantation, although fraught with some difficulties, offers the best long-term prognosis for patients in blast crisis. PMID:27226510

  13. Hypercalcemia of advanced chronic liver disease: a forgotten clinical entity!

    PubMed Central

    Kuchay, Mohammad Shafi; Mishra, Sunil Kumar; Farooqui, Khalid Jamal; Bansal, Beena; Wasir, Jasjeet Singh; Mithal, Ambrish

    2016-01-01

    Summary Hypercalcemia caused by advanced chronic liver disease (CLD) without hepatic neoplasia is uncommonly reported and poorly understood condition. We are reporting two cases of advanced CLD who developed hypercalcemia in the course of the disease. This diagnosis of exclusion was made only after meticulous ruling out of all causes of hypercalcemia. The unique feature of this type of hypercalcemia is its transient nature that may or may not require treatment. This clinical condition in patients with CLD should be kept in mind while evaluating the cause of hypercalcemia in them. PMID:27252737

  14. Advances in the management of chronic thromboembolic pulmonary hypertension.

    PubMed

    Papamatheakis, Demosthenes G; Kim, Nick H

    2015-09-01

    Chronic thromboembolic pulmonary hypertension (CTEPH), a potentially curable form of pulmonary hypertension with pulmonary thromboendarterectomy surgery, has been the focus of significant medical advances. In addition to new imaging modalities that are now used to help recognize and diagnose CTEPH, additional treatment options have emerged for inoperable cases. These include a newly approved medical therapy for inoperable disease or persistent/recurrent CTEPH as well as percutaneous balloon angioplasty of the pulmonary arteries. In this article, we summarize these recent advances in the field and review the related literature.

  15. CD49d and CD26 are independent prognostic markers for disease progression in patients with chronic lymphocytic leukemia.

    PubMed

    Ibrahem, Lamia; Elderiny, Wesam E; Elhelw, Loie; Ismail, Mohamed

    2015-08-01

    CLL is characterized by extremely variable clinical course. Several prognostic factors can predict disease progression and therapeutic outcomes in those patients. The aim was to evaluate the use of CD49d and CD26 as independent prognostic markers in CLL patients. The present study measured surface expression of CD49d and CD26 by three-color flow cytometry in a series of 103 untreated CLL patients. We evaluated the prognostic role of CD49d and CD26 to predict the risk of lymphocyte doubling, disease progression and overall survival. We confirmed that CD49d and CD26 were significant predictors of lymphocyte doubling(P<0.001 for both markers) and disease progression (P<0.001 for both markers) but insignificant for overall survival(P=0.303 and 0.519 respectively. Multivariate analysis between clinical parameters and flow cytometry markers revealed that CD49d and CD26 are independent prognostic markers for lymphocyte doubling (HR=1.487 P=007 and HR=2.248, P=0.014 respectively) and progression to a more advanced stage (HR=3.191, P=0.049 and HR=7.887, P=0.003). Also, concordant expression of both markers was found to improve their predictive power. Many studies reported that CD49d and CD26 combined analysis was found to improve their power to predict the risk of lymphocyte doubling and disease progression. CD49d and CD26 have independent prognostic value and we suggest its use as a part of routine panel for prognostic stratification of CLL.

  16. Lymphocyte subpopulations and the expression of intercellular adhesion molecules in chronic periodontitis.

    PubMed

    Cindrić, Gordan; Aurer, Andrej; Plancak, Darije; Ljerka, Jindra; Girotto, Miljena

    2004-12-01

    Immunological responses to invading bacteria play a major role in the course of inflammatory periodontal diseases, such as CP. It was suggested that one of the major elements in determining the course of the disease is the expression of cellular adhesion molecules. We therefore investigated the expression of cellular adhesion molecules, ICAM-1 and beta-1 integrins, capillary density and lymphocyte subpopulations in gingival biopsies obtained from 20 patients with CP who responded and 21 patient who failed to respond to initial treatment using immunohistochemical methods. We found no differences between the two groups in capillary density, ICAM-1 and beta-1 integrin expression. Patients who responded to treatment had a lymphocytic inflammatory infiltrate consisting predominantly of T cells, while those who failed to respond had an approximately equal number of T and B cells. Our findings support the role of host immunological mechanisms in determining the outcome of CP and argue against a major role of differential cellular adhesion molecule expression.

  17. Suppressed peripheral blood lymphocyte blastogenesis in pre- and postpartal sheep by chronic heat-stress, and suppressive property of heat-stressed sheep serum on lymphocytes.

    PubMed

    Niwano, Y; Becker, B A; Mitra, R; Caldwell, C W; Abdalla, E B; Johnson, H D

    1990-01-01

    Phytohemagglutinin (PHA) and concanavalin A (Con A)-induced blastogenesis of peripheral blood lymphocytes was examined in heat-stressed pre- and postpartal sheep. The peak responses of lymphocytes to PHA and Con A in heat-stressed sheep revealed significant reduction before and after parturition compared with those in the corresponding control animals kept under thermoneutral conditions. Furthermore, the effect of serum from control or heat-stressed sheep on PHA-induced lymphocyte blastogenesis was examined. Supplementation of serum from heat-stressed sheep significantly suppressed the blastogenesis of lymphocytes obtained from healthy sheep, bovine, and human donors. Unlike dexamethasone, heat-stressed sheep serum did not inhibit IL-2 production by PHA-stimulated human peripheral blood lymphocytes. These results indicate that the immunosuppression of heat-stressed sheep is in part mediated by serum factor(s) that can modulate T-cell function in a species nonspecific manner.

  18. Determination of genes and microRNAs involved in the resistance to fludarabine in vivo in chronic lymphocytic leukemia

    PubMed Central

    2010-01-01

    Background Chronic lymphocytic leukemia (CLL) cells are often affected by genomic aberrations targeting key regulatory genes. Although fludarabine is the standard first line therapy to treat CLL, only few data are available about the resistance of B cells to this purine nucleoside analog in vivo. Here we sought to increase our understanding of fludarabine action and describe the mechanisms leading to resistance in vivo. We performed an analysis of genomic aberrations, gene expression profiles, and microRNAs expression in CLL blood B lymphocytes isolated during the course of patients' treatment with fludarabine. Results In sensitive patients, the differentially expressed genes we identified were mainly involved in p53 signaling, DNA damage response, cell cycle and cell death. In resistant patients, uncommon genomic abnormalities were observed and the resistance toward fludarabine could be characterized based on the expression profiles of genes implicated in lymphocyte proliferation, DNA repair, and cell growth and survival. Of particular interest in some patients was the amplification of MYC (8q) observed both at the gene and transcript levels, together with alterations of myc-transcriptional targets, including genes and miRNAs involved in the regulation of cell cycle and proliferation. Differential expression of the sulfatase SULF2 and of miR-29a, -181a, and -221 was also observed between resistant and sensitive patients before treatment. These observations were further confirmed on a validation cohort of CLL patients treated with fludarabine in vitro. Conclusion In the present study we identified genes and miRNAs that may predict clinical resistance of CLL to fludarabine, and describe an interesting oncogenic mechanism in CLL patients resistant to fludarabine by which the complete MYC-specific regulatory network was altered (DNA and RNA levels, and transcriptional targets). These results should prove useful for understanding and overcoming refractoriness to

  19. 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.

  20. [New insights in the treatment of chronic lymphocytic leukemia and role of the biologist in the monitoring of the treatments].

    PubMed

    Troussard, Xavier; Cornet, Édouard

    2016-01-01

    Chronic lymphocytic leukemia (CLL) is the most common hematologic malignancy in France. Much progress has been made in recent years in understanding the pathophysiology of the disease, the definition of diagnostic criteria (>5 G/L of clonal B-lymphocytes), identification of prognostic criteria, including a better understanding of fragile patients, high risk patients and even more recently by the emergence of new highly effective drugs, doing discuss their place in the wide therapeutic panel we have. The treatment of patients with CLL is indicated in patients with progressive stage A, stage B or stage C. The new drugs currently available include not only the new generation of anti-CD20 monoclonal antibodies, type I (ofatumumab) or type II (obinutuzumab), Bcl-2 inhibitors (GDC-0199/ABT-199) and now the new small molecules available orally, including Bruton tyrosine kinase inhibitor (BTK) and phosphor-inositide 3-kinase (PI3K) inhibitor. The role of the biologist in monitoring a patient treated for CLL is essential, the latter to make the diagnosis of CLL, the search for prognostic factors (Binet stage, lymphocyte doubling time, looking for a 17p deletion or TP53 mutations, study of mutational profile of heavy chain genes of immunoglobulins IGHV) and biological monitoring of the different treatments. We will study in this paper the results obtained with these drugs, insisting today more than ever on the need to set up a clinical and biological complementarity to allow optimal medical management of patients with CLL. The mechanisms of actions are discussed, as well as the response criteria we should use to evaluate the effectiveness of these treatments in clinical practice. PMID:27029723

  1. 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. PMID:25689772

  2. Highlights in the treatment of chronic lymphocytic leukemia from the 2014 meeting of the American Society of Hematology.

    PubMed

    Molica, Stefano

    2015-06-01

    The latest Annual Meeting of the American Society of Hematology, held in San Francisco, included data on novel-targeted agents active in the treatment of chronic lymphocytic leukemia (CLL). MABTENANCE and PROLONG study suggest that either rituximab or ofatumumab improves progression-free survival in CLL. According to final analysis of CLL-10 trial, rituximab and bendamustine may have a role in the upfront treatment of fit elderly patients. Further insight into the use of ibrutinib, a first-in-class covalent Bruton’s tyrosine kinase-inhibitor that is currently approved for patients with relapsed/refractory CLL and with del(17p), was also presented. Idelalisib, a selective inhibitor of PI3K delta, demonstrated its activity with manageable toxicity in previously untreated patients ≥65 years with CLL or small lymphocytic lymphoma. Finally, a series Phase I/II studies of BCL-2 inhibitor (i.e., venetoclax, GDC-0199) used alone or in combination provide promising results in patients with relapsed/refractory CLL.

  3. 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

  4. PARP1 expression, activity and ex vivo sensitivity to the PARP inhibitor, talazoparib (BMN 673), in chronic lymphocytic leukaemia

    PubMed Central

    Herriott, Ashleigh; Tudhope, Susan J.; Junge, Gesa; Rodrigues, Natalie; Patterson, Miranda J.; Woodhouse, Laura; Lunec, John; Hunter, Jill E.; Mulligan, Evan A.; Cole, Michael; Allinson, Lisa M.; Wallis, Jonathan P.; Marshall, Scott; Wang, Evelyn; Curtin, Nicola J.; Willmore, Elaine

    2015-01-01

    In chronic lymphocytic leukemia (CLL), mutation and loss of p53 and ATM abrogate DNA damage signalling and predict poorer response and shorter survival. We hypothesised that poly (ADP-ribose) polymerase (PARP) activity, which is crucial for repair of DNA breaks induced by oxidative stress or chemotherapy, may be an additional predictive biomarker and a target for therapy with PARP inhibitors. We measured PARP activity in 109 patient-derived CLL samples, which varied widely (192 – 190052 pmol PAR/106 cells) compared to that seen in healthy volunteer lymphocytes (2451 – 7519 pmol PAR/106 cells). PARP activity was associated with PARP1 protein expression and endogenous PAR levels. PARP activity was not associated with p53 or ATM loss, Binet stage, IGHV mutational status or survival, but correlated with Bcl-2 and Rel A (an NF-kB subunit). Levels of 8-hydroxy-2′-deoxyguanosine in DNA (a marker of oxidative damage) were not associated with PAR levels or PARP activity. The potent PARP inhibitor, talazoparib (BMN 673), inhibited CD40L-stimulated proliferation of CLL cells at nM concentrations, independently of Binet stage or p53/ATM function. PARP activity is highly variable in CLL and correlates with stress-induced proteins. Proliferating CLL cells (including those with p53 or ATM loss) are highly sensitive to the PARP inhibitor talazoparib. PMID:26539646

  5. Inhibition of Syk with fostamatinib disodium has significant clinical activity in non-Hodgkin lymphoma and chronic lymphocytic leukemia

    PubMed Central

    Sharman, Jeff; Sweetenham, John; Johnston, Patrick B.; Vose, Julie M.; LaCasce, Ann; Schaefer-Cutillo, Julia; De Vos, Sven; Sinha, Rajni; Leonard, John P.; Cripe, Larry D.; Gregory, Stephanie A.; Sterba, Michael P.; Lowe, Ann M.; Levy, Ronald; Shipp, Margaret A.

    2010-01-01

    Certain malignant B cells rely on B-cell receptor (BCR)–mediated survival signals. Spleen tyrosine kinase (Syk) initiates and amplifies the BCR signal. In in vivo analyses of B-cell lymphoma cell lines and primary tumors, Syk inhibition induces apoptosis. These data prompted a phase 1/2 clinical trial of fostamatinib disodium, the first clinically available oral Syk inhibitor, in patients with recurrent B-cell non-Hodgkin lymphoma (B-NHL). Dose-limiting toxicity in the phase 1 portion was neutropenia, diarrhea, and thrombocytopenia, and 200 mg twice daily was chosen for phase 2 testing. Sixty-eight patients with recurrent B-NHL were then enrolled in 3 cohorts: (1) diffuse large B-cell lymphoma (DLBCL), (2) follicular lymphoma (FL), and (3) other NHL, including mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), mucosa-associated lymphoid tissue lymphoma, lymphoplasmacytic lymphomas, and small lymphocytic leukemia/chronic lymphocytic leukemia (SLL/CLL). Common toxicities included diarrhea, fatigue, cytopenias, hypertension, and nausea. Objective response rates were 22% (5 of 23) for DLBCL, 10% (2 of 21) for FL, 55% (6 of 11) for SLL/CLL, and 11% (1/9) for MCL. Median progression-free survival was 4.2 months. Disrupting BCR-induced signaling by inhibiting Syk represents a novel and active therapeutic approach for NHL and SLL/CLL. This trial was registered at www.clinicaltrials.gov as #NCT00446095. PMID:19965662

  6. The prognostic significance of surface dipeptidylpeptidase IV (CD26) expression in B-cell chronic lymphocytic leukemia.

    PubMed

    Matuszak, Magdalena; Lewandowski, Krzysztof; Czyż, Anna; Kiernicka-Parulska, Jolanta; Przybyłowicz-Chalecka, Anna; Jarmuż-Szymczak, Małgorzata; Lewandowska, Maria; Komarnicki, Mieczysław

    2016-08-01

    A number of factors related to B-cell chronic lymphocytic leukemia (B-CLL) patients' prognosis have been identified. However, still some factors better reflecting disease activity in individual cases are explored. The study aimed to evaluate prognostic significance of dipeptidylpeptidase IV/CD26 expression on B-CLL cells and its relationship with other well established prognostic factors. The study included 94 patients with newly diagnosed B-CLL and involved analysis of clinical, laboratory, flow-cytometry and cytogenetic data. Detailed analysis showed that CD26 expression on B-CLL cells correlates with Rai's clinical stage of the disease at diagnosis (p=0.034), β2-microglobulin concentration (p=0.012), lactic acid dehydrogenase activity (p=0.045) and absolute lymphocytes' count (p=0.027) in the blood. The multivariate analysis revealed that time to treatment (TTT) was significantly influenced by Rai clinical stage, LDH activity in blood and CD26 expression on B-CLL cell's. Moreover, in the multivariate analysis restricted to the group of patients with documented cytogenetic risk (n=36) CD26 expression, Rai clinical stage and cytogenetic profile remained their independent impact on TTT. The results of our study indicate that the CD26 expression should be incorporated in B-CLL patients risk assessment along with well known prognostic factors, since it seems to have a relationship with the tumor mass and influences TTT. PMID:27376546

  7. CD73-generated extracellular adenosine in chronic lymphocytic leukemia creates local conditions counteracting drug-induced cell death

    PubMed Central

    Serra, Sara; Horenstein, Alberto L.; Vaisitti, Tiziana; Brusa, Davide; Rossi, Davide; Laurenti, Luca; D'Arena, Giovanni; Coscia, Marta; Tripodo, Claudio; Inghirami, Giorgio; Robson, Simon C.; Gaidano, Gianluca; Malavasi, Fabio

    2011-01-01

    Extracellular adenosine (ADO), generated from ATP or ADP through the concerted action of the ectoenzymes CD39 and CD73, elicits autocrine and paracrine effects mediated by type 1 purinergic receptors. We have tested whether the expression of CD39 and CD73 by chronic lymphocytic leukemia (CLL) cells activates an adenosinergic axis affecting growth and survival. By immunohistochemistry, CD39 is widely expressed in CLL lymph nodes, whereas CD73 is restricted to proliferation centers. CD73 expression is highest on Ki-67+ CLL cells, adjacent to T lymphocytes, and is further localized to perivascular areas. CD39+/CD73+ CLL cells generate ADO from ADP in a time- and concentration-dependent manner. In peripheral blood, CD73 expression occurs in 97/299 (32%) CLL patients and pairs with CD38 and ZAP-70 expression. CD73-generated extracellular ADO activates type 1 purinergic A2A receptors that are constitutively expressed by CLL cells and that are further elevated in proliferating neoplastic cells. Activation of the ADO receptors increases cytoplasmic cAMP levels, inhibiting chemotaxis and limiting spontaneous drug-induced apoptosis of CLL cells. These data are consistent with the existence of an autocrine adenosinergic loop, and support engraftment of leukemic cells in growth-favorable niches, while simultaneously protecting from the action of chemotherapeutic agents. PMID:21998208

  8. Feasibility of Telomerase-Specific Adoptive T-cell Therapy for B-cell Chronic Lymphocytic Leukemia and Solid Malignancies.

    PubMed

    Sandri, Sara; Bobisse, Sara; Moxley, Kelly; Lamolinara, Alessia; De Sanctis, Francesco; Boschi, Federico; Sbarbati, Andrea; Fracasso, Giulio; Ferrarini, Giovanna; Hendriks, Rudi W; Cavallini, Chiara; Scupoli, Maria Teresa; Sartoris, Silvia; Iezzi, Manuela; Nishimura, Michael I; Bronte, Vincenzo; Ugel, Stefano

    2016-05-01

    Telomerase (TERT) is overexpressed in 80% to 90% of primary tumors and contributes to sustaining the transformed phenotype. The identification of several TERT epitopes in tumor cells has elevated the status of TERT as a potential universal target for selective and broad adoptive immunotherapy. TERT-specific cytotoxic T lymphocytes (CTL) have been detected in the peripheral blood of B-cell chronic lymphocytic leukemia (B-CLL) patients, but display low functional avidity, which limits their clinical utility in adoptive cell transfer approaches. To overcome this key obstacle hindering effective immunotherapy, we isolated an HLA-A2-restricted T-cell receptor (TCR) with high avidity for human TERT from vaccinated HLA-A*0201 transgenic mice. Using several relevant humanized mouse models, we demonstrate that TCR-transduced T cells were able to control human B-CLL progression in vivo and limited tumor growth in several human, solid transplantable cancers. TERT-based adoptive immunotherapy selectively eliminated tumor cells, failed to trigger a self-MHC-restricted fratricide of T cells, and was associated with toxicity against mature granulocytes, but not toward human hematopoietic progenitors in humanized immune reconstituted mice. These data support the feasibility of TERT-based adoptive immunotherapy in clinical oncology, highlighting, for the first time, the possibility of utilizing a high-avidity TCR specific for human TERT. Cancer Res; 76(9); 2540-51. ©2016 AACR.

  9. Elimination of Chronic Lymphocytic Leukemia Cells in Stromal Microenvironment by Targeting CPT with an Anti-Angina Drug Perhexiline

    PubMed Central

    Liu, Pan-pan; Liu, Jinyun; Jiang, Wen-qi; Carew, Jennifer S.; Ogasawara, Marcia A.; Pelicano, Hélène; Croce, Carlo M.; Estrov, Zeev; Xu, Rui-hua; Keating, Michael J.; Huang, Peng

    2016-01-01

    Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the western countries and is currently incurable due in part to difficulty in eliminating the leukemia cells protected by stromal microenvironment. Based on previous observations that CLL cells exhibit mitochondrial dysfunction and altered lipid metabolism and that carnitine palmitoyltransferases (CPT) play a major role in transporting fatty acid into mitochondria to support cancer cell metabolism, we tested several clinically relevant inhibitors of lipid metabolism for their ability to eliminate primary CLL cells. We discovered that Perhexiline, an anti-angina agent that inhibits CPT, was highly effective in killing CLL cells in stromal microenvironment at clinically achievable concentrations. These effective concentrations caused low toxicity to normal lymphocytes and normal stromal cells. Mechanistic study revealed that CLL cells expressed high levels of CPT1 and CPT2. Suppression of fatty acid transport into mitochondria by inhibiting CPT using Perhexiline resulted in a depletion of cardiolipin, a key component of mitochondrial membranes, and compromised mitochondrial integrity leading to rapid depolarization and massive CLL cell death. The therapeutic activity of Perhexiline was further demonstrated in vivo using a CLL transgenic mouse model. Perhexiline significantly prolonged the overall animal survival by only 4 drug injections. Our study suggests that targeting CPT using an anti-angina drug is able to effectively eliminate leukemia cells in vivo, and is a novel therapeutic strategy for potential clinical treatment of CLL. PMID:27065330

  10. A phase 2 study of idelalisib plus rituximab in treatment-naïve older patients with chronic lymphocytic leukemia

    PubMed Central

    Lamanna, Nicole; Kipps, Thomas J.; Flinn, Ian; Zelenetz, Andrew D.; Burger, Jan A.; Keating, Michael; Mitra, Siddhartha; Holes, Leanne; Yu, Albert S.; Johnson, David M.; Miller, Langdon L.; Kim, Yeonhee; Dansey, Roger D.; Dubowy, Ronald L.; Coutre, Steven E.

    2015-01-01

    Idelalisib is a first-in-class oral inhibitor of PI3Kδ that has shown substantial activity in patients with relapsed/refractory chronic lymphocytic leukemia (CLL). To evaluate idelalisib as initial therapy, 64 treatment-naïve older patients with CLL or small lymphocytic leukemia (median age, 71 years; range, 65-90) were treated with rituximab 375 mg/m2 weekly ×8 and idelalisib 150 mg twice daily continuously for 48 weeks. Patients completing 48 weeks without progression could continue to receive idelalisib on an extension study. The median time on treatment was 22.4 months (range, 0.8-45.8+). The overall response rate (ORR) was 97%, including 19% complete responses. The ORR was 100% in patients with del(17p)/TP53 mutations and 97% in those with unmutated IGHV. Progression-free survival was 83% at 36 months. The most frequent (>30%) adverse events (any grade) were diarrhea (including colitis) (64%), rash (58%), pyrexia (42%), nausea (38%), chills (36%), cough (33%), and fatigue (31%). Elevated alanine transaminase/aspartate transaminase was seen in 67% of patients (23% grade ≥3). The combination of idelalisib and rituximab was highly active, resulting in durable disease control in treatment-naïve older patients with CLL. These results support the further development of idelalisib as initial treatment of CLL. This study is registered at ClinicalTrials.gov as #NCT01203930. PMID:26472751

  11. Rapidly Fatal Dissemination of Merkel Cell Carcinoma in a Patient Treated with Alemtuzumab for Chronic Lymphocytic Leukemia.

    PubMed

    Yu, Kenneth K; Dasanu, Constantin A

    2016-01-01

    Alemtuzumab is FDA-approved for the treatment of chronic lymphocytic leukemia (CLL). Nonetheless, its use for this indication has fallen out of favor due to serious concerns for infectious complications and increased risks of second malignancies from the profound and lasting immunosuppression. We report here in a patient with a rapidly progressive metastatic Merkel cell carcinoma (MCC) who was previously treated with alemtuzumab and fludarabine for CLL. He developed profound lymphopenia and hypogammaglobulinemia. While the risk of MCC is increased in CLL, its rapid dissemination has not been previously reported with fludarabine alone. In light of the rapidly fatal outcome in our patient due to MCC, we advise caution with the use of alemtuzumab. In patients treated with alemtuzumab for nononcologic indications, aggressive surveillance for cutaneous malignancies should be implemented until its safety profile can be further characterized. PMID:27509643

  12. Complement dependent cytotoxicity (CDC) in chronic lymphocytic leukemia (CLL): Ofatumumab enhances alemtuzumab CDC and reveals cells resistant to activated complement

    PubMed Central

    Baig, Nisar A.; Taylor, Ronald P.; Lindorfer, Margaret A.; Church, Amy K.; LaPlant, Betsy R.; Pavey, Emily S.; Nowakowski, Grzegorz S.; Zent, Clive S.

    2016-01-01

    Complement dependent cytotoxicity (CDC) is an important mechanism of action for monoclonal antibodies (mAb) used in the treatment of chronic lymphocytic leukemia (CLL). We hypothesized that alemtuzumab (ALM) mediated CDC would be increased by addition of ofatumumab (OFA). CLL cells from 21 previously untreated patients with progressive disease were tested in vitro for mAb binding, complement activation, and CDC. The subpopulation of CDC resistant CLL cells was examined for levels of C3b and C5b-9 binding, and expression of complement regulatory proteins. OFA significantly increased complement activation and CDC in ALM-treated CLL cells suggesting that combining ALM and OFA could improve clinical outcome in patients with CLL. Approximately 10% of CLL cells were resistant to CDC because of lower levels of complement activation or decreased cytotoxicity of activated complement. Improvement of clinical responses will require determining the mechanisms of CDC resistance and developing methods to overcome this problem. PMID:22475085

  13. 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

  14. Malakoplakia of the Urinary Bladder in a Patient with Chronic Lymphocytic Leukemia Under Ibrutinib Therapy: A Case Report.

    PubMed

    Sachanas, Sotirios; Pangalis, Gerassimos A; Karouzakis, Petros; Koulieris, Efstathios; Moschogiannis, Maria; Kalpadakis, Christina; Yiakoumis, Xanthi; Rontogianni, Dimitra

    2016-09-01

    Malakoplakia, a rare granulomatous disease of infectious etiology, is commonly observed in immunocompromised patients. Chronic lymphocytic leukemia (CLL) is characterized by profound immune dysregulation resulting in significant infection-related morbidity and mortality, and several drugs used in CLL treatment have a severe immunosuppressive effect. Ibrutinib, has become a new standard-of-care in patients with CLL, especially for those harboring unfavorable genetic characteristics such as 17 p deletion, with however, unknown long-term immunological consequences. Here we report a case of a patient with CLL with 17 p deletion diagnosed with malakoplakia of the urinary bladder under ibrutinib therapy who developed severe hypogammaglobulinemia during treatment administration. Presumably, ibrutinib might contribute to the development of malakoplakia on the grounds of induced immunosuppression. This case report highlights the need for regular assessment of immunogammaglobulin adequacy during treatment with ibrutinib, considering that it should be given on a permanent basis. PMID:27630324

  15. Association between single nucleotide polymorphism-genotype and outcome of patients with chronic lymphocytic leukemia in a randomized chemotherapy trial

    PubMed Central

    Wade, Rachel; Di Bernardo, Maria Chiara; Richards, Sue; Rossi, Davide; Crowther-Swanepoel, Dalemari; Gaidano, Gianluca; Oscier, David G.; Catovsky, Daniel; Houlston, Richard S.

    2011-01-01

    Background There is variability in the outcome of patients with chronic lymphocytic leukemia with apparently the same stage of disease. Identifying genetic variants that influence patients’ outcome and response to treatment may provide important insights into the biology of the disease. Design and Methods We investigated the possibility that genetic variation influences outcome by conducting a genome-wide analysis of 346,831 single nucleotide polymorphisms in 356 patients entered into a phase III trial comparing the efficacy of fludarabine, chlorambucil, and fludarabine with cyclophosphamide as first-line treatment. Genotypes were linked to individual patients’ outcome data and response to chemotherapy. The association between genotype and progression-free survival was assessed by Cox regression analysis adjusting for treatment and clinicopathology. Results The strongest associations were shown for rs1949733 (ACOX3; P=8.22x10-7), rs1342899 (P=7.72x10−7) and rs11158493 (PPP2R5E; P=8.50×10−7). In addition, the 52 single nucleotide polymorphisms associated at P<10−4 included rs438034 (CENPF; P=4.86×10−6), previously correlated with cancer progression, and rs2255235 (B2M; P=3.10×10−5) and rs2064501 (IL22RA2; P=4.81×10−5) which map to B-cell genes. Conclusions Our findings provide evidence that genetic variation is a determinant of progression-free survival of patients with chronic lymphocytic leukemia. Specific associations warrant further analyses. (Clinicaltrials.gov identifier: NCT00004218) PMID:21659360

  16. Different spectra of recurrent gene mutations in subsets of chronic lymphocytic leukemia harboring stereotyped B-cell receptors.

    PubMed

    Sutton, Lesley-Ann; Young, Emma; Baliakas, Panagiotis; Hadzidimitriou, Anastasia; Moysiadis, Theodoros; Plevova, Karla; Rossi, Davide; Kminkova, Jana; Stalika, Evangelia; Pedersen, Lone Bredo; Malcikova, Jitka; Agathangelidis, Andreas; Davis, Zadie; Mansouri, Larry; Scarfò, Lydia; Boudjoghra, Myriam; Navarro, Alba; Muggen, Alice F; Yan, Xiao-Jie; Nguyen-Khac, Florence; Larrayoz, Marta; Panagiotidis, Panagiotis; Chiorazzi, Nicholas; Niemann, Carsten Utoft; Belessi, Chrysoula; Campo, Elias; Strefford, Jonathan C; Langerak, Anton W; Oscier, David; Gaidano, Gianluca; Pospisilova, Sarka; Davi, Frederic; Ghia, Paolo; Stamatopoulos, Kostas; Rosenquist, Richard

    2016-08-01

    We report on markedly different frequencies of genetic lesions within subsets of chronic lymphocytic leukemia patients carrying mutated or unmutated stereotyped B-cell receptor immunoglobulins in the largest cohort (n=565) studied for this purpose. By combining data on recurrent gene mutations (BIRC3, MYD88, NOTCH1, SF3B1 and TP53) and cytogenetic aberrations, we reveal a subset-biased acquisition of gene mutations. More specifically, the frequency of NOTCH1 mutations was found to be enriched in subsets expressing unmutated immunoglobulin genes, i.e. #1, #6, #8 and #59 (22-34%), often in association with trisomy 12, and was significantly different (P<0.001) to the frequency observed in subset #2 (4%, aggressive disease, variable somatic hypermutation status) and subset #4 (1%, indolent disease, mutated immunoglobulin genes). Interestingly, subsets harboring a high frequency of NOTCH1 mutations were found to carry few (if any) SF3B1 mutations. This starkly contrasts with subsets #2 and #3 where, despite their immunogenetic differences, SF3B1 mutations occurred in 45% and 46% of cases, respectively. In addition, mutations within TP53, whilst enriched in subset #1 (16%), were rare in subsets #2 and #8 (both 2%), despite all being clinically aggressive. All subsets were negative for MYD88 mutations, whereas BIRC3 mutations were infrequent. Collectively, this striking bias and skewed distribution of mutations and cytogenetic aberrations within specific chronic lymphocytic leukemia subsets implies that the mechanisms underlying clinical aggressiveness are not uniform, but rather support the existence of distinct genetic pathways of clonal evolution governed by a particular stereotyped B-cell receptor selecting a certain molecular lesion(s). PMID:27198719

  17. [Review of evidence of thalidomide and lenalidomide in different hematological diseases: chronic lymphocytic leukemia, primary amyloidosis, myelofibrosis and syndrome myelodysplastic].

    PubMed

    Jiménez Lozano, I; Juárez Jiménez, J C

    2013-01-01

    Lenalidomide is an immunomodulatory drug approved by the AEMPS and the EMA, in combination with dexamethasone, for the treatment of multiple myeloma in adult patients who have received at least one prior therapy. Moreover, it has recently been approved for the treatment of patients with transfusion-dependent anaemia due to low- or intermediate-1-risk myelodysplastic syndromes associated with an isolated deletion 5q cytogenetic abnormality when other therapeutic options are insufficient or inadequate. It has also shown to be active in other hematologic and no hematologic diseases. Growing evidence of its use entails a challenge when situating the drug in a cost-effective way to treat these diseases. On this article we review the available evidence on the use of lenalidomide in the second line treatment of patients with chronic lymphocytic leukemia, primary amyloidosis and primary myelofibrosis, and in the first line treatment of patients with myelodysplastic syndrome, and also the evidence of other immunomodulators. Different clinical practice guidelines and scientific evidence portals consider lenalidomide a valid alternative in the first-line treatment of patients with myelodysplastic syndromes, specially those with the deletion of 5q, and in second line for patients with chronic lymphocytic leukemia. However, the available evidence of lenalidomide in the treatment of patients with primary amyloidosis and primary myelofibrosis is limited, ant thus is not considered as the first choice treatment. In any case, the treatment of choice should consider the safety profile in each patient, the previous treatments that has received and the own therapeutic protocols of each center.

  18. Different spectra of recurrent gene mutations in subsets of chronic lymphocytic leukemia harboring stereotyped B-cell receptors

    PubMed Central

    Sutton, Lesley-Ann; Young, Emma; Baliakas, Panagiotis; Hadzidimitriou, Anastasia; Moysiadis, Theodoros; Plevova, Karla; Rossi, Davide; Kminkova, Jana; Stalika, Evangelia; Pedersen, Lone Bredo; Malcikova, Jitka; Agathangelidis, Andreas; Davis, Zadie; Mansouri, Larry; Scarfò, Lydia; Boudjoghra, Myriam; Navarro, Alba; Muggen, Alice F.; Yan, Xiao-Jie; Nguyen-Khac, Florence; Larrayoz, Marta; Panagiotidis, Panagiotis; Chiorazzi, Nicholas; Niemann, Carsten Utoft; Belessi, Chrysoula; Campo, Elias; Strefford, Jonathan C.; Langerak, Anton W.; Oscier, David; Gaidano, Gianluca; Pospisilova, Sarka; Davi, Frederic; Ghia, Paolo; Stamatopoulos, Kostas; Rosenquist, Richard

    2016-01-01

    We report on markedly different frequencies of genetic lesions within subsets of chronic lymphocytic leukemia patients carrying mutated or unmutated stereotyped B-cell receptor immunoglobulins in the largest cohort (n=565) studied for this purpose. By combining data on recurrent gene mutations (BIRC3, MYD88, NOTCH1, SF3B1 and TP53) and cytogenetic aberrations, we reveal a subset-biased acquisition of gene mutations. More specifically, the frequency of NOTCH1 mutations was found to be enriched in subsets expressing unmutated immunoglobulin genes, i.e. #1, #6, #8 and #59 (22–34%), often in association with trisomy 12, and was significantly different (P<0.001) to the frequency observed in subset #2 (4%, aggressive disease, variable somatic hypermutation status) and subset #4 (1%, indolent disease, mutated immunoglobulin genes). Interestingly, subsets harboring a high frequency of NOTCH1 mutations were found to carry few (if any) SF3B1 mutations. This starkly contrasts with subsets #2 and #3 where, despite their immunogenetic differences, SF3B1 mutations occurred in 45% and 46% of cases, respectively. In addition, mutations within TP53, whilst enriched in subset #1 (16%), were rare in subsets #2 and #8 (both 2%), despite all being clinically aggressive. All subsets were negative for MYD88 mutations, whereas BIRC3 mutations were infrequent. Collectively, this striking bias and skewed distribution of mutations and cytogenetic aberrations within specific chronic lymphocytic leukemia subsets implies that the mechanisms underlying clinical aggressiveness are not uniform, but rather support the existence of distinct genetic pathways of clonal evolution governed by a particular stereotyped B-cell receptor selecting a certain molecular lesion(s). PMID:27198719

  19. Palliative care for patients with advance chronic kidney disease.

    PubMed

    Douglas, C A

    2014-01-01

    Over the past three decades there has been a dramatic rise in the number of patients with advanced chronic kidney disease. The fastest expanding group receiving dialysis has been the elderly. However, for those patients who are very elderly with co-morbidity, dialysis may not offer a survival advantage. Therefore, active conservative management is a growing service offered by many renal units in the UK and focuses on non-dialytic correction of fluid and electrolyes, management of renal anaemia, and assessment and management of symptoms. The five-year survival of a patient over 75 years of age starting dialysis is 20% and if a patient is over 75 years, has co-morbidity, or a poor performance status, dialysis may not offer any survival advantage. Whether a patient is managed by dialysis or by conservative management the symptom burden suffered is high. These symptoms are under-recognised and often managed poorly because of increased drug toxicity in renal failure. This complex group of patients require close working between renal, palliative care, medicine for the elderly, and community teams, to allow best quality of life and end of life care. This review describes some of the challenges in providing Advanced Care Planning for dialysis and conservatively managed patients, highlights the symptom burden of patients with advanced chronic kidney disease, and offers guidance in how to manage the symptoms effectively.

  20. Cellular and humoral immune reactions in chronic active liver disease. II. Lymphocyte subsets and viral antigens in liver biopsies of patients with acute and chronic hepatitis B.

    PubMed Central

    Eggink, H F; Houthoff, H J; Huitema, S; Wolters, G; Poppema, S; Gips, C H

    1984-01-01

    The characteristics and distribution of the inflammatory infiltrate in liver biopsies of 25 patients with hepatitis B viral (HBV) infection were studied in relation to the distribution and expression of HBV antigens. Mononuclear subsets were characterized with monoclonal (OKT, OKM, Leu) antibodies to surface antigens. For the demonstration of viral antigens directly conjugated antibodies to surface (HBsAg), core (HBcAg) and 'e' (HBeAg) antigen were used. For the study of mutual relations all methods were performed on serial cut tissue sections. In chronic active hepatitis B (CAH-B, n = 12) OKT8+ lymphocytes of T cell origin were the only cell type present in areas with liver cell degeneration and T cell cytotoxicity appears to be the only immune mechanism. In chronic persistent hepatitis B (CPH-B, n = 7) the only conspicuous feature was the presence of many Leu 3+ lymphocytes of the helper/inducer population in the portal tracts. In acute hepatitis B (AHB, n = 6) OKT8+ cells of non-T origin (OKT1-,3-) and Leu 7+ cells of presumed natural killer (NK) potential predominated in the areas with liver cell necrosis, and non-T cell cytotoxicity appears to be the predominant immune mechanism. In none of these disease entities a positive spatial relation could be established between the cytotoxic cells and the demonstrable expression of HBV antigens in hepatocytes. It is concluded that differences in immunological reaction pattern may explain the different course in the three forms of HBV infection studied. Images Fig. 1 Fig. 2 PMID:6713726

  1. Multiple mechanisms contribute to impairment of type 1 interferon production during chronic lymphocytic choriomeningitis virus infection of mice.

    PubMed

    Lee, Lian Ni; Burke, Shannon; Montoya, Maria; Borrow, Persephone

    2009-06-01

    Type 1 IFNs, innate cytokines with important effector and immunomodulatory properties, are rapidly induced in the acute phase of many virus infections; however, this is generally a transient response that is not sustained during virus persistence. To gain insight into mechanisms that can contribute to down-regulation of type 1 IFN production during virus persistence, we analyzed type 1 IFN production during acute and chronic lymphocytic choriomeningitis virus (LCMV) infection. High-level type 1 IFN production was transiently up-regulated in cells including plasmacytoid and conventional dendritic cells (DCs) following LCMV infection of mice, but LCMV persistence was associated with only low-level type 1 IFN production. Nonetheless, chronically infected mice were able to up-regulate type 1 IFN production in response to TLR3, 7, and 9 ligands, albeit less efficiently than uninfected mice. Splenic DC numbers in mice chronically infected with LCMV were decreased, and the remaining cells exhibited a reduced response to TLR stimulation. LCMV-infected cell lines efficiently up-regulated type 1 IFN production following TLR ligation and infection with a DNA virus, but exhibited a defect in type 1 IFN induction following infection with Sendai, an RNA virus. This block in type 1 IFN production by infected cells, together with abnormalities in DC numbers and functions, likely contribute to the low-level type 1 IFN production in mice chronically infected with LCMV. Impairment of type 1 IFN production may both promote virus persistence and impact on host immunocompetence. Understanding the mechanisms involved may assist in development of strategies for control of virus persistence and superinfection. PMID:19454715

  2. Recent advances in understanding of chronic kidney disease

    PubMed Central

    Yamaguchi, Junna; Tanaka, Tetsuhiro; Nangaku, Masaomi

    2015-01-01

    Chronic kidney disease (CKD) is defined as any condition that causes reduced kidney function over a period of time. Fibrosis, tubular atrophy and interstitial inflammation are the hallmark of pathological features in CKD. Regardless of initial insult, CKD has some common pathways leading CKD to end-stage kidney disease, including hypoxia in the tubulointerstitium and proteinuria. Recent advances in genome editing technologies and stem cell research give great insights to understand the pathogenesis of CKD, including identifications of the origins of renal myofibroblasts and tubular epithelial cells upon injury. Environmental factors such as hypoxia, oxidative stress, and epigenetic factors in relation to CKD are also discussed. PMID:26937272

  3. [Advances in the research of biological characters and pathophysiological effects of dendritic epidermal T lymphocytes].

    PubMed

    Li, Y S; He, W F; Wu, J

    2016-01-01

    The maturation of dendritic epidermal T lymphocytes (DETCs) in thymus needs ligand-mediated positive selection, and positive selection together with V3γ(+) γδT lymphocytes intrinsic program features order DETCs to specifically migrate to epidermis. Positive selection promotes DETCs to express CD122, which is vital for DETCs to survive and proliferate in skin. DETCs possess memory-like phenotype and are able to rapidly respond to danger signals when they move out from thymus. NKG2D, junctional adhesion molecule-like protein and 2B4 are demonstrated to participate in DETCs activation, except for ligands of T lymphocytes receptor. Effective DETCs secrete cytokines such as interferon-γ, insulin-like growth factor-2, keratinocyte growth factor and gain cytotoxicity to directly kill tumor cells. DETCs participate in skin immune surveillance, regulation of local inflammation, and wound healing promotion. PMID:27426071

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

    ClinicalTrials.gov

    2016-06-02

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

  5. Chronic granulomatous pneumonia and lymphocytic responses induced by inhaled beryllium metal in A/J and C3H/HeJ mice

    SciTech Connect

    Nikula, K.J.; Swafford, D.S.; Hoover, M.D.; Tohulka, M.D.; Finch, G.L.

    1997-12-31

    Inhalation of beryllium (Be) has been associated with 2 syndromes: an acute chemical pneumonitis and a granulomatous lung disease known as chronic beryllium disease (CBD). The purpose of this study was to establish a mouse model of CBD using the inhalation route of exposure. A/J (H-2a haplotype) and C3H/HeJ (H-2{sup k}) Mice were exposed once for 90 min in nose-only exposure tubes to aerosols of Be metal. Six mo later, lung histopathologic responses were assessed. Further analyses defined the phenotypic profile of lymphocytes in pulmonary lesions and evaluated proliferation of lymphocytes in situ and in response to Be in vitro. Responses were similar in both strains of mice. Most Be-exposed mice had minimal to mild interstitial fibrosis. The majority of lymphocytes in interstitial infiltrates and in microgranulomas were CD4+ T cells. Interstitial compact aggregates of lymphocytes contained B cells centrally and CD4+ cells peripherally. Lymphocyte labeling indices, used to assess proliferation in situ, were significantly greater within microgranulomas compared to compact lymphocytic aggregates. Lymphocyte stimulation indices in response to BeSO{sub 4} in vitro were not positive in blood, spleen, or tracheobronchial lymph node samples. Be-specific immune responses and nonspecific inflammatory responses to toxic and foreign-body properties of Be may have contributed to the histopathology in both strains of mice. The interstitial mononuclear cell infiltrates, presence of microgranulomas, multinucleated foreign-body and Langhans giant cells, interstitial fibrosis, and CD4+ T-cell predominance with local proliferation are features similar to CBD in humans. The chronic lung disease induced in these mice by inhaled Be can be used to investigate the importance of variables such as dose, exposure pattern, and physicochemical form of Be in producing this disease. 29 refs., 6 figs., 3 tabs.

  6. 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

  7. The evolution of treatment strategies for patients with chronic myeloid leukemia relapsing after allogeneic bone marrow transplantation: Can tyrosine kinase inhibitors replace donor lymphocyte infusions?

    PubMed Central

    Zeidner, Joshua F.; Zahurak, Marianna; Rosner, Gary L.; Gocke, Christopher D.; Jones, Richard J.; Smith, Douglas

    2014-01-01

    The optimal treatment for chronic myeloid leukemia (CML) relapsing following allogeneic bone marrow transplantation (alloBMT) is unknown. We performed a single-center retrospective analysis of 71 consecutive patients undergoing alloBMT for CML from 1995–2008. A multi-state model was used to quantify the cumulative incidences of complete molecular response (CMR) and death following alloBMT. The primary analysis was the comparison of three treatment interventions (tyrosine kinase inhibitor: TKI, donor lymphocyte infusion: DLI, and TKI+DLI) for relapsed disease post-alloBMT. Forty-five (63%) patients relapsed post-alloBMT (molecular relapse: n=16, cytogenetic relapse: n=20, hematologic relapse: n=2, advanced phase relapse: n=7) and 40 patients underwent one of three treatments: TKI-only (n=13), DLI-only (n=11), or TKI+DLI (n=16). Although not statistically significant, the TKI-only group had the highest cumulative incidence of CMR and the lowest cumulative incidence of death compared to DLI and TKI+DLI. These data support the finding that TKI therapy is active in the post-alloBMT setting. PMID:24712979

  8. Fluorescence lifetime imaging of DAPI-stained nuclei as a novel diagnostic tool for the detection and classification of B-cell chronic lymphocytic leukemia.

    PubMed

    Yahav, Gilad; Hirshberg, Abraham; Salomon, Ophira; Amariglio, Ninette; Trakhtenbrot, Luba; Fixler, Dror

    2016-07-01

    B-cell chronic lymphocytic leukaemia (B-CLL) and B-cell precursor acute lymphoblastic leukaemia (B-ALL) are the most common type of leukaemia in adults and children, respectively. Today, fluorescence in situ hybridization (FISH) is the standard for detecting chromosomal aberrations that reflect adverse and favorable outcome. This study revealed a new, simple, and fast diagnostic tool to detect pathological cells by measuring and imaging the fluorescence lifetime (FLT) using FLT imaging microscopy (FLIM) of the peripheral blood (PB) cells of B-CLL samples that were labeled with the DNA binder, DAPI. The FLT of DAPI in healthy individuals was found to be 2.66 ± 0.12 ns. In contrast, PB cells of B-CLL and BM cells of B-ALL patients were characterized by a specific group distribution of the FLT values. The FLT of DAPI was divided into four subgroups, relative to 2.66 ns: short+, normal, prolonged, and prolonged+. These alterations could be related to different chromatin arrangements of B-CLL and B-ALL interphase nuclei. Notably, extremely long FLT of nuclear DAPI correlate with the presence of extra chromosome 12, while moderate increases compared to normal characterize the deletion of p53. Such correlations potentially enable a FLT-based rapid automatic diagnosis and classification of B-CLL even when the frequency of genetic and chromosomal abnormalities is low. © 2016 International Society for Advancement of Cytometry. PMID:27315046

  9. Progression of benign prostatic hyperplasia is associated with pro-inflammatory mediators and chronic activation of prostate-infiltrating lymphocytes

    PubMed Central

    Sundberg, Berit; Mattsson, Jonas; Henningsohn, Lars; Levitsky, Victor; Uhlin, Michael

    2016-01-01

    Benign prostatic hyperplasia (BPH) is a common chronic non-malignant condition whose prevalence substantially increases with age. Immune cell infiltration and pro-inflammatory mediators have been implicated in the pathogenesis. Here, we characterized 21 extracellular markers on prostate-infiltrating lymphocytes (PILs) and analyzed expression of 26 soluble proteins in prostate tissue obtained from BPH patients (n = 31). These data were correlated with clinical parameters and compared with peripheral blood mononuclear cells (PBMCs) (n = 10). Increased frequencies of T cells expressing co-inhibitory receptors LAG-3, PD-1, TIM-3 or CTLA-4, and co-stimulatory receptors CD28, OX40 or 4-1BB were observed in BPH tissue compared to PBMCs. These findings are consistent with chronic activation and possible functional exhaustion of PILs that may be further augmented by several identified pro-inflammatory factors, such as IL-8 and MCP-1, promoting inflammation and chemotaxis of immune cells to the prostate. Prostate size and plasma prostate-specific antigen levels positively correlated with IL-8 and MCP-1 concentrations, and frequencies of T cells expressing CTLA-4 and TIM-3. It remains to be established whether the link between inflammation and BPH progression supported by our findings reflects a progressive failure of the immune system leading to decreased immune surveillance and development of prostate cancer. PMID:26993768

  10. Progression of benign prostatic hyperplasia is associated with pro-inflammatory mediators and chronic activation of prostate-infiltrating lymphocytes.

    PubMed

    Norström, Melissa M; Rådestad, Emelie; Sundberg, Berit; Mattsson, Jonas; Henningsohn, Lars; Levitsky, Victor; Uhlin, Michael

    2016-04-26

    Benign prostatic hyperplasia (BPH) is a common chronic non-malignant condition whose prevalence substantially increases with age. Immune cell infiltration and pro-inflammatory mediators have been implicated in the pathogenesis. Here, we characterized 21 extracellular markers on prostate-infiltrating lymphocytes (PILs) and analyzed expression of 26 soluble proteins in prostate tissue obtained from BPH patients (n = 31). These data were correlated with clinical parameters and compared with peripheral blood mononuclear cells (PBMCs) (n = 10). Increased frequencies of T cells expressing co-inhibitory receptors LAG-3, PD-1, TIM-3 or CTLA-4, and co-stimulatory receptors CD28, OX40 or 4-1BB were observed in BPH tissue compared to PBMCs. These findings are consistent with chronic activation and possible functional exhaustion of PILs that may be further augmented by several identified pro-inflammatory factors, such as IL-8 and MCP-1, promoting inflammation and chemotaxis of immune cells to the prostate. Prostate size and plasma prostate-specific antigen levels positively correlated with IL-8 and MCP-1 concentrations, and frequencies of T cells expressing CTLA-4 and TIM-3. It remains to be established whether the link between inflammation and BPH progression supported by our findings reflects a progressive failure of the immune system leading to decreased immune surveillance and development of prostate cancer. PMID:26993768

  11. Waiting times for the appearance of cytotoxic T-lymphocyte escape mutants in chronic HIV-1 infection

    SciTech Connect

    Liu Yi . E-mail: yiliu197@u.washington.edu; Mullins, James I.; Mittler, John E.

    2006-03-30

    The failure of HIV-1 to escape at some cytotoxic T-lymphocyte (CTL) epitopes has generally been explained in terms of viral fitness costs or ineffective or attenuated CTL responses. Relatively little attention has been paid to the evolutionary time required for escape mutants to be detected. This time is significantly affected by selection, mutation rates, the presence of other advantageous mutations, and the effective population size of HIV-1 in vivo (typically estimated to be {approx}10{sup 3} in chronically infected patients, though one study has estimated it to be {approx}10{sup 5}). Here, we use a forward simulator with experimentally estimated HIV-1 parameters to show that these delays can be substantial. For an effective population size of 10{sup 3}, even highly advantageous mutants (s = 0.5) may not be detected for a couple of years in chronically infected patients, while moderately advantageous escape mutants (s = 0.1) may not be detected for up to 10 years. Even with an effective population size of 10{sup 5}, a moderately advantageous escape mutant (s = 0.1) may not be detected in the population within 2 years if it has to compete with other selectively advantageous mutants. Stochastic evolutionary forces, therefore, in addition to viral fitness costs and ineffective or attenuated CTL responses, must be taken into account when assessing the selection of CTL escape mutations.

  12. 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

  13. Cellular Immunotherapy Following Chemotherapy in Treating Patients With Recurrent Non-Hodgkin Lymphomas, Chronic Lymphocytic Leukemia or B-Cell Prolymphocytic Leukemia

    ClinicalTrials.gov

    2016-07-29

    Post-transplant Lymphoproliferative Disorder; B-Cell Prolymphocytic Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; B-Cell Lymphoma, Unclassifiable, With Features Intermediate Between Diffuse Large B-Cell Lymphoma and Burkitt Lymphoma; B-Cell Lymphoma, Unclassifiable, With Features Intermediate Between Diffuse Large B-Cell Lymphoma and Classical Hodgkin Lymphoma; Recurrent Lymphoplasmacytic Lymphoma

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

    PubMed

    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

    2016-05-01

    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

  15. Immunoglobulin transcript sequence and somatic hypermutation computation from unselected RNA-seq reads in chronic lymphocytic leukemia

    PubMed Central

    Blachly, James S.; Ruppert, Amy S.; Zhao, Weiqiang; Long, Susan; Flynn, Joseph; Flinn, Ian; Jones, Jeffrey; Maddocks, Kami; Andritsos, Leslie; Ghia, Emanuela M.; Rassenti, Laura Z.; Kipps, Thomas J.; de la Chapelle, Albert; Byrd, John C.

    2015-01-01

    Immunoglobulins (Ig) are produced by B lymphocytes as secreted antibodies or as part of the B-cell receptor. There is tremendous diversity of potential Ig transcripts (>1 × 1012) as a result of hundreds of germ-line gene segments, random nucleotide incorporation during joining of gene segments into a complete transcript, and the process of somatic hypermutation at individual nucleotides. This recombination and mutation process takes place in the maturing B cell and is responsible for the diversity of potential epitope recognition. Cancers arising from mature B cells are characterized by clonal production of Ig heavy (IGH@) and light chain transcripts, although whether the sequence has undergone somatic hypermutation is dependent on the maturation stage at which the neoplastic clone arose. Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults and arises from a mature B cell with either mutated or unmutated IGH@ transcripts, the latter having worse prognosis and the assessment of which is routinely performed in the clinic. Currently, IGHV mutation status is assessed by Sanger sequencing and comparing the transcript to known germ-line genes. In this paper, we demonstrate that complete IGH@ V-D-J sequences can be computed from unselected RNA-seq reads with results equal or superior to the clinical procedure: in the only discordant case, the clinical transcript was out-of-frame. Therefore, a single RNA-seq assay can simultaneously yield gene expression profile, SNP and mutation information, as well as IGHV mutation status, and may one day be performed as a general test to capture multidimensional clinically relevant data in CLL. PMID:25787252

  16. Development of Tumor-Reactive T Cells After Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplant for Chronic Lymphocytic Leukemia

    PubMed Central

    Nishida, Tetsuya; Hudecek, Michael; Kostic, Ana; Bleakley, Marie; Warren, Edus H.; Maloney, David; Storb, Rainer; Riddell, Stanley R.

    2009-01-01

    Purpose Allogeneic NM-HSCT can result in durable remission of chronic lymphocytic leukemia (CLL). It is thought that the efficacy of NM-HSCT is mediated by recognition of tumor cells by T cells in the donor stem cell graft. We evaluated the development of cytotoxic T lymphocytes (CTL) specific for CLL after NM-HSCT to determine if their presence correlated with antitumor efficacy. Experimental Design Peripheral blood mononuclear cells obtained from twelve transplant recipients at intervals after NM-HSCT were stimulated in vitro with CLL cells. Polyclonal T cell lines and CD8+ T cell clones were derived from these cultures and evaluated for lysis of donor and recipient target cells including CLL. The presence and specificity of responses was correlated with clinical outcomes. Results Eight of the 12 patients achieved remission or a major antitumor response and all eight developed CD8+ and CD4+ T cells specific for antigens expressed by CLL. A clonal analysis of the CD8+ T cell response identified T cells specific for multiple minor histocompatibility (H) antigens expressed on CLL in six of the responding patients. A significant fraction of the CD8+ T cell response in some patients was also directed against non-shared tumor-specific antigens. By contrast, CLL-reactive T cells were not detected in the four patients who had persistent CLL after NM-HSCT, despite the development of GVHD. Conclusions The development of a diverse T cell response specific for minor H and tumor-associated antigens expressed by CLL predicts an effective GVL response after NM-HSCT. PMID:19567591

  17. 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

  18. Pharmacological and protein profiling suggest venetoclax (ABT-199) as optimal partner with ibrutinib in chronic lymphocytic leukemia

    PubMed Central

    Cervantes-Gomez, Fabiola; Lamothe, Betty; Woyach, Jennifer A.; Wierda, William G.; Keating, Michael J.; Balakrishnan, Kumudha; Gandhi, Varsha

    2015-01-01

    Purpose Bruton’s tyrosine kinase (BTK) is a critical enzyme in the B-cell receptor pathway and is inhibited by ibrutinib due to covalent binding to the kinase domain. Though ibrutinib results in impressive clinical activity in chronic lymphocytic leukemia (CLL), most patients achieve only partial remission due to residual disease. We performed a pharmacologic profiling of residual circulating CLL cells from patients receiving ibrutinib to identify optimal agents that could induce cell death of these lymphocytes. Experimental design Ex vivo serial samples of CLL cells from patients on ibrutinib were obtained prior and after (weeks 2, 4, and 12) the start of treatment. These cells were incubated with PI3K inhibitors (idelalisib or IPI-145), bendamustine, additional ibrutinib, or BCL-2 antagonists (ABT-737 or ABT-199) and cell death was measured. In vitro investigations complemented ex vivo studies. Immunoblots for BTK signaling pathway and antiapoptotic proteins were performed. Results The BCL-2 antagonists, especially ABT-199, induced high cell death during ex vivo incubations. In concert with the ex vivo data, in vitro combinations also resulted highly cytotoxicity. Serial samples of CLL cells obtained before and 2, 4, 12, or 36 weeks after the start of ibrutinib showed inhibition of BTK activity and sensitivity to ABTs. Among the three BCL-2 family anti-apoptotic proteins that are overexpressed in CLL, levels of MCL-1 and BCL-XL were decreased after ibrutinib while ABT-199 selectively antagonizes BCL-2. Conclusions Our biological and molecular results suggest that ibrutinib and ABT-199 combination should be tested clinically against CLL. PMID:25829398

  19. Surrogate molecular markers for IGHV mutational status in chronic lymphocytic leukemia for predicting time to first treatment.

    PubMed

    Morabito, Fortunato; Cutrona, Giovanna; Mosca, Laura; D'Anca, Marianna; Matis, Serena; Gentile, Massimo; Vigna, Ernesto; Colombo, Monica; Recchia, Anna Grazia; Bossio, Sabrina; De Stefano, Laura; Maura, Francesco; Manzoni, Martina; Ilariucci, Fiorella; Consoli, Ugo; Vincelli, Iolanda; Musolino, Caterina; Cortelezzi, Agostino; Molica, Stefano; Ferrarini, Manlio; Neri, Antonino

    2015-08-01

    ZAP-70 is a marker of clinical outcome in chronic lymphocytic leukemia (CLL), however its assessment suffers from a lack of standardization consensus. To identify novel markers able to surrogate IGHV mutational status, CD19(+)CD5(+)-B-lymphocytes from 216 patients enrolled in a prospective study (ClinicalTrial.gov Identifier:NCT00917540), underwent gene expression profiling. Samples were split into CLL-Training (n=102) and CLL-Validation (n=114) sets, and an independent supervised analysis for IGHV mutational status was performed considering all genes with gene expression equal or above that of ZAP-70. Thirty-one genes (23 up- and 8 down-regulated) and 23 genes (18 up- and 5 down-regulated) satisfied these criteria in the CLL-Training and CLL-Validation sets, respectively, and 20 common genes (15 up and 5 down) were found to be differentially regulated in both sets. Two (SNORA70F, NRIP1) of the down-regulated and 6 (SEPT10, ZNF667, TGFBR3, MBOAT1, LPL, CRY1) of the up-regulated genes were significantly associated with a reduced risk of disease progression in both sets. Forcing the afore-mentioned genes in a Cox multivariate model together with IGHV mutational status, only CRY1 (HR=2.3, 95% CI: 1.1-4.9, P=.027) and MBOAT1 (HR=2.1, 95% CI: 1.1-3.7, P=.018) retained their independent prognostic impact, supporting the hypothesis that these genes may potentially act as surrogates for predicting IGHV mutational status.

  20. Programmed Death-1 and Its Ligand Are Novel Immunotolerant Molecules Expressed on Leukemic B Cells in Chronic Lymphocytic Leukemia

    PubMed Central

    Mertens, Daniel; Tomczak, Waldemar; Wlasiuk, Paulina; Kosior, Kamila; Piechnik, Agnieszka; Bojarska-Junak, Agnieszka; Dmoszynska, Anna; Giannopoulos, Krzysztof

    2012-01-01

    Programmed death-1 (PD-1) is an immunoreceptor predominantly expressed on exhausted T cells, which through an interaction with its ligand (PD-L1), controls peripheral tolerance by limiting effector functions of T lymphocytes. qRT-PCR for PD-1, PD-L1 and their splicing forms as well as flow cytometric assessment of surface expression was performed in a cohort of 58 chronic lymphocytic leukemia (CLL) patients. In functional studies, we assessed the influence of the proliferative response of leukemic B-cells induced by IL-4 and CD40L on PD-1 transcripts and expression on the protein level. The median level of PD-1, but not PD-L1, transcripts in CLL patients was higher in comparison to healthy volunteers (HVs, n = 43, p = 0.0057). We confirmed the presence of PD-1 and PD-L1 on the CLL cell surface, and found the expression of PD-1, but not PD-L1, to be higher among CLL patients in comparison to HVs (47.2% vs. 14.8%, p<0.0001). The Kaplan-Meier curves for the time to progression and overall survival in groups with high and low surface expression of PD-1 and PD-L1 revealed no prognostic value in CLL patients. After stimulation with IL-4 and CD40L, protein expression of PD-1 was significantly increased in samples that responded and up-regulated CD38. PD-1, which is aberrantly expressed both at mRNA and cell surface levels in CLL cells might represent a novel immunotolerant molecule involved in the pathomechanism of the disease, and could provide a novel target for future therapies. PMID:22532845

  1. Immunoglobulin transcript sequence and somatic hypermutation computation from unselected RNA-seq reads in chronic lymphocytic leukemia.

    PubMed

    Blachly, James S; Ruppert, Amy S; Zhao, Weiqiang; Long, Susan; Flynn, Joseph; Flinn, Ian; Jones, Jeffrey; Maddocks, Kami; Andritsos, Leslie; Ghia, Emanuela M; Rassenti, Laura Z; Kipps, Thomas J; de la Chapelle, Albert; Byrd, John C

    2015-04-01

    Immunoglobulins (Ig) are produced by B lymphocytes as secreted antibodies or as part of the B-cell receptor. There is tremendous diversity of potential Ig transcripts (>1 × 10(12)) as a result of hundreds of germ-line gene segments, random nucleotide incorporation during joining of gene segments into a complete transcript, and the process of somatic hypermutation at individual nucleotides. This recombination and mutation process takes place in the maturing B cell and is responsible for the diversity of potential epitope recognition. Cancers arising from mature B cells are characterized by clonal production of Ig heavy (IGH@) and light chain transcripts, although whether the sequence has undergone somatic hypermutation is dependent on the maturation stage at which the neoplastic clone arose. Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults and arises from a mature B cell with either mutated or unmutated IGH@ transcripts, the latter having worse prognosis and the assessment of which is routinely performed in the clinic. Currently, IGHV mutation status is assessed by Sanger sequencing and comparing the transcript to known germ-line genes. In this paper, we demonstrate that complete IGH@ V-D-J sequences can be computed from unselected RNA-seq reads with results equal or superior to the clinical procedure: in the only discordant case, the clinical transcript was out-of-frame. Therefore, a single RNA-seq assay can simultaneously yield gene expression profile, SNP and mutation information, as well as IGHV mutation status, and may one day be performed as a general test to capture multidimensional clinically relevant data in CLL. PMID:25787252

  2. Generation of non-MHC restricted killing in cultures stimulated with B cells from chronic lymphocytic leukaemia patients: phenotypic characterization of the precursor and effector cells.

    PubMed Central

    Matera, L; Foa, R; Malavasi, F; Bellone, G; Funaro, A; Veglia, F; Santoli, D

    1988-01-01

    Freshly isolated B cells from chronic lymphocytic leukaemia patients (B-CLL) have been previously shown to induce a strong proliferative response and high levels of NK-like activity in lymphocytes from healthy donors. The present paper deals with the origin, mitotic state, target spectrum and cell surface phenotype of the NK-like effectors generated after stimulation with B-CLL. Experiments using large granular lymphocytes (LGL) and T cells as responders demonstrated that most of the precursors of the newly generated NK-like effectors express the CD3 antigen. The induction of NK-like activity paralleled cell activation, as judged by blast transformation, thymidine uptake and appearance of cell surface activation markers. The newly generated NK-like effectors displayed a T cell phenotype and a broader target repertoire than native NK cells. PMID:3261664

  3. [The characteristic of proliferative activity of thymocytes and peripheral blood lymphocytes in the offspring of females with experimental chronic liver diseases of various aetiology].

    PubMed

    Briukhin, G V; Fedosov, A A

    2006-01-01

    The aim of the study was a comparative analysis of the proliferative activity of thymocytes and peripheral blood lymphocytes in the offspring of female rats with chronic liver pathology of various genesis. In adult female Wistar rats toxic and autoimmune forms of liver lesions were modeled. The offspring of these experimental animals was studied at different time points of postnatal ontogenesis. Proliferative activity of thymocytes and lymphocytes was estimated by counting the proportion of cells with multiple nucleolar organizing regions (AgNORs) and using the cytofluorometric method with acridine orange. In the offspring of experimental animals, the depression of proliferative activity of thymocytes as well as the increase of the proliferative activity of peripheral blood lymphocytes were found at all the time points studied. This was indicated by a change in a relative number of AgNORs-activated cells and a decrease of nucleic acid content in cortical thymocytes. PMID:17201321

  4. Febuxostat for hyperuricemia in patients with advanced chronic kidney disease.

    PubMed

    Akimoto, Tetsu; Morishita, Yoshiyuki; Ito, Chiharu; Iimura, Osamu; Tsunematsu, Sadao; Watanabe, Yuko; Kusano, Eiji; Nagata, Daisuke

    2014-01-01

    Febuxostat is a nonpurine xanthine oxidase (XO) inhibitor, which recently received marketing approval. However, information regarding the experience with this agent among advanced chronic kidney disease (CKD) patients is limited. In the current study, we investigated the effects of oral febuxostat in patients with advanced CKD with asymptomatic hyperuricemia. We demonstrated, for the first time, that not only the serum levels of uric acid (UA) but also those of 8-hydroxydeoxyguanosine, an oxidative stress marker, were significantly reduced after six months of febuxostat treatment, with no adverse events. These results encouraged us to pursue further investigations regarding the clinical impact of lowering the serum UA levels with febuxostat in advanced CKD patients in terms of concomitantly reducing oxidative stress via the blockade of XO. More detailed studies with a larger number of subjects and assessments of the effects of multiple factors affecting hyperuricemia, such as age, sex, and dietary habits, would shed light on the therapeutic challenges of treating asymptomatic hyperuricemia in patients with various stages of CKD. PMID:25210423

  5. [Integrated care for patients with advanced chronic obstructive pulmonary disease].

    PubMed

    Jassem, Ewa; Górecka, Dorota; Krakowiak, Piotr; Kozielski, Jerzy; Słomiński, J Marek; Krajnik, Małgorzata; Fal, Andrzej M

    2010-01-01

    Chronic obstructive pulmonary disease (COPD) is the third cause of mortality and disability (assessed by DALY) among patients above 60 year old. Severe and very severe COPD (FEV(1) = equal or less than 50% and 30% of expected value, respectively) is estimated at 20% of all COPD patients. Advanced COPD usually leads to physical and mental deterioration, the patients often manage with the problems caused by the disease and other comorbidities poorly. This leads to increased risk of COPD exacerbations and further deterioration of the patient's status, increased costs of medical care and eventually increased risk of death. Current organization of medical care for those patients does not provide adequate health and social support for them. However, it seems that introducing an integrated approach proposed by World Health Organization, could improve the situation of advanced COPD patients. In Poland, this kind of care has been provided in advanced cancer patients throughout stationary palliative care units and hospices during the last several years. This experience should be helpful in integrating actions of general practitioners and specialized nurses, as well as providing access for the specialists' consultations according to the individual needs of the patients. It should also allow for broad cooperation with auxiliary staff, such as social workers, medical assistants and volunteers, as well as psychologists and clergymen (especially in the terminal phase of the disease).

  6. Cost-effectiveness of adding rituximab to fludarabine and cyclophosphamide for treatment of chronic lymphocytic leukemia in Ukraine

    PubMed Central

    Mandrik, Olena; Corro Ramos, Isaac; Knies, Saskia; Al, Maiwenn; Severens, Johan L

    2015-01-01

    The aim of this study was to assess the cost-effectiveness, from a health care perspective, of adding rituximab to fludarabine and cyclophosphamide scheme (FCR versus FC) for treatment-naïve and refractory/relapsed Ukrainian patients with chronic lymphocytic leukemia. A decision-analytic Markov cohort model with three health states and 1-month cycle time was developed and run within a life time horizon. Data from two multinational, prospective, open-label Phase 3 studies were used to assess patients’ survival. While utilities were generalized from UK data, local resource utilization and disease-associated treatment, hospitalization, and side effect costs were applied. The alternative scenario was performed to assess the impact of lower life expectancy of the general population in Ukraine on the incremental cost-effectiveness ratio (ICER) for treatment-naïve patients. One-way, two-way, and probabilistic sensitivity analyses were conducted to assess the robustness of the results. The ICER (in US dollars) of treating chronic lymphocytic leukemia patients with FCR versus FC is US$8,704 per quality-adjusted life year gained for treatment-naïve patients and US$11,056 for refractory/relapsed patients. When survival data were modified to the lower life expectancy of the general population in Ukraine, the ICER for treatment-naïve patients was higher than US$13,000. This value is higher than three times the current gross domestic product per capita in Ukraine. Sensitivity analyses have shown a high impact of rituximab costs and a moderate impact of differences in utilities on the ICER. Furthermore, probabilistic sensitivity analyses have shown that for refractory/relapsed patients the probability of FCR being cost-effective is higher than for treatment-naïve patients and is close to one if the threshold is higher than US$15,000. State coverage of rituximab treatment may be considered a cost-effective treatment for the Ukrainian population under conditions of economic

  7. Specific inhibition of in vitro Candida-induced lymphocyte proliferation by polysaccharidic antigens present in the serum of patients with chronic mucocutaneous candidiasis.

    PubMed Central

    Fischer, A; Ballet, J J; Griscelli, C

    1978-01-01

    A specific inhibitory activity of in vitro proliferative responses of normal human lymphocytes to Candida metabolic antigen was found in the serum of 6 out of 23 children with chronic mucocutaneous candidiasis. In each of the six patients, the presence of an inhibitory activity was associated with Candida-specific cellular defects, characterized by a negative-skin test and a lack of in vitro lymphocyte proliferation. The presence of a circulating inhibitor was detected during relapses of the disease and disappeared under antifungal therapy. This inhibitory effect was not associated with any toxicity on tested lymphocytes. The factor was shown to be nondialysable, thermostable, nonprecipitable with ammonium sulfate and absorbable on anti-Candida antibodies or concanavalin A-coupled agarose columns. Altogether, these results suggest that the inhibitory factor is not an immunoglobulin, but rather a polysaccharidic antigen of Candida albicans. An inhibition of Candida-induced proliferative response of normal human lymphocytes was also obtained by addition of polysacharide antigens or purified mannans from C. albicans to cultures. Candida polysaccharidic antigens appeared, therefore, to be involved in specific depression of cellular functions observed in chronic candidiasis. PMID:361754

  8. Cytomegalovirus infection does not impact on survival or time to first treatment in patients with chronic lymphocytic leukemia

    PubMed Central

    Damery, Sarah; Hudson, Christopher; Maurer, Matthew J.; Cerhan, James R.; Pachnio, Annette; Begum, Jusnara; Slager, Susan L.; Fegan, Christopher; Man, Stephen; Pepper, Christopher; Shanafelt, Tait D.; Pratt, Guy; Moss, Paul A. H.

    2016-01-01

    Human cytomegalovirus (HCMV) is a widely prevalent herpes virus which establishes a state of chronic infection. The establishment of CMV‐specific immunity controls viral reactivation and leads to the accumulation of very large numbers of virus‐specific T cells which come to dominate the immune repertoire. There is concern that this may reduce the immune response to heterologous infections and HCMV infection has been associated with reduced survival in elderly people. Patients with chronic lymphocytic leukemia (B‐CLL) suffer from a state of immune suppression but have a paradoxical increase in the magnitude of the CMV‐specific T cell and humoral immune response. As such, there is now considerable interest in how CMV infection impacts on the clinical outcome of patients with B‐CLL. Utilizing a large prospective cohort of patients with B‐CLL (n = 347) we evaluated the relationship between HCMV seropositivity and patient outcome. HCMV seropositive patients had significantly worse overall survival than HCMV negative patients in univariate analysis (HR = 2.28, 95% CI: 1.34–3.88; P = 0.002). However, CMV seropositive patients were 4 years older than seronegative donors and this survival difference was lost in multivariate modeling adjusted for age and other validated prognostic markers (P = 0.34). No significant difference was found in multivariate modeling between HCMV positive and negative patients in relation to the time to first treatment (HR = 1.12, 95% CI: 0.68–1.84; P = 0.65). These findings in a second independent cohort of 236 B‐CLL patients were validated. In conclusion no evidence that HCMV impacts on the clinical outcome of patients with B‐CLL was found. Am. J. Hematol. 91:776–781, 2016. © 2016 Wiley Periodicals, Inc. PMID:27124884

  9. TP53 mutations are early events in chronic lymphocytic leukemia disease progression and precede evolution to complex karyotypes.

    PubMed

    Lazarian, Gregory; Tausch, Eugen; Eclache, Virginie; Sebaa, Amel; Bianchi, Vincent; Letestu, Remi; Collon, Jean-Francois; Lefebvre, Valerie; Gardano, Laura; Varin-Blank, Nadine; Soussi, Thierry; Stilgenbauer, Stephen; Cymbalista, Florence; Baran-Marszak, Fanny

    2016-10-15

    TP53 abnormalities lead to resistance to purine analogues and are found in over 40% of patients with refractory chronic lymphocytic leukemia (CLL). At diagnosis, no more than 5% of patients carry the 17p deletion, most cases harbour mutations within the other TP53 allele. The incidence of a TP53 mutation as the only alteration is approximately 5%, but this depends on the sensitivity of the technique. Recently, having a complex karyotype has been considered a strong adverse prognostic factor. However, there are no longitudinal studies simultaneously examining the presence of the 17p deletion, TP53 mutations and karyotype abnormalities. We conducted a retrospective longitudinal study of 31 relapsed/refractory CLL patients. Two to six blood samples per patient were analyzed, with a median follow-up of 8 years. In this report, we assessed the sequence of events of TP53 clonal evolution and correlated the presence of TP53 abnormalities to genetic instability during progression and treatment. Next-generation sequencing allowed the early detection of TP53 mutated clones and was able to be performed on a routine basis, demonstrating an excellent correlation between the Illumina and Ion Torrent technologies. We concluded that TP53 mutations are early events and precede clonal evolution to complex karyotypes. We strongly recommend the early and iterated detection of TP53 mutations in progressive cases. PMID:27270786

  10. Alternative splice variants of AID are not stoichiometrically present at the protein level in chronic lymphocytic leukemia.

    PubMed

    Rebhandl, Stefan; Huemer, Michael; Zaborsky, Nadja; Gassner, Franz Josef; Catakovic, Kemal; Felder, Thomas Klaus; Greil, Richard; Geisberger, Roland

    2014-07-01

    Activation-induced deaminase (AID) is a DNA-mutating enzyme that mediates class-switch recombination as well as somatic hypermutation of antibody genes in B cells. Due to off-target activity, AID is implicated in lymphoma development by introducing genome-wide DNA damage and initiating chromosomal translocations such as c-myc/IgH. Several alternative splice transcripts of AID have been reported in activated B cells as well as malignant B cells such as chronic lymphocytic leukemia (CLL). As most commercially available antibodies fail to recognize alternative splice variants, their abundance in vivo, and hence their biological significance, has not been determined. In this study, we assessed the protein levels of AID splice isoforms by introducing an AID splice reporter construct into cell lines and primary CLL cells from patients as well as from WT and TCL1(tg) C57BL/6 mice (where TCL1 is T-cell leukemia/lymphoma 1). The splice construct is 5'-fused to a GFP-tag, which is preserved in all splice isoforms and allows detection of translated protein. Summarizing, we show a thorough quantification of alternatively spliced AID transcripts and demonstrate that the corresponding protein abundances, especially those of splice variants AID-ivs3 and AID-ΔE4, are not stoichiometrically equivalent. Our data suggest that enhanced proteasomal degradation of low-abundance proteins might be causative for this discrepancy.

  11. MicroRNAs in chronic lymphocytic leukemia: miRacle or miRage for prognosis and targeted therapies?

    PubMed

    Van Roosbroeck, Katrien; Calin, George A

    2016-04-01

    Chronic lymphocytic leukemia (CLL) is a heterogeneous disease and has a highly variable clinical course with survival ranging from a couple of months to several decades. MicroRNAs (miRNAs), small non-coding RNAs that regulate transcription and translation of genes, have been found to be involved in CLL initiation, progression, and resistance to therapy. In addition, they can be used as prognostic biomarkers and as targets for novel therapies. In this review, we describe the association between miRNAs and the cytogenetic aberrations commonly found in CLL, as well as with other prognostic factors. We describe the presence of miRNAs as extracellular entities in the plasma and serum of CLL patients and discuss their role in resistance to therapy. Finally, we will explore the potential of targeted miRNA therapy for the treatment of CLL, with a special emphasis on MRX34, the first miRNA mimic that is currently being evaluated for clinical use. PMID:27040698

  12. Treatment practice in the elderly patient with chronic lymphocytic leukemia-analysis of the combined SEER and Medicare database.

    PubMed

    Satram-Hoang, Sacha; Reyes, Carolina; Hoang, Khang Q; Momin, Faiyaz; Skettino, Sandra

    2014-08-01

    The median age at diagnosis of chronic lymphocytic leukemia (CLL) is 72, but patients enrolled in randomized trials are often a decade younger. Therapy selection and outcomes in the older, comorbid population are less understood. We evaluated treatment patterns and outcomes among 2,985 first primary CLL patients from the linked Surveillance, Epidemiology, and End Results-Medicare database. There were 151 chlorambucil (CLB), 594 rituximab monotherapy (R-mono), 696 rituximab + intravenous chemotherapy (R + IV Chemo), and 1,544 IV chemo-only patients. Patients administered CLB and R-mono were the oldest and had the highest comorbidity burden while patients receiving R + IV Chemo were the youngest and had the lowest comorbidity burden (p < 0.0001). In the multivariate survival analysis, receipt of R + IV Chemo was associated with significantly lower mortality risk vs. IV Chemo-only (hazard ratio (HR) = 0.73; 95 % confidence interval (CI) 0.62-0.87) and a non-significant mortality risk reduction with R-mono vs. CLB (HR = 0.47; 95 % CI: 0.21-1.05). Older age and increasing comorbidity score were significantly associated with higher mortality. These findings suggest that chemoimmunotherapy is more effective than chemotherapy in an elderly population with a high prevalence of comorbidity, and this extends the conclusions from clinical trials in younger, medically fit patients. PMID:24638841

  13. Isolation of a novel chronic lymphocytic leukemic (CLL) cell line and development of an in vivo mouse model of CLL.

    PubMed

    Kellner, Joshua; Wierda, William; Shpall, Elizabeth; Keating, Michael; McNiece, Ian

    2016-01-01

    Leukemic cell lines have become important tools for studies of disease providing a monoclonal cell population that can be extensively expanded in vitro while preserving leukemic cellular characteristics. However, studies of chronic lymphocytic leukemia (CLL) have been impeded in part by the lack of continuous human cell lines. CLL cells have a high spontaneous apoptosis rate in vitro and exhibit minimal proliferation in xenograft models. Therefore, there is a need for development of primary CLL cell lines and we describe the isolation of such a line from the bone marrow of a CLL patient (17p deletion and TP53 mutation) which has been in long term culture for more than 12 months with continuous proliferation. The CLL cell line (termed MDA-BM5) which was generated in vitro with continuous co-culture on autologous stromal cells is CD19+CD5+ and shows an identical pattern of somatic hypermutation as determined in the patient's bone marrow (BM), confirming the origin of the cells from the original CLL clone. MDA-BM5 cells were readily transplantable in NOD/SCID gamma null mice (NSG) with disease developing in the BM, liver and spleen. BM cells from quaternary serial transplantation in NSG mice demonstrated the presence of CD19+CD5+ cells with Ig restricted to lambda which is consistent with the original patient cells. These studies describe a new CLL cell line from a patient with del(17p) that provides a unique model for in vitro and in vivo studies. PMID:26601610

  14. Angiopoietin-2 mRNA expression is increased in chronic lymphocytic leukemia patients with poor prognostic features.

    PubMed

    Vrbacky, F; Smolej, L; Vroblova, V; Pekova, S; Hrudkova, M; Cervinka, M; Pecka, M; Krejsek, J; Maly, J

    2010-08-01

    Several studies have demonstrated the potential prognostic importance of angiogenesis in chronic lymphocytic leukemia (CLL). Elevated expression of angiopoietin-2 (Ang-2), an angiogenic cytokine, was recently reported in CLL. However, data regarding prognostic significance of Ang-2 in CLL are limited. Therefore, we quantitated Ang-2 mRNA in purified mononuclear cells of 33 untreated CLL patients and compared the transcript levels to traditional as well as modern prognostic factors in patients with CLL (clinical stage, disease course, IgVH mutation status, CD38, and ZAP-70 expression). Elevated Ang-2 mRNA concentrations were detected in 12 cases; 21 patients had very low or undetectable levels of Ang-2 transcript. There was significant association between high Ang-2 mRNA levels and unmutated IgVH genes (n=27, P=0.010) and with CD38 expression (n=32, P=0.011), but not with ZAP-70 expression (n=32, P=0.784), Rai stage (n=33, P=0.305) or stable versus progressive clinical course (n=33, P=0.443). There was a trend towards shorter progression-free survival in patients with high Ang-2 expression; however, it did not reach statistical significance (P=0.090). Our pilot data show that Ang-2 mRNA is differentially expressed in patients with CLL and its increased expression appears to be associated with poor prognostic features. Further studies are needed to confirm the results in a larger patient cohort.

  15. Treatment practice in the elderly patient with chronic lymphocytic leukemia-analysis of the combined SEER and Medicare database.

    PubMed

    Satram-Hoang, Sacha; Reyes, Carolina; Hoang, Khang Q; Momin, Faiyaz; Skettino, Sandra

    2014-08-01

    The median age at diagnosis of chronic lymphocytic leukemia (CLL) is 72, but patients enrolled in randomized trials are often a decade younger. Therapy selection and outcomes in the older, comorbid population are less understood. We evaluated treatment patterns and outcomes among 2,985 first primary CLL patients from the linked Surveillance, Epidemiology, and End Results-Medicare database. There were 151 chlorambucil (CLB), 594 rituximab monotherapy (R-mono), 696 rituximab + intravenous chemotherapy (R + IV Chemo), and 1,544 IV chemo-only patients. Patients administered CLB and R-mono were the oldest and had the highest comorbidity burden while patients receiving R + IV Chemo were the youngest and had the lowest comorbidity burden (p < 0.0001). In the multivariate survival analysis, receipt of R + IV Chemo was associated with significantly lower mortality risk vs. IV Chemo-only (hazard ratio (HR) = 0.73; 95 % confidence interval (CI) 0.62-0.87) and a non-significant mortality risk reduction with R-mono vs. CLB (HR = 0.47; 95 % CI: 0.21-1.05). Older age and increasing comorbidity score were significantly associated with higher mortality. These findings suggest that chemoimmunotherapy is more effective than chemotherapy in an elderly population with a high prevalence of comorbidity, and this extends the conclusions from clinical trials in younger, medically fit patients.

  16. Outcomes after allogeneic hematopoietic cell transplantation with nonmyeloablative or myeloablative conditioning regimens for treatment of lymphoma and chronic lymphocytic leukemia

    PubMed Central

    Storer, Barry E.; Maloney, David G.; Sandmaier, Brenda M.; Martin, Paul J.; Storb, Rainer

    2008-01-01

    Allogeneic conventional hematopoietic cell transplantation (HCT) can be curative treatment for lymphoid malignancies, but it has been characterized by high nonrelapse mortality (NRM). Here, we compared outcomes among patients with lymphoma or chronic lymphocytic leukemia given either nonmyeloablative (n = 152) or myeloablative (n = 68) conditioning. Outcomes were stratified by the HCT-specific comorbidity index. Patients in the nonmyeloablative group were older, had more previous treatment and more comorbidities, more frequently had unrelated donors, and more often had malignancy in remission compared with patients in the myeloablative group. Patients with indolent versus aggressive malignancies were equally distributed among both cohorts. After HCT, patients without comorbidities both in the nonmyeloablative and myeloablative cohorts had comparable NRM (P = .74), overall survival (P = .75), and progression-free survival (P = .40). No significant differences were observed (P = .91, P = .89, and P = .40, respectively) after adjustment for pretransplantation variables. Patients with comorbidities experienced lower NRM (P = .009) and better survival (P = .04) after nonmyeloablative conditioning. These differences became more significant (P < .001 and .007, respectively) after adjustment for other variables. Further, nonmyeloablative patients with comorbidities had favorable adjusted progression-free survival (P = .01). Patients without comorbidities could be enrolled in prospective randomized studies comparing different conditioning intensities. Younger patients with comorbidities might benefit from reduced conditioning intensity. PMID:17916744

  17. The Dohner fluorescence in situ hybridization prognostic classification of chronic lymphocytic leukaemia (CLL): the CLL Research Consortium experience.

    PubMed

    Van Dyke, Daniel L; Werner, Lillian; Rassenti, Laura Z; Neuberg, Donna; Ghia, Emanuella; Heerema, Nyla A; Dal Cin, Paola; Dell Aquila, Marie; Sreekantaiah, Chandrika; Greaves, Andrew W; Kipps, Thomas J; Kay, Neil E

    2016-04-01

    This study revisited the Dohner prognostic hierarchy in a cohort of 1585 well-documented patients with chronic lymphocytic leukaemia. The duration of both time to first treatment (TTFT) and overall survival (OS) were significantly longer than observed previously, and this is at least partly due to improved therapeutic options. Deletion 13q remains the most favourable prognostic group with median TTFT and OS from fluorescence in situ hybridization (FISH) testing of 72 months and >12 years, respectively. Deletion 11q had the poorest median TTFT (22 months) and 17p deletion the poorest median OS (5 years). The percentages of abnormal nuclei were significantly associated with differential TTFT for the trisomy 12, 13q and 17p deletion cohorts but not for the 11q deletion cohort. From the date of the first FISH study, patients with >85% 13q deletion nuclei had a notably shorter TTFT (24 months). Patients with ≤20% 17p deletion nuclei had longer median TTFT and OS from the date of the first FISH study (44 months and 11 years), and were more likely to be IGHV mutated.

  18. Signal transducer and activator of transcription (STAT)-3 regulates microRNA gene expression in chronic lymphocytic leukemia cells

    PubMed Central

    2013-01-01

    Backgrounds Approximately 1,000 microRNAs (miRs) are present in the human genome; however, little is known about the regulation of miR transcription. Because miR levels are deregulated in chronic lymphocytic leukemia (CLL) and signal transducer and activator of transcription (STAT)-3 is constitutively activated in CLL, we sought to determine whether STAT3 affects the transcription of miR genes in CLL cells. Methods We used publically available data from the ENCODE project to identify putative STAT3 binding sites in the promoters of miR genes. Then we transfected CLL cells with STAT3-shRNA or with an empty vector, and to determine which miRs are differentially expressed, we used a miR microarray approach followed by validation of the microarray results for 6 miRs using quantitative real-time polymerase chain reaction (qRT-PCR). Results We identified putative STAT3 binding sites in 160 promoter regions of 200 miRs, including miR-21, miR-29, and miR-155, whose levels have been reported to be upregulated in CLL. Levels of 72 miRs were downregulated (n = 63) or upregulated (n = 9). qRT-PCR confirmed the array data in 5 of 6 miRs. Conclusions The presence of activated STAT3 has a profound effect on miR expression in CLL cells. PMID:23725032

  19. Induction of TAp73 by platinum-based compounds to overcome drug resistance in p53 dysfunctional chronic lymphocytic leukemia

    PubMed Central

    Tonino, Sanne H.; Mulkens, Chantal E.; van Laar, Jacoline; Derks, Ingrid A. M.; Suo, Guangli; Boer, Fransien Croon-de; van Oers, Marinus H. J.; Eldering, Eric; Wang, Jean Y.; Kater, Arnon P.

    2015-01-01

    In chronic lymphocytic leukemia (CLL), strategies to overcome drug resistance due to p53 dysfunction are highly needed. Platinum-based compounds such as cisplatinum (CDDP) are active in fludarabine-refractory CLL through a largely unknown mechanism. We analyzed the mechanism of action of CDDP in the context of p53 dysfunctionality. In vitro treatment with CDDP did not induce death in quiescent CLL cells, but did induce apoptosis in CD40-ligand (and CpG) stimulated and proliferating cells, irrespective of p53 function. In the p53 dysfunctional prolymphocytic cell-line MEC1, CDDP treatment resulted in apoptosis, cell cycle arrest and ABL1-dependent expression of TAp73, CDKN1A, PUMA and BID. TAp73 RNA-interference decreased sensitivity to CDDP. Finally, both in vitro stimulated CLL cells and lymph node (LN) derived CLL cells showed increased TAp73 expression in comparison with quiescent peripheral blood derived cells. Activity of CDDP may therefore be mediated by TAp73, especially in the context of activation such as occurs in the LN microenvironment. PMID:25511680

  20. Trisomy 12 chronic lymphocytic leukemia cells exhibit upregulation of integrin signaling that is modulated by NOTCH1 mutations

    PubMed Central

    Riches, John C.; O’Donovan, Conor J.; Kingdon, Sarah J.; McClanahan, Fabienne; Clear, Andrew J.; Neuberg, Donna S.; Werner, Lillian; Croce, Carlo M.; Ramsay, Alan G.; Rassenti, Laura Z.; Kipps, Thomas J.; Gribben, John G.

    2014-01-01

    The leukocyte adhesion cascade is important in chronic lymphocytic leukemia (CLL), as it controls migration of malignant cells into the pro-survival lymph node microenvironment. Circulating trisomy 12 CLL cells have increased expression of the integrins CD11a and CD49d, as well as CD38, but the tissue expression of these and other molecules, and the functional and clinical sequelae of these changes have not been described. Here, we demonstrate that circulating trisomy 12 CLL cells also have increased expression of the integrins CD11b, CD18, CD29, and ITGB7, and the adhesion molecule CD323. Notably, there was reduced expression of CD11a, CD11b, and CD18 in trisomy 12 cases with NOTCH1 mutations compared with wild type. Trisomy 12 cells also exhibit upregulation of intracellular integrin signaling molecules CALDAG-GEFI, RAP1B, and Ras-related protein ligand, resulting in enhanced very late antigen-4 [VLA-4] directed adhesion and motility. CD38 expression in CLL has prognostic significance, but the increased CD38 expression in trisomy 12 CLL cells must be taken into account in this subgroup, and the threshold of CD38 positivity should be raised to 40% for this marker to retain its prognostic value. In conclusion, trisomy 12 CLL cells exhibit functional upregulation of integrin signaling, with β2-integrin expression being modulated by NOTCH1 mutation status. PMID:24829201

  1. Does total body irradiation conditioning improve outcomes of myeloablative human leukocyte antigen-identical sibling transplantations for chronic lymphocytic leukemia?

    PubMed

    Sabloff, Mitchell; Sobecks, Ronald M; Ahn, Kwang Woo; Zhu, Xiaochun; de Lima, Marcos; Brown, Jennifer R; Inamoto, Yoshihiro; Holland, H Kent; Aljurf, Mahmoud D; Laughlin, Mary J; Kamble, Rammurti T; Hsu, Jack W; Wirk, Baldeep M; Seftel, Matthew; Lewis, Ian D; Arora, Mukta; Alyea, Edwin P; Kalaycio, Matt E; Cortes, Jorge; Maziarz, Richard T; Gale, Robert Peter; Saber, Wael

    2014-03-01

    An allogeneic hematopoietic cell transplantation from an HLA-identical donor after high-dose (myeloablative) pretransplantation conditioning is an effective therapy for some people with chronic lymphocytic leukemia (CLL). Because CLL is a highly radiosensitive cancer, we hypothesized that total body irradiation (TBI) conditioning regimens may be associated with better outcomes than those without TBI. To answer this, we analyzed data from 180 subjects with CLL receiving myeloablative doses of TBI (n = 126) or not (n = 54), who received transplants from an HLA-identical sibling donor between 1995 and 2007 and reported to the Center for International Blood & Marrow Transplant Research. At 5 years, treatment-related mortality was 48% (95% confidence interval [CI], 39% to 57%) versus 50% (95% CI, 36% to 64%); P = NS. Relapse rates were 17% (95% CI, 11% to 25%) versus 22% (95% CI, 11% to 35%); P = NS. Five-year progression-free survival and overall survival were 34% (95% CI, 26% to 43%) versus 28% (95% CI, 15% to 42%); P = NS and 42% (95% CI, 33% to 51%) versus 33% (95% CI, 19% to 48%); P = NS, respectively. The single most common cause of death in both cohorts was recurrent/progressive CLL. No variable tested in the multivariate analysis was found to significantly affect these outcomes, including having failed fludarabine. Within the limitations of this study, we found no difference in HLA-identical sibling transplantation outcomes between myeloablative TBI and chemotherapy pretransplantation conditioning in persons with CLL.

  2. HLA ligandome analysis identifies the underlying specificities of spontaneous antileukemia immune responses in chronic lymphocytic leukemia (CLL)

    PubMed Central

    Kowalewski, Daniel J.; Schuster, Heiko; Backert, Linus; Berlin, Claudia; Kahn, Stefan; Kanz, Lothar; Salih, Helmut R.; Rammensee, Hans-Georg; Stevanovic, Stefan; Stickel, Juliane Sarah

    2015-01-01

    The breakthrough development of clinically effective immune checkpoint inhibitors illustrates the potential of T-cell–based immunotherapy to effectively treat malignancies. A remaining challenge is to increase and guide the specificities of anticancer immune responses, e.g., by therapeutic vaccination or by adoptive T-cell transfer. By analyzing the landscape of naturally presented HLA class I and II ligands of primary chronic lymphocytic leukemia (CLL), we delineated a novel category of tumor-associated T-cell antigens based on their exclusive and frequent representation in the HLA ligandome of leukemic cells. These antigens were validated across different stages and mutational subtypes of CLL and found to be robustly represented in HLA ligandomes of patients undergoing standard chemo-/immunotherapy. We demonstrate specific immune recognition of these antigens exclusively in CLL patients, with the frequencies of representation in CLL ligandomes correlating with the frequencies of immune recognition by patient T cells. Moreover, retrospective survival analysis revealed survival benefits for patients displaying immune responses to these antigens. These results directly imply these nonmutant self-peptides as pathophysiologically relevant tumor antigens and encourages their implementation for cancer immunotherapy. PMID:25548167

  3. Clinical grade production of IL-10 producing regulatory Tr1 lymphocytes for cell therapy of chronic inflammatory diseases.

    PubMed

    Brun, Valérie; Bastian, Hervé; Neveu, Virginie; Foussat, Arnaud

    2009-05-01

    IL-10 producing regulatory type 1 (Tr1) cells represents a subpopulation of CD4(+) regulatory cells able to prevent in vitro bystander T-cell proliferation and to cure ongoing chronic colitis in mice. In order to assess the efficacy and tolerance of Tr1 cell therapy in a Phase I/IIa clinical trial in patients displaying severe Crohn's disease, we set up a reproducible manufacturing process for the GMP production of human ovalbumin specific Tr1 cells. Procedures used for Tr1-cell production include the use of Drosophila derived artificial Antigen Presenting Cells transfected with specific stimulatory molecules. Characterization of the human cell therapy product shows an in vitro suppressive activity on T-cell proliferation dependent on the production of both IL-10 and TGF-beta. Manufactured Tr1 cells display a regulatory phenotype including Foxp3, GITR and CTLA-4 surface expression. In vitro toxicity studies of human Tr1 cell product show a safety profile compatible with the use of these regulatory Tr1 lymphocytes for cell therapy. PMID:19539556

  4. Association of interleukin-6 and interleukin-8 with poor prognosis in elderly patients with chronic lymphocytic leukemia.

    PubMed

    Yoon, Ju-Yoon; Lafarge, Sandrine; Dawe, Dave; Lakhi, Sunjay; Kumar, Rajat; Morales, Carmen; Marshall, Aaron; Gibson, Spencer B; Johnston, James B

    2012-09-01

    In population studies, the relative survival in chronic lymphocytic leukemia (CLL) decreases with age. In this study, we demonstrated in a cohort of 189 patients from a CLL clinic that overall survival was lower in the sub-cohort of patients aged ≥ 70 years, but causes of death were similar for all age groups, being progressive CLL, secondary malignancies and infections. As normal individuals age, the plasma levels of inflammatory cytokines, such as interleukin-6 (IL-6) and IL-8, can increase. In our patients with CLL, IL-6, IL-8 and tumor necrosis factor-α (TNF-α) levels increased with age to a greater degree than in normal individuals, and the levels correlated closely with plasma β(2)-microglobulin and with one another. In addition, in patients ≥ 70 years, IL-6 was found to be a better prognostic marker than immunoglobulin variable heavy chain gene (IgV(H)) status. In vitro studies demonstrated that IL-6 and IL-8 could enhance the binding of CLL cells to stromal cells, suggesting that their clinical activity may be mediated through their effects on the microenvironment. Thus, plasma IL-6 is an important prognostic marker for the elderly with CLL, and this study highlights that the utility of prognostic markers may depend on patient age.

  5. The relationship between typical and atypical B-cell chronic lymphocytic leukemia. A comparative genomic hybridization-based study.

    PubMed

    O'Connor, S J; Su'ut, L; Morgan, G J; Jack, A S

    2000-09-01

    B-cell chronic lymphocytic leukemia (CLL) can be classified as typical or atypical based on morphologic and immunophenotypic features. The relationship between these 2 groups is uncertain, and there is some evidence they may be different entities. We used comparative genomic hybridization (CGH) to explore the cytogenetic relationship between typical and atypical B-cell CLL. Results showed a similar pattern of chromosome gains and losses detected in typical and atypical B-cell CLL, suggesting they are related disorders. Gain on chromosome 12 material occurred in cases that were apparently normal by interphase fluorescence in situ hybridization (FISH). The common region mapped to chromosome 12q21. Gains on chromosome 4 were present in 74% (32) of cases analyzed and were confirmed by interphase FISH in 30% (13) of cases. We previously have shown the strong association between trisomy 12 as detected by FISH and CD11a expression in atypical B-cell CLL. In the present study, CGH demonstrated additional gains on 12p and 12q outside the common amplified region of 12q21 in these patients. PMID:10989646

  6. lncRNA profiling in early-stage chronic lymphocytic leukemia identifies transcriptional fingerprints with relevance in clinical outcome.

    PubMed

    Ronchetti, D; Manzoni, M; Agnelli, L; Vinci, C; Fabris, S; Cutrona, G; Matis, S; Colombo, M; Galletti, S; Taiana, E; Recchia, A G; Bossio, S; Gentile, M; Musolino, C; Di Raimondo, F; Grilli, A; Bicciato, S; Cortelezzi, A; Tassone, P; Morabito, F; Ferrarini, M; Neri, A

    2016-01-01

    Long non-coding RNAs (lncRNAs) represent a novel class of functional RNA molecules with an important emerging role in cancer. To elucidate their potential pathogenetic role in chronic lymphocytic leukemia (CLL), a biologically and clinically heterogeneous neoplasia, we investigated lncRNAs expression in a prospective series of 217 early-stage Binet A CLL patients and 26 different subpopulations of normal B-cells, through a custom annotation pipeline of microarray data. Our study identified a 24-lncRNA-signature specifically deregulated in CLL compared with the normal B-cell counterpart. Importantly, this classifier was validated on an independent data set of CLL samples. Belonging to the lncRNA signature characterizing distinct molecular CLL subgroups, we identified lncRNAs recurrently associated with adverse prognostic markers, such as unmutated IGHV status, CD38 expression, 11q and 17p deletions, and NOTCH1 mutations. In addition, correlation analyses predicted a putative lncRNAs interplay with genes and miRNAs expression. Finally, we generated a 2-lncRNA independent risk model, based on lnc-IRF2-3 and lnc-KIAA1755-4 expression, able to distinguish three different prognostic groups in our series of early-stage patients. Overall, our study provides an important resource for future studies on the functions of lncRNAs in CLL, and contributes to the discovery of novel molecular markers with clinical relevance associated with the disease. PMID:27611921

  7. Inter- and intra-patient clonal and subclonal heterogeneity of chronic lymphocytic leukaemia: evidences from circulating and lymph nodal compartments.

    PubMed

    Del Giudice, Ilaria; Marinelli, Marilisa; Wang, Jiguang; Bonina, Silvia; Messina, Monica; Chiaretti, Sabina; Ilari, Caterina; Cafforio, Luciana; Raponi, Sara; Mauro, Francesca R; Di Maio, Valeria; De Propris, Maria S; Nanni, Mauro; Ciardullo, Carmela; Rossi, Davide; Gaidano, Gianluca; Guarini, Anna; Rabadan, Raul; Foà, Robin

    2016-02-01

    Whole exome sequencing and copy number aberration (CNA) analysis were performed on cells taken from peripheral blood (PB) and lymph nodes (LN) of patients with chronic lymphocytic leukaemia (CLL). Of 64 non-silent somatic mutations, 54 (84·4%) were clonal in both compartments, 3 (4·7%) were PB-specific and 7 (10·9%) were LN-specific. Most of the LN- or PB-specific mutations were subclonal in the other corresponding compartment (variant frequency 0·5-5·3%). Of 41 CNAs, 27 (65·8%) were shared by both compartments and 7 (17·1%) were LN- or PB-specific. Overall, 6 of 9 cases (66·7%) showed genomic differences between the compartments. At subsequent relapse, Case 10, with 6 LN-specific lesions, and Case 100, with 6 LN-specific and 8 PB-specific lesions, showed, in the PB, the clonal expansion of LN-derived lesions with an adverse impact: SF3B1 mutation, BIRC3 deletion, del8(p23·3-p11·1), del9(p24·3-p13·1) and gain 2(p25·3-p14). CLL shows an intra-patient clonal heterogeneity according to the disease compartment, with both LN and PB-specific mutations/CNAs. The LN microenvironment might contribute to the clonal selection of unfavourable lesions, as LN-derived mutations/CNAs can appear in the PB at relapse.

  8. Stereotyped subset #1 chronic lymphocytic leukemia: a direct link between B-cell receptor structure, function, and patients' prognosis.

    PubMed

    Del Giudice, Ilaria; Chiaretti, Sabina; Santangelo, Simona; Tavolaro, Simona; Peragine, Nadia; Marinelli, Marilisa; Ilari, Caterina; Raponi, Sara; Messina, Monica; Nanni, Mauro; Mauro, Francesca Romana; Piciocchi, Alfonso; Bontempi, Katia; Rossi, Davide; Gaidano, Gianluca; Guarini, Anna; Foà, Robin

    2014-01-01

    Chronic lymphocytic leukemia (CLL) with stereotyped B-cell receptor (BCR) belonging to subset #1 (IGHV1-5-7/ IGKV1-39) display a poor outcome. To characterize their genetic and genomic features and BCR function, we selected 20 subset #1 CLL from a series of 579 cases. Subset #1 CLL, all showing unmutated IGHV, were associated with the presence of del(11q) (50%) in comparison with unmutated CLL, unmutated stereotyped CLL other than subset #1 and with cases using the same IGHV genes but a heterogeneous VH CDR3 (non-subset #1 CLL). There were no distinctive features regarding CD38, ZAP-70, and TP53 disruption. NOTCH1, SF3B1, and BIRC3 were mutated in 15%, 0%, and 5% of cases, respectively, while BIRC3 was deleted in 22% of cases. Microarray unsupervised analysis on 80 unmutated/mutated/stereotyped/non-stereotyped CLL showed a tight clustering of subset #1 cases. Their genomic signature exhibited several differentially expressed transcripts involved in BCR signal transduction, apoptosis regulation, cell proliferation, and oxidative processes, regardless of del(11q). Accordingly, BCR ligation with anti-IgM revealed a significant higher proliferation of subset #1 versus unmutated non-subset #1 CLL, both at baseline and after 24–48 hr stimulation. Subset #1 CLL represent a paradigmatic example of the direct link between BCR structure, function, and patients prognosis.

  9. FDA Approval: Ibrutinib for Patients with Previously Treated Mantle Cell Lymphoma and Previously Treated Chronic Lymphocytic Leukemia.

    PubMed

    de Claro, R Angelo; McGinn, Karen M; Verdun, Nicole; Lee, Shwu-Luan; Chiu, Haw-Jyh; Saber, Haleh; Brower, Margaret E; Chang, C J George; Pfuma, Elimika; Habtemariam, Bahru; Bullock, Julie; Wang, Yun; Nie, Lei; Chen, Xiao-Hong; Lu, Donghao Robert; Al-Hakim, Ali; Kane, Robert C; Kaminskas, Edvardas; Justice, Robert; Farrell, Ann T; Pazdur, Richard

    2015-08-15

    On November 13, 2013, the FDA granted accelerated approval to ibrutinib (IMBRUVICA capsules; Pharmacyclics, Inc.) for the treatment of patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. On February 12, 2014, the FDA granted accelerated approval for the treatment of patients with chronic lymphocytic leukemia (CLL) who have received at least one prior therapy. Ibrutinib is a first-in-class Bruton's tyrosine kinase (BTK) inhibitor that received all four expedited programs of the FDA: Fast-Track designation, Breakthrough Therapy designation, Priority Review, and Accelerated Approval. Both approvals were based on overall response rate (ORR) and duration of response (DOR) in single-arm clinical trials in patients with prior treatment. In MCL (N = 111), the complete and partial response rates were 17.1% and 48.6%, respectively, for an ORR of 65.8% [95% confidence interval (CI), 56.2%-74.5%]. The median DOR was 17.5 months (95% CI, 15.8-not reached). In CLL (N = 48), the ORR was 58.3% (95% CI, 43.2%-72.4%), and the DOR ranged from 5.6 to 24.2 months. The most common adverse reactions (≥ 30% in either trial) were thrombocytopenia, diarrhea, neutropenia, bruising, upper respiratory tract infection, anemia, fatigue, musculoskeletal pain, peripheral edema, and nausea.

  10. 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.

  11. Tumor antigen ROR1 targeted drug delivery mediated selective leukemic but not normal B cell cytotoxicity in chronic lymphocytic leukemia

    PubMed Central

    Mani, Rajeswaran; Mao, Yicheng; Frissora, Frank W.; Chiang, Chi-Ling; Wang, Jiang; Zhao, Yuan; Wu, Yun; Yu, Bo; Yan, Ribai; Mo, Xiaokui; Yu, Lianbo; Flynn, Joseph; Jones, Jeffrey; Andritsos, Leslie; Baskar, Sivasubramanian; Rader, Christoph; Phelps, Mitch A; Chen, Ching-Shih; Lee, Robert J.; Byrd, John C.; Lee, L. James; Muthusamy, Natarajan

    2014-01-01

    Selective cytotoxicity to cancer cells without compromising their normal counterparts pose a huge challenge for traditional drug design. Here we developed a tumor antigen targeted delivery of immunonanoparticle carrying a novel non-immunosuppressive FTY720 derivative OSU-2S with potent cytotoxicity against leukemic B cells. OSU-2S induces activation of protein phosphatase 2A, phosphorylation and nuclear translocation of SHP1S591 and deregulation of multiple cellular processes in chronic lymphocytic leukemia (CLL) resulting in potent cytotoxicity. To preclude OSU-2S mediated effects on these ubiquitous phosphatases in unintended cells and avoid potential adverse effects we developed a OSU-2S targeted delivery immunonanoparticles (2A2-OSU-2S-ILP), that mediated selective cytotoxicity of CLL but not normal B cells through targeting receptor tyrosine kinase ROR1 expressed in leukemic but not normal B cells. Developing a novel spontaneous CLL mouse model expressing human ROR1 (hROR1) in all leukemic B cells, we demonstrate the therapeutic benefit of enhanced survival with 2A2-OSU-2S-ILP in-vivo. The newly developed non-immunosuppressive OSU-2S, its delivery using human CLL directed immunonanoparticles and the novel transgenic mouse model of CLL that expresses hROR1 exclusively in leukemic B cell surface are highly innovative and can be applied to CLL and other ROR1+ malignancies including mantle cell lymphoma and acute lymphoblastic leukemia. PMID:24947019

  12. The BH3-only protein Puma plays an essential role in p53-mediated apoptosis of chronic lymphocytic leukemia cells.

    PubMed

    Zhu, Hai-Jia; Liu, Ling; Fan, Lei; Zhang, Li-Na; Fang, Cheng; Zou, Zhi-Jian; Li, Jian-Yong; Xu, Wei

    2013-12-01

    The purpose of this study was to explore the characteristics and functions of BH3-only proteins Puma, Noxa and Bim in the prognosis, therapy and drug resistance of chronic lymphocytic leukemia (CLL). Puma, Noxa and Bim mRNAs were evaluated by real-time quantitative reverse transcriptase-polymerase chain reaction, and correlations between their expression levels and CLL prognostic markers were analyzed. Primary CLL samples were treated in vitro with fludarabine to investigate the role of Puma, Noxa and Bim in the response to chemotherapeutic drugs which act through activation of the p53 pathway. We found that a low expression level of Puma was associated with some markers of poor prognosis. However, the level of Noxa or Bim was not different in patients with CLL with variant clinical features and prognostic factors. Puma expression was up-regulated after fludarabine treatment in primary CLL cells, but there was no significant difference for Noxa and Bim. Up-regulation of Puma occurred only in CLL cells with functional p53. CLL cells with p53 abnormalities were deficient in the activation of Puma by chemotherapeutics. These results suggest that a lack of Puma induction may contribute to the development of resistance to anticancer agents in CLL.

  13. BTK inhibition results in impaired CXCR4 chemokine receptor surface expression, signaling and function in chronic lymphocytic leukemia

    PubMed Central

    Chen, S-S; Chang, B Y; Chang, S; Tong, T; Ham, S; Sherry, B; Burger, J A; Rai, K R; Chiorazzi, N

    2016-01-01

    Bruton's tyrosine kinase (BTK) is involved in the regulation of B-cell growth, migration and adhesion. The importance of BTK in cell trafficking is emphasized by the clonal contraction proceeded by lymphocytosis typical for the enzyme inhibitor, ibrutinib, in B-cell malignancies, including chronic lymphocytic leukemia (CLL). Here, we investigated BTK regulation of leukemic B-cell trafficking in a mouse model of aggressive TCL1 CLL-like disease. Inhibiting BTK by ibrutinib reduced surface membrane (sm) levels of CXCR4 but not CXCR5, CD49d and other adhesion/homing receptors. Decreased smCXCR4 levels resulted from blocking receptor signal transduction, which in turn aborted cycling from and to the membrane. This resulted in rapid re-distribution of CLL cells from spleens and lymph nodes into the circulation. CLL cells with impaired smCXCR4 from BTK inhibition failed to home to spleens. These functional changes mainly resulted from inhibition of CXCR4 phosphorylation at Ser339, mediated directly by blocking BTK enzymatic activity and indirectly by affecting the function of downstream targets PLCγ2 and PKCμ, and eventually synthesis of PIM-1 and BTK itself. Our data identify CXCR4 as a key regulator in BTK-mediated CLL-cell retention and have elucidated a complex set of not previously described mechanisms responsible for these effects. PMID:26582643

  14. Monoclonal B-cell lymphocytosis and early-stage chronic lymphocytic leukemia: diagnosis, natural history, and risk stratification

    PubMed Central

    Strati, Paolo

    2015-01-01

    Monoclonal B lymphocytosis (MBL) is defined as the presence of a clonal B-cell population in the peripheral blood with fewer than 5 × 109/L B-cells and no other signs of a lymphoproliferative disorder. The majority of cases of MBL have the immunophenotype of chronic lymphocytic leukemia (CLL). MBL can be categorized as either low count or high count based on whether the B-cell count is above or below 0.5 × 109/L. Low-count MBL can be detected in ∼5% of adults over the age of 40 years when assessed using standard-sensitivity flow cytometry assays. A number of biological and genetic characteristics distinguish low-count from high-count MBL. Whereas low-count MBL rarely progresses to CLL, high-count MBL progresses to CLL requiring therapy at a rate of 1% to 2% per year. High-count MBL is distinguished from Rai 0 CLL based on whether the B-cell count is above or below 5 × 109/L. Although individuals with both high-count MBL and CLL Rai stage 0 are at increased risk of infections and second cancers, the risk of progression requiring treatment and the potential to shorten life expectancy are greater for CLL. This review highlights challenging questions regarding the classification, risk stratification, management, and supportive care of patients with MBL and CLL. PMID:26065657

  15. BCR Signaling Inhibitors: an Overview of Toxicities Associated with Ibrutinib and Idelalisib in Patients with Chronic Lymphocytic Leukemia

    PubMed Central

    Falchi, Lorenzo; Baron, Jessica M.; Orlikowski, Carrie Anne; Ferrajoli, Alessandra

    2016-01-01

    The B-cell receptor (BCR) signaling inhibitors ibrutinib and idelalisib are revolutionizing the treatment of chronic lymphocytic leukemia (CLL) and other B-cell malignancies. These oral agents, both alone and in combination with other drugs, have shown remarkable clinical activity in relapsed or refractory CLL across all risk groups, and have been approved by the Food and Drug Administration for this indication. Preliminary data suggest that an even greater benefit can be expected in treatment-naïve CLL patients. Both ibrutinib and idelalisib are well tolerated by most patients, including older, frailer individuals. Toxicities are usually mild and self-resolving. Clinicians must, however, be aware of a number of peculiar adverse events, the effects of which can be severe enough to limit the clinical use of these agents. In this review, we survey the salient aspects of the pharmacology and clinical experience with the use of BCR signaling inhibitors for the treatment of patients with CLL. We next focus on both the most common and the most clinically significant toxicities associated with these drugs. PMID:26977270

  16. 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

  17. SAMHD1 is mutated recurrently in chronic lymphocytic leukemia and is involved in response to DNA damage

    PubMed Central

    Clifford, Ruth; Louis, Tania; Robbe, Pauline; Ackroyd, Sam; Burns, Adam; Timbs, Adele T.; Wright Colopy, Glen; Dreau, Helene; Sigaux, Francois; Judde, Jean Gabriel; Rotger, Margalida; Telenti, Amalio; Lin, Yea-Lih; Pasero, Philippe; Maelfait, Jonathan; Titsias, Michalis; Cohen, Dena R.; Henderson, Shirley J.; Ross, Mark T.; Bentley, David; Hillmen, Peter; Pettitt, Andrew; Rehwinkel, Jan; Knight, Samantha J. L.; Taylor, Jenny C.; Crow, Yanick J.

    2014-01-01

    SAMHD1 is a deoxynucleoside triphosphate triphosphohydrolase and a nuclease that restricts HIV-1 in noncycling cells. Germ-line mutations in SAMHD1 have been described in patients with Aicardi-Goutières syndrome (AGS), a congenital autoimmune disease. In a previous longitudinal whole genome sequencing study of chronic lymphocytic leukemia (CLL), we revealed a SAMHD1 mutation as a potential founding event. Here, we describe an AGS patient carrying a pathogenic germ-line SAMHD1 mutation who developed CLL at 24 years of age. Using clinical trial samples, we show that acquired SAMHD1 mutations are associated with high variant allele frequency and reduced SAMHD1 expression and occur in 11% of relapsed/refractory CLL patients. We provide evidence that SAMHD1 regulates cell proliferation and survival and engages in specific protein interactions in response to DNA damage. We propose that SAMHD1 may have a function in DNA repair and that the presence of SAMHD1 mutations in CLL promotes leukemia development. PMID:24335234

  18. Difficulties associated with the diagnosis of mycosis of the oral cavity and throat in chronic lymphocytic leukemia (CLL).

    PubMed

    Kaczmarczyk, Dariusz; Morawiec-Sztandera, Alina; Niedźwiecka, Izabela; Kurnatowski, Piotr

    2011-01-01

    Cases of fungal infections are being encountered more often in clinical practice. The factors associated with a high risk of mycoses include, among others, corticosteroidotherapy, the administration antibiotics with wide spectrum of antibacterial properties, neutropenia, neoplasms. Fungi may play a role in cancer formation, may act as a complication in the course of treatment, and may mimic a neoplastic process by giving a similar clinical picture. In the case of fungal throat infection, patients complain of increased body temperature, a general feeling of weakness, malaise, headache, spontaneous pain intensifying during swallowing, a feeling of an obstacle in the throat or a cough. A physical examination may reveal congestion of the mucosa followed by a unilateral crater ulceration often covered with fat, as well as a thick coating, which is accompanied by foetor ex ore. The submandibular and neck lymph nodes are often greatly enlarged and painful. These symptoms may resemble those associated with the neoplastic process and changes in the course of systemic diseases (agranulocytosis). A correct diagnosis in these cases is necessary for adequate therapy. Chronic lymphocytic leukemia (CLL) is the most common type of leukemia among adults in Europe and North America. It is estimated that in Poland, CLL affects approximately 1,400 people per year. In this paper, a case of 62-years old patient with CLL with fungal infection of oral cavity and throat is presented.

  19. Ionizing radiation exposures in treatments of solid neoplasms are not associated with subsequent increased risks of chronic lymphocytic leukemia.

    PubMed

    Radivoyevitch, Tomas; Sachs, Rainer K; Gale, Robert Peter; Smith, Mitchell R; Hill, Brian T

    2016-04-01

    Exposure to ionizing radiation is not thought to cause chronic lymphocytic leukemia (CLL). Challenging this notion are recent data suggesting CLL incidence may be increased by radiation exposure from the atomic bombs (after many decades), uranium mining and nuclear power facility accidents. To assess the effects of therapeutic ionizing radiation for the treatment of solid neoplasms we studied CLL risks in data from the Surveillance, Epidemiology, and End Results (SEER) Program. Specifically, we compared the risks of developing CLL in persons with a 1(st) non-hematologic cancer treated with or without ionizing radiation. We controlled for early detection effects on CLL risk induced by surveillance after 1(st) cancer diagnoses by forming all-time cumulative CLL relative risks (RR). We estimate such CLL RR to be 1.20 (95% confidence interval, 1.17, 1.23) for persons whose 1(st) cancer was not treated with ionizing radiation and 1.00 (0.96, 1.05) for persons whose 1(st) cancer was treated with ionizing radiations. These results imply that diagnosis of a solid neoplasm is associated with an increased risk of developing CLL only in persons whose 1(st) cancer was not treated with radiation therapy. PMID:26922774

  20. Exosomes released by chronic lymphocytic leukemia cells induce the transition of stromal cells into cancer-associated fibroblasts.

    PubMed

    Paggetti, Jerome; Haderk, Franziska; Seiffert, Martina; Janji, Bassam; Distler, Ute; Ammerlaan, Wim; Kim, Yeoun Jin; Adam, Julien; Lichter, Peter; Solary, Eric; Berchem, Guy; Moussay, Etienne

    2015-08-27

    Exosomes derived from solid tumor cells are involved in immune suppression, angiogenesis, and metastasis, but the role of leukemia-derived exosomes has been less investigated. The pathogenesis of chronic lymphocytic leukemia (CLL) is stringently associated with a tumor-supportive microenvironment and a dysfunctional immune system. Here, we explore the role of CLL-derived exosomes in the cellular and molecular mechanisms by which malignant cells create this favorable surrounding. We show that CLL-derived exosomes are actively incorporated by endothelial and mesenchymal stem cells ex vivo and in vivo and that the transfer of exosomal protein and microRNA induces an inflammatory phenotype in the target cells, which resembles the phenotype of cancer-associated fibroblasts (CAFs). As a result, stromal cells show enhanced proliferation, migration, and secretion of inflammatory cytokines, contributing to a tumor-supportive microenvironment. Exosome uptake by endothelial cells increased angiogenesis ex vivo and in vivo, and coinjection of CLL-derived exosomes and CLL cells promoted tumor growth in immunodeficient mice. Finally, we detected α-smooth actin-positive stromal cells in lymph nodes of CLL patients. These findings demonstrate that CLL-derived exosomes actively promote disease progression by modulating several functions of surrounding stromal cells that acquire features of cancer-associated fibroblasts.

  1. Ionizing radiation exposures in treatments of solid neoplasms are not associated with subsequent increased risks of chronic lymphocytic leukemia.

    PubMed

    Radivoyevitch, Tomas; Sachs, Rainer K; Gale, Robert Peter; Smith, Mitchell R; Hill, Brian T

    2016-04-01

    Exposure to ionizing radiation is not thought to cause chronic lymphocytic leukemia (CLL). Challenging this notion are recent data suggesting CLL incidence may be increased by radiation exposure from the atomic bombs (after many decades), uranium mining and nuclear power facility accidents. To assess the effects of therapeutic ionizing radiation for the treatment of solid neoplasms we studied CLL risks in data from the Surveillance, Epidemiology, and End Results (SEER) Program. Specifically, we compared the risks of developing CLL in persons with a 1(st) non-hematologic cancer treated with or without ionizing radiation. We controlled for early detection effects on CLL risk induced by surveillance after 1(st) cancer diagnoses by forming all-time cumulative CLL relative risks (RR). We estimate such CLL RR to be 1.20 (95% confidence interval, 1.17, 1.23) for persons whose 1(st) cancer was not treated with ionizing radiation and 1.00 (0.96, 1.05) for persons whose 1(st) cancer was treated with ionizing radiations. These results imply that diagnosis of a solid neoplasm is associated with an increased risk of developing CLL only in persons whose 1(st) cancer was not treated with radiation therapy.

  2. A Canadian perspective on bendamustine for the treatment of chronic lymphocytic leukemia and non-Hodgkin lymphoma

    PubMed Central

    Van der Jagt, R.; Laneuville, P.; MacDonald, D.; Stewart, D.; Christofides, A.; Sehn, L.H.

    2012-01-01

    Despite the success of standard treatments in chronic lymphocytic leukemia (cll) and non-Hodgkin lymphoma (nhl), patients are often unable to tolerate aggressive regimens, and they require effective alternatives. Bendamustine is a bifunctional alkylator with unique properties that significantly distinguish it from other agents in its class. In untreated cll, bendamustine has demonstrated rates of response and progression-free survival (pfs) that are superior to those with chlorambucil, with an acceptable toxicity profile. In the relapsed setting, combination treatment with bendamustine–rituximab (br) has demonstrated promising activity in high-risk patients such as those refractory to fludarabine or alkylating agents. In untreated patients with indolent nhl and mantle cell lymphoma, br has demonstrated a pfs significantly longer than that achieved with r-chop (rituximab–cyclophosphamide–doxorubicin–vincristine–prednisone), with significantly reduced toxicity. In the relapsed setting, br has demonstrated rates of response and pfs superior to those with fludarabine–rituximab, with comparable toxicity. In the United States and Europe, bendamustine has been approved for the treatment of cll and indolent nhl; its approval in Canada is pending and eagerly awaited. Once available, bendamustine will benefit many Canadian patients with nhl and cll. PMID:22670095

  3. Chronic lymphocytic leukaemia and radiation: findings among workers at five US nuclear facilities and a review of the recent literature.

    PubMed

    Schubauer-Berigan, Mary K; Daniels, Robert D; Fleming, Donald A; Markey, Andrea M; Couch, James R; Ahrenholz, Steven H; Burphy, Jenneh S; Anderson, Jeri L; Tseng, Chih-Yu

    2007-12-01

    The aetiology of chronic lymphocytic leukaemia (CLL) is largely unknown. Despite compelling evidence for ionising radiation as a cause of most forms of leukaemia, CLL was not found to be radiogenic in early studies. Herein we describe the recent evidence for causation of CLL by ionising and non-ionising radiation, including a nested case-control study conducted within a cohort of 94 517 US workers at four nuclear weapons facilities and a nuclear naval shipyard. Forty-three cases of CLL deaths and 172 age-matched controls were identified with follow-up up to between 1990 and 1996. Radiation exposure from external sources and plutonium (lagged 10 years) was assessed for each worker, based on monitoring records. The excess relative rate (ERR) was estimated for workers receiving elevated doses compared to unexposed workers, controlling for possible risk factors. The ERR per 10 mSv was -0.020 (95% confidence interval: <0, 0.14) based on all exposed workers. However, for workers receiving <100 mSv, the ERR per 10 mSv was 0.20 (-0.035, 0.96). Recent studies of uranium miners and other populations have shown elevations of CLL possibly associated with ionising and non-ionising radiation. New studies should use incident cases and sufficient latency to account for the expected lengthy induction period for CLL.

  4. A Comprehensive Evaluation of the Prognostic Significance of 13q Deletions in Patients with B-Chronic Lymphocytic Leukemia

    PubMed Central

    Van Dyke, Daniel L.; Shanafelt, Tait D.; Call, Timothy G.; Zent, Clive S.; Smoley, Stephanie A.; Rabe, Kari G.; Schwager, Susan M.; Sonbert, Jessica C.; Slager, Susan L.; Kay, Neil E.

    2009-01-01

    Summary Deletion 13q14 on fluorescence in situ hybridization (FISH) analysis is the most common cytogenetic abnormality in chronic lymphocytic leukemia (CLL), and is a favorable prognostic biomarker when detected as a sole abnormality. We intensively interrogated clinical outcome in 323 consecutive, untreated CLL patients with isolated 13q- identified within two years of diagnosis. We also analyzed outcome in 217 additional patients with deletion 11q22.3 or 17p13.1, or trisomy 12 based on whether these occurred in isolation or in conjunction with 13q-. Patients with a heterozygous 13q- and those with a homozygous deletion had similar time to first treatment (TFT) and overall survival (OS). In contrast, a higher percentage of 13q- nuclei was associated with significantly shorter TFT (p<0.001). The 5-year untreated rate was 79% for patients with isolated 13q- in ≤65.5% of nuclei compared to 38% among those with 13q- in >65.5% of nuclei (p<0.001). The percentage of nuclei exhibiting 13q- remained an independent predictor of TFT after controlling for ZAP-70, IgVH, or CD38 (all p<0.001). Among patients with 13q- plus one other FISH abnormality, concomitant 13q- appeared to attenuate the shorter survival associated with 17p- (p=0.019). The clinical implications of 13q- in CLL appear more complex than originally appreciated. PMID:19895615

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

    PubMed

    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

    2016-03-01

    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

  6. Hsp90 inhibition increases SOCS3 transcript and regulates migration and cell death in chronic lymphocytic leukemia

    PubMed Central

    Chen, Timothy L.; Gupta, Nikhil; Lehman, Amy; Ruppert, Amy S.; Yu, Lianbo; Oakes, Christopher C.; Claus, Rainer; Plass, Christoph; Maddocks, Kami J.; Andritsos, Leslie; Jones, Jeffery A.; Lucas, David M.; Johnson, Amy J.; Byrd, John C.; Hertlein, Erin

    2016-01-01

    Epigenetic or transcriptional silencing of important tumor suppressors has been described to contribute to cell survival and tumorigenesis in chronic lymphocytic leukemia (CLL). Using gene expression microarray analysis, we found that thousands of genes are repressed more than 2-fold in CLL compared to normal B cells; however therapeutic approaches to reverse this have been limited in CLL. Following treatment with the Hsp90 inhibitor 17-DMAG, a significant number of these repressed genes were significantly re-expressed. One of the genes significantly repressed in CLL and up-regulated by 17-DMAG was suppressor of cytokine signaling 3, (SOCS3). SOCS3 has been shown to be silenced in solid tumors as well as myeloid leukemia; however little is known about the regulation in CLL. We found that 17-DMAG induces expression of SOCS3 by via the activation of p38 signaling, and subsequently inhibits AKT and STAT3 phosphorylation resulting in downstream effects on cell migration and survival. We therefore suggest that SOCS3 is an important signaling protein in CLL, and Hsp90 inhibitors represent a novel approach to target transcriptional repression in B cell lymphoproliferative disorders which exhibit a substantial degree of gene repression. PMID:27107422

  7. 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. PMID:24130782

  8. Whole-genome sequencing reveals activation-induced cytidine deaminase signatures during indolent chronic lymphocytic leukaemia evolution.

    PubMed

    Kasar, S; Kim, J; Improgo, R; Tiao, G; Polak, P; Haradhvala, N; Lawrence, M S; Kiezun, A; Fernandes, S M; Bahl, S; Sougnez, C; Gabriel, S; Lander, E S; Kim, H T; Getz, G; Brown, J R

    2015-01-01

    Patients with chromosome 13q deletion or normal cytogenetics represent the majority of chronic lymphocytic leukaemia (CLL) cases, yet have relatively few driver mutations. To better understand their genomic landscape, here we perform whole-genome sequencing on a cohort of patients enriched with these cytogenetic characteristics. Mutations in known CLL drivers are seen in only 33% of this cohort, and associated with normal cytogenetics and unmutated IGHV. The most commonly mutated gene in our cohort, IGLL5, shows a mutational pattern suggestive of activation-induced cytidine deaminase (AID) activity. Unsupervised analysis of mutational signatures demonstrates the activities of canonical AID (c-AID), leading to clustered mutations near active transcriptional start sites; non-canonical AID (nc-AID), leading to genome-wide non-clustered mutations, and an ageing signature responsible for most mutations. Using mutation clonality to infer time of onset, we find that while ageing and c-AID activities are ongoing, nc-AID-associated mutations likely occur earlier in tumour evolution. PMID:26638776

  9. 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

  10. Tiam1/Rac1 signals contribute to the proliferation and chemoresistance, but not motility, of chronic lymphocytic leukemia cells.

    PubMed

    Hofbauer, Sebastian W; Krenn, Peter W; Ganghammer, Sylvia; Asslaber, Daniela; Pichler, Ulrike; Oberascher, Karin; Henschler, Reinhard; Wallner, Michael; Kerschbaum, Hubert; Greil, Richard; Hartmann, Tanja N

    2014-04-01

    Signals from the tumor microenvironment promote the migration, survival, and proliferation of chronic lymphocytic leukemia (CLL) cells. Rho GTPases control various signaling pathways downstream of microenvironmental cues. Here, we analyze the function of Rac1 in the motility and proliferation of CLL cells. We found decreased transcription of the Rac guanine nucleotide exchange factors Tiam1 and Vav1 in unstimulated peripheral blood CLL cells with almost complete loss of Tiam1 but increased transcription of the potential Rac antagonist RhoH. Consistently, stimulation of CLL cells with the chemokine CXCL12 induced RhoA but not Rac1 activation, whereas chemokine-induced CLL cell motility was Rac1-independent. Coculture of CLL cells with activated T cells induced their activation and subsequent proliferation. Here, Tiam1 expression was induced in the malignant cells in line with increased Ki-67 and c-Myc expression. Rac1 or Tiam1 knockdown using siRNA or treatment with the Tiam1/Rac inhibitor NSC-23766 attenuated c-Myc transcription. Furthermore, treatment of CLL cells with NSC-23766 reduced their proliferation. Rac inhibition also antagonized the chemoresistance of activated CLL cells toward fludarabine. Collectively, our data suggest a dynamic regulation of Rac1 function in the CLL microenvironment. Rac inhibition could be of clinical use by selectively interfering with CLL cell proliferation and chemoresistance.

  11. 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. PMID:24782504

  12. BTK inhibition results in impaired CXCR4 chemokine receptor surface expression, signaling and function in chronic lymphocytic leukemia.

    PubMed

    Chen, S-S; Chang, B Y; Chang, S; Tong, T; Ham, S; Sherry, B; Burger, J A; Rai, K R; Chiorazzi, N

    2016-04-01

    Bruton's tyrosine kinase (BTK) is involved in the regulation of B-cell growth, migration and adhesion. The importance of BTK in cell trafficking is emphasized by the clonal contraction proceeded by lymphocytosis typical for the enzyme inhibitor, ibrutinib, in B-cell malignancies, including chronic lymphocytic leukemia (CLL). Here, we investigated BTK regulation of leukemic B-cell trafficking in a mouse model of aggressive TCL1 CLL-like disease. Inhibiting BTK by ibrutinib reduced surface membrane (sm) levels of CXCR4 but not CXCR5, CD49d and other adhesion/homing receptors. Decreased smCXCR4 levels resulted from blocking receptor signal transduction, which in turn aborted cycling from and to the membrane. This resulted in rapid re-distribution of CLL cells from spleens and lymph nodes into the circulation. CLL cells with impaired smCXCR4 from BTK inhibition failed to home to spleens. These functional changes mainly resulted from inhibition of CXCR4 phosphorylation at Ser339, mediated directly by blocking BTK enzymatic activity and indirectly by affecting the function of downstream targets PLCγ2 and PKCμ, and eventually synthesis of PIM-1 and BTK itself. Our data identify CXCR4 as a key regulator in BTK-mediated CLL-cell retention and have elucidated a complex set of not previously described mechanisms responsible for these effects. PMID:26582643

  13. Phenotypic and Functional Analysis of Activated Regulatory T Cells Isolated from Chronic Lymphocytic Choriomeningitis Virus-infected Mice.

    PubMed

    Park, Hyo Jin; Oh, Ji Hoon; Ha, Sang-Jun

    2016-01-01

    Regulatory T (Treg) cells, which express Foxp3 as a transcription factor, are subsets of CD4(+) T cells. Treg cells play crucial roles in immune tolerance and homeostasis maintenance by regulating the immune response. The primary role of Treg cells is to suppress the proliferation of effector T (Teff) cells and the production of cytokines such as IFN-γ, TNF-α, and IL-2. It has been demonstrated that Treg cells' ability to inhibit the function of Teff cells is enhanced during persistent pathogen infection and cancer development. To clarify the function of Treg cells under resting or inflamed conditions, a variety of in vitro suppression assays using mouse or human Treg cells have been devised. The main aim of this study is to develop a method to compare the differences in phenotype and suppressive function between resting and activated Treg cells. To isolate activated Treg cells, mice were infected with lymphocytic choriomeningitis virus (LCMV) clone 13 (CL13), a chronic strain of LCMV. Treg cells isolated from the spleen of LCMV CL13-infected mice exhibited both the activated phenotype and enhanced suppressive activity compared with resting Treg cells isolated from naïve mice. Here, we describe the basic protocol for ex vivo phenotype analysis to distinguish activated Treg cells from resting Treg cells. Furthermore, we describe a protocol for the measurement of the suppressive activity of fully activated Treg cells. PMID:27404802

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

    PubMed

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

    2014-06-12

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

  15. To treat or not to treat: metabolomics reveals biomarkers for treatment indication in chronic lymphocytic leukaemia patients

    PubMed Central

    Ferrarini, Alessia; Rupérez, Francisco J.; Kulczynska, Agnieszka; Bolkun, Lukasz; Kloczko, Janusz; Kretowski, Adam; Urbanowicz, Alina; Ciborowski, Michal; Barbas, Coral

    2016-01-01

    In chronic lymphocytic leukaemia (CLL), the clinical course of patients is heterogeneous. Some present an aggressive disease onset and require immediate therapy, while others remain without treatment for years. Current disease staging systems developed by Rai and Binet may be useful in forecasting patient survival time, but do not discriminate between stable and progressive forms of the disease in the early stages. Recently ample attention has been directed towards identifying new disease prognostic markers capable of predicting clinical aggressiveness at diagnosis. In the present study serum samples from stable (n = 51) and progressive (n = 42) CLL patients and controls (n = 45) were used with aim to discover metabolic indicators of disease status. First an LC-MS based metabolic fingerprinting method was used to analyse selected samples in order to find a potential markers discriminating aggressive from indolent patients. Ten of these discovered markers were validated on the whole set of samples with an independent analytical technique. Linoleamide (p = 0.002) in addition to various acylcarnitines (p = 0.001–0.000001) showed to be significant markers of CLL in its aggressive form. Acetylcarnitine (p = 0.05) and hexannoylcarnitine (p = 0.005) were also distinguishable markers of indolent subjects. Forming a panel of selected acylcarnitines and fatty acid amides, it was possible to reach a potentially highly specific and sensitive diagnostic approach (AUC = 0.766). PMID:26988915

  16. High LEF1 expression predicts adverse prognosis in chronic lymphocytic leukemia and may be targeted by ethacrynic acid

    PubMed Central

    Wu, Wei; Zhu, Huayuan; Fu, Yuan; Shen, Wenyi; Miao, Kourong; Hong, Min; Xu, Wei; Fan, Lei; Young, Ken H.; Liu, Peng; Li, Jianyong

    2016-01-01

    Aberrant activation of lymphoid enhancer-binding factor-1 (LEF1) has been identified in several cancers, including chronic lymphocytic leukemia (CLL). As a key transcription factor of the Wnt/β-catenin pathway, LEF1 helps to regulate important genes involved in tumor cell death mechanisms. In this study, we determined LEF1 gene expression levels in CLL (n = 197) and monoclonal B-cell lymphocytosis (MBL) (n = 6) patients through real-time RT-PCR. LEF1 was significantly up-regulated in both MBL and CLL patients compared with normal B cells. Treatment-free survival (TFS) time and overall survival (OS) time were much longer in CLL patients with low LEF1 expression than in those with high LEF1 levels. Furthermore, Wnt inhibitor ethacrynic acid (EA) induced both apoptosis and necroptosis in primary CLL cells. EA also enhanced the cytotoxicity of both fludarabine and cyclophosphamide against CLL cells in vitro. Finally, we demonstrated that EA functions by inhibiting the recruitment of LEF1 to DNA promoters and restoring cylindromatosis (CYLD) expression in CLL cells. Our results showed, for the first time, that high LEF1 expression is associated with poor survival for CLL patients. Combined with other chemotherapeutic drugs, EA may be a promising therapeutic agent for CLL. PMID:26950276

  17. lncRNA profiling in early-stage chronic lymphocytic leukemia identifies transcriptional fingerprints with relevance in clinical outcome

    PubMed Central

    Ronchetti, D; Manzoni, M; Agnelli, L; Vinci, C; Fabris, S; Cutrona, G; Matis, S; Colombo, M; Galletti, S; Taiana, E; Recchia, A G; Bossio, S; Gentile, M; Musolino, C; Di Raimondo, F; Grilli, A; Bicciato, S; Cortelezzi, A; Tassone, P; Morabito, F; Ferrarini, M; Neri, A

    2016-01-01

    Long non-coding RNAs (lncRNAs) represent a novel class of functional RNA molecules with an important emerging role in cancer. To elucidate their potential pathogenetic role in chronic lymphocytic leukemia (CLL), a biologically and clinically heterogeneous neoplasia, we investigated lncRNAs expression in a prospective series of 217 early-stage Binet A CLL patients and 26 different subpopulations of normal B-cells, through a custom annotation pipeline of microarray data. Our study identified a 24-lncRNA-signature specifically deregulated in CLL compared with the normal B-cell counterpart. Importantly, this classifier was validated on an independent data set of CLL samples. Belonging to the lncRNA signature characterizing distinct molecular CLL subgroups, we identified lncRNAs recurrently associated with adverse prognostic markers, such as unmutated IGHV status, CD38 expression, 11q and 17p deletions, and NOTCH1 mutations. In addition, correlation analyses predicted a putative lncRNAs interplay with genes and miRNAs expression. Finally, we generated a 2-lncRNA independent risk model, based on lnc-IRF2-3 and lnc-KIAA1755-4 expression, able to distinguish three different prognostic groups in our series of early-stage patients. Overall, our study provides an important resource for future studies on the functions of lncRNAs in CLL, and contributes to the discovery of novel molecular markers with clinical relevance associated with the disease. PMID:27611921

  18. [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. PMID:26821425

  19. [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.

  20. [The activity of 2',5'-oligoadenylate-synthetase in rat spleen lymphocytes in the chronic ethanol intoxication and administration of zinc acetate].

    PubMed

    Chaĭka, V O; Kompanets', I V; Hadiliia, O P; Kharchenko, O I; Ostapchenko, L I

    2010-01-01

    It was shown that the activity of interferon-induced enzyme 2',5'-oligoadenylate-synthetase is suppressed in rat spleen lymphocytes under the chronic alcohol intoxication. The values of enzyme activity were minimal under the long-term action of etanol (21 day). The combined administration of zinc acetate and etanol to rats causes the increase of enzyme activity, the effect is most expressed on the late stages of alcohol intoxication development.

  1. Case 212: chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids.

    PubMed

    Bag, Asim K; Davenport, Jake J; Hackney, James R; Roy, Rasmoni; Fathallah-Shaykh, Hassan M

    2014-12-01

    History A previously healthy 23-year-old white man presented to the emergency department of our hospital with a 2-month history of dysarthria, progressively worsening vertigo, and difficulty walking. A diagnosis of retinitis pigementosa was made in this patient's childhood. He did not have any history of congenital syphilis. He did not have a history of nausea or vomiting, fever, weight loss, headache, photophobia, seizure, extremity weakness, or sensory disturbance. Physical examination revealed dysarthria, dysmetria, and ataxia. Kernig and Brudzinski signs were absent, and pathergy test results were negative. Laboratory evaluation revealed normal complete and differential blood counts and normal serum chemistry, including a normal serum angiotensin-converting enzyme level. Analysis of his serum was negative for antinuclear antibody (or ANA), cytoplasmic antineutrophil cvtoplasmic antibody (or cANCA), Sjögren syndrome antigens A and B (SS-A and SS-B, respectively), antitissue transglutaminase and antiendomysial antibodies, and paraneoplastic profile. Serum analysis was also negative for human immunodeficiency virus type 1 and type 2 RNA, Venereal Disease Research Laboratory (VDRL) test, rapid plasma regain (RPR), and fluorescent treponemal antibody absorption. Cerebrospinal fluid (CSF) analysis revealed clear fluid, a normal glucose level (64 mg/dL [3.6 mmol/L]; normal range, 40-70 mg/dL [2.2-3.9 mmol/L]), an elevated protein level (97 mg/dL; normal range, 12-60 mg/dL), and an elevated white blood cell count (7/mm(3) [0.007 ×10(9)/L] in tube 1 and 17/mm(3) [0.017 × 10(9)/L] in tube 2) with 84% lymphocytes. CSF immunoglobulin G level was elevated (30.1 mg/dL; normal, <5.9 mg/dL); however, there were no oligoclonal bands. Gram staining, acid-fast staining, and lactic acid, cryptococcal antigen, histoplasma antigen, herpes simplex virus polymerase chain reaction, VDRL, and RPR test results for CSF were negative. CSF did not grow any bacteria, fungus, or acid

  2. Effect of Bicarbonate Supplementation on Renal Function and Nutritional Indices in Predialysis Advanced Chronic Kidney Disease

    PubMed Central

    Jeong, Jiwon; Kwon, Soon Kil

    2014-01-01

    Current practice guidelines recommend alkali therapy in patients with chronic kidney disease (CKD) and metabolic acidosis to prevent complications. This study aims to investigate the effect of oral sodium bicarbonate supplementation on the progression of renal function and nutritional indices in patients with predialysis advanced CKD. Forty patients with predialysis stage 5 CKD(estimated glomerular filtration rate, eGFR <15mL/min per 1.73m2) and 40 patients with stage 4 CKD (eGFR 15 to 30mL/min per 1.73m2) who had a total CO2 less than 22mEq/L were assigned into the bicarbonate treatment group or control group for 12 months. In stage 4 CKD, there were significant differences in the changes of eGFR during the study between the treatment group and the control group (-2.30±4.49 versus -6.58±6.32mL/min/1.73m2, p<0.05). However, in stage 5 CKD, there were no significant differences in the change of eGFR during the study between the two groups (-2.10±2.06 versus -3.23±1.95mL/min/1.73 m2).There were no significant differences in the changes of nutritional indices such as albumin, prealbumin, transferrin, total lymphocyte count (TLC), and Ondodera's prognostic nutritional index (OPNI) during the study between the two groups. In stage 5 CKD, there were significant differences in the changes of TLC and OPNI between the two groups. In conclusion, our results demonstrate that bicarbonate supplementation slows the rate of decline of renal function in stage 4 CKD and improves nutritional indices in stage 5 CKD. Alkali therapy in advanced CKD may have beneficial effect on renal function and malnutrition. PMID:25606047

  3. Antibody and Plasmablast Response to 13-Valent Pneumococcal Conjugate Vaccine in Chronic Lymphocytic Leukemia Patients – Preliminary Report

    PubMed Central

    Pasiarski, Marcin; Rolinski, Jacek; Grywalska, Ewelina; Stelmach-Goldys, Agnieszka; Korona-Glowniak, Izabela; Gozdz, Stanislaw; Hus, Iwona; Malm, Anna

    2014-01-01

    Background Chronic lymphocytic leukemia (CLL) leads to significant immune system dysfunction. The predominant clinical presentation in 50% of patients involves recurrent, often severe, infections. Infections are also the most common (60–80%) cause of deaths in CLL patients. The scope of infections varies with the clinical stage of the disease. Treatment-naive patients typically present with respiratory tract infections caused by encapsulated bacteria Streptococcus pneumoniae and Haemophilus influenzae. Since 2012, the 13-valent pneumococcal conjugate vaccine (PCV13) has been recommended in the United States and some EU countries for pneumococcal infection prevention in patients with CLL (besides the long-standing standard, 23-valent pneumococcal polysaccharide vaccine, PPV23). The aim of this study was to compare the immune response to PCV13 in 24 previously untreated CLL patients and healthy subjects. Methods Both groups were evaluated for: the levels of specific pneumococcal antibodies, the levels of IgG and IgG subclasses and selected peripheral blood lymphocyte subpopulations including the frequency of plasmablasts before and after immunization. Results Adequate response to vaccination, defined as an at least two-fold increase in specific pneumococcal antibody titers versus pre-vaccination baseline titers, was found in 58.3% of CLL patients and 100% of healthy subjects. Both the CLL group and the control group demonstrated a statistically significant increase in the IgG2 subclass levels following vaccination (P = 0.0301). After vaccination, the frequency of plasmablasts was significantly lower (P<0.0001) in CLL patients in comparison to that in controls. Patients who responded to vaccination had lower clinical stage of CLL as well as higher total IgG, and IgG2 subclass levels. No significant vaccine-related side effects were observed. Conclusions PCV13 vaccination in CLL patients is safe and induces an effective immune response in a considerable

  4. [Influence of chronic irradiation on the distribution of blood lymphocyte subpopulations among professionals of the atomic industry].

    PubMed

    Selivanova, E I; Zamulaeva, I A; Saenko, A S

    2014-01-01

    The aim of the study was to investigate the effects of chronic exposure to ionizing radiation on the cellular immunity of employees of the nuclear industry. Peripheral blood samples were studied in 195 employees of Physics and Power Engineering Institute (PPEI, Obninsk), who professionallycontacted with sources ofionizing radiation and were under individual dosimetric control. The median cumulative dose was 61.2 mSv, the average duration of work at the enterprise -27 ± 5 years. The control group consisted of 57 healthy individuals of a similar age and sex who did not have contact with sources of radiation. Indicators of the cellular immunity were determined by flow cytometry. Comparison of a cell-mediated immunity was conducted separately in the two age groups (20-40 and 41-70 years). The significant reduction inthe relative content of CD4+CD8 T-helper cells and the increase in the relative content of CD3-CD16, CD56+ NK-cells were found in both age groups of the PPEI employees in comparison with the age-matched control groups (p < 0.05). Separate analysis of the results in the low dose group (up to 50 mSv) demonstrated reducing the relative content of T-helper cells and increasing the proportion of NK-cells (as in the analysis of whole groups without taking into account the cumulative dose), as well as reducing the proportion of CD8+CD25+ activated lymphocytes in PPEI employees as compared to the age-matched control. Multiple regression analysis of the immunological parameters dependence on age and dose established a significant correlation of the relative content of CD3-CD19+ B-cells (r = -0.284, p = 2.9 x 10(-4)) and CD19+CD5+ B1-lymphocytes (r = -0.241, p = 0.002) with the dose of employees regardless of age, indicating the relationship of the changes in the B-cell component of immune system with the radiation factor. PMID:25764816

  5. Selective IAP inhibition results in sensitization of unstimulated but not CD40-stimulated chronic lymphocytic leukaemia cells to TRAIL-induced apoptosis.

    PubMed

    Zhuang, Jianguo; Laing, Naomi; Oates, Melanie; Lin, Ke; Johnson, Gillian; Pettitt, Andrew R

    2014-12-01

    Despite recent advances in therapy, chronic lymphocytic leukaemia (CLL) remains incurable and new treatment strategies are therefore urgently required. Inhibitor of apoptosis proteins (IAPs) are over-expressed in CLL, suggesting both a role in disease pathogenesis and the potential for therapeutic targeting. To explore these questions, we evaluated the effects on primary CLL cells of AZD5582, a novel potent and selective inhibitor of IAPs. AZD5582 at nanomolar concentrations induced extensive degradation of cIAP-1 and cIAP-2, but minimally of X chromosome-linked IAP (XIAP). However, these effects of AZD5582 produced little or no direct cytotoxicity, nor did they sensitize CLL cells to p53-dependent killing by fludarabine or p53-independent killing by dexamethasone. In contrast, AZD5582 significantly enhanced apoptosis induced by the death receptor (DR) agonist tumour necrosis factor-related apoptosis-inducing ligand (TRAIL). Importantly, killing by TRAIL plus AZD5582 was independent of adverse prognostic features including TP53 deletion which is strongly associated with chemoresistance in CLL. Coculture experiments involving transfected mouse fibroblasts expressing human CD40L (CD154) to mimic the effect of T cells at sites of tissue involvement showed that CD40 stimulation almost completely prevented the killing of CLL cells by TRAIL plus AZD5582 despite up-regulating TRAIL receptors 1 and 2. In conclusion, our findings confirm the rate-limiting, upstream involvement of IAPs in the extrinsic but not intrinsic apoptotic pathway of CLL cells and suggest that drug combinations that simultaneously activate DRs and inhibit IAPs may have therapeutic potential in patients with CLL who have failed T-cell-depleting chemotherapy.

  6. Association between B-cell receptor responsiveness and disease progression in B-cell chronic lymphocytic leukemia: results from single cell network profiling studies.

    PubMed

    Cesano, Alessandra; Perbellini, Omar; Evensen, Erik; Chu, Charles C; Cioffi, Federica; Ptacek, Jason; Damle, Rajendra N; Chignola, Roberto; Cordeiro, James; Yan, Xiao-jie; Hawtin, Rachael E; Nichele, Ilaria; Ware, Jodi R; Cavallini, Chiara; Lovato, Ornella; Zanotti, Roberta; Rai, Kanti R; Chiorazzi, Nicholas; Pizzolo, Giovanni; Scupoli, Maria T

    2013-04-01

    While many prognostic markers in B-cell chronic lymphocytic leukemia provide insight into the biology of the disease, few have been demonstrated to be useful in the daily management of patients. B-cell receptor signaling is a driving event in the progression of B-cell chronic lymphocytic leukemia and markers of B-cell receptor responsiveness have been shown to be of prognostic value. Single cell network profiling, a multiparametric flow cytometry-based assay, allows functional signaling analysis at the level of the single cell. B-cell receptor signaling proteins (i.e. p-SYK, p-NF-κB p65, p-ERK, p-p38, p-JNK) were functionally characterized by single cell network profiling in samples from patients with B-cell chronic lymphocytic leukemia in an exploratory study (n=27) after stimulation with anti-IgM. Significant associations of single cell network profiling data with clinical outcome (i.e. time to first treatment), as assessed by Cox regression models, were then confirmed in patients' samples in two other sequential independent studies, i.e. test study 1 (n=30), and test study 2 (n=37). In the exploratory study, higher responsiveness of the B-cell receptor signaling proteins to anti-IgM was associated with poor clinical outcomes. Patients' clustering based on signaling response was at least as powerful in discriminating different disease courses as traditional prognostic markers. In an unselected subgroup of patients with Binet stage A disease (n=21), increased anti-IgM-modulated p-ERK signaling was shown to be a significant, independent predictor of shorter time to first treatment. This result was independently confirmed in two test cohorts from distinct populations of patients. In conclusion, these findings support the utility of the single cell network profiling assay in elucidating signaling perturbations with the potential for the development of a clinically useful prognostic test in patients with early stage B-cell chronic lymphocytic leukemia. These data

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

    ClinicalTrials.gov

    2014-04-03

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

  8. An overview of advance care planning for patients with advanced chronic kidney disease: The basics.

    PubMed

    Wasylynuk, Betty Ann; Davison, Sara N

    2016-01-01

    As the number of Canadians living with end-stage kidney disease (ESKD) continues to grow, even higher numbers are living with advanced chronic kidney disease (CKD). Many of these people will eventually require renal replacement therapy (RRT), either dialysis or transplantation. More than 50% of patients starting RRT today are aged 65 or older, with the fastest growing group being patients 75 years and older. Despite advances to dialysis technology and dialysis care, the mortality rates remain high and dialysis patients' end-of-life care may not align with their preferences or values. Advance care planning (ACP) is an essential component of quality comprehensive kidney care. Kidney care teams develop strong relationships with their patients and are well positioned to integrate ACP into routine kidney care. This article defines ACP, outlines the essential components of ACP, and discusses the benefits, challenges, and special considerations of ACP. By enhancing the kidney care team's understanding of ACP, this article aims to assist in integrating ACP into routine kidney care for patients with advanced CKD. PMID:27215058

  9. Th17 and Th1 Lymphocytes Are Correlated with Chronic Periodontitis.

    PubMed

    Chen, Xiao-Tao; Chen, Li-Li; Tan, Jing-Yi; Shi, Dan-Hui; Ke, Ting; Lei, Li-Hong

    2016-01-01

    T cells are involved in the homeostasis of periodontal tissues and mediate bone loss in periodontitis, but the involvement of T-helper cells in chronic periodontitis (CP) in a Chinese population is still unclear. This study aimed to assess the distribution of peripheral and local T helper (Th17) and Th1 in CP. Sixty-eight patients with CP and 43 healthy controls were recruited from April 2012 to July 2014 at the Department of Stomatology, People's Hospital of Xinjiang Uygur Autonomous Region (China). The proportions of Th17 (CD3(+)CD4(+)IL-17(+)) and Th1 (CD3(+)CD4(+)IFN-γ(+)) T-cells in peripheral blood samples were assessed by flow cytometry. Immunohistochemistry was used to quantify interleukin-17 (IL-17) and interferon-gamma (IFN-γ) protein levels in gingival biopsy samples. mRNA levels of IL-17, IFN-γ RORγt, and T-bet in gingival biopsy samples were measured by quantitative real-time polymerase chain reaction (qRT-PCR). The proportions of circulating Th17 cells and Th1 cells were both more abundant in CP patients than in controls (Th17: 1.05% ± 0.87% vs. 0.62% ± 0.49%, P < 0.01; Th1: 13.93% ± 7.94% vs. 8.22% ± 4.50%, P < 0.001). Positive correlations were obtained between the proportion of circulating Th17 cells and probing depth (PD) (r = 0.320, P = 0.001) and between the proportion of circulating Th1 cells and PD (r = 0.372, P < 0.001). IL-17 and IFN-γ protein levels in gingival biopsy samples were markedly increased in CP compared to controls (both P < 0.05). Relative IFN-γ, IL-17A, and T-bet mRNA levels in CP biopsies were higher compared to controls (all P < 0.05). These results suggest that elevated peripheral and local Th17 and Th1 cells might be involved in the pathogenesis of CP. PMID:27019379

  10. Molecular cloning of human T-cell lymphotrophic virus type I-like proviral genome from the peripheral lymphocyte DNA of a patient with chronic neurologic disorders

    SciTech Connect

    Reddy, E.P.; Mettus, R.V.; DeFreitas, E.; Wroblewska, Z.; Cisco, M.; Koprowski, H. )

    1988-05-01

    Human T-cell lymphotropic virus type 1 (HTLV-I), the etiologic agent of human T-cell leukemia, has recently been shown to be associated with neurologic disorders such as tropical spastic paraparesis, HTLV-associated myelopathy, and possibly with multiple sclerosis. In this communication, the authors have examined one specific case of neurologic disorder that can be classified as multiple sclerosis or tropical spastic paraparesis. The patient suffering from chronic neurologic disorder was found to contain antibodies to HTLV-I envelope and gag proteins in his serum and cerebrospinal fluid. Lymphocytes from peripheral blood and cerebrospinal fluid of the patient were shown to express viral RNA sequences by in situ hybridization. Southern blot analysis of the patient lymphocyte DNA revealed the presence of HTLV-I-related sequences. Blot-hybridization analysis of the RNA from fresh peripheral lymphocytes stimulated with interleukin 2 revealed the presence of abundant amounts of genomic viral RNA with little or no subgenomic RNA. They have clones the proviral genome from the DNA of the peripheral lymphocytes and determined its restriction map. This analysis shows that this proviral genome is very similar if not identical to that of the prototype HTLV-I genome.

  11. Phenotypic modulation of chronic lymphocytic leukemia cells by phorbol ester: induction of IgM secretion and changes in the expression of B cell-associated surface antigens.

    PubMed

    Gordon, J; Mellstedt, H; Aman, P; Biberfeld, P; Klein, G

    1984-01-01

    Freshly explanted neoplastic populations from 22 cases of phenotypically well-characterized chronic type B lymphocytic leukemia were studied for their capacity to respond to the phorbol ester TPA in vitro. In all but four cases the secretion of IgM was either induced or increased, often to a high level. In contrast, the export of free immunoglobulin (Ig) light chains, an almost consistent feature of the B lymphocytic leukemias, remained relatively constant after TPA treatment. Parallel changes in leukemic cell surface phenotype were probed with both "conventional" and monoclonal antibodies, revealing some modulation of markers in every case investigated. A diminution in the level of surface Ig (preferentially IgD) and the accumulation of cytoplasmic Ig observed after phorbol ester treatment were accompanied by a corresponding reduction or loss of the B1 antigen and usually of B2 when present. The most consistent change induced by TPA was the appearance of BB-1, a marker of activated B lymphocytes, which was rarely expressed on fresh leukemic cells. Another marker of activated lymphocytes, LB-1, was also often induced or increased in its expression after exposure of the cells to TPA. The magnitude of the TPA response appeared to relate to the stage of maturation arrest of the individual leukemic clones rather than to any clinical parameter explored. The significance of the findings to normal B cell differentiation and their potential clinical utility are discussed.

  12. HDAC isoenzyme expression is deregulated in chronic lymphocytic leukemia B-cells and has a complex prognostic significance

    PubMed Central

    Van Damme, Michaël; Crompot, Emerence; Meuleman, Nathalie; Mineur, Philippe; Bron, Dominique; Lagneaux, Laurence; Stamatopoulos, Basile

    2012-01-01

    Histone deacetylases (HDACs) play a crucial role in chromatin structure and, consequently, gene expression. Their deregulation has been reported in various cancers. We performed a complete and comprehensive study of the expression of 18 HDACs (including Sirtuin; SIRT) by real-time PCR in a cohort of 200 chronic lymphocytic leukemia (CLL) patients with a median follow-up of 77 mo, and compared it with the results obtained from normal B cells. We also compared HDAC expression at diagnosis and after relapse. We observed significant deregulation (mostly upregulation) of HDACs in CLL. In terms of clinical significance, only HDAC6 was significantly correlated with treatment-free survival (TFS), whereas HDAC3 and SIRT2, 3 and 6 were correlated with overall survival (OS). A multivariate Cox regression stepwise analysis indicated that HDAC6, 7 and 10 and SIRT3 were TFS independent predictors. Interestingly, poor prognosis was associated with an overexpression of HDAC7 and 10 but an underexpression of HDAC6 and SIRT3. Therefore, these factors were combined in a TFS score: patients with a score of 0–1–2, 3 and 4 had a median TFS of 107, 57 and 26 mo, respectively (HR = 4.03, p < 0.0001). For OS, SIRT5 and 6 allowed stratification into 3 groups, with a median OS of > 360, 237 and 94 mo (HR = 6.38, p < 0.0001). However, we could not find statistical differences in HDAC expression after relapse. These results, validated by a 5-fold cross-validation, highlight the complex impact of HDAC expression in CLL clinical course. PMID:23108383

  13. A Molecular Score by Quantitative PCR as a New Prognostic Tool at Diagnosis for Chronic Lymphocytic Leukemia Patients

    PubMed Central

    Stamatopoulos, Basile; Meuleman, Nathalie; De Bruyn, Cécile; Pieters, Karlien; Anthoine, Géraldine; Mineur, Philippe; Bron, Dominique; Lagneaux, Laurence

    2010-01-01

    Background Several markers have been proposed to predict the outcome of chronic lymphocytic leukemia (CLL) patients. However, discordances exist between the current prognostic factors, indicating that none of these factors are totally perfect. Methodology/Principal Findings Here, we compared the prognostic power of new RNA-based markers in order to construct a quantitative PCR (qPCR) score composed of the most powerful factors. ZAP70, LPL, CLLU1, microRNA-29c and microRNA-223 were measured by real time PCR in a cohort of 170 patients with a median follow-up of 64 months (range3-330). For each patient, cells were obtained at diagnosis and RNA was extracted from purified CD19 cells. The best markers were included in a qPCR score, which was thereafter compared to each individual factor. Statistical analysis showed that all five RNA-based markers can predict treatment-free survival (TFS), but only ZAP70, LPL and microRNA-29c could significantly predict overall survival (OS). These three markers were thus included in a simple qPCR score that was able to significantly predict TFS and OS by dividing patients into three groups (0/3, 1-2/3 and 3/3). Median TFS were >210, 61 and 24 months (P<0.0001) and median OS were >330, 242 and 137 months (P<0.0001), respectively. Interestingly, TFS results were also confirmed in Binet stage A patients (P<0.0001). When compared to other classical factors, this score displays the highest univariate Cox hazard ratio (TFS: HR = 9.45 and OS: HR = 13.88) but also provides additional prognostic information. Conclusions In our hands, this score is the most powerful tool for CLL risk stratification at the time of diagnosis. PMID:20862275

  14. Opposite Prognostic Significance of Cellular and Serum Circulating MicroRNA-150 in Patients with Chronic Lymphocytic Leukemia

    PubMed Central

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

    2015-01-01

    MicroRNAs (or miRs) play a crucial role in chronic lymphocytic leukemia (CLL) physiopathology and prognosis. In addition, circulating microRNAs in body fluids have been proposed as new biomarkers. We investigated the expression of matched cellular and serum circulating microRNA-150 by quantitative real-time PCR (qPCR) from purified CD19+ cells or from CLL serums obtained at diagnosis in a cohort of 273/252 CLL patients with a median follow-up of 78 months (range 7–380) and correlated it to other biological or clinical parameters. We showed that miR-150 was significantly overexpressed in CLL cells/serums compared with healthy subjects (P < 0.0001). Among CLL patients, a low cellular miR-150 expression level was associated with tumor burden, disease aggressiveness and poor prognostic factors. In contrast, a high level of serum miR-150 was associated with tumor burden markers and some markers of poor prognosis. Similarly, cellular and serum miR-150 also predicted treatment-free survival (TFS) and overall survival (OS) in an opposite manner: patients with low cellular/serum miR-150 levels have median TFS of 40/111 months compared with high-level patients who have a median TFS of 122/60 months (P < 0.0001/P = 0.0066). Similar results were observed for OS. We also found that cellular and serum miR-150 levels vary in an opposite manner during disease progression and that cellular miR-150 could be regulated by its release into the extracellular space. Cellular and serum levels of miR-150 are associated with opposite clinical prognoses and could be used to molecularly monitor disease evolution as a new prognostic factor in CLL. PMID:25584781

  15. Randomized controlled trials in relapsed/refractory chronic lymphocytic leukemia: a systematic review and meta-analysis.

    PubMed

    Police, Rachel L; Trask, Peter C; Wang, Jianmin; Olivares, Robert; Khan, Shahnaz; Abbe, Adeline; Colosia, Ann; Njue, Annete; Sherrill, Beth; Ruiz-Soto, Rodrigo; Kaye, James A; Hamadani, Mehdi

    2015-04-01

    This systematic literature review with meta-analysis was conducted on the clinical efficacy and safety of interventions used in the treatment of chronic lymphocytic leukemia (CLL). We systematically searched databases (PubMed, Cochrane Library, and Embase; 1997 to August 2, 2012), conference abstracts, bibliographic reference lists, recent reviews, and Clinicaltrials.gov. Primary efficacy outcomes were objective response rate, progression-free survival, and overall survival. Safety end points were Grade 3/4 toxicities, serious adverse events, withdrawals because of toxicity, and deaths due to toxicity. Studies were selected if they were randomized controlled trials (RCTs) reporting on the efficacy or safety of relapsed or refractory CLL and if outcomes for CLL were reported separately from trials that included other lymphoid neoplasms. We used the Bucher method for conducting adjusted indirect comparisons within a meta-analysis. We identified 6 RCTs of pharmacologic treatment for relapsed/refractory CLL. The most common drugs investigated (alone or in combination) were fludarabine and cyclophosphamide. When reported, median overall survival ranged from 27.3 to 52.9 months, and overall response rate from 58% to 82%. Although meta-analysis of efficacy results was considered, details are not presented because only 3 studies qualified and the common comparator treatment was not clinically relevant. The relatively small number of RCTs, few overlapping treatment arms, and variability in end points studied make it difficult to formally compare therapies for relapsed/refractory CLL. Significant variability in RCT features presents a further challenge to meaningful comparisons. Additional well-designed RCTs are needed to fully understand the relative efficacy and safety of older and more recently developed therapies. PMID:25445467

  16. Epstein-Barr virus DNA load in chronic lymphocytic leukemia is an independent predictor of clinical course and survival

    PubMed Central

    Visco, Carlo; Falisi, Erika; Young, Ken H.; Pascarella, Michela; Perbellini, Omar; Carli, Giuseppe; Novella, Elisabetta; Rossi, Davide; Giaretta, Ilaria; Cavallini, Chiara; Scupoli, Maria Teresa; De Rossi, Anita; D'Amore, Emanuele Stefano Giovanni; Rassu, Mario; Gaidano, Gianluca; Pizzolo, Giovanni; Ambrosetti, Achille; Rodeghiero, Francesco

    2015-01-01

    The relation between Epstein-Barr virus (EBV) DNA load and clinical course of patients with chronic lymphocytic leukemia (CLL) is unknown. We assessed EBV DNA load by quantitative PCR at CLL presentation in mononuclear cells (MNC) of 220 prospective patients that were enrolled and followed-up in two major Institutions. In 20 patients EBV DNA load was also assessed on plasma samples. Forty-one age-matched healthy subjects were tested for EBV DNA load on MNC. Findings were validated in an independent retrospective cohort of 112 patients with CLL. EBV DNA load was detectable in 59%, and high (≥2000 copies/µg DNA) in 19% of patients, but it was negative in plasma samples. EBV DNA load was significantly higher in CLL patients than in healthy subjects (P < .0001). No relation was found between high EBV load and clinical stage or biological variables, except for 11q deletion (P = .004), CD38 expression (P = .003), and NOTCH1 mutations (P = .05). High EBV load led to a 3.14-fold increase in the hazard ratio of death and to a shorter overall survival (OS; P = .001). Poor OS was attributable, at least in part, to shorter time-to-first-treatment (P = .0008), with no higher risk of Richter's transformation or second cancer. Multivariate analysis selected high levels of EBV load as independent predictor of OS after controlling for confounding clinical and biological variables. EBV DNA load at presentation is an independent predictor of OS in patients with CLL. PMID:26087198

  17. Torque Teno Virus 10 Isolated by Genome Amplification Techniques from a Patient with Concomitant Chronic Lymphocytic Leukemia and Polycythemia Vera

    PubMed Central

    Chu, Charles C; Zhang, Lu; Dhayalan, Arjun; Agagnina, Briana M; Magli, Amanda R; Fraher, Gia; Didier, Sebastien; Johnson, Linda P; Kennedy, William J; Damle, Rajendra N; Yan, Xiao-Jie; Patten, Piers E M; Teichberg, Saul; Koduru, Prasad; Kolitz, Jonathan E; Allen, Steven L; Rai, Kanti R; Chiorazzi, Nicholas

    2011-01-01

    An infectious etiology has been proposed for many human cancers, but rarely have specific agents been identified. One difficulty has been the need to propagate cancer cells in vitro to produce the infectious agent in detectable quantity. We hypothesized that genome amplification from small numbers of cells could be adapted to circumvent this difficulty. A patient with concomitant chronic lymphocytic leukemia (CLL) and polycythemia vera (PV) requiring therapeutic phlebotomy donated a large amount of phlebotomized blood to test this possibility. Using genome amplification methods, we identified a new isolate (BIS8-17) of torque teno virus (TTV) 10. The presence of blood isolate sequence 8-17 (BIS8-17) in the original plasma was confirmed by polymerase chain reaction (PCR), validating the approach, since TTV is a known plasma virus. Subsequent PCR testing of plasmas from additional patients showed that BIS8-17 had a similar incidence (~20%) in CLL (n = 48) or PV (n = 10) compared with healthy controls (n = 52). CLL cells do not harbor BIS8-17; PCR did not detect it in CLL peripheral blood genomic deoxyribonucleic acid (DNA) (n = 20). CLL patient clinical outcome or prognostic markers (immunoglobulin heavy chain variable region [IGHV ] mutation, CD38 or zeta-chain associated protein kinase 70kDa [ZAP-70]) did not correlate with BIS8-17 infection. Although not causative to our knowledge, this is the first reported isolation and detection of TTV in either CLL or PV. TTV could serve as a covirus with another infectious agent or TTV variant with rearranged genetic components that contribute to disease pathogenesis. These results prove that this method identifies infectious agents and provides an experimental methodology to test correlation with disease. PMID:21953418

  18. Expression level of DEK in chronic lymphocytic leukemia is regulated by fludarabine and Nutlin-3 depending on p53 status

    PubMed Central

    Wang, Dong-Mei; Liu, Ling; Fan, Lei; Zou, Zhi-Jian; Zhang, Li-Na; Yang, Shu; Li, Jian-Yong; Xu, Wei

    2012-01-01

    Human oncogene DEK has been shown to be upregulated in a number of neoplasms. The purpose of this study was to investigate DEK expression level in chronic lymphocytic leukemia (CLL), analyze the correlation between DEK expression and CLL prognostic markers, and characterize the role of DEK in the response to either chemotherapeutic drugs or nongenotoxic activators of the p53 pathway. DEK mRNA was evaluated by real-time quantitative reverse transcriptase-polymerase chain reaction (qPCR), and primary CLL samples were treated in vitro with either fludarabine or Nutlin-3 to explore the interaction of p53 status and DEK mRNA expression. The median expression levels of DEK mRNA were 6.792 × 10−2 (1.438 × 10−2−3.201 × 10−1) in 65 patients with CLL. A marked increase of DEK mRNA expression was observed in the CLL patients with unmutated immunoglobulin heavy chain variable (IGHV) gene (p = 0.025), CD38-positive (p = 0.047), del(17p13) (p = 0.006). Both fludarabine and Nutlin-3 significantly downregulated DEK in the primary CLL cells which were with normal function of p53, or without deletion or mutation of p53 (p = 0.042, p = 0.038; p = 0.021, p = 0.017; p = 0.037, p = 0.017). However, the downregulation of DEK was not observed in the primary CLL cells which were with dysfunction of p53, or with deletion or mutation of p53 (p = 0.834, p = 0.477; p = 0.111, p = 0.378; p = 0.263, p = 0.378). These data show that DEK might be applied for the assessment of prognosis in patients with CLL, and fludarabine and Nutlin-3 regulate DEK expression depended on p53 status. PMID:23052131

  19. Phase 2 study of a combined immunochemotherapy using rituximab and fludarabine in patients with chronic lymphocytic leukemia.

    PubMed

    Schulz, Holger; Klein, Saskia Karina; Rehwald, Ute; Reiser, Marcel; Hinke, Axel; Knauf, Wolfgang-Ulrich; Aulitzky, Walter-Erich; Hensel, Manfred; Herold, Michael; Huhn, Dieter; Hallek, Michael; Diehl, Volker; Engert, Andreas

    2002-11-01

    This multicenter phase 2 trial investigated safety and efficacy of a new immunochemotherapeutic regimen combining rituximab (R) and fludarabine (F) in patients with fludarabine- and anthracycline-naive chronic lymphocytic leukemia (CLL). The rationale for using R + F includes single-agent efficacy of both drugs, in vitro synergism of R and F, and no apparent overlapping toxicity. Of 31 eligible patients with B-CLL enrolled, 20 were previously untreated and 11 relapsed. Treatment consisted of fludarabine administered at standard doses (25 mg/m(2)/d; days 1-5, 29-33, 57-61, and 85-89) and rituximab (375 mg/m(2)/d) given on days 57, 85, 113, and 151. Side effects such as fever, chills, and exanthema were generally mild (National Cancer Institute Common Toxicity Criteria [NCI-CTC] grade 1/2 in 48% and grade 3 and/or 4 in 3% of patients). Fever and chills were mainly associated with the first rituximab infusion. Hematologic toxicity included neutropenia (grade 1 and/or 2 in 26%, grade 3 and/or 4 in 42%) and thrombocytopenia (grade 1 and/or 2 in 19%, grade 3 and/or 4 in 9%). One patient died of cerebral bleeding during prolonged thrombocytopenia after the second cycle of fludarabine. There were a total of 32 infections in 16 patients, none of which was fatal. The overall response rate (complete remission [CR] and partial remission [PR]) was 87% (27 of 31 evaluable patients). In 20 previously untreated patients, 17 (85%) responded. Ten of 31 patients achieved CR (5 of 20 untreated; 5 of 11 pretreated; 9 of 21 Binet stage B, 1 of 10 Binet stage C). The median duration of response was 75 weeks. We conclude that the combination of rituximab and fludarabine is feasible and effective in patients with B-CLL. PMID:12384407

  20. Molecular history of Richter syndrome: origin from a cell already present at the time of chronic lymphocytic leukemia diagnosis.

    PubMed

    Rossi, Davide; Spina, Valeria; Forconi, Francesco; Capello, Daniela; Fangazio, Marco; Rasi, Silvia; Martini, Maurizio; Gattei, Valter; Ramponi, Antonio; Larocca, Luigi M; Bertoni, Francesco; Gaidano, Gianluca

    2012-06-15

    Richter syndrome (RS) represents the transformation of chronic lymphocytic leukemia to aggressive lymphoma. We explored intraclonal diversification (ID) of immunoglobulin genes in order to (i) follow the evolutionary history of the RS clone (ii) compare the role of ID in clonally related RS vs. clonally unrelated cases. Most (10/11, 90.9%) clonally related RS stem from the predominant clone observed at CLL diagnosis. One single RS had a transformation pattern compatible with sequential evolution from a secondary CLL subclone. Once RS transformation had occurred, all secondary CLL subclones disappeared and were substituted by the dominant RS clone with its own descendants. These observations suggest that genetic lesions associated with RS transformation are acquired by a cell belonging to the original CLL clone, rather than being progressively accumulated by later CLL subclones. Accordingly, most (9/11, 81.1%) clonally related RS harbored a genetic lesion disrupting TP53 that was already present, though at subclonal levels, in 5/11 (45.5%) samples of the paired CLL phase. A fraction of clonally related RS switched off ID (4/11, 36.4%) or reduced the levels of ID (5/11, 45.4%) at transformation. Conversely, all clonally unrelated RS harbored ID and were characterized by a significantly higher mutation frequency compared to clonally related RS (median: 1.18 × 10(-3) vs. 0.13 × 10(-3); p =0.002). These data indicate that (i) clonally related RS stems from a cell that is already present within the initial CLL clone and (ii) clonally unrelated and clonally related RS are biologically distinct disorders also in terms of antigen affinity maturation.

  1. microRNA-34b/c on chromosome 11q23 is aberrantly methylated in chronic lymphocytic leukemia

    PubMed Central

    Deneberg, Stefan; Kanduri, Meena; Ali, Dina; Bengtzen, Sofia; Karimi, Mohsen; Qu, Ying; Kimby, Eva; Mansouri, Larry; Rosenquist, Richard; Lennartsson, Andreas; Lehmann, Sören

    2014-01-01

    A commonly deleted region in chronic lymphocytic leukemia (CLL) is the 11q22–23 region, which encompasses the ATM gene. Evidence suggests that tumor suppressor genes other than ATM are likely to be involved in CLL with del(11q). A microRNA (miR) cluster including the miR-34b and miR-34c genes is located, among other genes, within the commonly deleted region (CDR) at 11q. Interestingly, these miRs are part of the TP53 network and have been shown to be epigenetically regulated. In this study, we investigated the expression and methylation status of these miRs in a well-characterized cohort of CLL, including cases with/without 11q-deletion. We show that the miR-34b/c promoter was aberrantly hypermethylated in a large proportion of CLL cases (48%, 25/52 cases). miR-34b/c expression correlated inversely to DNA methylation (P = 0.003), and presence of high H3K37me3 further suppressed expression regardless of methylation status. Furthermore, increased miR-34b/c methylation inversely correlated with the presence of 11q-deletion, indicating that methylation and del(11q) independently silence these miRs. Finally, 5-azacytidine and trichostatin A exposure synergistically increased the expression of miR-34b/c in CLL cells, and transfection of miR-34b or miR-34c into HG3 CLL cells significantly increased apoptosis. Altogether, our novel data suggest that miR-34b/c is a candidate tumor suppressor that is epigenetically silenced in CLL. PMID:24686393

  2. Chronic lymphocytic leukemia and B and T cells differ in their response to cyclic nucleotide phosphodiesterase inhibitors.

    PubMed

    Meyers, John A; Su, Derrick W; Lerner, Adam

    2009-05-01

    Phosphodiesterase (PDE)4 inhibitors, which activate cAMP signaling by reducing cAMP catabolism, are known to induce apoptosis in B lineage chronic lymphocytic leukemia (CLL) cells but not normal human T cells. The explanation for such differential sensitivity remains unknown. In this study, we report studies contrasting the response to PDE4 inhibitor treatment in CLL cells and normal human T and B cells. Affymetrix gene chip analysis in the three cell populations following treatment with the PDE4 inhibitor rolipram identified a set of up-regulated transcripts with unusually high fold changes in the CLL samples, several of which are likely part of compensatory negative feedback loops. The high fold changes were due to low basal transcript levels in CLL cells, suggesting that cAMP-mediated signaling may be unusually tightly regulated in this cell type. Rolipram treatment augmented cAMP levels and induced ATF-1/CREB serine 63/133 phosphorylation in both B lineage cell types but not T cells. As treatment with the broad-spectrum PDE inhibitor 3-isobutyl-1-methylxanthine induced T cell CREB phosphorylation, we tested a series of family-specific PDE inhibitors for their ability to mimic 3-isobutyl-1-methylxanthine-induced ATF-1/CREB phosphorylation. Whereas PDE3 inhibitors alone had no effect, the combination of PDE3 and PDE4 inhibitors induced ATF-1/CREB serine 63/133 phosphorylation in T cells. Consistent with this observation, PDE3B transcript and protein levels were low in CLL cells but easily detectable in T cells. Combined PDE3/4 inhibition did not induce T cell apoptosis, suggesting that cAMP-mediated signal transduction that leads to robust ATF-1/CREB serine 63/133 phosphorylation is not sufficient to induce apoptosis in this lymphoid lineage.

  3. TLR-9 and IL-15 Synergy Promotes the In Vitro Clonal Expansion of Chronic Lymphocytic Leukemia B Cells

    PubMed Central

    Gupta, Rashmi; Boyle, Erin; Nieto, Jennifer; Lee, Hyunjoo; Stein, Joanna; Bandovic, Jela; Stankovic, Tatjana; Barrientos, Jacqueline; Kolitz, Jonathan E.; Allen, Steven L.; Rai, Kanti; Chu, Charles C.; Chiorazzi, Nicholas

    2015-01-01

    Clinical progression of B cell chronic lymphocytic leukemia (B-CLL) reflects the clone’s Ag receptor (BCR) and involves stroma-dependent B-CLL growth within lymphoid tissue. Uniformly elevated expression of TLR-9, occasional MYD88 mutations, and BCR specificity for DNA or Ags physically linked to DNA together suggest that TLR-9 signaling is important in driving B-CLL growth in patients. Nevertheless, reports of apoptosis after B-CLL exposure to CpG oligodeoxynucleotide (ODN) raised questions about a central role for TLR-9. Because normal memory B cells proliferate vigorously to ODN+IL-15, a cytokine found in stromal cells of bone marrow, lymph nodes, and spleen, we examined whether this was true for B-CLL cells. Through a CFSE-based assay for quantitatively monitoring in vitro clonal proliferation/survival, we show that IL-15 precludes TLR-9–induced apoptosis and permits significant B-CLL clonal expansion regardless of the clone’s BCR mutation status. A robust response to ODN+IL-15 was positively linked to presence of chromosomal anomalies (trisomy-12 or ataxia telangiectasia mutated anomaly + del13q14) and negatively linked to a very high proportion of CD38+ cells within the blood-derived B-CLL population. Furthermore, a clone’s intrinsic potential for in vitro growth correlated directly with doubling time in blood, in the case of B-CLL with Ig H chain V region–unmutated BCR and <30% CD38+ cells in blood. Finally, in vitro high-proliferator status was statistically linked to diminished patient survival. These findings, together with immunohistochemical evidence of apoptotic cells and IL-15–producing cells proximal to B-CLL pseudofollicles in patient spleens, suggest that collaborative ODN and IL-15 signaling may promote in vivo B-CLL growth. PMID:26136429

  4. Chlorambucil plus rituximab with or without maintenance rituximab as first-line treatment for elderly chronic lymphocytic leukemia patients.

    PubMed

    Foà, Robin; Del Giudice, Ilaria; Cuneo, Antonio; Del Poeta, Giovanni; Ciolli, Stefania; Di Raimondo, Francesco; Lauria, Francesco; Cencini, Emanuele; Rigolin, Gian Matteo; Cortelezzi, Agostino; Nobile, Francesco; Callea, Vincenzo; Brugiatelli, Maura; Massaia, Massimo; Molica, Stefano; Trentin, Livio; Rizzi, Rita; Specchia, Giorgina; Di Serio, Francesca; Orsucci, Lorella; Ambrosetti, Achille; Montillo, Marco; Zinzani, Pier Luigi; Ferrara, Felicetto; Morabito, Fortunato; Mura, Maria Angela; Soriani, Silvia; Peragine, Nadia; Tavolaro, Simona; Bonina, Silvia; Marinelli, Marilisa; De Propris, Maria Stefania; Starza, Irene Della; Piciocchi, Alfonso; Alietti, Alessandra; Runggaldier, Eva Josephine; Gamba, Enrica; Mauro, Francesca Romana; Chiaretti, Sabina; Guarini, Anna

    2014-05-01

    In a phase II trial, we evaluated chlorambucil and rituximab (CLB-R) as first-line induction treatment with or without R as maintenance for elderly chronic lymphocytic leukemia (CLL) patients. Treatment consisted of eight 28-day cycles of CLB (8 mg/m(2) /day, days 1-7) and R (day 1 of cycle 3, 375 mg/m(2) ; cycles 4-8, 500 mg/m(2) ). Responders were randomized to 12 8-week doses of R (375 mg/m(2) ) or observation. As per intention-to-treat analysis, 82.4% (95% CI, 74.25-90.46%) of 85 patients achieved an overall response (OR), 16.5% a complete response (CR), 2.4% a CR with incomplete bone marrow recovery. The OR was similar across Binet stages (A 86.4%, B 81.6%, and C 78.6%) and age categories (60-64 years, 92.3%; 65-69, 85.2%; 70-74, 75.0%; ≥75, 81.0%). CLB-R was well tolerated. After a median follow-up of 34.2 months, the median progression-free survival (PFS) was 34.7 months (95% CI, 33.1-39.5). TP53 abnormalities, complex karyotype, and low CD20 gene expression predicted lack of response; SF3B1 mutation and BIRC3 disruption low CR rates. IGHV mutations significantly predicted PFS. R maintenance tended towards a better PFS than observation and was safe and most beneficial for patients in partial response and for unmutated IGHV cases. CLB-R represents a promising option for elderly CLL patients.

  5. Dicer Gene Expression as a Prognostic Factor in Acute Lymphoblastic Leukemia and Chronic Lymphocytic Leukemia in Fars Province

    PubMed Central

    Farzaneh, Mohamad Reza; Shahryari, Jahanbanoo; Safaei, Akbar; Valibeigi, Behnaz; Davani, Shahrbanou Karimi; Tabibi, Narjes

    2016-01-01

    Alterations in the expression of microRNAs (miRNAs) have been proposed to play a role in the pathogenesis of acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL). Dicer is one of the main regulators of miRNA biogenesis, and deregulation of its expression has been indicated as a possible cause of miRNA alterations observed in various cancers. Our aim was to analyze the expression of the Dicer protein and its relationship with ALL and CLL. This cross-sectional study was performed from 2010 to 2012 in Shahid Faghihi Hospital, Shiraz, Iran. In this study, 30 patients with CLL, 21 patients with ALL, 10 child healthy donors, and 19 adult healthy donors were recruited. The patients’ samples were checked via flow cytometry, immunohistochemistry, and immunocytochemistry. The controls’ samples were also examined in the hematology ward. Total RNA was extracted from the bone marrow and peripheral blood samples of the patients and controls. Then, reverse-transcription polymerase chain reaction was used to estimate the level of Dicer miRNA. The outcomes of the expression analysis of Dicer revealed statistically significant differences between the ALL patients/child healthy controls (mean±SD, 0.19±0.28 vs. 0.73±0.12; P<0.001) and the CLL patients/adult healthy controls (mean±SD, 0.24±0.25 vs. 0.41±0.28; P=0.033). This is the first piece of evidence showing that the expression of the Dicer gene greatly decreased in the patients with ALL in comparison to the child controls. The expression of the Dicer gene was also downregulated in the patients with CLL compared to the adult controls. Given the above findings, the expression of Dicer may play an important role in the progression and prognosis of these diseases. PMID:27217607

  6. Association of the Neutrophil-to-Lymphocyte Ratio with Lung Function and Exacerbations in Patients with Chronic Obstructive Pulmonary Disease

    PubMed Central

    Lee, Heock; Um, Soo-Jung; Kim, Yun Seong; Kim, Deog Kyeom; Jang, An Soo; Choi, Hye Sook; Kim, Yee Hyung; Kim, Tae Eun; Yoo, Kwang Ha; Jung, Ki-Suck

    2016-01-01

    Background The ratio of neutrophils to lymphocytes (NLR) is a widely available marker of inflammation. Several types of inflammatory cells and mediators have been found to be involved in the progression of chronic obstructive pulmonary disease (COPD). We sought to evaluate the association of the NLR with severity of airflow limitation and disease exacerbations in a COPD population. Methods We analyzed 885 patients from the Korean COPD Subtype Study cohort that recruited subjects with COPD from 44 referral hospitals. We determined the relationship of NLR levels to severity of lung function using a linear regression model. In addition, we analyzed the experiences of COPD exacerbation according to the NLR quartiles. Results NLR levels were inversely associated with severity of airflow limitation as measured by FEV1% predicted and absolute values after adjustments for age, gender, body mass index, pack-years of smoking, and the use of inhaled corticosteroid (P<0.001, respectively). In the multivariate binary regression model, the NLR 4th quartile (vs. 1st quartile) was found to be a significant predictor of exacerbations during 1-year follow-up (OR = 2.05, 95% CI = 1.03 to 4.06, P = 0.041). Adding an NLR to FEV1 significantly improved prediction for exacerbations during 1-year follow-up as measured by the net reclassification improvement (NRI = 7.8%, P = 0.032) and the integrated discrimination improvement (IDI = 0.014, P = 0.021). Conclusions The NLR showed a significant inverse relationship to airflow limitation and was a prognostic marker for future exacerbations in patients with COPD. PMID:27258044

  7. Prognostic impact of Epstein-Barr virus (EBV)-DNA copy number at diagnosis in chronic lymphocytic leukemia

    PubMed Central

    Xia, Yi; Gale, Robert Peter; Chen, Rui-Ze; Yang, Yu-Qiong; Wang, Li; Qu, Xiao-Yan; Qiu, Hai-Rong; Cao, Lei; Hong, Min; Wang, Rong; Wang, Yan; Fan, Lei; Chen, Yao-Yu; Hu, Zhi-Bin; Li, Jian-Yong; Xu, Wei

    2016-01-01

    Epstein-Barr virus (EBV)-DNA is detected in the blood of some persons with chronic lymphocytic leukemia (CLL) at diagnosis. Whether this is important in the development or progression of CLL is controversial. We interrogated associations between blood EBV-DNA copy number and biological and clinical variables in 243 new-diagnosed consecutive subjects with CLL. Quantification of EBV-DNA copies was done by real-time quantitative PCR (RQ-PCR). All subjects had serological evidence of prior EBV-infection. However, only 24 subjects (10%) had a EBV-DNA-positive test at diagnosis. EBV-DNA-positive subjects at diagnosis had lower hemoglobin concentrations and platelet levels, higher thymidine kinase-1 and serum ferritin levels, un-mutated IGHV genes and a greater risk of Richter transformation compared with EBV-DNA-negative subjects. Percent CD20-, CD148- and ZAP70-positive cells and mean fluorescence intensity (MFI) of each cluster designation were also increased in EBV-DNA-positive subjects at diagnosis. EBV-DNA test positivity was associated with a briefer time-to-treatment interval (HR 1.85; [95% confidence interval, 1.13, 3.03]; P=0.014) and worse survival (HR 2.77; [1.18, 6.49]; P=0.019). Reduction in EBV copies was significantly associated with therapy-response. A positive blood EBV-DNA test at diagnosis and sequential testing of EBV copies during therapy were significantly associated with biological and clinical variables, time-to-treatment, therapy-response and survival. If validated these data may be added to CLL prognostic scoring systems. PMID:26539641

  8. Novel insights in chronic lymphocytic leukemia: are we getting closer to understanding the pathogenesis of the disease?

    PubMed

    Caligaris-Cappio, Federico; Ghia, Paolo

    2008-09-20

    Chronic lymphocytic leukemia (CLL) has unique epidemiologic, biologic, and clinical features. The progressively emerging picture leads us to consider that the critical genes for malignant CLL cells are those regulated by a number of microRNAs revealed by refined cytogenetic and molecular studies, and that the key molecule is the B-cell receptor (BCR). The hypothesis that CLL cells might be selected by some sort of antigenic pressure is strengthened by numerous findings indicating that a BCR-mediated stimulation plays a relevant role in the natural history of the disease and that autoantigens, as well as molecular structures instrumental in eliminating and scavenging apoptotic cells and pathogenic bacteria, may be relevant in triggering and/or facilitating the evolution of CLL. An important question is whether the tiny monoclonal B-cell populations phenotypically similar to CLL (that occur in the peripheral blood of about 3.5% of healthy individuals and are termed monoclonal B lymphocytosis) might be a critical step in the development of CLL. All relevant events of CLL occur in tissues in which a number of cellular and molecular interactions shape a microenvironment conducive to the accumulation of malignant cells and favor the organization of proliferating cells in focal aggregates of variable size that form the pseudofollicular proliferation centers. Given the impact that understanding the pathogenesis of CLL might have on the development of new treatments, the purposes of this review are to discuss whether the novel insights in CLL are leading us closer to understanding the tenet of the disease; to define the emerging new, stimulating questions; and to unfold the major challenges that still need to be addressed.

  9. HPLC-based Assay to Monitor Extracellular Nucleotide/Nucleoside Metabolism in Human Chronic Lymphocytic Leukemia Cells.

    PubMed

    Serra, Sara; Deaglio, Silvia

    2016-01-01

    This method describes a sensitive, specific, reliable and reproducible reverse phase high-performance liquid chromatography (RP-HPLC) assay developed and validated for the quantification of extracellular purine nucleotides and nucleosides produced by purified chronic lymphocytic leukemia (CLL) cells under different culture conditions. The chromatographic separation of adenosine 5'-monophosphate (AMP), adenosine (ADO) and inosine (INO) is performed at RT on a silica-based, reversed-phase column that is used for polar compound retention. The method includes a binary mobile phase, which consists of 7 mM ammonium acetate and acetonitrile with a flow rate of 1.00 ml/min. The eluates are monitored using a Photodiode Array UV detector set at 260 nm. A standard calibration curve is generated to calculate the equation for the analytical quantification of each purine compound. System control, data acquisition and analysis are then performed. Applying this protocol, AMP, INO and ADO elute at 7, 11 and 11.9 min, respectively, and the total run time for each sample is 20 min. This protocol may be applied to different cell types and cell lines (both suspension and adherent), using culture media as matrix. The advantages are easy and fast sample preparation and the requirement of a small amount of supernatant for analysis. Furthermore, the use of a serum-free medium allows skipping the protein precipitation step with acetonitrile that impacts the final concentration of purine compounds. One of the limitations of the method is the requirement of the equilibration column run before each single sample run, making the total run time of the experiment longer and preventing high throughput screening applications. PMID:27500417

  10. Dicer Gene Expression as a Prognostic Factor in Acute Lymphoblastic Leukemia and Chronic Lymphocytic Leukemia in Fars Province.

    PubMed

    Farzaneh, Mohamad Reza; Shahryari, Jahanbanoo; Safaei, Akbar; Valibeigi, Behnaz; Davani, Shahrbanou Karimi; Tabibi, Narjes

    2016-05-01

    Alterations in the expression of microRNAs (miRNAs) have been proposed to play a role in the pathogenesis of acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL). Dicer is one of the main regulators of miRNA biogenesis, and deregulation of its expression has been indicated as a possible cause of miRNA alterations observed in various cancers. Our aim was to analyze the expression of the Dicer protein and its relationship with ALL and CLL. This cross-sectional study was performed from 2010 to 2012 in Shahid Faghihi Hospital, Shiraz, Iran. In this study, 30 patients with CLL, 21 patients with ALL, 10 child healthy donors, and 19 adult healthy donors were recruited. The patients' samples were checked via flow cytometry, immunohistochemistry, and immunocytochemistry. The controls' samples were also examined in the hematology ward. Total RNA was extracted from the bone marrow and peripheral blood samples of the patients and controls. Then, reverse-transcription polymerase chain reaction was used to estimate the level of Dicer miRNA. The outcomes of the expression analysis of Dicer revealed statistically significant differences between the ALL patients/child healthy controls (mean±SD, 0.19±0.28 vs. 0.73±0.12; P<0.001) and the CLL patients/adult healthy controls (mean±SD, 0.24±0.25 vs. 0.41±0.28; P=0.033). This is the first piece of evidence showing that the expression of the Dicer gene greatly decreased in the patients with ALL in comparison to the child controls. The expression of the Dicer gene was also downregulated in the patients with CLL compared to the adult controls. Given the above findings, the expression of Dicer may play an important role in the progression and prognosis of these diseases. PMID:27217607

  11. Molecular history of Richter syndrome: origin from a cell already present at the time of chronic lymphocytic leukemia diagnosis.

    PubMed

    Rossi, Davide; Spina, Valeria; Forconi, Francesco; Capello, Daniela; Fangazio, Marco; Rasi, Silvia; Martini, Maurizio; Gattei, Valter; Ramponi, Antonio; Larocca, Luigi M; Bertoni, Francesco; Gaidano, Gianluca

    2012-06-15

    Richter syndrome (RS) represents the transformation of chronic lymphocytic leukemia to aggressive lymphoma. We explored intraclonal diversification (ID) of immunoglobulin genes in order to (i) follow the evolutionary history of the RS clone (ii) compare the role of ID in clonally related RS vs. clonally unrelated cases. Most (10/11, 90.9%) clonally related RS stem from the predominant clone observed at CLL diagnosis. One single RS had a transformation pattern compatible with sequential evolution from a secondary CLL subclone. Once RS transformation had occurred, all secondary CLL subclones disappeared and were substituted by the dominant RS clone with its own descendants. These observations suggest that genetic lesions associated with RS transformation are acquired by a cell belonging to the original CLL clone, rather than being progressively accumulated by later CLL subclones. Accordingly, most (9/11, 81.1%) clonally related RS harbored a genetic lesion disrupting TP53 that was already present, though at subclonal levels, in 5/11 (45.5%) samples of the paired CLL phase. A fraction of clonally related RS switched off ID (4/11, 36.4%) or reduced the levels of ID (5/11, 45.4%) at transformation. Conversely, all clonally unrelated RS harbored ID and were characterized by a significantly higher mutation frequency compared to clonally related RS (median: 1.18 × 10(-3) vs. 0.13 × 10(-3); p =0.002). These data indicate that (i) clonally related RS stems from a cell that is already present within the initial CLL clone and (ii) clonally unrelated and clonally related RS are biologically distinct disorders also in terms of antigen affinity maturation. PMID:21796624

  12. Novel biologic agents for non-Hodgkin lymphoma and chronic lymphocytic leukemia-part 2: adoptive cellular immunotherapy, small-molecule inhibitors, and immunomodulation.

    PubMed

    Siddiqi, Tanya; Rosen, Steven T

    2015-04-01

    Globally, the incidence of non-Hodgkin lymphoma is increasing. Aggressive non-Hodgkin lymphomas like diffuse large B-cell lymphoma are treated with curative intent in the frontline setting, but indolent diseases like chronic lymphocytic leukemia/small lymphocytic lymphoma are not considered to be curable in general. Additionally, relapsed/refractory non-Hodgkin lymphomas have a poor overall outcome, with treatment response durations often decreasing with each relapse. Novel therapies are sought to improve outcomes in this patient population. In a two-part review, we describe the promising new biologic therapies that have emerged over the last 5 years, some approved by the US Food and Drug Administration and others undergoing active investigation. In Part 1, we discussed monoclonal antibodies. Here, in Part 2, we discuss adoptive cellular immunotherapies, small-molecule inhibitors, and immunomodulatory agents. We also mention other novel therapies on the horizon.

  13. PI3K Signaling in B and T Lymphocytes: New Developments and Therapeutic Advances

    PubMed Central

    So, Lomon; Fruman, David A.

    2012-01-01

    Synopsis Activation of phosphoinositide 3-kinase (PI3K) is a shared response to engagement of diverse types of transmembrane receptors. Depending on the cell type and stimulus, PI3K activation can promote different fates including proliferation, survival, migration and differentiation. The diverse roles of PI3K signaling are well illustrated by studies of lymphocytes, the cells that mediate adaptive immunity. Genetic and pharmacological experiments have shown that PI3K activation regulates many steps in the development, activation and differentiation of both B and T cells. These findings have prompted the development of PI3K inhibitors for the treatment of autoimmunity and inflammatory diseases. However, PI3K activation has both positive and negative roles in immune system activation. Consequently, while PI3K suppression can attenuate immune responses it can also enhance inflammation, disrupt peripheral tolerance and promote autoimmunity. An exciting discovery is that a selective inhibitor of the p110δ catalytic isoform of PI3K, CAL-101, achieves impressive clinical efficacy in certain B cell malignancies. A model is emerging in which p110δ inhibition disrupts signals from the lymphoid microenvironment, leading to release of leukemia and lymphoma cells from their protective niche. These encouraging findings have given further momentum to PI3K drug development efforts in both cancer and immune diseases. PMID:22364281

  14. Prognostic value of lymphocyte/monocyte ratio in advanced Hodgkin lymphoma: correlation with International Prognostic Score and tumor associated macrophages.

    PubMed

    Jakovic, Ljubomir R; Mihaljevic, Biljana S; Andjelic, Bosko M; Bogdanovic, Andrija D; Perunicic Jovanovic, Maja D; Babic, Dragan D; Bumbasirevic, Vladimir Z

    2016-08-01

    We studied the prognostic significance of the absolute lymphocyte/monocyte count ratio (ALC/AMC), its contribution to the prognostic value of the International Prognostic Score (IPS), and evaluated if ALC/AMC could serve as a proxy for the frequency of CD68 + tumor-associated macrophages (TAMs) in 101 patients with advanced Hodgkin lymphoma (HL). The receiver operating characteristic (ROC) curve identified best cut-off values of 2.0 for ALC/AMC and 25% for CD68 + TAM. Patients with ALC/AMC < 2, IPS > 2 and > 25% CD68 + TAM had an inferior overall survival (OS) and event-free survival (EFS). Spearman's test also uncovered a significant correlation between the ALC/AMC and TAM. Multivariate analysis identified ALC/AMC < 2, IPS > 2 and > 25% CD68 + TAM as poor prognostic factors of OS and EFS. After evaluating ALC/AMC and IPS, we stratified patients into three progressively-worse-outcome groups (low-risk: 0 risk factors; intermediate: 1 risk factor; high: 2 risk factors). Our study encourages the combination of ALC/AMC with IPS, for refining risk prediction in advanced HL patients.

  15. [Advances on Extrocorporeal Photochemotherapy in the Treatment of Chronic Graft-Versus-Host Disease].

    PubMed

    Chen, Run-Zhe; Chen, Bao-An; Cheng, Jian

    2015-08-01

    Chronic graft-versus-host disease (cGVHD) is a common complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT), which is also one of the major causes of patients' death following transplantation. Recently, extracorporeal photochemotherapy (ECP) has shown a considerable efficacy in cGVHD treatment, which is based on the infusion of autologous peripheral blood mononuclear cells collected by aphesis, incubated with the photoactivable drug 8-methoxypsoralen (8-MOP) and UV-A irradiation. The therapeutic effect of ECP is mainly achieved by the induction of cell apoptosis, influencing the function of dendritic cells and the induction of immune tolerance. ECP has many advantages in the treatment of cGVHD, such as no increasing the risk of infection in patients, unaffecting the graft-versus-leukemia effect, nearly no side effect and so on. Many medical centers have done a lot of research on the treatment of cGVHD in both children and adults by using ECP and achieved good results. CD19(+) CD21(-) B lymphocytes, serum BAFF and serum TNFα can be used to measure and early evaluate the efficacy of ECP treatment. The effect of ECP is associated with many factors, and certain complications may occur during the treatment. At present, the application of ECP treatment is limited by the unclear mechanisms, varying treatment cycles in different studies, and small number of patients in clinical research. In the near future, with deeper basic research, increasing the case number and standard clinical treatment, ECP will have a more extensive application prospects. This review focuses mainly on the clinical advances of ECP in the treatment of cGVHD. PMID:26314474

  16. Effect of levamisole and methisoprinol on in vitro lymphocyte reactivity in chronically irradiated subjects and patients affected by neoplasias

    SciTech Connect

    Campo, M.; Chiavaro, I.; Canfarotta, C.; Stivala, F.; Berrardini, A.

    1982-01-01

    The data of this experiment show that Levamisole moderately stimulates T-lymphocyte proliferation and efficiency in vitro and methisoprinol markedly does so when both drugs act in combination with PHA in subjects with severely impaired cell-mediated responsiveness, whereas they do not exert any effect on lymphocytes in normal subjects. B-lymphocyte in vitro responsiveness does not appear to be affected by the immunomodulators, except for some cases of cancer of the stomach wherein B-lymphocyte responsiveness is stimulated in vitro by Levamisole and more evidently by Methisoprinol. These data support the use of Methisoprinol or Levamisole in therapy, and further investigations regarding the mechanisms whereby they might act and the dose-effect relationship which might show to be important for the type of desired immunomodulation would appear appropriate.

  17. Chronic advanced liver disease and impotence: cause and effect?

    PubMed

    Cornely, C M; Schade, R R; Van Thiel, D H; Gavaler, J S

    1984-01-01

    The prevalence of impotence is increased in males who chronically abuse alcohol. Further, impotence may occur in the absence of liver disease in such men. In contrast, no data is available concerning the prevalence of impotence in nonalcoholic men with advanced liver disease. To investigate the relationship between alcohol and impotence in cirrhotic men, a self-administered questionnaire was completed by male alcoholic cirrhotics admitted to the medical service as well as by nonalcoholic cirrhotic liver transplant candidates admitted to the medical and surgical services of Presbyterian-University Hospital. Each participant was asked whether or not he had experienced impotence and if so, to report the frequency and duration of his impotence. The frequency of impotence was recorded on a weighted scale with four gradations: 4 = always; 3 = usually; 2 = sometimes; 1 = seldom. In addition, measures of hepatic injury and function as well as measures of the functional integrity of the hypothalamic-pituitary-gonadal axis for each subject evaluated were obtained. Fourteen of the 20 alcoholics with cirrhosis and 10 of the 40 nonalcoholic liver transplant candidates with cirrhosis reported a history of impotence. The association between impotence and alcohol abuse was significant. The impotence index developed by multiplying the frequency by the duration of impotency for each individual demonstrated a more severe degree of impotence in the alcoholics as compared to the nonalcoholics (p less than 0.01). The alcoholics also had lower plasma levels of testosterone and greater plasma levels of gonadotropins as compared to the nonalcoholics.(ABSTRACT TRUNCATED AT 250 WORDS)

  18. Expression of functional sphingosine-1 phosphate receptor-1 is reduced by B cell receptor signaling and increased by inhibition of PI3 kinase δ but not SYK or BTK in chronic lymphocytic leukemia cells.

    PubMed

    Till, Kathleen J; Pettitt, Andrew R; Slupsky, Joseph R

    2015-03-01

    BCR signaling pathway inhibitors such as ibrutinib, idelalisib, and fostamatinib (respective inhibitors of Bruton's tyrosine kinase, PI3Kδ, and spleen tyrosine kinase) represent a significant therapeutic advance in B cell malignancies, including chronic lymphocytic leukemia (CLL). These drugs are distinctive in increasing blood lymphocytes while simultaneously shrinking enlarged lymph nodes, suggesting anatomical redistribution of CLL cells from lymph nodes into the blood. However, the mechanisms underlying this phenomenon are incompletely understood. In this study, we showed that the egress receptor, sphingosine-1-phosphate (S1P) receptor 1 (S1PR1), was expressed at low levels in normal germinal centers and CLL lymph nodes in vivo but became upregulated on normal B cells and, to a variable and lesser extent, CLL cells following in vitro incubation in S1P-free medium. Spontaneous recovery of S1PR1 expression on normal B and CLL cells was prevented by BCR cross-linking, whereas treatment of CLL cells with idelalisib increased S1PR1 expression and migration toward S1P, the greatest increase occurring in cases with unmutated IgH V region genes. Intriguingly, ibrutinib and fostamatinib had no effect on S1PR1 expression or function. Conversely, chemokine-induced migration, which requires integrin activation and is essential for the entry of lymphocytes into lymph nodes as well as their retention, was blocked by ibrutinib and fostamatinib, but not idelalisib. In summary, our results suggest that different BCR signaling inhibitors redistribute CLL cells from lymph nodes into the blood through distinct mechanisms: idelalisib actively promotes egress by upregulating S1PR1, whereas fostamatinib and ibrutinib may reduce CLL cell entry and retention by suppressing chemokine-induced integrin activation.

  19. Relationship Between Radiation-Induced Apoptosis of T Lymphocytes and Chronic Toxicity in Patients With Prostate Cancer Treated by Radiation Therapy: A Prospective Study

    SciTech Connect

    Foro, Palmira; Algara, Manuel; Lozano, Joan; Rodriguez, Nuria; Sanz, Xavier; Torres, Erica; Carles, Joan; Reig, Anna; Membrive, Ismael; Quera, Jaume; Fernandez-Velilla, Enric; Pera, Oscar; Lacruz, Marti; Bellosillo, Beatriz

    2014-04-01

    Purpose: To assess the correlation of radiation-induced apoptosis in vitro of CD4 and CD8 T lymphocytes with late toxicity of prostate cancer patients treated with radiation therapy. Methods and Materials: 214 patients were prospectively included in the study. Peripheral blood was drawn from patients before treatment and irradiated with 8 Gy. The percentage of CD4+ and CD8+ T lymphocytes that underwent radiation-induced apoptosis was assessed by flow cytometry. Toxicity and mortality were correlated in 198 cases with pretreatment apoptosis and clinical and biological variables by use of a Cox proportional hazards model. Results: The mean percentage of CD4+ and CD8+ T lymphocyte radiation-induced apoptosis was 28.58% (±14.23) and 50.76% (±18.9), respectively. Genitourinary (GU) toxicity was experienced by 39.9% of patients, while gastrointestinal (GI) toxicity was experienced by 19.7%. The probability of development of GU toxicity was nearly doubled (hazard ratio [HR] 1.99, P=.014) in those patients in whom the percentage of in vitro radiation-induced apoptosis of CD4+ T-lymphocytes was ≤28.58%. It was also almost double in patients who received doses ≥50 Gy in 65% of the bladder volume (V65 ≥50) (HR 1.92, P=.048). No correlation was found between GI toxicity and any of the variables studied. The probability of death during follow-up, after adjustment for different variables, was 2.7 times higher in patients with a percentage of CD8+ T lymphocyte apoptosis ≤50.76% (P=.022). Conclusions: In conclusion, our study shows, in the largest prospective cohort of prostate cancer patients undergoing radiation therapy, that in vitro radiation-induced apoptosis of CD4+ T lymphocytes assessed before radiation therapy was associated with the probability of developing chronic GU toxicity. In addition, the radiation dose received in the urinary bladder (V65 ≥50) affected the occurrence of GU toxicity. Finally, we also demonstrate that radiation-induced apoptosis of

  20. Treatment for Chronic Pain in Patients With Advanced Cancer

    ClinicalTrials.gov

    2010-11-07

    Chronic Myeloproliferative Disorders; Leukemia; Lymphoma; Multiple Myeloma and Plasma Cell Neoplasm; Myelodysplastic Syndromes; Pain; Precancerous/Nonmalignant Condition; Small Intestine Cancer; Unspecified Adult Solid Tumor, Protocol Specific

  1. Gene expression profiling reveals differences in microenvironment interaction between patients with chronic lymphocytic leukemia expressing high versus low ZAP70 mRNA

    PubMed Central

    Stamatopoulos, Basile; Haibe-Kains, Benjamin; Equeter, Carole; Meuleman, Nathalie; Sorée, Anne; De Bruyn, Cécile; Hanosset, Delphine; Bron, Dominique; Martiat, Philippe; Lagneaux, Laurence

    2009-01-01

    Background Zeta-associated protein 70 (ZAP70) is a widely recognized prognostic factor in chronic lymphocytic leukemia, but mechanisms by which its higher expression leads to a poor outcome must still be fully explained. Design and Methods In an attempt to unveil unfavorable cellular properties linked to high ZAP70 expression, we used gene expression profiling to identify genes associated with disparities in B cells from chronic lymphocytic leukemia patients expressing high versus low ZAP70 mRNA, measured by quantitative real-time PCR. Two groups of 7 patients were compared, selected on the basis of either high or low ZAP70 mRNA expression. Results Twenty-seven genes were differentially expressed with an FDR<10%, and several genes were significant predictors of treatment-free survival (TFS) and/or overall survival; PDE8A and FCRL family genes (down-regulated in ZAP70+ patients) could predict TFS and overall survival; ITGA4 mRNA (up-regulated in ZAP70+ patients) could significantly predict overall survival. Importantly, gene set enrichment analysis revealed overrepresentation of adhesion/migration genes. We therefore investigated in vitro adhesion/migration capacity of chronic lymphocytic leukemia cells into a stromal microenvironment or in response to conditioned medium. We showed that ZAP70+ cells had better adhesion/migration capacities and only ZAP70+ patient cells responded to microenvironment contact by CXCR4 downregulation. Conclusions We concluded that several prognostic factors are the reflection of microenvironment interactions and that the increased adhesion/migratory capacity of ZAP70+ cells in their microenvironment can explain their better survival and thus the aggressiveness of the disease. PMID:19377082

  2. Targeted next-generation sequencing in chronic lymphocytic leukemia: a high-throughput yet tailored approach will facilitate implementation in a clinical setting.

    PubMed

    Sutton, Lesley-Ann; Ljungström, Viktor; Mansouri, Larry; Young, Emma; Cortese, Diego; Navrkalova, Veronika; Malcikova, Jitka; Muggen, Alice F; Trbusek, Martin; Panagiotidis, Panagiotis; Davi, Frederic; Belessi, Chrysoula; Langerak, Anton W; Ghia, Paolo; Pospisilova, Sarka; Stamatopoulos, Kostas; Rosenquist, Richard

    2015-03-01

    Next-generation sequencing has revealed novel recurrent mutations in chronic lymphocytic leukemia, particularly in patients with aggressive disease. Here, we explored targeted re-sequencing as a novel strategy to assess the mutation status of genes with prognostic potential. To this end, we utilized HaloPlex targeted enrichment technology and designed a panel including nine genes: ATM, BIRC3, MYD88, NOTCH1, SF3B1 and TP53, which have been linked to the prognosis of chronic lymphocytic leukemia, and KLHL6, POT1 and XPO1, which are less characterized but were found to be recurrently mutated in various sequencing studies. A total of 188 chronic lymphocytic leukemia patients with poor prognostic features (unmutated IGHV, n=137; IGHV3-21 subset #2, n=51) were sequenced on the HiSeq 2000 and data were analyzed using well-established bioinformatics tools. Using a conservative cutoff of 10% for the mutant allele, we found that 114/180 (63%) patients carried at least one mutation, with mutations in ATM, BIRC3, NOTCH1, SF3B1 and TP53 accounting for 149/177 (84%) of all mutations. We selected 155 mutations for Sanger validation (variant allele frequency, 10-99%) and 93% (144/155) of mutations were confirmed; notably, all 11 discordant variants had a variant allele frequency between 11-27%, hence at the detection limit of conventional Sanger sequencing. Technical precision was assessed by repeating the entire HaloPlex procedure for 63 patients; concordance was found for 77/82 (94%) mutations. In summary, this study demonstrates that targeted next-generation sequencing is an accurate and reproducible technique potentially suitable for routine screening, eventually as a stand-alone test without the need for confirmation by Sanger sequencing.

  3. 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. ...

  4. 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

  5. Outcomes of HLA Matched Sibling Donor Hematopoietic Cell Transplantation in Chronic Lymphocytic Leukemia: Myeloablative vs. Reduced-Intensity Conditioning Regimens

    PubMed Central

    Sobecks, Ronald M.; Leis, Jose F.; Gale, Robert Peter; Ahn, Kwang Woo; Zhu, Xiaochun; Sabloff, Mitchell; de Lima, Marcos; Brown, Jennifer R.; Inamoto, Yoshihiro; Hale, Gregory A.; Aljurf, Mahmoud D.; Kamble, Rammurti T.; Hsu, Jack W.; Pavletic, Steven Z.; Wirk, Baldeep; Seftel, Matthew D.; Lewis, Ian D.; Alyea, Edwin P.; Cortes, Jorge; Kalaycio, Matt E.; Maziarz, Richard T.; Saber, Wael

    2014-01-01

    Purpose Allogeneic hematopoietic cell transplantation (HCT) can cure some chronic lymphocytic leukemia (CLL) subjects. This study compared outcomes of myeloablative (MA) and reduced-intensity conditioning (RIC) transplants from HLA-matched sibling donors (MSD) for CLL. Patients and Methods From 1995–2007 there were 297 CLL subjects reported to the CIBMTR who received MA (N=163) and RIC (N=134) MSD HCT. The MA subjects were less often transplanted after 2000 and less commonly received anti-thymocyte globulin (4% vs. 13%, p=0.004) or prior antibody therapy (14% vs. 53%; p<0.001). Results RIC was associated with a greater likelihood of platelet recovery and less grade 2–4 acute GvHD compared to MA conditioning. 1 and 5-year treatment related mortality (TRM) were 24% (95% confidence intervals (CI), 16–33%) vs. 37% (95% CI, 30–45%; p=0.023), and 40% (95% CI, 29–51%) vs. 54% (95% CI, 46–62%; p=0.036), and the relapse/progression rates were 21% (95% CI, 14–29%) vs. 10% (95% CI, 6–15%; p=0.020), and 35% (95% CI, 26–46%) vs. 17% (95% CI, 12–24%; p=0.003). MA conditioning was associated with better progression-free (PFS) (relative risk (RR) 0.60; 95% CI, 0.37–0.97, p=0.038) and 3-year survival in transplants before 2001, but for subsequent years RIC was associated with better PFS and survival (RR 1.49 (95% CI, 0.92–2.42), p=0.10; and RR 1.86 (95% CI, 1.11–3.13), p=0.019). Pre-transplant disease status was the most important predictor of relapse (p=0.003) and PFS (p=0.0007) for both forms of transplant conditioning. Conclusion MA and RIC MSD transplants are effective for CLL. Future strategies to decrease TRM and reduce relapses are warranted. PMID:24880021

  6. 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

  7. 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

  8. Behavioral and Cognitive-Behavioral Approaches to Chronic Pain: Recent Advances and Future Directions.

    ERIC Educational Resources Information Center

    Keefe, Francis J.; And Others

    1992-01-01

    Reviews and highlights recent research advances and future research directions concerned with behavioral and cognitive-behavioral approaches to chronic pain. Reviews assessment research on studies of social context of pain, relationship of chronic pain to depression, cognitive variables affecting pain, and comprehensive assessment measures.…

  9. The Biopsychosocial Approach to Chronic Pain: Scientific Advances and Future Directions

    ERIC Educational Resources Information Center

    Gatchel, Robert J.; Peng, Yuan Bo; Peters, Madelon L.; Fuchs, Perry N.; Turk, Dennis C.

    2007-01-01

    The prevalence and cost of chronic pain is a major physical and mental health care problem in the United States today. As a result, there has been a recent explosion of research on chronic pain, with significant advances in better understanding its etiology, assessment, and treatment. The purpose of the present article is to provide a review of…

  10. Low-Dose Total Body Irradiation and Donor Peripheral Blood Stem Cell Transplant Followed by Donor Lymphocyte Infusion in Treating Patients With Non-Hodgkin Lymphoma, Chronic Lymphocytic Leukemia, or Multiple Myeloma

    ClinicalTrials.gov

    2016-10-24

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

  11. OSU-DY7, a novel D-tyrosinol derivative, mediates cytotoxicity in chronic lymphocytic leukaemia and Burkitt lymphoma through p38 mitogen-activated protein kinase pathway

    PubMed Central

    Bai, Li-Yuan; Ma, Yihui; Kulp, Samuel K.; Wang, Shu-Huei; Chiu, Chang-Fang; Frissora, Frank; Mani, Rajeswaran; Mo, Xiaokui; Jarjoura, David; Byrd, John C.; Chen, Ching-Shih; Muthusamy, Natarajan

    2013-01-01

    Summary Drug resistance and associated immune deregulation limit use of current therapies in chronic lymphocytic leukaemia (CLL), thus warranting alternative therapy development. Herein we demonstrate that OSU-DY7, a novel D-tyrosinol derivative targeting p38 mitogen-activated protein kinase (MAPK), mediates cytotoxicity in lymphocytic cell lines representing CLL (MEC-1), acute lymphoblastic leukaemia (697 cells), Burkitt lymphoma (Raji and Ramos) and primary B cells from CLL patients in a dose- and time-dependent manner. The OSU-DY7-induced cytotoxicity is dependent on caspase activation, as evidenced by induction of caspase-3 activation and poly (ADP-ribose) polymerase (PARP) cleavage and rescue of cytotoxicity by Z-VAD-FMK. Interestingly, OSU-DY7-induced cytotoxicity is mediated through activation of p38 MAPK, as evidenced by increased phosphorylation of p38 MAPK and downstream target protein MAPKAPK2. Pretreatment of B-CLL cells with SB202190, a specific p38 MAPK inhibitor, results in decreased MAPKAPK2 protein level with concomitant rescue of the cells from OSU-DY7-mediated cytotoxicity. Furthermore, OSU-DY7-induced cytotoxicity is associated with down regulation of p38 MAPK target BIRC5, that is rescued at protein and mRNA levels by SB202190. This study provides evidence for a role of OSU-DY7 in p38 MAPK activation and BIRC5 down regulation associated with apoptosis in B lymphocytic cells, thus warranting development of this alternative therapy for lymphoid malignancies. PMID:21470196

  12. 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.

  13. CD4+ T-lymphocyte telomere length is related to fibrosis stage, clinical outcome and treatment response in chronic hepatitis C virus infection

    PubMed Central

    Hoare, Matthew; Gelson, William T.H.; Das, Abhi; Fletcher, Jean M.; Davies, Susan E.; Curran, Martin D.; Vowler, Sarah L.; Maini, Mala K.; Akbar, Arne N.; Alexander, Graeme J.M.

    2010-01-01

    Background & Aims Increasing age is associated with impaired immune function and in chronic HCV infection specifically, with progressive fibrosis, liver failure, HCC and impaired responses to antiviral therapy. T-lymphocyte telomere length declines with age. We hypothesised that shorter T-lymphocyte telomere length would be associated with poor clinical outcome in HCV infection. Methods Circulating T-lymphocyte telomere length, an objective measure of immune senescence, was measured by flow-FISH in 135 HCV-RNA-positive, treatment-naïve patients and 41 healthy controls in relation to clinical outcome. Results Shorter CD4+CD45RO+ T-lymphocyte telomeres were associated with severe fibrosis (p = 0.003), independent of male sex (p = 0.04), CMV positivity (p = 0.003), previous HBV infection (p = 0.007), and age (p = ns) in viraemic patients compared to controls. There were inverse correlations between CD4+CD45RO+ telomere length and fibrosis stage (p <0.001), portal tract inflammatory grade (p = 0.035), prothrombin time (p <0.001) and bilirubin (p = 0.001). One hundred and twenty-four viraemic individuals were followed prospectively to a composite endpoint of death, hepatic decompensation or HCC. Independent of age, those with shorter CD4+CD45RO+ telomeres were less likely to be complication free after 2-years than those with longer telomeres (86% versus 96%, p = 0.009) with an age-adjusted hazard ratio of 0.93 (0.90–0.96). In addition, CD4+CD45RO+ telomere length predicted successful antiviral therapy (p = 0.001) independent of other factors. Conclusions CD4+ T-lymphocyte telomere length, independent of age, was related to inflammatory grade, fibrosis stage, laboratory indices of severity, subsequent hepatic decompensation and treatment outcome in patients with chronic HCV infection. PMID:20462651

  14. Blood neutrophil-lymphocyte ratio predicts survival in locally advanced cancer stomach treated with neoadjuvant chemotherapy FOLFOX 4.

    PubMed

    el Aziz, Lamiss Mohamed Abd

    2014-12-01

    Accurate predictors of survival for patients with advanced gastric cancer treated with neoadjuvant chemotherapy are currently lacking. In this study, we aimed to evaluate the prognostic significance of the neutrophil-lymphocyte ratio (NLR) in patients with stage III-IV gastric cancer who received neoadjuvant chemotherapy FOLFOX 4 as neoadjuvant chemotherapy. We enrolled 70 patients with stage III-IV cancer stomach in this study. Patients received FOLFOX 4 as neoadjuvant chemotherapy. Blood sample was collected before chemotherapy. The NLR was divided into two groups: high (>3) and low (≤ 3). Univariate analysis on progression-free survival (PFS) and overall survival (OS) was performed using the Kaplan-Meier and log-rank tests, and multivariate analysis was conducted using the Cox proportional hazards regression model. The toxicity was evaluated according to National Cancer Institute Common Toxicity Criteria. The univariate analysis showed that PFS and OS were both worse for patients with high NLR than for those with low NLR before chemotherapy (median PFS 28 and 44 months, respectively, P = 0.001; median OS 30 and 48 months, P = 0.001). Multivariate analysis showed that NLRs be