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

ClinicalTrials.gov

2017-10-10

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

Venetoclax: A novel B-cell lymphoma-2 inhibitor for chronic lymphocytic leukemia and other hematologic malignancies.

PubMed

Olin, Jacqueline L; Griffiths, Carrie L; Smith, Morgan B

2017-01-01

Patients with chronic lymphocytic leukemia with the 17p deletion have a poor prognosis and treatment options are limited. Venetoclax, a novel B-cell lymphoma-2 inhibitor, has been approved for treatment-experienced chronic lymphocytic leukemia patients with the 17p deletion. A phase 1 dose-escalation study to 400 mg daily showed overall response rates across all doses of 79% with a complete response achieved in 20%. A phase 2 multicenter open-label study demonstrated overall response rate of 79.4% of patients (95% confidence interval 70.5-86.6) with median duration of follow-up of 12.1 months (IQR 10.1-14.2). Tumor lysis syndrome has been observed during initiation and titration. Assessing risk of tumor lysis syndrome prior to therapy initiation is essential to provide appropriate prophylactic medications. Neutropenia, potentially warranting dose reduction or discontinuation, has been observed. Venetoclax has demonstrated activity in other leukemias, multiple myeloma, and lymphomas. Venetoclax has shown response, and is well tolerated in patients with highly resistant chronic lymphocytic leukemia. It has the potential to be part of the treatment armamentarium for other malignancies.

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

ClinicalTrials.gov

2018-01-26

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

Leukemia -- Chronic T-Cell Lymphocytic

MedlinePlus

... social workers, and patient advocates. Cancer.Net Guide Leukemia - Chronic T-Cell Lymphocytic Introduction Statistics Risk Factors Symptoms and Signs Diagnosis Stages Treatment Options About Clinical Trials Latest Research ...

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

Elevated expression of pleiotrophin in lymphocytic leukemia CD19+ B cells.

PubMed

Du, Chun-Xian; Wang, Lan; Li, Yan; Xiao, Wei; Guo, Qin-Lian; Chen, Fei; Tan, Xin-Ti

2014-10-01

Pleiotrophin (PTN) has been demonstrated to be strongly expressed in many fetal tissues, but seldom in healthy adult tissues. While PTN has been reported to be expressed in many types of tumors as well as at high serum concentrations in patients with many types of cancer, to date, there has been no report that PTN is expressed in leukemia, especially in lymphocytic leukemia. We isolated the CD19(+) subset of B cells from peripheral blood from healthy adults, B-cell acute lymphocytic leukemia (B-ALL) patients, and B-cell chronic lymphocytic leukemia (B-CLL) patients and examined these cells for PTN mRNA and protein expression. We used immunocytochemistry, western blotting, and enzyme-linked immunosorbent assay to show that PTN protein is highly expressed in CD19(+) B cells from B-ALL and B-CLL patients, but barely expressed in B cells from healthy adults. We also examined PTN expression at the nucleic acid level using reverse transcription polymerase chain reaction (RT-PCR) and northern blotting and detected a high levels of PTN transcripts in the CD19(+) B cells from both groups of leukemia patients, but very few in the CD19(+) B cells from the healthy controls. Interestingly, the quantity of the PTN transcripts correlated with the severity of disease. Moreover, suppression of PTN activity with an anti-PTN antibody promoted apoptosis of cells from leukemia patients and cell lines SMS-SB and JVM-2. This effect of the anti-PTN antibody suggests that PTN may be a new target for the treatment of lymphocytic leukemia. © 2014 APMIS. Published by John Wiley & Sons Ltd.

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

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

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

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

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

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

ClinicalTrials.gov

2017-10-11

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

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

PubMed

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

1994-01-01

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

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

Role of the B-cell receptor in chronic lymphocytic leukemia: where do we stand?

PubMed

Fais, Franco; Bruno, Silvia; Ghiotto, Fabio

2010-01-01

The past 15 years have witnessed an enormous effort in studying B-cell Chronic Lymphocytic Leukemia. A great number of researches brought significant novel information and a better understanding of the natural history of this disease. This mini review will focus on the studies related to the Immunoglobulin variable (IgV) genes rearrangements that compose the B-cell receptor (BcR) of the leukemic clones. These studies have defined a role for the antigen(s) in the paths that lead to leukemic clone generation/expansion and underscore the informative value represented by BcR analyses.

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

ClinicalTrials.gov

2018-04-13

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

High Mitochondrial DNA Stability in B-Cell Chronic Lymphocytic Leukemia

PubMed Central

Cerezo, María; Bandelt, Hans-Jürgen; Martín-Guerrero, Idoia; Ardanaz, Maite; Vega, Ana; Carracedo, Ángel; García-Orad, África; Salas, Antonio

2009-01-01

Background Chronic Lymphocytic Leukemia (CLL) leads to progressive accumulation of lymphocytes in the blood, bone marrow, and lymphatic tissues. Previous findings have suggested that the mtDNA could play an important role in CLL. Methodology/Principal Findings The mitochondrial DNA (mtDNA) control-region was analyzed in lymphocyte cell DNA extracts and compared with their granulocyte counterpart extract of 146 patients suffering from B-Cell CLL; B-CLL (all recruited from the Basque country). Major efforts were undertaken to rule out methodological artefacts that would render a high false positive rate for mtDNA instabilities and thus lead to erroneous interpretation of sequence instabilities. Only twenty instabilities were finally confirmed, most of them affecting the homopolymeric stretch located in the second hypervariable segment (HVS-II) around position 310, which is well known to constitute an extreme mutational hotspot of length polymorphism, as these mutations are frequently observed in the general human population. A critical revision of the findings in previous studies indicates a lack of proper methodological standards, which eventually led to an overinterpretation of the role of the mtDNA in CLL tumorigenesis. Conclusions/Significance Our results suggest that mtDNA instability is not the primary causal factor in B-CLL. A secondary role of mtDNA mutations cannot be fully ruled out under the hypothesis that the progressive accumulation of mtDNA instabilities could finally contribute to the tumoral process. Recommendations are given that would help to minimize erroneous interpretation of sequencing results in mtDNA studies in tumorigenesis. PMID:19924307

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

2018-03-26

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

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

AID protein expression in chronic lymphocytic leukemia/small lymphocytic lymphoma is associated with poor prognosis and complex genetic alterations.

PubMed

Leuenberger, Mona; Frigerio, Simona; Wild, Peter J; Noetzli, Franziska; Korol, Dimitri; Zimmermann, Dieter R; Gengler, Carole; Probst-Hensch, Nicole M; Moch, Holger; Tinguely, Marianne

2010-02-01

The biological behavior of chronic lymphocytic leukemia and small lymphocytic lymphoma is unpredictable. Nonetheless, non-mutated IgV(H) gene rearrangement, ATM (11q22-23) and p53 (17p13) deletion are recognized as unfavorable prognosticators in chronic lymphocytic leukemia. The mRNA expression of activation-induced cytidine deaminase (AID), an enzyme indispensable for somatic hypermutation processes, was claimed to be predictive of non-mutated chronic lymphocytic leukemia cells in blood. Here, we evaluated AID protein expression compared with known molecular and immunohistochemical prognostic indicators in 71 chronic lymphocytic leukemia/small lymphocytic lymphoma patients using a tissue microarray approach. We found AID heterogeneously expressed in tumor cells as shown by colocalization analysis for CD5 and CD23. Ki-67 positive paraimmunoblasts of the proliferation centers displayed the highest expression. This observation is reflected by a significant association of AID positivity with a high proliferation rate (P=0.012). ATM deletion was detected in 10% (6/63) of patients and p53 deletion in 19% (13/67) of patients. Moreover, both ATM (P=0.002) and p53 deletion (P=0.004) were significantly associated with AID. IgV(H) gene mutation was seen in 45% (27/60) of patients. Twenty-five percent (17/69) of patients with AID-positive chronic lymphocytic leukemia/small lymphocytic lymphoma displayed a shorter survival than AID-negative chronic lymphocytic leukemia/small lymphocytic lymphoma patients (61 vs 130 months, P=0.001). Although there was a trend, we could not show an association with the IgV(H) gene mutation status. Taken together, our study shows that AID expression is an indicator of an unfavorable prognosis in chronic lymphocytic leukemia/small lymphocytic lymphoma patients, although it is not a surrogate marker for the IgV(H) status. Furthermore, the microenvironment of proliferation centers seems to influence AID regulation and might be an initiating factor

[Chronic lymphocytic leukemia].

PubMed

Maurer, C; Hallek, M

2013-10-01

Chronic lymphocytic leukemia (CLL) is a lymphoproliferative disorder that accounts for approximately 30 % of adult leukemias and 25 % of Non-Hodgkin lymphomas (NHL). It is the most common form of leukemia in the western world (incidence 3-5/100 000). Elderly people are mainly affected, median age at diagnosis is around 70 years and there is a slight predominance in men. The etiology of the disease is unknown. The initial symptoms are nonspecific. Cervical lymphadenopathy and splenomegaly followed by general fatigue are seen most commonly. Other possible symptoms include night sweats, fever, loss of weight (so-called B symptoms) and frequent infections. Several patients develop autoimmune complications as autoimmune hemolytic anemia (AIHA) or immune thrombocytopenia (ITP). To confirm the diagnosis more than 5000 B-lymphocytes/µl need to be present. The expression of the typical surface markers CD5, CD19, and CD23 has to be confirmed by flow cytometry. Imaging studies as X-ray of the chest, ultrasound of the abdomen, or CT scan are used to assess the degree of lymphadenopathy or organomegaly. A bone marrow biopsy is not mandatory for the diagnosis. According to the European Binet staging system, CLL is divided into 3 stages (A, B and C). Patients in Binet stage A have 0 to 2 areas of node or organ enlargement with normal levels of hemoglobin and platelets. Binet stage B patients have 3 to 5 areas of node or organ enlargement and normal or slightly decreased levels of hemoglobin and platelets. Binet stage C patients have anemia (hemoglobin < 10 g/dl) and/or thrombocytopenia (platelet counts < 100 000/µl), with or without lymphadenopathy or organomegaly. As there is no survival benefit associated with early intervention, asymptomatic patients with early stage CLL (Binet stage A and B) are usually not treated but are followed on a "watch and wait" principle. Treatment indications include stage Binet C or signs of an active disease as rapidly progressive

Appearance and Disappearance of Chronic Myeloid Leukemia (CML) in Patient with Chronic Lymphocytic Leukemia (CLL).

PubMed

Payandeh, Mehrdad; Sadeghi, Edris; Khodarahmi, Reza; Sadeghi, Masoud

2014-10-01

Chronic lymphocytic leukemia (CLL) and chronic myeloid leukemia (CML) are the most common leukemias of the elderly (>43 year). However, the sequential occurrence of CML followed by CLL in the same patient is extremely rare. In our report, a 52-year-old female was diagnosed with CLL (type of bone marrow (BM) infiltration was nodular and interstitial) and was treated with chlorambucil. 64 months after the diagnosis of CLL, she developed CML. She was treated with imatinib (400mg/day). After a few months, signs of CML were disappeared and CLL became dominant. This is first reported case.

Deregulation of Apoptosis - Is it Still an Important Issue in Pathogenesis of Chronic Lymphocytic Leukemia?

PubMed

Podhorecka, Monika; Macheta, Arkadiusz; Bozko, Maria; Bozko, Andrzej; Malek, Nisar P; Bozko, Przemyslaw

2016-01-01

Chronic lymphocytic leukemia (CLL), a clonal expansion of B CD5+ cells, is the most common type of adult leukemia in western countries. The accumulation of neoplastic B-cells is primarily caused by prolonged life-span of these cells due to deregulation of apoptosis, and only marginally due to a higher proliferation rate. In spite of numerous reports characterizing particular mechanisms of B-CLL cell apoptosis, still relatively little is known about the complex regulation of this process. Therefore, more detailed research is required to understand the complicated mechanisms and regulatory processes of apoptosis in neoplastic B lymphocytes.

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

PubMed

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

2010-12-01

A small fraction of patients with chronic lymphocytic leukemia/small lymphocytic lymphoma develop Epstein-Barr virus-positive B-cell lymphoproliferative disorders. These Epstein-Barr virus-B-cell lymphoproliferative disorders are thought to be related to immune suppression induced by fludarabine/other chemotherapeutic regimens. As in other immunodeficiency-associated lymphoproliferative disorders, these disorders demonstrate a heterogeneous histological spectrum that ranges from polymorphic to monomorphic to classical Hodgkin lymphoma-like lesions. We report a case of concurrent classical Hodgkin lymphoma and plasmablastic lymphoma in a patient with chronic lymphocytic leukemia/small lymphocytic lymphoma treated with fludarabine. Both classical Hodgkin lymphoma and plasmablastic lymphoma were positive for Epstein-Barr virus-encoded RNA, whereas classical Hodgkin lymphoma was also positive for Epstein-Barr virus- latent membrane protein 1, suggesting a different viral latency. Immunoglobulin gene rearrangement studies demonstrated distinct clones in the plasmablastic lymphoma and chronic lymphocytic leukemia/small lymphocytic lymphoma. These findings suggest biclonal secondary lymphomas associated with iatrogenic immunodeficiency. Epstein-Barr virus-B-cell lymphoproliferative disorders in the setting of chronic lymphocytic leukemia/small lymphocytic lymphoma, in particular those arising after chemotherapy, should be separated from true Richter's transformation, and be categorized as (iatrogenic) immunodeficiency-associated lymphoproliferative disorder. Copyright © 2010 Elsevier Inc. All rights reserved.

Ibrutinib (PCI-32765) in chronic lymphocytic leukemia.

PubMed

Jain, Nitin; O'Brien, Susan

2013-08-01

B-cell receptor (BCR) signaling is essential for chronic lymphocytic leukemia (CLL) cell survival. Many kinases in the BCR signaling pathway are being studied as potential therapeutic targets. Ibrutinib (PCI-32765) is a novel first-in-class selective inhibitor of Bruton tyrosine kinase. Preclinical evidence suggests that ibrutinib inhibits CLL cell survival and proliferation and affects CLL cell migration and homing. Early clinical data in patients with CLL and non-Hodgkin lymphoma is encouraging. It is likely that ibrutinib and other drugs targeting the BCR pathway will become an integral component of CLL therapy. Copyright © 2013 Elsevier Inc. All rights reserved.

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

ClinicalTrials.gov

2017-07-18

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

T-cell 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.

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

ClinicalTrials.gov

2017-07-24

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

Chronic lymphocytic leukemia skin infiltration mimicking an ICD pocket infection: a case report.

PubMed

Snorek, M; Bulava, A; Vonke, I

2017-03-24

We are presenting a case report on an unreported and unusual cutaneous manifestation of chronic lymphocytic leukemia in a patient with an implantable cardioverter-defibrillator (ICD). A 65-year-old man with a history of chronic lymphocytic leukemia (CLL), previously treated with chlorambucil, was referred in October 2013 for extraction of a single chamber ICD due to a suspected device-related infection in the pulse generator area (left-hand side of Fig. 1). The ICD system (Current VR, St. Jude Medical, USA) had been implanted in November 2009. The patient complained of painless erythema with pruritus in the pocket area. Inflammatory blood parameters were C-reactive protein 17.3 mg/L and leucocytes 29.0 × 10 9 /L. Due to the atypical appearance of the pocket area we did not extract the device. Instead, we created an exploratory excision in the skin induration, which had been present for approximately 6 weeks, and conducted a microbiological and histological examination. All cultivation examinations were negative. However, we did histologically show skin infiltration by CD-5 positive low-grade B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma (B-CLL/SLL). Re-initiation of chemotherapy was not necessary and the skin induration completely disappeared within 2 months (right-hand side of Fig. 1). Complete removal of an ICD system carries considerable risk. In patients with a history of hematological disease, it is crucial to exclude cutaneous manifestations of the disease prior to device removal.

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

ClinicalTrials.gov

2017-02-21

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

Brick mortar exposure and chronic lymphocytic leukemia.

PubMed

Markovic-Denic, L; Jankovic, S; Marinkovic, J; Radovanovic, Z

1995-01-01

A case-control study of 130 patients with chronic lymphocytic leukemia (CLL) and 130 controls matched with respect to sex, age (2 years), type of residence (urban-rural) and area of residence (according to the national per capita income) was carried out. Conditional logistic regression analysis showed that, apart of four risk factors already described in the literature (work in a hazardous industry, hair dye use, family history of leukemia and exposure to electromagnetic radiation), brick mortar exposure was also significantly related to CLL.

MicroRNA profiling reveals distinct signatures in B cell chronic lymphocytic leukemias

PubMed Central

Calin, George Adrian; Liu, Chang-Gong; Sevignani, Cinzia; Ferracin, Manuela; Felli, Nadia; Dumitru, Calin Dan; Shimizu, Masayoshi; Cimmino, Amelia; Zupo, Simona; Dono, Mariella; Dell'Aquila, Marie L.; Alder, Hansjuerg; Rassenti, Laura; Kipps, Thomas J.; Bullrich, Florencia; Negrini, Massimo; Croce, Carlo M.

2004-01-01

Little is known about the expression levels or function of micro-RNAs (miRNAs) in normal and neoplastic cells, although it is becoming clear that miRNAs play important roles in the regulation of gene expression during development [Ambros, V. (2003) Cell 113, 673–676; McManus, M. T. (2003) Semin. Cancer Biol. 13, 253–258]. We now report the genomewide expression profiling of miRNAs in human B cell chronic lymphocytic leukemia (CLL) by using a microarray containing hundreds of human precursor and mature miRNA oligonucleotide probes. This approach allowed us to identify significant differences in miRNome expression between CLL samples and normal CD5+ B cells; data were confirmed by Northern blot analyses and real-time RT-PCR. At least two distinct clusters of CLL samples can be identified that were associated with the presence or absence of Zap-70 expression, a predictor of early disease progression. Two miRNA signatures were associated with the presence or absence of mutations in the expressed Ig variableregion genes or with deletions at 13q14, respectively. These data suggest that miRNA expression patterns have relevance to the biological and clinical behavior of this leukemia. PMID:15284443

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

PubMed

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

2017-03-01

Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are different manifestations of the same disease and managed in much the same way. The advent of novel CD20 monoclonal antibodies led to the development of effective chemoimmunotherapy regimens. More recently, small molecule inhibitors targeting kinases involved in a number of critical signaling pathways and a small molecule inhibitor of the BCL-2 family of proteins have demonstrated activity for the treatment of patients with CLL/SLL. These NCCN Guidelines Insights highlight important updates to the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for CLL/SLL for the treatment of patients with newly diagnosed or relapsed/refractory CLL/SLL. Copyright © 2017 by the National Comprehensive Cancer Network.

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

2015-09-08

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.

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).

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

ClinicalTrials.gov

2018-03-22

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

To the nucleolar bodies (nucleoli) in cells of the lymphocytic lineage in patients suffering from B - chronic lymphocytic leukemia.

PubMed

Smetana, K; Karban, J; Trneny, M

2010-01-01

The present study was undertaken to provide more information on nucleoli in lymphocytes of B - chronic lymphocytic leukemia. The computer assisted nucleolar and cytoplasmic RNA image densitometry, reflecting the nucleolar and cytoplasmic RNA concentration at the single cell level, demonstrated a remarkable stability during the differentiation and maturation of B- lymphocytes. In contrast, as it was expected, the nucleolar diameter during the lymphocytic development markedly decreased. Thus the nucleolar RNA content of leukemic B-lymphocytes was apparently related to the nucleolar size. In both immature and mature lymphocytes, the cytostatic treatment increased the incidence of micronucleoli, which represent the "inactive" type of nucleoli. However, the decreased values of the nucleolar diameter were statistically significant only in mature lymphocytes of treated patients. On the other hand, despite such observation, it must be mentioned that "large active" and "ring shaped resting" nucleoli were still present in immature and mature lymphocytes after the cytostatic therapy and such cells might represent a potential pool of proliferating cells. As it is generally accepted "large active nucleoli" with multiple fibrillar centers are known to be characteristic for proliferating cells. "Ring shaped resting nucleoli" are present in sleeping cells, which may be stimulated to return to the cell cycle and to proliferate again. In addition, the nucleolar RNA distribution also indicated that Gumprecht ghosts mostly originated from mature lymphocytes. Increased ratio of the nucleolar to cytoplasmic RNA density in Gumprecht ghosts or apoptotic cells and apoptotic bodies of the lymphocytic origin was related to the decreased cytoplasmic RNA concentration. The increased nucleolar size together with the markedly decreased cytoplasmic RNA concentration characteristic for Gumprecht ghosts just reflected the spreading of lymphocytes during smear preparations. In apoptotic cells or

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

PubMed

Kyle, Kristy N; Wright, Zachary

2010-04-01

Chylothorax secondary to chronic lymphocytic leukemia (CLL) was diagnosed in a feline leukemia virus (FeLV)-positive 8-year-old castrated male domestic shorthair feline. The leukemia resolved following therapy with chlorambucil, prednisone, cyclophosphamide, doxorubicin, and lomustine. To our knowledge, this is the first reported case of CLL in an FeLV-positive cat. Although a causative relationship cannot be proven, patients diagnosed with either disease may benefit from diagnostics to rule out the presence of the other concurrent condition. Copyright 2009 ISFM and AAFP. Published by Elsevier Ltd. All rights reserved.

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

ClinicalTrials.gov

2017-12-26

B-Cell Prolymphocytic Leukemia; Hypodiploidy; Loss of Chromosome 17p; Plasma Cell Leukemia; Progression of Multiple Myeloma or Plasma Cell Leukemia; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Non-Hodgkin Lymphoma; Recurrent Childhood Hodgkin Lymphoma; Recurrent Childhood Non-Hodgkin Lymphoma; Recurrent Chronic Lymphocytic Leukemia; Recurrent Plasma Cell Myeloma; Recurrent Small Lymphocytic Lymphoma; Refractory Childhood Hodgkin Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Non-Hodgkin Lymphoma; Refractory Plasma Cell Myeloma; Refractory Small Lymphocytic Lymphoma; t(14;16); t(4;14); T-Cell Prolymphocytic Leukemia; Waldenstrom Macroglobulinemia

Chronic Lymphocytic Leukemia Treatment (PDQ®)—Health Professional Version

Cancer.gov

Chronic lymphocytic leukemia (CLL) treatment options can include observation, steroids, chemotherapy, targeted therapy, and/or stem cell transplant. Get detailed information about newly diagnosed and recurrent CLL and available treatment modalities in this summary for clinicians.

Chronic lymphocytic leukemia.

PubMed

Kay, Neil E; Hamblin, Terry J; Jelinek, Diane F; Dewald, Gordon W; Byrd, John C; Farag, Sherif; Lucas, Margaret; Lin, Thomas

2002-01-01

This update of early stage B-cell chronic lymphocytic leukemia (B-CLL) embraces current information on the diagnosis, biology, and intervention required to more fully develop algorithms for management of this disease. Emphasis on early stage is based on the rapid advancement in our understanding of the disease parameters and our increasing ability to predict for a given early stage patient whether there is a need for more aggressive management. In Section I, Dr. Terry Hamblin addresses the nature of the disease, accurate diagnostic procedures, evidence for an early "preclinical" phase, the use of newer prognostic features to distinguish who will be likely to progress or not, and whether it is best to watch or treat early stage disease. In Section II, Dr. Neil Kay and colleagues address the biologic aspects of the disease and how they may relate to disease progression. Review of the newer insights into gene expression, recurring genetic defects, role of cytokines/autocrine pathways, and the interaction of the CLL B cell with the microenvironment are emphasized. The relationship of these events to both trigger disease progression and as opportunities for future therapeutic intervention even in early stage disease is also considered. In Section III, Dr. John Byrd and colleagues review the historical and now current approaches to management of the previously untreated progressive B-CLL patient. They discuss what decision tree could be used in the initial decision to treat a given patient. The use of single agents versus newer combination approaches such as chemoimmunotherapy are discussed here. In addition, the place of marrow transplant and some of the newer antibodies available for treatment of B-CLL are considered. Finally, a challenge to utilize our growing knowledge of the biology of B-CLL in the early stage B-CLL is proffered.

Prior history of non-melanoma skin cancer is associated with increased mortality in patients with chronic lymphocytic leukemia

PubMed Central

Toro, Jorge R.; Blake, Patrick W.; Björkholm, Magnus; Kristinsson, Sigurdur Y.; Wang, Zhuoqiao; Landgren, Ola

2009-01-01

We investigated whether a previous diagnosis of non-melanoma skin cancer among chronic lymphocytic leukemia patients is a predictor of poor outcome. Using the Swedish Cancer Registry, we conducted a population-based study to evaluate the survival patterns among chronic lymphocytic leukemia patients with and without non-melanoma skin cancer. Cox proportional hazards regression models were used and Kaplan-Meier curves were constructed. Of a total of 12,041 chronic lymphocytic leukemia cases identified, 236 cases, including 111 squamous cell cancer, had a prior history of non-melanoma skin cancer. Chronic lymphocytic leukemia patients with a prior history of non-melanoma skin cancer had a 1.29-fold (95% CI 1.10–1.52; p=0.0024) increased risk of dying; and those with a history of squamous cell cancer had a further elevated 1.86-fold (95% CI 1.46–2.36; p<0.0001) risk of dying. Kaplan-Meier plots showed that patients with a history of non-melanoma skin cancer, particularly those with squamous cell cancer, had significantly poorer survival than chronic lymphocytic leukemia patients without non-melanoma skin cancer (p<0.0001; log-rank test). Non-melanoma skin cancer may be a novel clinical predictor of worse chronic lymphocytic leukemia outcome. PMID:19794092

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

PubMed

Itchaki, Gilad; Brown, Jennifer R

2016-10-01

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

The top ten clues to understand the origin of chronic lymphocytic leukemia (CLL).

PubMed

García-Muñoz, Ricardo; Feliu, Jesús; Llorente, Luis

2015-01-01

The fundamental task of the immune system is to protect the individual from infectious organisms without serious injury to self. The essence of acquired immunity is molecular self/non self discrimination. Chronic lymphocytic leukemia is characterized by a global failure of immune system that begins with the failure of immunological tolerance mechanisms (autoimmunity) and finish with the incapacity to response to non-self antigens (immunodeficiency). Immunological tolerance mechanisms are involved in chronic lymphocytic leukemia (CLL) development. During B cell development some self-reactive B cells acquire a special BCR that recognize their own BCR. This self-autoantibody-self BCR interaction promotes survival, differentiation and proliferation of self-reactive B cells. Continuous self-autoantibody-self BCR interaction cross-linking induces an increased rate of surface BCR elimination, CD5+ expression, receptor editing and anergy. Unfortunately, some times this mechanisms increase genomic instability and promote additional genetic damage that immortalize self-reactive B cells and convert them into CLL like clones with the capability of clonal evolution and transformed CLL B cells. This review summarizes the immunological effects of continuous self-autoantibody-self BCR interaction cross-linking in the surface of self-reactive B cells and their role in CLL development. Copyright © 2014 Elsevier Ltd. All rights reserved.

Evidence for the replication of bovine leukemia virus in the B lymphocytes

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

Paul, P.S.; Pomeroy, K.A.; Johnson, D.W.

1977-06-01

Bovine peripheral blood lymphocytes from a cow with persistent lymphocytosis were separated on nylon wool columns into nylon-adherent and nonadherent populations. Nylon-adherent cells were highly enriched for surface immunoglobulin (SIg) bearing B lymphocytes (95.5%) and nonadherent cells for SIg negative non-B cells, presumably T lymphocytes (96.3%). The B lymphocytes were found to be the major producers for bovine leukemia virus. A total of 39% of the B-enriched cells, surviving after 72 hours in culture, produced bovine leukemia virus as compared with 0.5% of the non-B cells.

Prognosis of chronic lymphocytic leukemia from infrared spectra of lymphocytes

NASA Astrophysics Data System (ADS)

Schultz, Christian P.; Liu, Kan-Zhi; Johnston, James B.; Mantsch, Henry H.

1997-06-01

Peripheral mononuclear cells obtained from blood of normal individuals and from patients with chronic lymphocytic leukemia (CLL) were investigated by infrared spectroscopy and multivariate statistical analysis. Not only are the spectra of CLL cells different from those of normal cells, but hierarchical clustering also separated the CLL cells into a number of subclusters, based on their different DNA content, a fact which may provide a useful diagnostic tool for staging (progression of the disease) and multiple clone detection. Moreover, there is evidence for a correlation between the increased amount of DNA in the CLL cells and the in-vivo doubling time of the lymphocytes in a given patient.

The prohibitin-binding compound fluorizoline induces apoptosis in chronic lymphocytic leukemia cells through the upregulation of NOXA and synergizes with ibrutinib, 5-aminoimidazole-4-carboxamide riboside or venetoclax

PubMed Central

Cosialls, Ana M.; Pomares, Helena; Iglesias-Serret, Daniel; Saura-Esteller, José; Núñez-Vázquez, Sonia; González-Gironès, Diana M.; de la Banda, Esmeralda; Preciado, Sara; Albericio, Fernando; Lavilla, Rodolfo; Pons, Gabriel; González-Barca, Eva M.; Gil, Joan

2017-01-01

Fluorizoline is a new synthetic molecule that induces apoptosis by selectively targeting prohibitins. In the study herein, the pro-apoptotic effect of fluorizoline was assessed in 34 primary samples from patients with chronic lymphocytic leukemia. Fluorizoline induced apoptosis in chronic lymphocytic leukemia cells at concentrations in the low micromolar range. All primary samples were sensitive to fluorizoline irrespective of patients’ clinical or genetic features, whereas normal T lymphocytes were less sensitive. Fluorizoline increased the protein levels of the pro-apoptotic B-cell lymphoma 2 family member NOXA in chronic lymphocytic leukemia cells. Furthermore, fluorizoline synergized with ibrutinib, 5-aminoimidazole-4-carboxamide riboside or venetoclax to induce apoptosis. These results suggest that targeting prohibitins could be a new therapeutic strategy for chronic lymphocytic leukemia. PMID:28619845

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

PubMed Central

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

2017-01-01

Chronic lymphocytic leukemia (CLL) is the most prevalent leukemia in the adult population. Current efforts are focused on better understanding the intricate pathophysiology of the disease to develop successful targeted therapies. Ibrutinib is emerging as an important agent in this new age of targeted treatment for CLL. As a Bruton’s tyrosine kinase inhibitor, it blocks the signaling pathway that malignant B-lymphocytes need for growth and maturation. Ibrutinib’s role in therapy was further expanded recently when the US Food and Drug Administration approved its use in both frontline and salvage treatment for patients with CLL. This review assesses the effectiveness of ibrutinib in the frontline setting, its efficacy in various types of patients with CLL, and its safety and tolerability. PMID:28408842

The ibrutinib B-cell proliferation inhibition is potentiated in vitro by dexamethasone: Application to chronic lymphocytic leukemia.

PubMed

Manzoni, Delphine; Catallo, Régine; Chebel, Amel; Baseggio, Lucile; Michallet, Anne-Sophie; Roualdes, Olivier; Magaud, Jean-Pierre; Salles, Gilles; Ffrench, Martine

2016-08-01

New B-cell receptor-targeted therapies such as ibrutinib, a Bruton tyrosine kinase inhibitor, are now proposed for lymphoid pathologies. The putative benefits of its combination with glucocorticoids were evaluated here. We compared the effects of dexamethasone (DXM), ibrutinib and their in vitro combination on proliferation and metabolic stress markers in stimulated normal B-lymphocytes and in malignant lymphocytes from chronic lymphocytic leukemia (CLL) patients. In both cellular models, cell cycle progression was globally inhibited by DXM and/or ibrutinib. This inhibition was significantly amplified by DXM addition to ibrutinib and was related to a significant decrease in the expression of the cell cycle regulatory proteins CDK4 and cyclin E. Apoptosis increased especially with DXM/ibrutinib combination and was associated with a significant decrease in Mcl-1 expression. Treatment effects on metabolic stress were evaluated by DNA damage recognition after 53BP1 foci labeling. The percentage of cells with more than five 53BP1 foci decreased significantly with ibrutinib in normal and CLL lymphocytes. This decrease was strongly reinforced, in CLL, by DXM addition. Our data indicated that, in vitro, DXM potentiated antiproliferative effects of ibrutinib and decreased DNA damage in lymphoid B-cells. Thus their combination may be proposed for CLL treatment. Copyright © 2016 Elsevier Ltd. All rights reserved.

Further characterization of the circulating cell in chronic lymphocytic leukemia

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

Schutz, E.F.; Davis, S.; Rubin, A.D.

Peripheral lymphocytes from normal individuals and from patients with chronic lymphocytic leukemia (CLL) were cultured in vitro for 1-7 days. The growth response to phytohemagglutinin (PHA) was quantitated by the incorporation of tritiated uridine into RNA nucleotide during a 2-hr pulse with the radioisotope. While the maximum response in PHA-stimulated normal cultures appeared at 2-3 days, CLL cultures required 5-7 days to develop their maximal response, which was 50 percent-60 percent of the normal magnitude. Dilution of the number of normally reactive lymphocytes by culturing them with totally unreactive, mitomycin-treated cells produced a normal 72-hr maximal response, no matter whatmore » proportion of unreactive cells was included in the PHA-stimulated cultures. In addition, the response of peripheral lymphocytes from patients with myeloblastic leukemia, where large numbers of unreactive myeloblasts diluted the normal small lymphocytes, a depressed reaction occurred at the anticipated 2-3 days. Nylon fiber-adherent lymphocytes consisting of 85 percent immunoglobulin (Ig)-bearing cells responded minimally to PHA, but showed no evidence of a delay. When isolated from CLL patients, both fiber-adherent cells (ig-bearing) as well as non-fiber-adherent (sheep erythrocyte-rosetting) cells responded to PHA in a delayed fashion. Similarly, a case of CLL, in which 93.5 percent of the circulating lymphocytes bore sheep red blood cell receptors, showed its peak response to PHA at 7 days. Therefore, using surface marker criteria considered characteristic of normal T cells and B cells, the delayed response to PHA on the part of CLL lymphocytes was independent of thymic or nonthymic origin.« less

The prohibitin-binding compound fluorizoline induces apoptosis in chronic lymphocytic leukemia cells through the upregulation of NOXA and synergizes with ibrutinib, 5-aminoimidazole-4-carboxamide riboside or venetoclax.

PubMed

Cosialls, Ana M; Pomares, Helena; Iglesias-Serret, Daniel; Saura-Esteller, José; Núñez-Vázquez, Sonia; González-Gironès, Diana M; de la Banda, Esmeralda; Preciado, Sara; Albericio, Fernando; Lavilla, Rodolfo; Pons, Gabriel; González-Barca, Eva M; Gil, Joan

2017-09-01

Fluorizoline is a new synthetic molecule that induces apoptosis by selectively targeting prohibitins. In the study herein, the pro-apoptotic effect of fluorizoline was assessed in 34 primary samples from patients with chronic lymphocytic leukemia. Fluorizoline induced apoptosis in chronic lymphocytic leukemia cells at concentrations in the low micromolar range. All primary samples were sensitive to fluorizoline irrespective of patients' clinical or genetic features, whereas normal T lymphocytes were less sensitive. Fluorizoline increased the protein levels of the pro-apoptotic B-cell lymphoma 2 family member NOXA in chronic lymphocytic leukemia cells. Furthermore, fluorizoline synergized with ibrutinib, 5-aminoimidazole-4-carboxamide riboside or venetoclax to induce apoptosis. These results suggest that targeting prohibitins could be a new therapeutic strategy for chronic lymphocytic leukemia. Copyright© 2017 Ferrata Storti Foundation.

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

PubMed

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

2018-05-01

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

Activated Allogeneic NK Cells Preferentially Kill Poor Prognosis B-Cell Chronic Lymphocytic Leukemia Cells.

PubMed

Sánchez-Martínez, Diego; Lanuza, Pilar M; Gómez, Natalia; Muntasell, Aura; Cisneros, Elisa; Moraru, Manuela; Azaceta, Gemma; Anel, Alberto; Martínez-Lostao, Luis; Villalba, Martin; Palomera, Luis; Vilches, Carlos; García Marco, José A; Pardo, Julián

2016-01-01

Mutational status of TP53 together with expression of wild-type (wt) IGHV represents the most widely accepted biomarkers, establishing a very poor prognosis in B-cell chronic lymphocytic leukemia (B-CLL) patients. Adoptive cell therapy using allogeneic HLA-mismatched Natural killer (NK) cells has emerged as an effective and safe alternative in the treatment of acute myeloid and lymphoid leukemias that do not respond to traditional therapies. We have described that allogeneic activated NK cells eliminate hematological cancer cell lines with multidrug resistance acquired by mutations in the apoptotic machinery. This effect depends on the activation protocol, being B-lymphoblastoid cell lines (LCLs) the most effective stimulus to activate NK cells. Here, we have further analyzed the molecular determinants involved in allogeneic NK cell recognition and elimination of B-CLL cells, including the expression of ligands of the main NK cell-activating receptors (NKG2D and NCRs) and HLA mismatch. We present preliminary data suggesting that B-CLL susceptibility significantly correlates with HLA mismatch between NK cell donor and B-CLL patient. Moreover, we show that the sensitivity of B-CLL cells to NK cells depends on the prognosis based on TP53 and IGHV mutational status. Cells from patients with worse prognosis (mutated TP53 and wt IGHV ) are the most susceptible to activated NK cells. Hence, B-CLL prognosis may predict the efficacy of allogenic activated NK cells, and, thus, NK cell transfer represents a good alternative to treat poor prognosis B-CLL patients who present a very short life expectancy due to lack of effective treatments.

Sensitization of B-cell chronic lymphocytic leukemia cells to recombinant immunotoxin by immunostimulatory phosphorothioate oligodeoxynucleotides.

PubMed

Decker, Thomas; Hipp, Susanne; Kreitman, Robert J; Pastan, Ira; Peschel, Christian; Licht, Thomas

2002-02-15

A recombinant anti-CD25 immunotoxin, LMB-2, has shown clinical efficacy in hairy cell leukemia and T-cell neoplasms. Its activity in B-cell chronic lymphocytic leukemia (B-CLL) is inferior but might be improved if B-CLL cells expressed higher numbers of CD25 binding sites. It was recently reported that DSP30, a phosphorothioate CpG-oligodeoxynucleotide (CpG-ODN) induces immunogenicity of B-CLL cells by up-regulation of CD25 and other antigens. The present study investigated the antitumor activity of LMB-2 in the presence of DSP30. To this end, B-CLL cells from peripheral blood of patients were isolated immunomagnetically to more than 98% purity. Incubation with DSP30 for 48 hours augmented CD25 expression in 14 of 15 B-CLL samples, as assessed by flow cytometry. DSP30 increased LMB-2 cytotoxicity dose dependently whereas a control ODN with no CpG motif did not. LMB-2 displayed no antitumor cell activity in the absence of CpG-ODN as determined colorimetrically with an (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt (MTS) assay. In contrast, B-CLL growth was inhibited in 12 of 13 samples with 50% inhibition concentrations (IC(50)) in the range of LMB-2 plasma levels achieved in clinical studies. Two samples were not evaluable because of spontaneous B-CLL cell death in the presence of DSP30. Control experiments with an immunotoxin that does not recognize hematopoietic cells, and an anti-CD22 immunotoxin, confirmed that sensitization to LMB-2 was specifically due to up-regulation of CD25. LMB-2 was much less toxic to normal B and T lymphocytes compared with B-CLL cells. In summary, immunostimulatory CpG-ODNs efficiently sensitize B-CLL cells to a recombinant immunotoxin by modulation of its target. This new treatment strategy deserves further attention.

Chronic B-Cell Leukemias and Agent Orange

MedlinePlus

... of Medicine) of the National Academy of Sciences, Engineering, and Medicine focused on chronic lymphocytic leukemia in ... VA Plans, Budget, & Performance VA Claims Representation RESOURCES Careers at VA Employment Center Returning Service Members Vocational ...

Possible role of CD22, CD79b and CD20 expression in distinguishing small lymphocytic lymphoma from chronic lymphocytic leukemia.

PubMed

Jovanovic, Danijela; Djurdjevic, Predrag; Andjelkovic, Nebojsa; Zivic, Ljubica

2014-01-01

Flow cytometry has an important role in diagnosis and classification of B-cell lymphoproliferative disorders (BCLPDs). However, in distinguishing chronic lymphocytic leukemia (CLL) from small lymphocytic lymphoma (SLL) only clinical criteria are available so far. Aim of the study was to determine differences in the expression of common B cell markers (CD22, CD79b and CD20) on the malignant lymphocytes in the peripheral blood samples of CLL and SLL patients. Peripheral blood samples of 56 CLL and 11 SLL patients were analyzed by 5-color flow cytometry on the CD45/CD19/CD5 gate for CD22, CD79b and CD20. In the samples collected from the CLL patients, CD22 expression was detected in only 20% of patients in the low pattern, while in SLL patients the expression was medium and present in 90.9% of patients (p < 0.0001). For CD79b expression, statistical significance is reached both in the expression pattern, which was low/medium for CLL and high for SLL, and expression level (p = 0.006). The expression of CD20 was counted as the CD20/CD19 ratio. The average ratio was 0.512 in the CLL patients vs. 0.931 in the SLL patients (p = 0.0001). The pattern of expression and expression level of CD22, CD79b and CD20 in peripheral blood could be used for distinguishing SLL from CLL patients.

ZAP-70 staining in chronic lymphocytic leukemia.

PubMed

Villamor, Neus

2005-05-01

Chronic lymphocytic leukemia (CLL) is the most common chronic leukemia in Western countries. The disease has an extremely variable clinical course, and several prognostic features have been identified to assess individual risk. The configuration of the immunoglobulin variable heavy-chain gene (IgV(H)) is a strong predictor of the outcome. CLL patients with unmutated IgV(H) status have an aggressive clinical course and a short survival. Unfortunately, analysis of IgV(H) gene configuration is not available in most clinical laboratories. A small number of genes are differentially expressed between unmutated IgV(H) and mutated IgV(H) clinical forms of CLL. One of these genes is ZAP-70, which is detected in leukemic cells from patients with the unmutated IgV(H) form of CLL. Flow cytometry presents advantages over other methods to detect ZAP-70, and its quantification by flow cytometry has proved its predictive value. This unit focuses on protocols to quantify ZAP-70 by flow cytometry in CLL.

Host virus and pneumococcus-specific immune responses in high-count monoclonal B-cell lymphocytosis and chronic lymphocytic leukemia: implications for disease progression

PubMed Central

Criado, Ignacio; Muñoz-Criado, Santiago; Rodríguez-Caballero, Arancha; Nieto, Wendy G.; Romero, Alfonso; Fernández-Navarro, Paulino; Alcoceba, Miguel; Contreras, Teresa; González, Marcos; Orfao, Alberto; Almeida, Julia

2017-01-01

Patients diagnosed with chronic lymphocytic leukemia (CLL) display a high incidence of infections due to an associated immunodeficiency that includes hypogammaglobulinemia. A higher risk of infections has also been recently reported for high-count monoclonal B-cell lymphocytosis, while no information is available in low-count monoclonal B-cell lymphocytosis. Here, we evaluated the status of the humoral immune system in patients with chronic lymphocytic leukemia (n=58), as well as in low- (n=71) and high- (n=29) count monoclonal B-cell lymphocytosis versus healthy donors (n=91). Total free plasma immunoglobulin titers and specific levels of antibodies against cytomegalovirus, Epstein-Barr virus, influenza and S.pneumoniae were measured by nephelometry and ELISA-based techniques, respectively. Overall, our results show that both CLL and high-count monoclonal B-cell lymphocytosis patients, but not low-count monoclonal B-cell lymphocytosis subjects, present with relatively high levels of antibodies specific for the latent viruses investigated, associated with progressively lower levels of S.pneumoniae-specific immunoglobulins. These findings probably reflect asymptomatic chronic reactivation of humoral immune responses against host viruses associated with expanded virus-specific antibody levels and progressively decreased protection against other micro-organisms, denoting a severe humoral immunodeficiency state not reflected by the overall plasma immunoglobulin levels. Alternatively, these results could reflect a potential role of ubiquitous viruses in the pathogenesis of the disease. Further analyses are necessary to establish the relevance of such asymptomatic humoral immune responses against host viruses in the expansion of the tumor B-cell clone and progression from monoclonal B-cell lymphocytosis to CLL. PMID:28385786

2-Phenylacetylenesulfonamide (PAS) induces p53-independent apoptotic killing of B-chronic lymphocytic leukemia (CLL) cells.

PubMed

Steele, Andrew J; Prentice, Archibald G; Hoffbrand, A Victor; Yogashangary, Birunthini C; Hart, Stephen M; Lowdell, Mark W; Samuel, Edward R; North, Janet M; Nacheva, Elisabeth P; Chanalaris, Anastasios; Kottaridis, Panagiotis; Cwynarski, Kate; Wickremasinghe, R Gitendra

2009-08-06

We studied the actions of 2-phenylacetylenesulfonamide (PAS) on B-chronic lymphocytic leukemia (CLL) cells. PAS (5-20 microM) initiated apoptosis within 24 hours, with maximal death at 48 hours asassessed by morphology, cleavage of poly(ADP-ribose) polymerase (PARP), caspase 3 activation, and annexin V staining. PAS treatment induced Bax proapoptotic conformational change, Bax movement from the cytosol to the mitochondria, and cytochrome c release, indicating that PAS induced apoptosis via the mitochondrial pathway. PAS induced approximately 3-fold up-regulation of proapoptotic Noxa protein and mRNA levels. In addition, Noxa was found unexpectedly to be bound to Bcl-2 in PAS-treated cells. PAS treatment of CLL cells failed to up-regulate p53, suggesting that PAS induced apoptosis independently of p53. Furthermore, PAS induced apoptosis in CLL isolates with p53 gene deletion in more than 97% of cells. Normal B lymphocytes were as sensitive to PAS-induced Noxa up-regulation and apoptosis as were CLL cells. However, both T lymphocytes and bone marrow hematopoietic progenitor cells were relatively resistant to PAS. Our data suggest that PAS may represent a novel class of drug that induces apoptosis in CLL cells independently of p53 status by a mechanism involving Noxa up-regulation.

Recognition of Antigen-Specific B Cell Receptors From Chronic Lymphocytic Leukemia Patients By Synthetic Antigen Surrogates

PubMed Central

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

2014-01-01

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 discovery of non-peptidic 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 for discovery of other classes of antigen surrogates. PMID:25467125

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. Copyright © 2014 Elsevier Ltd. All rights reserved.

Real world outcomes and management strategies for venetoclax-treated chronic lymphocytic leukemia patients in the United States.

PubMed

Mato, Anthony R; Thompson, Meghan; Allan, John N; Brander, Danielle M; Pagel, John M; Ujjani, Chaitra S; Hill, Brian T; Lamanna, Nicole; Lansigan, Frederick; Jacobs, Ryan; Shadman, Mazyar; Skarbnik, Alan P; Pu, Jeffrey J; Barr, Paul M; Sehgal, Alison R; Cheson, Bruce D; Zent, Clive S; Tuncer, Hande H; Schuster, Stephen J; Pickens, Peter V; Shah, Nirav N; Goy, Andre; Winter, Allison M; Garcia, Christine; Kennard, Kaitlin; Isaac, Krista; Dorsey, Colleen; Gashonia, Lisa M; Singavi, Arun K; Roeker, Lindsey E; Zelenetz, Andrew; Williams, Annalynn; Howlett, Christina; Weissbrot, Hanna; Ali, Naveed; Khajavian, Sirin; Sitlinger, Andrea; Tranchito, Eve; Rhodes, Joanna; Felsenfeld, Joshua; Bailey, Neil; Patel, Bhavisha; Burns, Timothy F; Yacur, Melissa; Malhotra, Mansi; Svoboda, Jakub; Furman, Richard R; Nabhan, Chadi

2018-06-07

Venetoclax is a BCL2 inhibitor approved for 17p-deleted relapsed/refractory chronic lymphocytic leukemia with activity following kinase inhibitors. We conducted a multicenter retrospective cohort analysis of patients with CLL treated with venetoclax to describe outcomes, toxicities, and treatment selection following venetoclax discontinuation. A total of 141 chronic lymphocytic leukemia patients were included (98% relapsed/refractory). Median age at venetoclax initiation was 67 years (range 37-91), median prior therapies was 3 (0-11), 81% unmutated IGHV, 45% del(17p), and 26.8% complex karyotype (≥ 3 abnormalities). Prior to venetoclax initiation, 89% received a B-cell receptor antagonist. For tumor lysis syndrome prophylaxis, 93% received allopurinol, 92% normal saline, and 45% rasburicase. Dose escalation to the maximum recommended dose of 400 mg daily was achieved in 85% of patients. Adverse events of interest included neutropenia in 47.4%, thrombocytopenia in 36%, tumor lysis syndrome in 13.4%, neutropenic fever in 11.6%, and diarrhea in 7.3%. The overall response rate to venetoclax was 72% (19.4% complete remission). With a median follow up of 7 months, median progression free survival and overall survival for the entire cohort have not been reached. To date, 41 venetoclax treated patients have discontinued therapy and 24 have received a subsequent therapy, most commonly ibrutinib. In the largest clinical experience of venetoclax-treated chronic lymphocytic leukemia patients , the majority successfully completed and maintained a maximum recommended dose. Response rates and duration of response appear comparable to clinical trial data. Venetoclax was active in patients with mutations known to confer ibrutinib resistance. Optimal sequencing of newer chronic lymphocytic leukemia therapies requires further study. Copyright © 2018, Ferrata Storti Foundation.

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

ClinicalTrials.gov

2017-06-30

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

Defective immunoregulatory T-cell function in chronic lymphocytic leukemia

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

Han, T.; Ozer, H.; Henderson, E.S.

Chronic lymphocytic leukemia (CLL) of B-cell origin results in the malignant proliferation of small immunoglobulin-bearing lymphocytes. There is currently a controversy in the literature regarding both the ability of this leukemic population to differentiate into mature plasma cells, as well as the ability of apparently normal T cells from these patients to regulate allogeneic B-cell differentiation. In the present study we have examined the lymphocytes of CLL patients in various clinical stages of their disease and with different surface phenotypes of their leukemic B-cell population. Our results show that leukemic CLL B cells from all 20 patients (including one patientmore » with a monoclonal IgM paraprotein and another with a monoclonal IgG paraprotein) are incapable of further differentiation even in the absence of suppressor T cells and the presence of helper T lymphocytes. This lack of capacity to differentiate is unaffected by clinical stage, by therapy, or by the phenotype of the malignant population. Since the leukemic B population did not suppress normal allogeneic B-cell differentiation, the maturation deficit is evidently intrinsic to the leukemic clone rather than a result of activity of non-T suppressor cells. T helper function was also variably depressed in the blood of some patients with CLL, and this depression did not correlate with clinical stage, with therapy, or with the degree of lymphocytosis. Dysfunction of radiosensitive T suppressor cells was found to be the most consistent regulatory deficit of CLL T cells. Each of 11 patients whose leukemic cell population was of the ..mu..delta, ..mu cap alpha.., or ..mu.. phenotype had both helper and suppressor cell defects.« less

Adoptive cellular therapy for chronic lymphocytic leukemia and B cell malignancies. CARs and more.

PubMed

Castro, Januario E; Kipps, Thomas J

2016-03-01

Treatment of patients with chronic lymphocytic leukemia and other B cell malignancies is evolving very rapidly. We have observed the quick transition during the last couple of years, from chemo-immunotherapy based treatments to oral targeted therapies based on B cell receptor signaling and Bcl-2 inhibitors, as well as the increasing use of second generation glyco-engineered antibodies. The next wave of revolution in the treatment for this conditions is approaching and it will be based on strategies that harness the power of the immune system to fight cancer. In the center of this biotechnological revolution is cellular engineering, the field that had made possible to redirect the immune system effector cells to achieve a more effective and targeted adoptive cellular therapy. In this chapter, we will review the historical context of these scientific developments, the most recent basic and clinical research in the field and some opinions regarding the future of adoptive cellular therapy in CLL and other B cell malignancies. Copyright © 2016 Elsevier Ltd. All rights reserved.

Real-world results of ibrutinib in patients with relapsed or refractory chronic lymphocytic leukemia: data from 95 consecutive patients treated in a compassionate use program. A study from the Swedish Chronic Lymphocytic Leukemia Group

PubMed Central

Winqvist, Maria; Asklid, Anna; Andersson, PO; Karlsson, Karin; Karlsson, Claes; Lauri, Birgitta; Lundin, Jeanette; Mattsson, Mattias; Norin, Stefan; Sandstedt, Anna; Hansson, Lotta; Österborg, Anders

2016-01-01

Ibrutinib, a Bruton’s tyrosine kinase inhibitor is approved for relapsed/refractory and del(17p)/TP53 mutated chronic lymphocytic leukemia. Discrepancies between clinical trials and routine health-care are commonly observed in oncology. Herein we report real-world results for 95 poor prognosis Swedish patients treated with ibrutinib in a compassionate use program. Ninety-five consecutive patients (93 chronic lymphocytic leukemia, 2 small lymphocytic leukemia) were included in the study between May 2014 and May 2015. The median age was 69 years. 63% had del(17p)/TP53 mutation, 65% had Rai stage III/IV, 28% had lymphadenopathy ≥10cm. Patients received ibrutinib 420 mg once daily until progression. At a median follow-up of 10.2 months, the overall response rate was 84% (consistent among subgroups) and 77% remained progression-free. Progression-free survival and overall survival were significantly shorter in patients with del(17p)/TP53 mutation (P=0.017 and P=0.027, log-rank test); no other factor was significant in Cox proportional regression hazards model. Ibrutinib was well tolerated. Hematomas occurred in 46% of patients without any major bleeding. Seven patients had Richter’s transformation. This real-world analysis on consecutive chronic lymphocytic leukemia patients from a well-defined geographical region shows the efficacy and safety of ibrutinib to be similar to that of pivotal trials. Yet, del(17p)/TP53 mutation remains a therapeutic challenge. Since not more than half of our patients would have qualified for the pivotal ibrutinib trial (RESONATE), our study emphasizes that real-world results should be carefully considered in future with regards to new agents and new indications in chronic lymphocytic leukemia. PMID:27198718

Real-world results of ibrutinib in patients with relapsed or refractory chronic lymphocytic leukemia: data from 95 consecutive patients treated in a compassionate use program. A study from the Swedish Chronic Lymphocytic Leukemia Group.

PubMed

Winqvist, Maria; Asklid, Anna; Andersson, P O; Karlsson, Karin; Karlsson, Claes; Lauri, Birgitta; Lundin, Jeanette; Mattsson, Mattias; Norin, Stefan; Sandstedt, Anna; Hansson, Lotta; Österborg, Anders

2016-12-01

Ibrutinib, a Bruton's tyrosine kinase inhibitor is approved for relapsed/refractory and del(17p)/TP53 mutated chronic lymphocytic leukemia. Discrepancies between clinical trials and routine health-care are commonly observed in oncology. Herein we report real-world results for 95 poor prognosis Swedish patients treated with ibrutinib in a compassionate use program. Ninety-five consecutive patients (93 chronic lymphocytic leukemia, 2 small lymphocytic leukemia) were included in the study between May 2014 and May 2015. The median age was 69 years. 63% had del(17p)/TP53 mutation, 65% had Rai stage III/IV, 28% had lymphadenopathy ≥10cm. Patients received ibrutinib 420 mg once daily until progression. At a median follow-up of 10.2 months, the overall response rate was 84% (consistent among subgroups) and 77% remained progression-free. Progression-free survival and overall survival were significantly shorter in patients with del(17p)/TP53 mutation (P=0.017 and P=0.027, log-rank test); no other factor was significant in Cox proportional regression hazards model. Ibrutinib was well tolerated. Hematomas occurred in 46% of patients without any major bleeding. Seven patients had Richter's transformation. This real-world analysis on consecutive chronic lymphocytic leukemia patients from a well-defined geographical region shows the efficacy and safety of ibrutinib to be similar to that of pivotal trials. Yet, del(17p)/TP53 mutation remains a therapeutic challenge. Since not more than half of our patients would have qualified for the pivotal ibrutinib trial (RESONATE), our study emphasizes that real-world results should be carefully considered in future with regards to new agents and new indications in chronic lymphocytic leukemia. Copyright© Ferrata Storti Foundation.

CART19 to Treat B-Cell Leukemia or Lymphoma That Are Resistant or Refractory to Chemotherapy

ClinicalTrials.gov

2017-11-07

Hematopoietic/Lymphoid Cancer; Adult Acute Lymphoblastic Leukemia in Remission; B-cell Adult Acute Lymphoblastic Leukemia; B-cell Chronic Lymphocytic Leukemia; Prolymphocytic Leukemia; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Refractory Chronic Lymphocytic Leukemia; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Chronic Lymphocytic Leukemia; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Chronic Lymphocytic Leukemia; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma

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. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Symptomatic Hypercalcemia in a Patient with B-cell Chronic Lymphocytic Leukemia - A Case Report and Review of the Literature.

PubMed

Koutroumpakis, Efstratios; Lobe, Montgomery; McCarthy, Lezah; Mehdi, Syed

Hypercalcemia due to malignancy is well described in the literature and a common paraneoplastic finding in certain solid tumors. Hematologic malignancies, however, are less frequently associated with hypercalcemia with the exception of myelomas and T-cell lymphomas. This case report describes a patient with B-cell chronic lymphocytic leukemia (B-CLL) who developed symptomatic hypercalcemia. None of the pathogenetic mechanisms of malignancy-associated hypercalcemia already described in the literature could explain the pathogenesis of hypercalcemia in our patient. Calcium levels were normalized after initial treatment and remained within normal limits following treatment of the underlying B-CLL. The follow-up period was 26 months. The normalization of calcium levels was closely associated with the drop in the absolute lymphocyte count. Symptomatic hypercalcemia in B-CLL is exceedingly rare and only documented a few times in the literature. Hypercalcemia, in the present case, was not caused by any of the mechanisms already described in the literature and responded well to treatment of the underlying B-CLL. Copyright © 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

CD38 is a signaling molecule in B-cell chronic lymphocytic leukemia cells.

PubMed

Deaglio, Silvia; Capobianco, Andrea; Bergui, Luciana; Dürig, Jan; Morabito, Fortunato; Dührsen, Ulrich; Malavasi, Fabio

2003-09-15

The prognosis for patients with B-cell chronic lymphocytic leukemia (B-CLL) is generally less favorable for those expressing CD38. Our working hypothesis is that CD38 is not merely a marker in B-CLL, but that it plays a receptor role with pathogenetic potential ruling the proliferation of the malignant clone. CD38 levels were generally low in the patients examined and monoclonal antibody (mAb) ligation was inefficient in signaling. Other cellular models indicated that molecular density and surface organization are critical for CD38 functionality. Interleukin 2 (IL-2) induced a marked up-modulation and surface rearrangement of CD38 in all the patients studied. On reaching a specific expression threshold, CD38 becomes an efficient receptor in purified B-CLL cells. Indeed, mAb ligation is followed by Ca2+ fluxes and by a markedly increased proliferation. The unsuitability of CD38 to perform as a receptor is obviated through close interaction with the B-cell-receptor (BCR) complex and CD19. On mAb binding, CD38 translocates to the membrane lipid microdomains, as shown by a colocalization with the GM1 ganglioside and with CD81, a raft-resident protein. Finally, CD38 signaling in IL-2-treated B-CLL cells prolonged survival and induced the appearance of plasmablasts, providing a pathogenetic hypothesis for the occurrence of Richter syndrome.

Invasive aspergillosis related to ibrutinib therapy for chronic lymphocytic leukemia.

PubMed

Arthurs, Benjamin; Wunderle, Kathy; Hsu, Maylee; Kim, Suil

2017-01-01

We report a case of invasive pulmonary aspergillosis in a patient taking ibrutinib, a Bruton's tyrosine kinase inhibitor used to treat refractory chronic lymphocytic leukemia. We hypothesize that ibrutinib promoted this infection by suppressing innate immune responses against Aspergillus . Clinicians should be aware of potential Aspergillus infections in patients treated with this drug.

Morphologic identification of atypical chronic lymphocytic leukemia by digital microscopy.

PubMed

Marionneaux, S; Maslak, P; Keohane, E M

2014-08-01

Atypical chronic lymphocytic leukemia (aCLL) is a morphologic variant found in approximately 25% of patients with chronic lymphocytic leukemia (CLL). Although aCLL has a more aggressive course compared to typical CLL (tCLL), it is not usually reported. This retrospective study used digital microscopy to morphologically classify CLL patients as aCLL or tCLL, and determined the prevalence of prognostic markers in each group. CellaVision AB (Lund, Sweden) was used to evaluate lymphocyte morphology on archived blood films of 97 CLL patients, and results of their prognostic marker analysis at diagnosis were obtained. The unpaired t-test, Chi-square, or Fisher's Exact test were used for statistical analysis. 27% of CLL cases were morphologically classified as aCLL. The aCLL group had a higher prevalence of trisomy 12, unmutated IgVH, and CD38 expression (markers associated with poor prognosis), and a lower prevalence of 13q14 deletions compared to tCLL; this was statistically significant. Using digital imaging to identify aCLL is feasible, economical, and may provide clinically relevant prognostic information at diagnosis and during periodic monitoring. Further study of a larger number of patients is needed to assess the clinical utility of reporting aCLL morphology. © 2013 John Wiley & Sons Ltd.

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

Hyperkalemia complicating splenic irradiation of chronic lymphocytic leukemia

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

Kurlander, R.; Stein, R.S.; Roth, D.

1975-09-01

Hyperkalemia is an infrequent complication of the therapy of malignant disease. In previously reported cases, hyperkalemia following the institution of chemotherapy has been associated with acute renal failure. In this report, we present a patient with chronic lymphocytic leukemia who developed hyperkalemia following splenic irradiation. Necrosis of tumor cells, either as direct or an abscopal effect appears to be implicated as a cause of hyperkalemia. It seems appropriate to monitor potassium levels when therapy of a responsive tumor is instituted. (auth)

Remarkably similar antigen receptors among a subset of patients with chronic lymphocytic leukemia

PubMed Central

Ghiotto, Fabio; Fais, Franco; Valetto, Angelo; Albesiano, Emilia; Hashimoto, Shiori; Dono, Mariella; Ikematsu, Hideyuki; Allen, Steven L.; Kolitz, Jonathan; Rai, Kanti R.; Nardini, Marco; Tramontano, Anna; Ferrarini, Manlio; Chiorazzi, Nicholas

2004-01-01

Studies of B cell antigen receptors (BCRs) expressed by leukemic lymphocytes from patients with B cell chronic lymphocytic leukemia (B-CLL) suggest that B lymphocytes with some level of BCR structural restriction become transformed. While analyzing rearranged VHDJH and VLJL genes of 25 non–IgM-producing B-CLL cases, we found five IgG+ cases that display strikingly similar BCRs (use of the same H- and L-chain V gene segments with unique, shared heavy chain third complementarity-determining region [HCDR3] and light chain third complementarity-determining region [LCDR3] motifs). These H- and L-chain characteristics were not identified in other B-CLL cases or in normal B lymphocytes whose sequences are available in the public databases. Three-dimensional modeling studies suggest that these BCRs could bind the same antigenic epitope. The structural features of the B-CLL BCRs resemble those of mAb’s reactive with carbohydrate determinants of bacterial capsules or viral coats and with certain autoantigens. These findings suggest that the B lymphocytes that gave rise to these IgG+ B-CLL cells were selected for this unique BCR structure. This selection could have occurred because the precursors of the B-CLL cells were chosen for their antigen-binding capabilities by antigen(s) of restricted nature and structure, or because the precursors derived from a B cell subpopulation with limited BCR heterogeneity, or both. PMID:15057307

Management of chronic lymphocytic leukemia.

PubMed

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

2015-01-01

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

Molecular characterization of neoplastic and normal "sister" lymphoblastoid B-cell lines from chronic lymphocytic leukemia.

PubMed

Lanemo Myhrinder, Anna; Hellqvist, Eva; Bergh, Ann-Charlotte; Jansson, Mattias; Nilsson, Kenneth; Hultman, Per; Jonasson, Jon; Buhl, Anne Mette; Bredo Pedersen, Lone; Jurlander, Jesper; Klein, Eva; Weit, Nicole; Herling, Marco; Rosenquist, Richard; Rosén, Anders

2013-08-01

Chronic lymphocytic leukemia (CLL) B-cells resemble self-renewing CD5 + B-cells carrying auto/xeno-antigen-reactive B-cell receptors (BCRs) and multiple innate pattern-recognition receptors, such as Toll-like receptors and scavenger receptors. Integration of signals from BCRs with multiple surface membrane receptors determines whether the cells will be proliferating, anergic or apoptotic. To better understand the role of antigen in leukemogenesis, CLL cell lines producing monoclonal antibodies (mAbs) will facilitate structural analysis of antigens and supply DNA for genetic studies. We present here a comprehensive genotypic and phenotypic characterization of available CLL and normal B-cell-derived lymphoblastoid cell lines (LCLs) from the same individuals (n = 17). Authenticity and verification studies of CLL-patient origin were done by IGHV sequencing, fluorescence in situ hybridization (FISH) and DNA/short tandem repeat (STR) fingerprinting. Innate B-cell features, i.e. natural Ab production and CD5 receptors, were present in most CLL cell lines, but in none of the normal LCLs. This panel of immortalized CLL-derived cell lines is a valuable reference representing a renewable source of authentic Abs and DNA.

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. Copyright © 2013 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

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

PubMed

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

2017-03-01

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

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

Microenvironment interactions and B-cell receptor signaling in Chronic Lymphocytic Leukemia: implications for disease pathogenesis and treatment

PubMed Central

ten Hacken, Elisa; Burger, Jan A.

2015-01-01

Chronic Lymphocytic Leukemia (CLL) is a malignancy of mature B lymphocytes which are highly dependent on interactions with the tissue microenvironment for their survival and proliferation. Critical components of the microenvironment are monocyte-derived nurselike cells (NLCs), mesenchymal stromal cells, T cells and NK cells, which communicate with CLL cells through a complex network of adhesion molecules, chemokine receptors, tumor necrosis factor (TNF) family members, and soluble factors. (Auto-) antigens and/or autonomous mechanisms activate the B-cell receptor (BCR) and its downstream signaling cascade in secondary lymphatic tissues, playing a central pathogenetic role in CLL. Novel small molecule inhibitors, including the Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib and the phosphoinositide-3-kinase delta (PI3Kδ) inhibitor idelalisib, target BCR signaling and have become the most successful new therapeutics in this disease. We here review the cellular and molecular characteristics of CLL cells, and discuss the cellular components and key pathways involved in the cross-talk with their microenvironment. We also highlight the relevant novel treatment strategies, focusing on immunomodulatory agents and BCR signaling inhibitors and how these treatments disrupt CLL-microenvironment interactions. PMID:26193078

Extracts of chronic lymphocytic leukemia lymphocytes have a high level of DNA repair activity for O/sup 6/-methylguanine

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

Waldstein, E.A.; Cao, E.H.; Miller, M.E.

Extracts of peripheral lymphocytes from six individuals with chronic lymphocytic leukemia (CLL) were assayed for the ability to remove O/sup 6/-methylguanine (O/sup 6/MeGua) from exogenous DNA. The O/sup 6/MeGua-removing activity in CLL lymphocytes, predominantly B cells, was approximately 7-fold higher than in B lymphocytes of normal individuals and about 2-fold higher than in the unstimulated T type cells of normal persons. The activity measured in extracts of lymphocytes from three blood relatives was in the upper range of the normal distribution. Over 80% of the removal of O/sup 6/MeGua was accomplished by the transfer of the methyl group to cysteinemore » moieties of acceptor proteins in a stoichiometric reaction. If one assumes one acceptor group per acceptor protein, the calculated number of acceptor molecules per CLL lymphocyte falls between 91,000 and 220,000. Thus CLL lymphocytes do not show lower O/sup 6/MeGua-removing activity, in contrast to many tumor cell strains or transformed cell lines, which are reported to have a deficient methyl excision repair phenotype (Mer/sup -/). Instead, the CLL lymphocytes act as if they have a super-Mer/sup +/ phenotype.« less

Del(20q) in patients with chronic lymphocytic leukemia: A therapy-related abnormality involving lymphoid or myeloid cells

PubMed Central

Yin, C. Cameron; Tang, Guilin; Lu, Gary; Feng, Xiaoli; Keating, Michael J.; Medeiros, L. Jeffrey; Abruzzo, Lynne V.

2015-01-01

Del(20q), a common cytogenetic abnormality in myeloid neoplasms, is rare in chronic lymphocytic leukemia. We report 64 patients with chronic lymphocytic leukemia and del(20q), as the sole abnormality in 40, a stemline abnormality in 21, and a secondary abnormality in 3 cases. FISH analysis revealed an additional high-risk abnormality, del(11q) or del(17p), in 27/64 (42%) cases. In most cases, the leukemic cells showed atypical cytologic features, unmutated IGHV genes and ZAP70 positivity. The del(20q) was detected only after chemotherapy in all 27 cases with initial karyotypes available. With a median follow-up of 90 months, 30 patients (47%) died, most as a direct consequence of chronic lymphocytic leukemia. Eight patients developed a therapy-related myeloid neoplasm, seven with a complex karyotype. Combined morphologic and FISH analysis for del(20q) performed in 12 cases without morphologic evidence of a myeloid neoplasm localized the del(20q) to the chronic lymphocytic leukemia cells in 5 (42%) cases, and to myeloid/erythroid cells in 7 (58)% cases. The del(20q) was detected in myeloid cells in all 4 cases of myelodysplastic syndrome. In aggregate, these data indicate that chronic lymphocytic leukemia with del(20q) acquired after therapy is heterogeneous. In cases with morphologic evidence of dysplasia, the del(20q) likely resides in the myeloid lineage. However, in cases without morphologic evidence of dysplasia, the del(20q) may represent clonal evolution and disease progression. Combining morphologic analysis with FISH for del(20q) or performing FISH on immunomagnetically-selected subpopulations to localize the cell population with this abnormality may help guide patient management. PMID:25953391

JAK2 V617F positive essential thrombocythemia developing in a patient with CD5⁻ chronic lymphocytic leukemia.

PubMed

Wei, Ju; Wang, Chun; Qin, You-Wen; Zhu, Jun; Gao, Yang-Rong; Cai, Qi; Yan, Shi-Ke

2012-06-01

Coexistence of chronic lymphocytic leukemia (CLL) and essential thrombocythemia (ET) in a patient is extremely rare, with only 10 cases reported thus far in literature. This paper describes a 94-year-old male having atypical B-CLL with CD5⁻ (CD5⁻) phenotype and ET. In this patient, we performed interphase fluorescence in situ hybridization (FISH) analysis which revealed 13q14.3 deletion in 31% of B-lymphocyte nuclei and RB1 deletion in 27% of B-lymphocyte nuclei, but not in neutrophils and T-lymphocytes. Furthermore, we identified JAK2 V617F mutation in the peripheral blood nucleated cells and neutrophils, but not in the B- and T-lymphocyte populations. Therefore, it was concluded that the occurrence of CD5− B-CLL and ET in this patient was pathogenically independent.

BTK inhibitors in chronic lymphocytic leukemia: a glimpse to the future.

PubMed

Spaargaren, M; de Rooij, M F M; Kater, A P; Eldering, E

2015-05-07

The treatment of chronic lymphocytic leukemia (CLL) with inhibitors targeting B cell receptor signaling and other survival mechanisms holds great promise. Especially the early clinical success of Ibrutinib, an irreversible inhibitor of Bruton's tyrosine kinase (BTK), has received widespread attention. In this review we will focus on the fundamental and clinical aspects of BTK inhibitors in CLL, with emphasis on Ibrutinib as the best studied of this class of drugs. Furthermore, we summarize recent laboratory as well as clinical findings relating to the first cases of Ibrutinib resistance. Finally, we address combination strategies with Ibrutinib, and attempt to extrapolate its current status to the near future in the clinic.

Chronic Lymphocytic Leukemia B-Cell Normal Cellular Counterpart: Clues From a Functional Perspective

PubMed Central

Darwiche, Walaa; Gubler, Brigitte; Marolleau, Jean-Pierre; Ghamlouch, Hussein

2018-01-01

Chronic lymphocytic leukemia (CLL) is characterized by the clonal expansion of small mature-looking CD19+ CD23+ CD5+ B-cells that accumulate in the blood, bone marrow, and lymphoid organs. To date, no consensus has been reached concerning the normal cellular counterpart of CLL B-cells and several B-cell types have been proposed. CLL B-cells have remarkable phenotypic and gene expression profile homogeneity. In recent years, the molecular and cellular biology of CLL has been enriched by seminal insights that are leading to a better understanding of the natural history of the disease. Immunophenotypic and molecular approaches (including immunoglobulin heavy-chain variable gene mutational status, transcriptional and epigenetic profiling) comparing the normal B-cell subset and CLL B-cells provide some new insights into the normal cellular counterpart. Functional characteristics (including activation requirements and propensity for plasma cell differentiation) of CLL B-cells have now been investigated for 50 years. B-cell subsets differ substantially in terms of their functional features. Analysis of shared functional characteristics may reveal similarities between normal B-cell subsets and CLL B-cells, allowing speculative assignment of a normal cellular counterpart for CLL B-cells. In this review, we summarize current data regarding peripheral B-cell differentiation and human B-cell subsets and suggest possibilities for a normal cellular counterpart based on the functional characteristics of CLL B-cells. However, a definitive normal cellular counterpart cannot be attributed on the basis of the available data. We discuss the functional characteristics required for a cell to be logically considered to be the normal counterpart of CLL B-cells. PMID:29670635

Clonal dynamics towards the development of venetoclax resistance in chronic lymphocytic leukemia.

PubMed

Herling, Carmen D; Abedpour, Nima; Weiss, Jonathan; Schmitt, Anna; Jachimowicz, Ron Daniel; Merkel, Olaf; Cartolano, Maria; Oberbeck, Sebastian; Mayer, Petra; Berg, Valeska; Thomalla, Daniel; Kutsch, Nadine; Stiefelhagen, Marius; Cramer, Paula; Wendtner, Clemens-Martin; Persigehl, Thorsten; Saleh, Andreas; Altmüller, Janine; Nürnberg, Peter; Pallasch, Christian; Achter, Viktor; Lang, Ulrich; Eichhorst, Barbara; Castiglione, Roberta; Schäfer, Stephan C; Büttner, Reinhard; Kreuzer, Karl-Anton; Reinhardt, Hans Christian; Hallek, Michael; Frenzel, Lukas P; Peifer, Martin

2018-02-20

Deciphering the evolution of cancer cells under therapeutic pressure is a crucial step to understand the mechanisms that lead to treatment resistance. To this end, we analyzed whole-exome sequencing data of eight chronic lymphocytic leukemia (CLL) patients that developed resistance upon BCL2-inhibition by venetoclax. Here, we report recurrent mutations in BTG1 (2 patients) and homozygous deletions affecting CDKN2A/B (3 patients) that developed during treatment, as well as a mutation in BRAF and a high-level focal amplification of CD274 (PD-L1) that might pinpoint molecular aberrations offering structures for further therapeutic interventions.

Chronic Myelogenous Leukemia (CML)

MedlinePlus

... del paciente Transplant process Diseases treated by transplant Acute myeloid leukemia Adrenoleukodystrophy (ALD) Chronic Lymphocytic Leukemia (CLL) ... SCID) Sickle cell disease (SCD) Wiskott-Aldrich syndrome Acute lymphoblastic leukemia (ALL) Other diseases Treatment decisions Learn ...

Del(20q) in patients with chronic lymphocytic leukemia: a therapy-related abnormality involving lymphoid or myeloid cells.

PubMed

Yin, C Cameron; Tang, Guilin; Lu, Gary; Feng, Xiaoli; Keating, Michael J; Medeiros, L Jeffrey; Abruzzo, Lynne V

2015-08-01

Deletion 20q (Del(20q)), a common cytogenetic abnormality in myeloid neoplasms, is rare in chronic lymphocytic leukemia. We report 64 patients with chronic lymphocytic leukemia and del(20q), as the sole abnormality in 40, a stemline abnormality in 21, and a secondary abnormality in 3 cases. Fluorescence in situ hybridization (FISH) analysis revealed an additional high-risk abnormality, del(11q) or del(17p), in 25/64 (39%) cases. In most cases, the leukemic cells showed atypical cytologic features, unmutated IGHV (immunoglobulin heavy-chain variable region) genes, and ZAP70 positivity. The del(20q) was detected only after chemotherapy in all 27 cases with initial karyotypes available. With a median follow-up of 90 months, 30 patients (47%) died, most as a direct consequence of chronic lymphocytic leukemia. Eight patients developed a therapy-related myeloid neoplasm, seven with a complex karyotype. Combined morphologic and FISH analysis for del(20q) performed in 12 cases without morphologic evidence of a myeloid neoplasm localized the del(20q) to the chronic lymphocytic leukemia cells in 5 (42%) cases, and to myeloid/erythroid cells in 7 (58)% cases. The del(20q) was detected in myeloid cells in all 4 cases of myelodysplastic syndrome. In aggregate, these data indicate that chronic lymphocytic leukemia with del(20q) acquired after therapy is heterogeneous. In cases with morphologic evidence of dysplasia, the del(20q) likely resides in the myeloid lineage. However, in cases without morphologic evidence of dysplasia, the del(20q) may represent clonal evolution and disease progression. Combining morphologic analysis with FISH for del(20q) or performing FISH on immunomagnetically selected sub-populations to localize the cell population with this abnormality may help guide patient management.

Immunological aspects in chronic lymphocytic leukemia (CLL) development.

PubMed

García-Muñoz, Ricardo; Galiacho, Verónica Roldan; Llorente, Luis

2012-07-01

Chronic lymphocytic leukemia (CLL) is unique among B cell malignancies in that the malignant clones can be featured either somatically mutated or unmutated IGVH genes. CLL cells that express unmutated immunoglobulin variable domains likely underwent final development prior to their entry into the germinal center, whereas those that express mutated variable domains likely transited through the germinal center and then underwent final development. Regardless, the cellular origin of CLL remains unknown. The aim of this review is to summarize immunological aspects involved in this process and to provide insights about the complex biology and pathogenesis of this disease. We propose a mechanistic hypothesis to explain the origin of B-CLL clones into our current picture of normal B cell development. In particular, we suggest that unmutated CLL arises from normal B cells with self-reactivity for apoptotic bodies that have undergone receptor editing, CD5 expression, and anergic processes in the bone marrow. Similarly, mutated CLL would arise from cells that, while acquiring self-reactivity for autoantigens-including apoptotic bodies-in germinal centers, are also still subject to tolerization mechanisms, including receptor editing and anergy. We believe that CLL is a proliferation of B lymphocytes selected during clonal expansion through multiple encounters with (auto)antigens, despite the fact that they differ in their state of activation and maturation. Autoantigens and microbial pathogens activate BCR signaling and promote tolerogenic mechanisms such as receptor editing/revision, anergy, CD5+ expression, and somatic hypermutation in CLL B cells. The result of these tolerogenic mechanisms is the survival of CLL B cell clones with similar surface markers and homogeneous gene expression signatures. We suggest that both immunophenotypic surface markers and homogenous gene expression might represent the evidence of several attempts to re-educate self-reactive B cells.

Hemorrhagic pericardial effusion as the debut of acquired hemophilia in a chronic lymphocytic leukemia patient

PubMed Central

Bastida, José María; Cano-Mozo, María Teresa; Lopez-Cadenas, Felix; Vallejo, Victor Eduardo; Merchán, Soraya; Santos-Montón, Cecilia; González-Calle, David; Carrillo, Javier; Martín, Ana Africa; Torres-Hernández, Jose Angel; González, Marcos; Martín-Herrero, Francisco; Pabón, Pedro; González-Porras, Jose Ramon

2017-01-01

Abstract Background: Acquired hemophilia A (AHA) is a rare bleeding disease caused by autoantibodies against factor VIII. Spontaneous bleeding symptoms usually affect the skin and muscle, while pericardial effusion is an extremely rare manifestation. In the elderly, anticoagulant treatment is frequent and bleeding symptoms are usually associated with this. Clinical findings: We report a hemorrhagic pericardial effusion as the AHA debut in a patient with untreated chronic lymphocytic leukemia and anticoagulated with apixaban for atrial fibrillation and chronic arterial ischemia. The patient was treated with recombinant activated factor VII to control the active bleeding and corticosteroids and cyclophosphamide to eradicate the inhibitor. In addition, a briefly review of hematological malignancies associated to acquired hemophilia was performed. Particularities: a) anticoagulant treatment may confuse the suspicion of AHA and its diagnosis; b) hemorrhagic pericardial effusion is an extremely rare presentation; c) bypassing agents raise the risk of thromboembolism; d) hematological malignancies rarely cause AHA (<20% of cases). Conclusion: A multidisciplinary team is needed to diagnose and manage AHA effectively. The use of anticoagulants may lead to the misdiagnosis of clinical symptoms. Chronic lymphocytic leukemia is one of the main causes of hematological malignancies associated. The specific treatment of CLL is still recommended in the event of active disease. PMID:29381944

Cellular kinetics of CTL019 in relapsed/refractory B-cell acute lymphoblastic leukemia and chronic lymphocytic leukemia

PubMed Central

Maude, Shannon L.; Porter, David L.; Frey, Noelle; Wood, Patricia; Han, Xia; Waldron, Edward; Chakraborty, Abhijit; Awasthi, Rakesh; Levine, Bruce L.; Melenhorst, J. Joseph; Grupp, Stephan A.; June, Carl H.; Lacey, Simon F.

2017-01-01

Tisagenlecleucel (CTL019) is an investigational immunotherapy that involves reprogramming a patient’s own T cells with a transgene encoding a chimeric antigen receptor to identify and eliminate CD19-expressing cells. We previously reported that CTL019 achieved impressive clinical efficacy in patients with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL), including the expansion and persistence of CTL019 cells, which correlates with response to therapy. Here, we performed formal cellular kinetic analyses of CTL019 in a larger cohort of 103 patients treated with CTL019 in 2 different diseases (ALL and CLL). CTL019 was measured in peripheral blood and bone marrow, using quantitative polymerase chain reaction and flow cytometry. CTL019 levels in peripheral blood typically peaked at 10 to 14 days postinfusion and then declined slowly over time. Patients with complete response (CR)/CR with incomplete count recovery had higher levels of CTL019 in peripheral blood, with greater maximal concentration and area under the curve values compared with nonresponding patients (P < .0001 for each). CTL019 transgene levels were measurable up to 780 days in peripheral blood. CTL019 trafficking and persistence were observed in bone marrow and cerebrospinal fluid. CTL019 expansion correlated with severity of cytokine release syndrome (CRS) and preinfusion tumor burden in pediatric ALL. The results described here are the first detailed formal presentation of cellular kinetics across 2 diseases and highlight the importance of the application of in vivo cellular kinetic analyses to characterize clinical efficacy and CRS severity associated with CTL019 therapy. PMID:28935694

Partial versus Productive Immunoglobulin Heavy Locus Rearrangements in Chronic Lymphocytic Leukemia: Implications for B-Cell Receptor Stereotypy

PubMed Central

Tsakou, Eugenia; Agathagelidis, Andreas; Boudjoghra, Myriam; Raff, Thorsten; Dagklis, Antonis; Chatzouli, Maria; Smilevska, Tatjana; Bourikas, George; Merle-Beral, Helene; Manioudaki-Kavallieratou, Eleni; Anagnostopoulos, Achilles; Brüggemann, Monika; Davi, Frederic; Stamatopoulos, Kostas; Belessi, Chrysoula

2012-01-01

The frequent occurrence of stereotyped heavy complementarity-determining region 3 (VH CDR3) sequences among unrelated cases with chronic lymphocytic leukemia (CLL) is widely taken as evidence for antigen selection. Stereotyped VH CDR3 sequences are often defined by the selective association of certain immunoglobulin heavy diversity (IGHD) genes in specific reading frames with certain immunoglobulin heavy joining (IGHJ ) genes. To gain insight into the mechanisms underlying VH CDR3 restrictions and also determine the developmental stage when restrictions in VH CDR3 are imposed, we analyzed partial IGHD-IGHJ rearrangements (D-J) in 829 CLL cases and compared the productively rearranged D-J joints (that is, in-frame junctions without junctional stop codons) to (a) the productive immunoglobulin heavy variable (IGHV )-IGHD-IGHJ rearrangements (V-D-J) from the same cases and (b) 174 D-J rearrangements from 160 precursor B-cell acute lymphoblastic leukemia cases (pre-B acute lymphoblastic leukemia [ALL]). Partial D-J rearrangements were detected in 272/829 CLL cases (32.8%). Sequence analysis was feasible in 238 of 272 D-J rearrangements; 198 of 238 (83.2%) were productively rearranged. The D-J joints in CLL did not differ significantly from those in pre-B ALL, except for higher frequency of the IGHD7-27 and IGHJ6 genes in the latter. Among CLL carrying productively rearranged D-J, comparison of the IGHD gene repertoire in productive V-D-J versus D-J revealed the following: (a) overuse of IGHD reading frames encoding hydrophilic peptides among V-D-J and (b) selection of the IGHD3-3 and IGHD6-19 genes in V-D-J junctions. These results document that the IGHD and IGHJ gene biases in the CLL expressed VH CDR3 repertoire are not stochastic but are directed by selection operating at the immunoglobulin protein level. PMID:21968789

Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia.

PubMed

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

2013-07-04

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

Methylation status regulates lipoprotein lipase expression in chronic lymphocytic leukemia.

PubMed

Abreu, Cecilia; Moreno, Pilar; Palacios, Florencia; Borge, Mercedes; Morande, Pablo; Landoni, Ana Inés; Gabus, Raul; Dighiero, Guillermo; Giordano, Mirta; Gamberale, Romina; Oppezzo, Pablo

2013-08-01

Among different prognostic factors in chronic lymphocytic leukemia (CLL), we previously demonstrated that lipoprotein lipase (LPL) is associated with an unmutated immunoglobulin profile and clinical poor outcome. Despite the usefulness of LPL for CLL prognosis, its functional role and the molecular mechanism regulating its expression are still open questions. Interaction of CLL B-cells with the tissue microenvironment favors disease progression by promoting malignant B-cell growth. Since tissue methylation can be altered by environmental factors, we investigated the methylation status of the LPL gene and the possibility that overexpression could be associated with microenvironment signals. Our results show that a demethylated state of the LPL gene is responsible for its anomalous expression in unmutated CLL cases and that this expression is dependent on microenvironment signals. Overall, this work proposes that an epigenetic mechanism, triggered by the microenvironment, regulates LPL expression in CLL disease.

Moloney leukemia virus immortalizes B lymphocytes in vitro.

PubMed Central

Runnels, J; Serunian, L; Thursby, M; Rosenberg, N

1991-01-01

An in vitro culture system in which Moloney murine leukemia virus induces immortalization of mature B lymphocytes has been developed. The cell lines derived in this way are nontumorigenic, and virus production is not required to sustain them. This system provides a new in vitro model with which to study the stepwise process of transformation by retroviruses lacking oncogenes. Images PMID:1895405

Have we been wrong about ionizing radiation and chronic lymphocytic leukemia?

PubMed

Hamblin, Terry J

2008-04-01

It is almost axiomatic that chronic lymphocytic leukemia (CLL) is not caused by ionizing radiation. This assumption has been challenged recently by a critical re-appraisal of existing data. A recent paper implicated radon exposure in Czech uranium miners as a possible cause of CLL and in this issue of Leukemia Research the first paper examining the incidence of CLL among those exposed to radiation from the accident at the nuclear power plant in Chernobyl is published. It suggests that CLL occurring among the clean-up workers was of a more aggressive form than is normally seen in the community.

FcγRIIb expression in early stage chronic lymphocytic leukemia.

PubMed

Bosch, Rosa; Mora, Alba; Vicente, Eva Puy; Ferrer, Gerardo; Jansà, Sonia; Damle, Rajendra; Gorlatov, Sergey; Rai, Kanti; Montserrat, Emili; Nomdedeu, Josep; Pratcorona, Marta; Blanco, Laura; Saavedra, Silvana; Garrido, Ana; Esquirol, Albert; Garcia, Irene; Granell, Miquel; Martino, Rodrigo; Delgado, Julio; Sierra, Jorge; Chiorazzi, Nicholas; Moreno, Carol

2017-11-01

In normal B-cells, B-cell antigen receptor (BCR) signaling can be negatively regulated by the low-affinity receptor FcγRIIb (CD32b). To better understand the role of FcγRIIb in chronic lymphocytic leukemia (CLL), we correlated its expression on 155 samples from newly-diagnosed Binet A patients with clinical characteristics and outcome. FcγRIIb expression was similar in normal B-cells and leukemic cells, this being heterogenous among patients and within CLL clones. FcγRIIb expression did not correlate with well known prognostic markers [disease stage, serum beta-2 microglobulin (B2M), IGHV mutational status, expression of ZAP-70 and CD38, and cytogenetics] except for a weak concordance with CD49d. Moreover, patients with low FcγRIIb expression (69/155, 44.5%) required therapy earlier than those with high FcγRIIb expression (86/155, 55.5%) (median 151.4 months vs. not reached; p=.071). These results encourage further investigation on the role of FcγRIIb in CLL biology and prognostic significance in larger series of patients.

Post-transcriptional regulation of inducible nitric oxide synthase in chronic lymphocytic leukemia B cells in pro- and antiapoptotic culture conditions.

PubMed

Tiscornia, A C; Cayota, A; Landoni, A I; Brito, C; Oppezzo, P; Vuillier, F; Robello, C; Dighiero, G; Gabús, R; Pritsch, O

2004-01-01

Functional inducible NOS (iNOS) may be involved in the prolonged lifespan of chronic lymphocytic leukemia cells (B-CLL), although the exact mechanisms implicated remain elusive as yet. In this work, we have examined iNOS expression in normal B lymphocytes and B-CLL cells in pro- and antiapoptotic conditions. Our results demonstrate: (1) The existence of a new splice variant characterized by a complete deletion of exon 14 (iNOS 13-16(14del)), which was preferentially detected in normal B lymphocytes and may represent an isoform that could play a role in the regulation of enzyme activity. (2) The existence of another alternatively spliced iNOS mRNA transcript involving a partial deletion of the flavodoxin region (iNOS 13-16(neg)) was correlated to a decreased B-CLL cell viability. The 9-beta-D-arabinofuranosyl-2-fluoradenine or fludarabine (F-ara) treatment induced iNOS 13-16(neg) transcript variants, whereas IL-4 enhanced both the transcription of variants, including these exons (iNOS 13-16(pos)), and the expression of a 122 kDa iNOS protein. These results suggest that in B-CLL, a regulation process involving nitric oxide (.- NO) levels could occur by a post-transcriptional mechanism mediated by soluble factors. Our results also provide an insight into a new complementary proapoptotic action of F-ara in B-CLL by the induction of particular iNOS splice variants, leading to the activation of a caspase-3-dependent apoptotic pathway.

Bruton tyrosine kinase inhibition in chronic lymphocytic leukemia.

PubMed

Maddocks, Kami; Jones, Jeffrey A

2016-04-01

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia and remains incurable outside of the setting of allogeneic stem cell transplant. While the standard therapy for both initial and relapsed CLL has traditionally included monoclonal antibody therapy in combination with chemotherapy, there are patients with high-risk disease features including unmutated IgVH, del(11q22) and del(17p13) that are associated with poor overall responses to these therapies with short time to relapse and shortened overall survival. Additionally, many of these therapies have a high rate of infectious toxicity in a population already at increased risk. Targeting the B-cell receptor (BCR) signaling pathway has emerged as a promising therapeutic advance in a variety of B-cell malignancies, including CLL. Bruton agammaglobulinemia tyrosine kinase (Btk) is a tyrosine kinase in the BCR pathway critical to the survival of both normal and malignant B cells and inhibition of this kinase has shown to block the progression of CLL. Ibrutinib, a first in class oral inhibitor of Btk, has shown promise as a very effective agent in the treatment of CLL-in both relapsed and upfront therapy, alone and in combination with other therapies, and in patients of all-risk disease-which has led to its approval in relapsed CLL and as frontline therapy in patients with the high-risk del(17p13) disease. Several studies are ongoing to evaluate the efficacy and safety of ibrutinib in combination with chemotherapy as frontline treatment for CLL and investigation into newer-generation Btk inhibitors is also underway. Copyright © 2016 Elsevier Inc. All rights reserved.

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

The clinical safety of ibrutinib in chronic lymphocytic leukemia.

PubMed

Molica, Stefano

2015-10-01

Ibrutinib , a targeted inhibitor of B-cell receptor signaling, achieved impressive clinical results for patients with chronic lymphocytic leukemia (CLL). These results allowed the approval of ibrutinib for the treatment of patients with CLL who have received at least one prior therapy and those with a 17p deletion regardless of line of therapy. Comprehensive data from either Phase I-II or randomized Phase III studies are analyzed in this article. In addition, we reviewed data on the prevalence and the clinical management of some peculiar toxicities ibrutinib related such as lymphocytosis, major bleeding and atrial fibrillation. Ibrutinib has radically changed the scenery of relapsed/refractory CLL treatment and established an important paradigm in the molecularly targeted approach of this disease. Discontinuation of ibrutinib is rarely due to adverse events related to the drug. Patients who discontinue treatment represent a challenge to the physicians because treatment options are very limited.

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

PubMed

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

2017-08-10

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

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

2017-10-23

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

Competitive Transfer of αCD19-TCRz-CD28 and αCD19-TCRz-CD137 CAR-T Cells for B-cell Leukemia/Lymphoma

ClinicalTrials.gov

2017-03-14

Hematopoietic/Lymphoid Cancer; Adult Acute Lymphoblastic Leukemia in Remission; B-cell Adult Acute Lymphoblastic Leukemia; B-cell Chronic Lymphocytic Leukemia; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Refractory Chronic Lymphocytic Leukemia; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Chronic Lymphocytic Leukemia; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Chronic Lymphocytic Leukemia; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma

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. Copyright © 2016 Elsevier Inc. All rights reserved.

Ibrutinib synergizes with MDM-2 inhibitors in promoting cytotoxicity in B chronic lymphocytic leukemia.

PubMed

Voltan, Rebecca; Rimondi, Erika; Melloni, Elisabetta; Rigolin, Gian Matteo; Casciano, Fabio; Arcidiacono, Maria Vittoria; Celeghini, Claudio; Cuneo, Antonio; Zauli, Giorgio; Secchiero, Paola

2016-10-25

The aim of this study was to investigate the anti-leukemic activity of the Bruton tyrosine kinase inhibitor Ibrutinib in combination with the small molecule MDM-2 inhibitor Nutlin-3 in preclinical models. The potential efficacy of the Ibrutinib/Nutlin-3 combination was evaluated in vitro in a panel of B leukemic cell lines (EHEB, JVM-2, JVM-3, MEC-1, MEC-2) and in primary B-chronic lymphocytic leukemia (B-CLL) patient samples, by assessing cell viability, cell cycle profile, apoptosis and intracellular pathway modulations. Validation of the combination therapy was assessed in a B leukemic xenograft mouse model. Ibrutinib exhibited variable anti-leukemic activity in vitro and the combination with Nutlin-3 synergistically enhanced the induction of apoptosis independently from the p53 status. Indeed, the Ibrutinib/Nutlin-3 combination was effective in promoting cytotoxicity also in primary B-CLL samples carrying 17p13 deletion and/or TP53 mutations, already in therapy with Ibrutinib. Molecular analyses performed on both B-leukemic cell lines as well as on primary B-CLL samples, while confirming the switch-off of the MAPK and PI3K pro-survival pathways by Ibrutinib, indicated that the synergism of action with Nutlin-3 was independent by p53 pathway and was accompanied by the activation of the DNA damage cascade signaling through the phosphorylation of the histone protein H2A.X. This observation was confirmed also in the JVM-2 B leukemic xenograft mouse model. Taken together, our data emphasize that the Ibrutinib/Nutlin-3 combination merits to be further evaluated as a therapeutic option for B-CLL.

Ibrutinib synergizes with MDM-2 inhibitors in promoting cytotoxicity in B chronic lymphocytic leukemia

PubMed Central

Melloni, Elisabetta; Rigolin, Gian Matteo; Casciano, Fabio; Arcidiacono, Maria Vittoria; Celeghini, Claudio; Cuneo, Antonio; Zauli, Giorgio; Secchiero, Paola

2016-01-01

Objective The aim of this study was to investigate the anti-leukemic activity of the Bruton tyrosine kinase inhibitor Ibrutinib in combination with the small molecule MDM-2 inhibitor Nutlin-3 in preclinical models. Methods The potential efficacy of the Ibrutinib/Nutlin-3 combination was evaluated in vitro in a panel of B leukemic cell lines (EHEB, JVM-2, JVM-3, MEC-1, MEC-2) and in primary B-chronic lymphocytic leukemia (B-CLL) patient samples, by assessing cell viability, cell cycle profile, apoptosis and intracellular pathway modulations. Validation of the combination therapy was assessed in a B leukemic xenograft mouse model. Results Ibrutinib exhibited variable anti-leukemic activity in vitro and the combination with Nutlin-3 synergistically enhanced the induction of apoptosis independently from the p53 status. Indeed, the Ibrutinib/Nutlin-3 combination was effective in promoting cytotoxicity also in primary B-CLL samples carrying 17p13 deletion and/or TP53 mutations, already in therapy with Ibrutinib. Molecular analyses performed on both B-leukemic cell lines as well as on primary B-CLL samples, while confirming the switch-off of the MAPK and PI3K pro-survival pathways by Ibrutinib, indicated that the synergism of action with Nutlin-3 was independent by p53 pathway and was accompanied by the activation of the DNA damage cascade signaling through the phosphorylation of the histone protein H2A.X. This observation was confirmed also in the JVM-2 B leukemic xenograft mouse model. Conclusions Taken together, our data emphasize that the Ibrutinib/Nutlin-3 combination merits to be further evaluated as a therapeutic option for B-CLL. PMID:27661115

Chromosome aberrations detected by conventional karyotyping using novel mitogens in chronic lymphocytic leukemia with "normal" FISH: correlations with clinicobiologic parameters.

PubMed

Rigolin, Gian Matteo; Cibien, Francesca; Martinelli, Sara; Formigaro, Luca; Rizzotto, Lara; Tammiso, Elisa; Saccenti, Elena; Bardi, Antonella; Cavazzini, Francesco; Ciccone, Maria; Nichele, Ilaria; Pizzolo, Giovanni; Zaja, Francesco; Fanin, Renato; Galieni, Piero; Dalsass, Alessia; Mestichelli, Francesca; Testa, Nicoletta; Negrini, Massimo; Cuneo, Antonio

2012-03-08

It is unclear whether karyotype aberrations that occur in regions uncovered by the standard fluorescence in situ hybridization (FISH) panel have prognostic relevance in chronic lymphocytic leukemia (CLL). We evaluated the significance of karyotypic aberrations in a learning cohort (LC; n = 64) and a validation cohort (VC; n = 84) of patients with chronic lymphocytic leukemia with "normal" FISH. An abnormal karyotype was found in 21.5% and 35.7% of cases in the LC and VC, respectively, and was associated with a lower immunophenotypic score (P = .030 in the LC, P = .035 in the VC), advanced stage (P = .040 in the VC), and need for treatment (P = .002 in the LC, P = < .0001 in the VC). The abnormal karyotype correlated with shorter time to first treatment and shorter survival in both the LC and the VC, representing the strongest prognostic parameter. In patients with chronic lymphocytic leukemia with normal FISH, karyotypic aberrations by conventional cytogenetics with novel mitogens identify a subset of cases with adverse prognostic features.

Venetoclax-Rituximab in Relapsed or Refractory Chronic Lymphocytic Leukemia.

PubMed

Seymour, John F; Kipps, Thomas J; Eichhorst, Barbara; Hillmen, Peter; D'Rozario, James; Assouline, Sarit; Owen, Carolyn; Gerecitano, John; Robak, Tadeusz; De la Serna, Javier; Jaeger, Ulrich; Cartron, Guillaume; Montillo, Marco; Humerickhouse, Rod; Punnoose, Elizabeth A; Li, Yan; Boyer, Michelle; Humphrey, Kathryn; Mobasher, Mehrdad; Kater, Arnon P

2018-03-22

Venetoclax inhibits BCL2, an antiapoptotic protein that is pathologically overexpressed and that is central to the survival of chronic lymphocytic leukemia cells. We evaluated the efficacy of venetoclax in combination with rituximab in patients with relapsed or refractory chronic lymphocytic leukemia. In this randomized, open-label, phase 3 trial, we randomly assigned 389 patients to receive venetoclax for up to 2 years (from day 1 of cycle 1) plus rituximab for the first 6 months (venetoclax-rituximab group) or bendamustine plus rituximab for 6 months (bendamustine-rituximab group). The trial design did not include crossover to venetoclax plus rituximab for patients in the bendamustine-rituximab group in whom progression occurred. The primary end point was investigator-assessed progression-free survival. After a median follow-up period of 23.8 months, the rate of investigator-assessed progression-free survival was significantly higher in the venetoclax-rituximab group (32 events of progression or death in 194 patients) than in the bendamustine-rituximab group (114 events in 195 patients); the 2-year rates of progression-free survival were 84.9% and 36.3%, respectively (hazard ratio for progression or death, 0.17; 95% confidence interval [CI], 0.11 to 0.25; P<0.001 by the stratified log-rank test). The benefit was maintained across all clinical and biologic subgroups, including the subgroup of patients with chromosome 17p deletion; the 2-year rate of progression-free survival among patients with chromosome 17p deletion was 81.5% in the venetoclax-rituximab group versus 27.8% in the bendamustine-rituximab group (hazard ratio, 0.13; 95% CI, 0.05 to 0.29), and the 2-year rate among those without chromosome 17p deletion was 85.9% versus 41.0% (hazard ratio, 0.19; 95% CI, 0.12 to 0.32). The benefit of venetoclax plus rituximab over bendamustine plus rituximab was confirmed by an independent review committee assessment of progression-free survival and other secondary

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

ClinicalTrials.gov

2014-08-04

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

Update on signal inhibitors in chronic lymphocytic leukemia.

PubMed

Boddu, Prajwal; Jain, Nitin

2018-04-01

The last decade has seen major progress in our understanding of the pathobiology of chronic lymphocytic leukemia (CLL) and the identification of potential new therapeutic targets. As a result, researchers have developed novel targeted therapies, several of which are already approved and many of which are in advanced stages of clinical development. These new agents are much less toxic than chemoimmunotherapy and may be preferred for their superior efficacy in patients with certain high-risk features, such as del(17p). The place of these therapies in CLL management is becoming better defined, and they are gradually replacing traditional forms of chemoimmunotherapy. This review provides an update on the clinical data regarding various signal transduction inhibitors in CLL.

Immunoglobulin heavy chain V-D-J gene rearrangement and mutational status in Uruguayan patients with chronic lymphocytic leukemia.

PubMed

Bianchi, Sergio; Moreno, Pilar; Landoni, Ana Inés; Naya, Hugo; Oppezzo, Pablo; Dighiero, Guillermo; Gabús, Raúl; Pritsch, Otto

2010-11-01

B-cell chronic lymphocytic leukemia (CLL) is characterized by the accumulation of long-lived circulating clonal leukemic B-cells, although the etiopathogenesis remains unclear. The incidence of CLL is variable in different regions around the world. While it is the most frequent chronic leukemia in Western countries, it has a low incidence in Asia. In this work we have investigated the immunoglobulin heavy chain gene rearrangements and mutational status in 80 Uruguayan patients with CLL, and compared these results with those obtained in other geographic regions. Our results demonstrate that Uruguayan patients with CLL display an IGHV gene usage which resembles that observed in Mediterranean countries and exhibits certain differences compared with Brazilian and Asian series, as expected, considering the ethnic basis of the Uruguayan population. This suggests that genetic influences could be important in the development and etiopathogenesis of CLL, but larger studies are necessary to substantiate this possibility.

Targeting BTK with Ibrutinib in Relapsed Chronic Lymphocytic Leukemia

PubMed Central

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

2013-01-01

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

Immunological changes with kinase inhibitor therapy for chronic lymphocytic leukemia.

PubMed

Pleyer, Christopher; Wiestner, Adrian; Sun, Clare

2018-05-15

Ibrutinib and idelalisib are kinase inhibitors that have revolutionized the treatment of chronic lymphocytic leukemia (CLL). Capable of inducing durable remissions, these agents also modulate the immune system. Both ibrutinib and idelalisib abrogate the tumor-supporting microenvironment by disrupting cell-cell interactions, modulating the T-cell compartment, and altering the cytokine milieu. Ibrutinib also partially restores T-cell and myeloid defects associated with CLL. In contrast, immune-related adverse effects, including pneumonitis, colitis, hepatotoxicity, and infections are of particular concern with idelalisib. While opportunistic infections and viral reactivations occur with both ibrutinib and idelalisib, these complications are less common and less severe with ibrutinib, especially when used as monotherapy without additional immunosuppressive agents. This review discusses the impact of ibrutinib and idelalisib on the immune system, including infectious and auto-immune complications as well as their specific effects on the B-cell, T-cell, and myeloid compartment.

Chronic lymphocytic leukemia and infection risk in the era of targeted therapies: Linking mechanisms with infections.

PubMed

Hilal, Talal; Gea Banacloche, Juan C; Leis, Jose F

2018-03-16

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the world. Patient with CLL are at particular risk for infections due to inherent disease-related immune dysfunction in addition to the effect of certain systemic therapies on the immune system. The advent of B-cell receptor (BCR) inhibitors such as ibrutinib and idelalisib has led to a practice change that utilizes these targeted agents in the treatment of CLL, either in place of chemoimmunotherapy (CIT) or in later line settings. In this paper, we review the pathophysiology of immune dysfunction in CLL, the spectrum of immunodeficiency with the various therapeutic agents along with prevention strategies with a focus on targeted therapies. Copyright © 2018 Elsevier Ltd. All rights reserved.

Signal Transduction in the Chronic Leukemias: Implications for Targeted Therapies

PubMed Central

Ahmed, Wesam; Van Etten, Richard A.

2013-01-01

The chronic leukemias, including chronic myeloid leukemia (CML), the Philadelphia-negative myeloproliferative neoplasms (MPNs), and chronic lymphocytic leukemia (CLL), have been characterized extensively for abnormalities of cellular signaling pathways. This effort has led to the elucidation of the central role of dysregulated tyrosine kinase signaling in the chronic myeloid neoplasms and of constitutive B-cell receptor signaling in CLL. This, in turn, has stimulated the development of small molecule inhibitors of these signaling pathways for therapy of chronic leukemia. Although the field is still in its infancy, the clinical results with these agents have ranged from encouraging (CLL) to spectacular (CML). In this review, we summarize recent studies that have helped to define the signaling pathways critical to the pathogenesis of the chronic leukemias. We also discuss correlative studies emerging from clinical trials of drugs targeting these pathways. PMID:23307472

Venetoclax for the treatment of chronic lymphocytic leukemia.

PubMed

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

2017-11-01

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

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

PubMed

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

2016-12-01

Chronic lymphocytic leukemia is a disease of the elderly, and despite major advances in treatment, remains incurable. The Cancer Registry of Norway has registered data on patients with chronic lymphocytic leukemia since 1953. We aimed to analyze trends in incidence and survival of chronic lymphocytic leukemia in Norway. We identified 7664 patients reported with chronic lymphocytic leukemia to the registry between 1953 and 2012. We gathered information on sex, age at diagnosis, date of death and basis for diagnosis. The age-standardized incidence increased from 0.6/100.000 person-years in 1953 to 3.1/100,000 person-years in 2012. We found a significant decrease in median age between 1993-2002 and 2003-2012 (75 vs. 72 years, 95%CI: 2.52-3.98, P < 0.001). Men were diagnosed at a significantly younger age than women. Immunophenotyping has become the most important diagnostic method after 2002. Median observed survival increased from 3 years in 1952-1963 to 8.5 years in 2003-2012. Five- and 10-year age-standardized net survival increased throughout the whole period across age groups and reached 79% and 57%, respectively. Median observed survival was significantly shorter in men than in women in 1993-2002 (4.9 vs. 6.1 years, P < 0.001). The gap between survival rates for men and women was diminishing in 2003-2012 in patients younger than 60 years while it remained considerable in older patients. Despite an aging Norwegian population, chronic lymphocytic leukemia (CLL) patients become younger at diagnosis. A fourfold increase in incidence, a prolonged survival, and major changes in diagnostic methods in Norway were observed. © 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Development of acute myeloid leukemia in patients with untreated chronic lymphocytic leukemia.

PubMed

Ito, Shoko; Fujiwara, Shin-Ichiro; Mashima, Kiyomi; Umino, Kento; Minakata, Daisuke; Nakano, Hirofumi; Yamasaki, Ryoko; Kawasaki, Yasufumi; Sugimoto, Miyuki; Ashizawa, Masahiro; Yamamoto, Chihiro; Hatano, Kaoru; Okazuka, Kiyoshi; Sato, Kazuya; Oh, Iekuni; Ohmine, Ken; Suzuki, Takahiro; Muroi, Kazuo; Kanda, Yoshinobu

2017-05-01

The development of acute myeloid leukemia (AML) in patients with untreated chronic lymphocytic leukemia (CLL) is rare. We experienced a 65-year-old man who developed AML with aberrant CD7 expression and monoallelic CEBPA mutation during watchful waiting for CLL. He failed to achieve complete response (CR) by standard induction therapy for AML. We retrospectively reviewed 27 patients who developed AML with untreated CLL published between 1973 and 2016. The median age at diagnosis of AML was 68 years, and the median duration between the diagnoses of AML and CLL was 4.2 years. Diagnosis of AML and CLL was made simultaneously in 16 patients. The CR rate of AML was 42.9%, and the median survival was only 1.5 months after the diagnosis of AML. Patients who achieved CR tended to survive longer than those who did not. Our results demonstrated that the development of AML in patients with untreated CLL was associated with a poor response to chemotherapy and an extremely poor prognosis.

Novel role of prostate apoptosis response-4 tumor suppressor in B-cell chronic lymphocytic leukemia.

PubMed

McKenna, Mary K; Noothi, Sunil K; Alhakeem, Sara S; Oben, Karine Z; Greene, Joseph T; Mani, Rajeswaran; Perry, Kathryn L; Collard, James P; Rivas, Jacqueline R; Hildebrandt, Gerhard; Fleischman, Roger; Durbin, Eric B; Byrd, John C; Wang, Chi; Muthusamy, Natarajan; Rangnekar, Vivek M; Bondada, Subbarao

2018-04-25

Prostate apoptosis response-4 (Par-4), a pro-apoptotic tumor suppressor protein, is down regulated in many cancers including renal cell carcinoma, glioblastoma, endometrial and breast cancer. Par-4 induces apoptosis selectively in various types of cancer cells but not normal cells. We found that chronic lymphocytic leukemia (CLL) cells from human patients and from the Eµ-Tcl1 mice constitutively express Par-4 in greater amounts than normal B-1 or B-2 cells. Interestingly, knockdown of Par-4 in human CLL derived Mec-1 cells results in a robust increase in p21/WAF1 expression and decreased growth due to delayed G1 to S cell cycle transition. Lack of Par-4 also increased the expression of p21 and delayed CLL growth in Eμ-Tcl1 mice. Par-4 expression in CLL cells required constitutively active B-cell receptor (BCR) signaling, as inhibition of BCR signaling with FDA approved drugs caused a decrease in Par-4 mRNA and protein, and an increase in apoptosis. In particular, activities of Lyn, a Src family kinase, spleen tyrosine kinase and Bruton's tyrosine kinase are required for Par-4 expression in CLL cells, suggesting a novel regulation of Par-4 through BCR signaling. Together, these results suggest that Par-4 may play a novel pro-growth rather than pro-apoptotic role in CLL and could be targeted to enhance the therapeutic effects of BCR signaling inhibitors. Copyright © 2018 American Society of Hematology.

Identification of three subgroups of B cell chronic lymphocytic leukemia based upon mutations of BCL-6 and IgV genes.

PubMed

Capello, D; Fais, F; Vivenza, D; Migliaretti, G; Chiorazzi, N; Gaidano, G; Ferrarini, M

2000-05-01

Although B cell chronic lymphocytic leukemia (B-CLL) has been traditionally viewed as a tumor of virgin B cells, this notion has been recently questioned by data suggesting that a fraction of B-CLL derives from antigen experienced B cells. In order to further clarify the histogenetic derivation of this lymphoproliferation, we have analyzed the DNA sequences of the 5' non-coding region of BCL-6 proto-oncogene in 28 cases of B-CLL. Mutations of BCL-6 proto-oncogene, a zinc finger transcription factor implicated in lymphoma development, represent a histogenetic marker of B cell transit through the germinal center (GC) and occur frequently in B cell malignancies derived from GC or post-GC B cells. For comparison, the same tumor panel was analyzed for somatic mutations of the rearranged immunoglobulin variable (IgV) genes, which are known to be acquired at the time of B cell transit through the GC. Sequence analyses of BCL-6 and IgV genes allowed the definition of three groups of B-CLL. Group I B-CLL displayed mutations of both BCL-6 and IgV genes (10/28; 36%). Group II B-CLL displayed mutated IgV genes, but a germline BCL-6 gene (5/28; 18%). Finally, group III B-CLL included the remaining cases (13/28; 46%) that were characterized by the absence of somatic mutations of both BCL-6 and IgV genes. Overall, the distribution of BCL-6 and IgV mutations in B-CLL reinforce the notion that this leukemia is histogenetically heterogeneous and that a substantial subgroup of these lymphoproliferations derives from post-germinal center B cells.

Enhanced CDC of B cell chronic lymphocytic leukemia cells mediated by rituximab combined with a novel anti-complement factor H antibody.

PubMed

Winkler, Mark T; Bushey, Ryan T; Gottlin, Elizabeth B; Campa, Michael J; Guadalupe, Eross S; Volkheimer, Alicia D; Weinberg, J Brice; Patz, Edward F

2017-01-01

Rituximab therapy for B cell chronic lymphocytic leukemia (B-CLL) has met with mixed success. Among several factors to which resistance can be attributed is failure to activate complement dependent cytotoxicity (CDC) due to protective complement regulatory proteins, including the soluble regulator complement factor H (CFH). We hypothesized that rituximab killing of non-responsive B-CLL cells could be augmented by a novel human monoclonal antibody against CFH. The B cells from 11 patients with B-CLL were tested ex vivo in CDC assays with combinations of CFH monoclonal antibody, rituximab, and a negative control antibody. CDC of rituximab non-responsive malignant B cells from CLL patients could in some cases be augmented by the CFH monoclonal antibody. Antibody-mediated cytotoxicity of cells was dependent upon functional complement. In one case where B-CLL cells were refractory to CDC by the combination of rituximab plus CFH monoclonal antibody, additionally neutralizing the membrane complement regulatory protein CD59 allowed CDC to occur. Inhibiting CDC regulatory proteins such as CFH holds promise for overcoming resistance to rituximab therapy in B-CLL.

Murine genetically engineered and human xenograft models of chronic lymphocytic leukemia.

PubMed

Chen, Shih-Shih; Chiorazzi, Nicholas

2014-07-01

Chronic lymphocytic leukemia (CLL) is a genetically complex disease, with multiple factors having an impact on onset, progression, and response to therapy. Genetic differences/abnormalities have been found in hematopoietic stem cells from patients, as well as in B lymphocytes of individuals with monoclonal B-cell lymphocytosis who may develop the disease. Furthermore, after the onset of CLL, additional genetic alterations occur over time, often causing disease worsening and altering patient outcomes. Therefore, being able to genetically engineer mouse models that mimic CLL or at least certain aspects of the disease will help us understand disease mechanisms and improve treatments. This notwithstanding, because neither the genetic aberrations responsible for leukemogenesis and progression nor the promoting factors that support these are likely identical in character or influences for all patients, genetically engineered mouse models will only completely mimic CLL when all of these factors are precisely defined. In addition, multiple genetically engineered models may be required because of the heterogeneity in susceptibility genes among patients that can have an effect on genetic and environmental characteristics influencing disease development and outcome. For these reasons, we review the major murine genetically engineered and human xenograft models in use at the present time, aiming to report the advantages and disadvantages of each. Copyright © 2014 Elsevier Inc. All rights reserved.

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. Copyright© Ferrata Storti Foundation.

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. Copyright © 2016 Elsevier Inc. All rights reserved.

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

Recurrent skin eruption in patient with chronic lymphocytic leukemia and lymphocytic infiltrates of the dermis resembling Sweet's syndrome.

PubMed

Wawrzycki, B; Chodorowska, G; Pietrzak, A; Krasowska, D W; Wąsik, Sz; Dybiec, E; Lotti, T; Hercegova, J

2011-12-01

Sweet's syndrome (acute febrile dermatosis) is characterized by fever, peripheral neutrophil leukocytosis, acute onset of tender erythematous skin lesions (papules, nodules or plaques), and histological findings of a dense infiltrate consisting predominantly of mature neutrophils. Malignancy-associated Sweet's syndrome constitutes approximately 21% of patients, the majority of whom suffer from hematologic disorder. We report the case of patient with chronic lymphocytic leukemia with recurrent eruptions of tender, pseudovesiculated nodules and plaques with good response to corticosteroid therapy, resembling Sweet's syndrome. However, histological examination revealed lymphocytic infiltrate in the dermis, which made impossible to establish diagnosis of acute febrile dermatosis according to diagnostic criteria. Association of the skin eruptions with leukemia was implied by improvement of skin lesions after chemotherapy. We present review of the literature reporting cases with atypical histopathological presentations which preceded classical histological appearances, that were mainly associated with hematological malignancies and discuss them in the context of our patient.

Is chronic lymphocytic leukemia a contraindication for radon and thermotherapy?--a case report.

PubMed

Falkenbach, A; Jäger, U

2001-01-15

A growing number of patients presenting for radon-thermotherapy have a history of malignant disease. The question as to whether malignancies in general are a contraindication for radon treatment or mild hyperthermia during spa therapy is still a subject of controversy. We report a patient with osteoarthritis and a frozen shoulder who repeatedly underwent speleotherapeutic radon and hyperthermia treatment in the gallery of the Gasteiner Heilstollen, Austria, despite concomitant chronic lymphocytic leukemia (B-CLL, Rai stage 0). After nine courses of radon-thermotherapy over eight years, no apparent negative impact on CLL was noted. The purpose of this case report is to encourage discussion as to whether CLL or other past or present malignancies must be considered a contraindication for spa treatment such as radon-thermotherapy.

A novel adoptive transfer model of chronic lymphocytic leukemia suggests a key role for T lymphocytes in the disease

PubMed Central

Bagnara, Davide; Kaufman, Matthew S.; Calissano, Carlo; Marsilio, Sonia; Patten, Piers E. M.; Simone, Rita; Chum, Philip; Yan, Xiao-Jie; Allen, Steven L.; Kolitz, Jonathan E.; Baskar, Sivasubramanian; Rader, Christoph; Mellstedt, Hakan; Rabbani, Hodjattallah; Lee, Annette; Gregersen, Peter K.; Rai, Kanti R.

2011-01-01

Chronic lymphocytic leukemia (CLL) is an incurable adult disease of unknown etiology. Understanding the biology of CLL cells, particularly cell maturation and growth in vivo, has been impeded by lack of a reproducible adoptive transfer model. We report a simple, reproducible system in which primary CLL cells proliferate in nonobese diabetes/severe combined immunodeficiency/γcnull mice under the influence of activated CLL-derived T lymphocytes. By cotransferring autologous T lymphocytes, activated in vivo by alloantigens, the survival and growth of primary CFSE-labeled CLL cells in vivo is achieved and quantified. Using this approach, we have identified key roles for CD4+ T cells in CLL expansion, a direct link between CD38 expression by leukemic B cells and their activation, and support for CLL cells preferentially proliferating in secondary lymphoid tissues. The model should simplify analyzing kinetics of CLL cells in vivo, deciphering involvement of nonleukemic elements and nongenetic factors promoting CLL cell growth, identifying and characterizing potential leukemic stem cells, and permitting preclinical studies of novel therapeutics. Because autologous activated T lymphocytes are 2-edged swords, generating unwanted graph-versus-host and possibly autologous antitumor reactions, the model may also facilitate analyses of T-cell populations involved in immune surveillance relevant to hematopoietic transplantation and tumor cytoxicity. PMID:21385850

Tumor Lysis Syndrome in Chronic Lymphocytic Leukemia with Novel Targeted Agents.

PubMed

Cheson, Bruce D; Heitner Enschede, Sari; Cerri, Elisa; Desai, Monali; Potluri, Jalaja; Lamanna, Nicole; Tam, Constantine

2017-11-01

Tumor lysis syndrome (TLS) is an uncommon but potentially life-threatening complication associated with the treatment of some cancers. If left untreated, TLS may result in acute renal failure, cardiac dysrhythmia, neurologic complications, seizures, or death. Tumor lysis syndrome is most commonly observed in patients with hematologic malignancies with a high proliferation rate undergoing treatment with very effective therapies. In chronic lymphocytic leukemia (CLL), historically, TLS has been observed less often, owing to a low proliferation rate and slow response to chemotherapy. New targeted therapies have recently been approved in the treatment of CLL, including the oral kinase inhibitors, idelalisib and ibrutinib, and the B-cell lymphoma-2 protein inhibitor, venetoclax. Several others are also under development, and combination strategies of these agents are being explored. This review examines the diagnosis, prevention, and management of TLS and summarizes the TLS experience in CLL clinical trials with newer targeted agents. Overall, the risk of TLS is small, but the consequences may be fatal; therefore, patients should be monitored carefully. Therapies capable of eliciting rapid response and combination regimens are increasingly being evaluated for treatment of CLL, which may pose a higher risk of TLS. For optimal management, patients at risk for TLS require prophylaxis and close monitoring with appropriate tests and appropriate management to correct laboratory abnormalities, which allows for safe and effective disease control. Tumor lysis syndrome (TLS) is a potentially fatal condition observed with hematologic malignancies, caused by release of cellular components in the bloodstream from rapidly dying tumor cells. The frequency and severity of TLS is partly dependent upon the biology of the disease and type of therapy administered. Novel targeted agents highly effective at inducing rapid cell death in chronic lymphocytic leukemia (CLL) may pose a risk for

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

PubMed

Okamoto, Koh; 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.

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

PubMed Central

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

2016-01-01

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

Simultaneous presence of two hematological malignancies: chronic lymphocytic leukemia and myelofibrosis in a patient.

PubMed

Palta, Anshu; Garg, Shailja; Chauhan, Sandeep; Varma, Neelam

2011-03-01

Coexistence of chronic lymphocytic leukemia (CLL) with myelofibrosis is a rare association with only isolated case reports in the literature. We report an unusual case of CLL in which the cause of anemia was coexistent myelofibrosis. In a case of CLL presenting with refractory anemia, besides common causes like autoimmune hemolytic anemia and marrow infiltration, other causes like myelofibrosis should be searched for.

Igs expressed by chronic lymphocytic leukemia B cells show limited binding-site structure variability.

PubMed

Marcatili, Paolo; Ghiotto, Fabio; Tenca, Claudya; Chailyan, Anna; Mazzarello, Andrea N; Yan, Xiao-Jie; Colombo, Monica; Albesiano, Emilia; Bagnara, Davide; Cutrona, Giovanna; Morabito, Fortunato; Bruno, Silvia; Ferrarini, Manlio; Chiorazzi, Nicholas; Tramontano, Anna; Fais, Franco

2013-06-01

Ag selection has been suggested to play a role in chronic lymphocytic leukemia (CLL) pathogenesis, but no large-scale analysis has been performed so far on the structure of the Ag-binding sites (ABSs) of leukemic cell Igs. We sequenced both H and L chain V(D)J rearrangements from 366 CLL patients and modeled their three-dimensional structures. The resulting ABS structures were clustered into a small number of discrete sets, each containing ABSs with similar shapes and physicochemical properties. This structural classification correlates well with other known prognostic factors such as Ig mutation status and recurrent (stereotyped) receptors, but it shows a better prognostic value, at least in the case of one structural cluster for which clinical data were available. These findings suggest, for the first time, to our knowledge, on the basis of a structural analysis of the Ab-binding sites, that selection by a finite quota of antigenic structures operates on most CLL cases, whether mutated or unmutated.

Diagnosis, treatment, and nursing care of patients with chronic leukemia.

PubMed

Breed, Cheryl D

2003-05-01

To provide an update on the impact of new information about the molecular biology of chronic leukemia and new treatment modalities available to patients. Published articles, books, and research studies. There has been significant progress in the diagnosis and management of chronic myeloid and chronic lymphocytic leukemia. New therapies provide more options for patients and longer treatment periods. With increasing treatment options and longer survival, patients with chronic myelogenous or chronic lymphocytic leukemia need increased education, support, and assistance with symptom management. Nurses caring for these patients must remain knowledgeable about new treatments and their management.

Concurrent chronic lymphocytic leukemia cutis and acute myelogenous leukemia cutis in a patient with untreated CLL.

PubMed

Miller, M K; Strauchen, J A; Nichols, K T; Phelps, R G

2001-08-01

Patients who have chronic lymphocytic leukemia (CLL) are known to have a high frequency of second malignant neoplasms. However, acute myelogenous leukemia (AML) occurring concurrent with or after a diagnosis of CLL is extremely rare. In this article we report a case of AML developing in a 55-year-old male with a 6-year history of untreated CLL. The diagnosis was facilitated by touch preparation of a skin punch biopsy specimen. The patient presented with a two-week history of fever, weakness, anasarca, and a skin rash. Physical examination revealed pink to skin-colored firm papules, which coalesced into indurated plaques on his trunk, upper extremities, and face. The lesions, in combination with generalized edema, produced a leonine facies. Touch prep of the biopsy showed medium to large blasts, large monocytoid cells, and numerous small mature lymphocytes, providing the preliminary diagnosis of a second, previously undiagnosed myelomonocytic malignancy in this patient. The initial diagnosis was subsequently confirmed by histologic, cytochemical, immunohistochemical and flow cytometry studies. This is the first reported case of CLL with concurrent AML in which rapid touch prep of a skin punch biopsy facilitated diagnosis.

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.

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

PubMed

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

2014-12-11

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.

Ibrutinib for treatment of chronic lymphocytic leukemia.

PubMed

Vela, Cory M; McBride, Ali; Jaglowski, Samantha M; Andritsos, Leslie A

2016-03-15

The pharmacology, pharmacokinetics, pharmacodynamics, clinical efficacy, and safety of ibrutinib are described. Ibrutinib is a first-in-class oral inhibitor of Bruton tyrosine kinase (BTK) approved for treatment of relapsed chronic lymphocytic leukemia (CLL). Ibrutinib blocks downstream signaling of the B-cell receptor, disrupting stromal microenvironment interactions and B-cell cytokine signaling. BTK inhibition has been shown to be effective in relapsed or refractory CLL. A recent Phase III study evaluated ibrutinib (420 mg daily) versus ofatumumab (consistent with labeling) in relapsed or refractory CLL with a primary endpoint of progression free survival (PFS, n = 391). After a median follow-up period of 9.4 months, a PFS was not attained in ibrutinib-treated individuals with and without deletion 17p. In contrast, ofatumumab-treated individuals experienced a PFS of 8.1 months and those with deletion 17p experienced a PFS of 5.8 months. Major hemorrhage was reported in 2 (1%) patients treated with ibrutinib, and a total of 8 (4%) patients discontinued treatment due to toxicity or adverse reactions. Partial response or partial response with lymphocytosis was achieved in 63% of ibrutinib-treated individuals as determined by independent assessments. Overall, ibrutinib reduced the rate of mortality by 57%. Ibrutinib is a first-in-class, orally active, irreversible BTK inhibitor with a novel mechanism of action. This unique mechanism of action and high overall response rates observed in clinical trials make ibrutinib an attractive second-line option in patients who have disease progression while receiving monoclonal antibody therapy or chemoimmunotherapy. Copyright © 2016 by the American Society of Health-System Pharmacists, Inc. All rights reserved.

Receptor tyrosine kinase-like orphan receptor 1 (ROR-1): An emerging target for diagnosis and therapy of chronic lymphocytic leukemia.

PubMed

Aghebati-Maleki, Leili; Shabani, Mahdi; Baradaran, Behzad; Motallebnezhad, Morteza; Majidi, Jafar; Yousefi, Mehdi

2017-04-01

Chronic lymphocytic leukemia (CLL) is characterized by reposition of malignant B cells in the blood, bone marrow, spleen and lymph nodes. It remains the most common leukemia in the Western world. Within the recent years, major breakthroughs have been made to prolong the survival and improve the health of patients. Despite these advances, CLL is still recognized as a disease without definitive cure. New treatment approaches, based on unique targets and novel drugs, are highly desired for CLL therapy. The Identification and subsequent targeting of molecules that are overexpressed uniquely in malignant cells not normal ones play critical roles in the success of anticancer therapeutic strategies. In this regard, ROR family proteins are known as a subgroup of protein kinases which have gained huge popularity in the scientific community for the diagnosis and treatment of different cancer types. ROR1 as an antigen exclusively expressed on the surface of tumor cells can be a target for immunotherapy. ROR-1 targeting using different approaches such as siRNA, tyrosine kinase inhibitors, cell therapy and antibody induces tumor growth suppression in cancer cells. In the current review, we aim to present an overview of the efforts and scientific achievements in targeting ROR family, particularly ROR-1, for the diagnosis and treatment of chronic lymphocytic leukemia (CLL). Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Chronic Lymphocytic Leukemia as an Unusual Cause of Rapid Airway Compromise

PubMed Central

Ezzell, Erin E.; Renshaw, John S.

2017-01-01

Chronic Lymphocytic Leukemia (CLL) is the most prevalent form of non-Hodgkin's lymphoma (NHL) in Western countries predominantly affecting adults over the age of 65. CLL is commonly indolent in nature but can present locally and aggressively at extranodal sites. Although CLL may commonly present with cervical lymphadenopathy, manifestation in nonlymphoid regions of the head and neck is not well described. CLL causing upper airway obstruction is even more uncommon. We describe a case of a patient with known history of CLL and stable lymphocytosis that developed an enlarging lymphoid base of tongue (BOT) mass resulting in rapid airway compromise. PMID:28396813

Metabolism pathways in chronic lymphocytic leukemia

PubMed Central

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

2016-01-01

Alterations in CLL cell metabolism have been studied by several investigators. Unlike normal B lymphocytes or other leukemia cells, CLL cells, like adipocytes, store lipids and utilize free fatty acids (FFA) to produce chemical energy. None of the recently identified mutations in CLL directly affects metabolic pathways, suggesting that genetic alterations do not directly contribute to CLL cells’ metabolic reprogramming. Conversely, recent data suggest that activation of STAT3 or downregulation of microRNA-125 levels plays a crucial role in the utilization of FFA to meet CLL cells’ metabolic needs. STAT3, known to be constitutively activated in CLL, increases the levels of lipoprotein lipase that mediates lipoprotein uptake and shifts CLL cells’ metabolism towards utilization of FFA. Herein we review the evidence for altered lipid metabolism, increased mitochondrial activity, and formation of reactive oxygen species in CLL cells, and discuss possible therapeutic strategies to inhibit lipid metabolism pathways in patient with CLL. PMID:26643954

Locally disordered methylation forms the basis of intratumor methylome variation in chronic lymphocytic leukemia.

PubMed

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

2014-12-08

Intratumoral heterogeneity plays a critical role in tumor evolution. To define the contribution of DNA methylation to heterogeneity within tumors, we performed genome-scale bisulfite sequencing of 104 primary chronic lymphocytic leukemias (CLLs). Compared with 26 normal B cell samples, CLLs consistently displayed higher intrasample variability of DNA methylation patterns across the genome, which appears to arise from stochastically disordered methylation in malignant cells. Transcriptome analysis of bulk and single CLL cells revealed that methylation disorder was linked to low-level expression. Disordered methylation was further associated with adverse clinical outcome. We therefore propose that disordered methylation plays a similar role to that of genetic instability, enhancing the ability of cancer cells to search for superior evolutionary trajectories. Copyright © 2014 Elsevier Inc. All rights reserved.

Ongoing In Vivo Immunoglobulin Class Switch DNA Recombination in Chronic Lymphocytic Leukemia B Cells1

PubMed Central

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

2015-01-01

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 Sμ→Sγ, Sμ→Sα, and Sμ→Sε as well as sequential Sγ→Sα and Sγ→Sε CSR. Similar CLL B cells express transcripts for activation-induced cytidine deaminase, a critical component of the CSR machinery, and contain germline IH-CH and mature VHDJH-CH transcripts encoded by multiple Cγ, Cα, and Cε 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. PMID:12444172

Autologous and allogeneic stem cell transplantations for poor-risk chronic lymphocytic leukemia

PubMed Central

Gribben, John G.; Zahrieh, David; Stephans, Katherine; Bartlett-Pandite, Lini; Alyea, Edwin P.; Fisher, David C.; Freedman, Arnold S.; Mauch, Peter; Schlossman, Robert; Sequist, Lecia V.; Soiffer, Robert J.; Marshall, Blossom; Neuberg, Donna; Ritz, Jerome; Nadler, Lee M.

2005-01-01

We report here on the long-term follow-up on 162 patients with high-risk chronic lymphocytic leukemia (CLL) who have undergone hematopoietic stem cell transplantation (SCT) at a single center from 1989 to 1999. Twenty-five patients with human leukocyte antigen (HLA)-matched sibling donors underwent T-cell-depleted allogeneic SCT, and 137 patients without HLA-matched sibling donors underwent autologous SCT. The 100-day mortality was 4% for both groups, but later morbidity and mortality were negatively affected on outcome. Progression-free survival was significantly longer following autologous than allogeneic SCT, but there was no difference in overall survival and no difference in the cumulative incidence of disease recurrence or deaths without recurrence between the 2 groups. At a median follow-up of 6.5 years there is no evidence of a plateau of progression-free survival. The majority of patients treated with donor lymphocyte infusions after relapse responded, demonstrating a significant graft-versus-leukemia effect in CLL. From these findings we have altered our approach for patients with high-risk CLL and are currently exploring the role of related and unrelated allogeneic SCT following reduced-intensity conditioning regimens. PMID:16131571

Generation of B-cell chronic lymphocytic leukemia (B-CLL)-reactive T-cell lines and clones from HLA class I-matched donors using modified B-CLL cells as stimulators: implications for adoptive immunotherapy.

PubMed

Hoogendoorn, M; Wolbers, J Olde; Smit, W M; Schaafsma, M R; Barge, R M Y; Willemze, R; Falkenburg, J H F

2004-07-01

Allogeneic stem cell transplantation following reduced-intensity conditioning is being evaluated in patients with advanced B-cell chronic lymphocytic leukemia (B-CLL). The curative potential of this procedure is mediated by donor-derived alloreactive T cells, resulting in a graft-versus-leukemia effect. However, B-CLL may escape T-cell-mediated immune reactivity since these cells lack expression of costimulatory molecules. We examined the most optimal method to transform B-CLL cells into efficient antigen-presenting cells (APC) using activating cytokines, by triggering toll-like receptors (TLRs) using microbial pathogens and by CD40 stimulation with CD40L-transfected fibroblasts. CD40 activation in the presence of IL-4 induced strongest upregulation of costimulatory and adhesion molecules on B-CLL cells and induced the production of high amounts of IL-12 by the leukemic cells. In contrast to primary B-CLL cells as stimulator cells, these malignant APCs were capable of inducing the generation of B-CLL-reactive CD8(+) CTL lines and clones from HLA class I-matched donors. These CTL lines and clones recognized and killed primary B-CLL as well as patient-derived lymphoblasts, but not donor cells. These results show the feasibility of ex vivo generation of B-CLL-reactive CD8(+) CTLs. This opens new perspectives for adoptive immunotherapy, following allogeneic stem cell transplantation in patients with advanced B-CLL.

Intraclonal Cell Expansion and Selection Driven by B Cell Receptor in Chronic Lymphocytic Leukemia

PubMed Central

Colombo, Monica; Cutrona, Giovanna; Reverberi, Daniele; Fabris, Sonia; Neri, Antonino; Fabbi, Marina; Quintana, Giovanni; Quarta, Giovanni; Ghiotto, Fabio; Fais, Franco; Ferrarini, Manlio

2011-01-01

The mutational status of the immunoglobulin heavy-chain variable region (IGHV) genes utilized by chronic lymphocytic leukemia (CLL) clones defines two disease subgroups. Patients with unmutated IGHV have a more aggressive disease and a worse outcome than patients with cells having somatic IGHV gene mutations. Moreover, up to 30% of the unmutated CLL clones exhibit very similar or identical B cell receptors (BcR), often encoded by the same IG genes. These “stereotyped” BcRs have been classified into defined subsets. The presence of an IGHV gene somatic mutation and the utilization of a skewed gene repertoire compared with normal B cells together with the expression of stereotyped receptors by unmutated CLL clones may indicate stimulation/selection by antigenic epitopes. This antigenic stimulation may occur prior to or during neoplastic transformation, but it is unknown whether this stimulation/selection continues after leukemogenesis has ceased. In this study, we focused on seven CLL cases with stereotyped BcR Subset #8 found among a cohort of 700 patients; in six, the cells expressed IgG and utilized IGHV4-39 and IGKV1-39/IGKV1D-39 genes, as reported for Subset #8 BcR. One case exhibited special features, including expression of IgM or IgG by different subclones consequent to an isotype switch, allelic inclusion at the IGH locus in the IgM-expressing cells and a particular pattern of cytogenetic lesions. Collectively, the data indicate a process of antigenic stimulation/selection of the fully transformed CLL cells leading to the expansion of the Subset #8 IgG-bearing subclone. PMID:21541442

Analysis of alterations of oncogenes and tumor suppressor genes in chronic lymphocytic leukemia.

PubMed Central

Gaidano, G.; Newcomb, E. W.; Gong, J. Z.; Tassi, V.; Neri, A.; Cortelezzi, A.; Calori, R.; Baldini, L.; Dalla-Favera, R.

1994-01-01

B cell chronic lymphocytic leukemia (B-CLL) represents the most frequent adult leukemia in the Western world. The molecular pathogenesis of B-CLL is largely unknown. Although initial reports on small panels of cases had suggested a role for Bcl-1 and Bcl-2 oncogene activation in B-CLL, later investigations failed to confirm these data. Among tumor suppressor genes, p53 mutations have been reported in a fraction of cases. In this study, we have attempted a conclusive definition of the involvement of dominantly acting oncogenes (Bcl-1 and Bcl-2) and tumor suppressor loci (p53, 6q-) in 100 cases of B-CLL selected for their CD5 positivity and Rai's stage (0 to IV). Rearrangements of Bcl-1 and Bcl-2 and deletions of 6q and 17p were analyzed by Southern blot using multiple probes. Mutational analysis (single strand conformation polymorphism and polymerase chain reaction direct sequencing) was used to assay p53 inactivation. No alterations of Bcl-1 or Bcl-2 were detected in the 100 cases tested. Mutations of p53 were found in 10/100 cases without any significant association with clinical stage. Deletions of 6q were present in 4/100 cases. Overall, our data indicate that: 1) contrary to previous reports, Bcl-1 and Bcl-2 rearrangements are not involved in CD5+ B-CLL pathogenesis and 2) p53 mutations are present in 10% of cases at all stages of the disease. Images Figure 1 Figure 2 Figure 3 PMID:8203469

CLL2-BXX Phase II trials: sequential, targeted treatment for eradication of minimal residual disease in chronic lymphocytic leukemia.

PubMed

Cramer, Paula; von Tresckow, Julia; Bahlo, Jasmin; Engelke, Anja; Langerbeins, Petra; Fink, Anna-Maria; Fischer, Kirsten; Wendtner, Clemens-Martin; Kreuzer, Karl-Anton; Stilgenbauer, Stephan; Böttcher, Sebastian; Eichhorst, Barbara; Hallek, Michael

2018-03-01

Four Phase II trials (clinical trials numbers: NCT02345863, NCT02401503, NCT02445131 and NCT02689141) evaluate a different combination of targeted agents in an all-comer population of approximately 60 patients with chronic lymphocytic leukemia irrespective of prior treatment, physical fitness and genetic risk factors. Patients with a higher tumor load start with a debulking treatment with bendamustine. The subsequent induction and maintenance treatment with an anti-CD20 antibody (obinutuzumab or ofatumumab) and a targeted oral agent (ibrutinib, idelalisib or venetoclax) are continued until achievement of a complete response and minimal residual disease negativity. This strategy represents a new era of chronic lymphocytic leukemia therapy where chemotherapy is increasingly replaced by targeted agents and treatment duration is tailored to the patient's individual tumor load and response.

The clinically active BTK inhibitor PCI-32765 targets B-cell receptor- and chemokine-controlled adhesion and migration in chronic lymphocytic leukemia.

PubMed

de Rooij, Martin F M; Kuil, Annemieke; Geest, Christian R; Eldering, Eric; Chang, Betty Y; Buggy, Joseph J; Pals, Steven T; Spaargaren, Marcel

2012-03-15

Small-molecule drugs that target the B-cell antigen receptor (BCR) signalosome show clinical efficacy in the treatment of B-cell non-Hodgkin lymphoma. These agents, including the Bruton tyrosine kinase (BTK) inhibitor PCI-32765, display an unexpected response in patients with chronic lymphocytic leukemia (CLL): a rapid and sustained reduction of lymphadenopathy accompanied by transient lymphocytosis, which is reversible upon temporary drug deprivation. We hypothesized that this clinical response reflects impaired integrin-mediated adhesion and/or migration. Here, we show that PCI-32765 strongly inhibits BCR-controlled signaling and integrin α(4)β(1)-mediated adhesion to fibronectin and VCAM-1 of lymphoma cell lines and primary CLL cells. Furthermore, PCI-32765 also inhibits CXCL12-, CXCL13-, and CCL19-induced signaling, adhesion, and migration of primary CLL cells. Our data indicate that inhibition of BTK by PCI-32765 overcomes BCR- and chemokine-controlled integrin-mediated retention and homing of malignant B cells in their growth- and survival-supporting lymph node and bone marrow microenvironment, which results in clinically evident CLL regression.

CD47 Agonist Peptides Induce Programmed Cell Death in Refractory Chronic Lymphocytic Leukemia B Cells via PLCγ1 Activation: Evidence from Mice and Humans

PubMed Central

Attout, Tarik; Boullet, Heloïse; Herbi, Linda; Vela, Laura; Barbier, Sandrine; Chateau, Danielle; Chapiro, Elise; Nguyen-Khac, Florence; Davi, Frédéric; Le Garff-Tavernier, Magali; Moumné, Roba; Sarfati, Marika; Karoyan, Philippe; Merle-Béral, Hélène; Launay, Pierre; Susin, Santos A.

2015-01-01

Background Chronic lymphocytic leukemia (CLL), the most common adulthood leukemia, is characterized by the accumulation of abnormal CD5+ B lymphocytes, which results in a progressive failure of the immune system. Despite intense research efforts, drug resistance remains a major cause of treatment failure in CLL, particularly in patients with dysfunctional TP53. The objective of our work was to identify potential approaches that might overcome CLL drug refractoriness by examining the pro-apoptotic potential of targeting the cell surface receptor CD47 with serum-stable agonist peptides. Methods and Findings In peripheral blood samples collected from 80 patients with CLL with positive and adverse prognostic features, we performed in vitro genetic and molecular analyses that demonstrate that the targeting of CD47 with peptides derived from the C-terminal domain of thrombospondin-1 efficiently kills the malignant CLL B cells, including those from high-risk individuals with a dysfunctional TP53 gene, while sparing the normal T and B lymphocytes from the CLL patients. Further studies reveal that the differential response of normal B lymphocytes, collected from 20 healthy donors, and leukemic B cells to CD47 peptide targeting results from the sustained activation in CLL B cells of phospholipase C gamma-1 (PLCγ1), a protein that is significantly over-expressed in CLL. Once phosphorylated at tyrosine 783, PLCγ1 enables a Ca2+-mediated, caspase-independent programmed cell death (PCD) pathway that is not down-modulated by the lymphocyte microenvironment. Accordingly, down-regulation of PLCγ1 or pharmacological inhibition of PLCγ1 phosphorylation abolishes CD47-mediated killing. Additionally, in a CLL-xenograft model developed in NOD/scid gamma mice, we demonstrate that the injection of CD47 agonist peptides reduces tumor burden without inducing anemia or toxicity in blood, liver, or kidney. The limitations of our study are mainly linked to the affinity of the peptides

Chronic Lymphocytic Leukemia-Derived IL-10 Suppresses Antitumor Immunity.

PubMed

Alhakeem, Sara S; McKenna, Mary K; Oben, Karine Z; Noothi, Sunil K; Rivas, Jacqueline R; Hildebrandt, Gerhard C; Fleischman, Roger A; Rangnekar, Vivek M; Muthusamy, Natarajan; Bondada, Subbarao

2018-04-30

Chronic lymphocytic leukemia (CLL) patients progressively develop an immunosuppressive state. CLL patients have more plasma IL-10, an anti-inflammatory cytokine, than healthy controls. In vitro human CLL cells produce IL-10 in response to BCR cross-linking. We used the transgenic Eμ-T cell leukemia oncogene-1 ( TCL1 ) mouse CLL model to study the role of IL-10 in CLL associated immunosuppression. Eμ-TCL mice spontaneously develop CLL because of a B cell-specific expression of the oncogene, TCL1. Eμ- TCL1 mouse CLL cells constitutively produce IL-10, which is further enhanced by BCR cross-linking, CLL-derived IL-10 did not directly affect survival of murine or human CLL cells in vitro. We tested the hypothesis that the CLL-derived IL-10 has a critical role in CLL disease in part by suppressing the host immune response to the CLL cells. In IL-10R -/- mice, wherein the host immune cells are unresponsive to IL-10-mediated suppressive effects, there was a significant reduction in CLL cell growth compared with wild type mice. IL-10 reduced the generation of effector CD4 and CD8 T cells. We also found that activation of BCR signaling regulated the production of IL-10 by both murine and human CLL cells. We identified the transcription factor, Sp1, as a novel regulator of IL-10 production by CLL cells and that it is regulated by BCR signaling via the Syk/MAPK pathway. Our results suggest that incorporation of IL-10 blocking agents may enhance current therapeutic regimens for CLL by potentiating host antitumor immune response. Copyright © 2018 by The American Association of Immunologists, Inc.

BTKC481S-Mediated Resistance to Ibrutinib in Chronic Lymphocytic Leukemia

PubMed Central

Ruppert, Amy S.; Guinn, Daphne; Lehman, Amy; Blachly, James S.; Lozanski, Arletta; Heerema, Nyla A.; Zhao, Weiqiang; Coleman, Joshua; Jones, Daniel; Abruzzo, Lynne; Gordon, Amber; Mantel, Rose; Smith, Lisa L.; McWhorter, Samantha; Davis, Melanie; Doong, Tzyy-Jye; Ny, Fan; Lucas, Margaret; Chase, Weihong; Jones, Jeffrey A.; Flynn, Joseph M.; Maddocks, Kami; Rogers, Kerry; Jaglowski, Samantha; Andritsos, Leslie A.; Awan, Farrukh T.; Blum, Kristie A.; Grever, Michael R.; Lozanski, Gerard; Johnson, Amy J.; Byrd, John C.

2017-01-01

Purpose Therapeutic targeting of Bruton tyrosine kinase (BTK) with ibrutinib in chronic lymphocytic leukemia has led to a paradigm shift in therapy, and relapse has been uncommon with current follow-up. Acquired mutations in BTK and PLCG2 can cause relapse, but data regarding the prevalence and natural history of these mutations are limited. Patients and Methods Patients accrued to four sequential studies of ibrutinib were included in these analyses. Deep sequencing for BTK and PLCG2 was performed retrospectively on patients who experienced relapse and prospectively on a screening population. Results With a median follow-up time of 3.4 years, the estimated cumulative incidence of progression at 4 years is 19% (95% CI, 14% to 24%). Baseline karyotypic complexity, presence of del(17)(p13.1), and age less than 65 years were risk factors for progression. Among patients who experienced relapse, acquired mutations of BTK or PLCG2 were found in 85% (95% CI, 71% to 94%), and these mutations were detected an estimated median of 9.3 months (95% CI, 7.6 to 11.7 months) before relapse. Of a group of 112 patients examined prospectively, eight patients have experienced relapse, and all of these patients had acquired resistance mutations before relapse. A resistance mutation was detected in an additional eight patients who have not yet met criteria for clinical relapse. Conclusion Relapse of chronic lymphocytic leukemia after ibrutinib is an issue of increasing clinical significance. We show that mutations in BTK and PLCG2 appear early and have the potential to be used as a biomarker for future relapse, suggesting an opportunity for intervention. PMID:28418267

Cross-talk between chronic lymphocytic leukemia (CLL) tumor B cells and mesenchymal stromal cells (MSCs): implications for neoplastic cell survival

PubMed Central

Facco, Monica; Chiodin, Giorgia; Frezzato, Federica; Martini, Veronica; Gattazzo, Cristina; Lessi, Federica; Giorgi, Carlo Alberto; Visentin, Andrea; Castelli, Monica; Severin, Filippo; Zambello, Renato; Piazza, Francesco; Semenzato, Gianpietro; Trentin, Livio

2015-01-01

Leukemic cells from Chronic Lymphocytic Leukemia (CLL) patients interact with stromal cells of the surrounding microenvironment. Mesenchymal Stromal Cells (MSCs) represent the main population in CLL marrow stroma, which may play a key role for disease support and progression. In this study we evaluated whether MSCs influence in vitro CLL cell survival. MSCs were isolated from the bone marrow of 46 CLL patients and were characterized by flow cytometry analysis. Following co-culture of MSCs and leukemic B cells, we demonstrated that MSCs were able to improve leukemic B cell viability, this latter being differently dependent from the signals coming from MSCs. In addition, we found that the co-culture of MSCs with leukemic B cells induced an increased production of IL-8, CCL4, CCL11, and CXCL10 chemokines. As far as drug resistance is concerned, MSCs counteract the cytotoxic effect of Fludarabine/Cyclophosphamide administration in vivo, whereas they do not protect CLL cells from the apoptosis induced by the kinase inhibitors Bafetinib and Ibrutinib. The evidence that leukemic clones are conditioned by environmental stimuli suggest new putative targets for therapy in CLL patients. PMID:26517523

How I manage ibrutinib-refractory chronic lymphocytic leukemia

PubMed Central

2017-01-01

The introduction of the Bruton tyrosine kinase (BTK) inhibitor ibrutinib has dramatically changed the management of chronic lymphocytic leukemia (CLL). Although responses have been durable in the majority of patients, relapses do occur, especially in the high-risk patient population. Most relapses occur as the result of acquired mutations in BTK and PLCG2, which may facilitate success with alternative targeted therapies. As outcomes after ibrutinib relapse have been reported to be poor, specific strategies are needed for this patient population. Here, I discuss the diagnosis and management of ibrutinib-refractory CLL. The focus will be on common clinical scenarios that can be mistaken for relapse and how to accurately determine which patients are relapsing. Because there is no established standard of care, I discuss currently available options for standard therapy and existing clinical data. I also discuss new agents with the potential to be effective in patients refractory to ibrutinib. Finally, I discuss strategies for long-term disease control in this patient population. PMID:28096090

[Transcription map of the 13q14 region, frequently deleted in B-cell chronic lymphocytic leukemia patients].

PubMed

Tiazhelova, T V; Ivanov, D V; Makeeva, N V; Kapanadze, B I; Nikitin, E A; Semov, A B; Sangfeldt, O; Grander, D; Vorob'ev, A I; Einhorn, S; Iankovskiĭ, N K; Baranova, A V

2001-11-01

Deletions in the region located between the STS markers D13S1168 and D13S25 on chromosome 13 are the most frequent genomic changes in patients with B-cell chronic lymphocytic leukemia (B-CLL). After sequencing of this region, two novel candidate genes were identified: C13orf1 (chromosome 13 open reading frame 1) and PLCC (putative large CLL candidate). Analysis of the repeat distribution revealed two subregions differing in composition of repetitious DNA and gene organization. The interval D13S1168-D13S319 contains 131 Alu repeats accounting for 24.8% of its length, whereas the interval GCT16C05-D13S25, which is no more than 180 kb away from the former one is extremely poor in Alu repeats (4.1% of the total length). Both intervals contain almost the same amount of the LINE-type repeats L1 and L2 (20.3 and 21.24%, respectively). In the chromosomal region studied, 29 Alu repeats were found to belong to the evolutionary young subfamily Y, which is still capable of amplifying. A considerable proportion of repeats of this type with similar nucleotide sequences may contribute to the recombinational activity of the chromosomal region 13q14.3, which is responsible for its rearrangements in some tumors in humans.

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

PubMed Central

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

2014-01-01

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

Genetically Engineered Lymphocyte Therapy in Treating Patients With Lymphoma That is Resistant or Refractory to Chemotherapy

ClinicalTrials.gov

2015-09-27

Hematopoietic/Lymphoid Cancer; Adult Acute Lymphoblastic Leukemia in Remission; B-cell Adult Acute Lymphoblastic Leukemia; B-cell Chronic Lymphocytic Leukemia; Prolymphocytic Leukemia; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Refractory Chronic Lymphocytic Leukemia; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Chronic Lymphocytic Leukemia; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Chronic Lymphocytic Leukemia; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma

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

PubMed

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

2014-01-01

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

Second Malignancy Risks After Non-Hodgkin's Lymphoma and Chronic Lymphocytic Leukemia: Differences by Lymphoma Subtype

PubMed Central

Morton, Lindsay M.; Curtis, Rochelle E.; Linet, Martha S.; Bluhm, Elizabeth C.; Tucker, Margaret A.; Caporaso, Neil; Ries, Lynn A.G.; Fraumeni, Joseph F.

2010-01-01

Purpose Previous studies have shown increased risks of second malignancies after non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL); however, no earlier investigation has quantified differences in risk of new malignancy by lymphoma subtype. Patients and Methods We evaluated second cancer and leukemia risks among 43,145 1-year survivors of CLL/small lymphocytic lymphoma (SLL), diffuse large B-cell lymphoma (DLBCL), or follicular lymphoma (FL) from 11 Surveillance, Epidemiology, and End Results (SEER) population-based registries during 1992 to 2006. Results Among patients without HIV/AIDS–related lymphoma, lung cancer risks were significantly elevated after CLL/SLL and FL but not after DLBCL (standardized incidence ratio [SIR], CLL/SLL = 1.42, FL = 1.28, DLBCL = 1.00; Poisson regression P for difference among subtypes, PDiff = .001). A similar pattern was observed for risk of cutaneous melanoma (SIR: CLL/SLL = 1.92, FL = 1.60, DLBCL = 1.06; PDiff = .004). Acute nonlymphocytic leukemia risks were significantly elevated after FL and DLBCL, particularly among patients receiving initial chemotherapy, but not after CLL/SLL (SIR: CLL/SLL = 1.13, FL = 5.96, DLBCL = 4.96; PDiff < .001). Patients with HIV/AIDS–related lymphoma (n = 932) were predominantly diagnosed with DLBCL and had significantly and substantially elevated risks for second anal cancer (SIR = 120.50) and Kaposi's sarcoma (SIR = 138.90). Conclusion Our findings suggest that differing immunologic alterations, treatments (eg, alkylating agent chemotherapy), genetic susceptibilities, and other risk factors (eg, viral infections, tobacco use) among lymphoma subtypes contribute to the patterns of second malignancy risk. Elucidating these patterns may provide etiologic clues to lymphoma as well as to the second malignancies. PMID:20940199

Novel treatments for chronic lymphocytic leukemia and moving forward.

PubMed

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

2014-01-01

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

Clinical and biological relevance of genomic heterogeneity in chronic lymphocytic leukemia.

PubMed

Friedman, Daphne R; Lucas, Joseph E; Weinberg, J Brice

2013-01-01

Chronic lymphocytic leukemia (CLL) is typically regarded as an indolent B-cell malignancy. However, there is wide variability with regards to need for therapy, time to progressive disease, and treatment response. This clinical variability is due, in part, to biological heterogeneity between individual patients' leukemias. While much has been learned about this biological variation using genomic approaches, it is unclear whether such efforts have sufficiently evaluated biological and clinical heterogeneity in CLL. To study the extent of genomic variability in CLL and the biological and clinical attributes of genomic classification in CLL, we evaluated 893 unique CLL samples from fifteen publicly available gene expression profiling datasets. We used unsupervised approaches to divide the data into subgroups, evaluated the biological pathways and genetic aberrations that were associated with the subgroups, and compared prognostic and clinical outcome data between the subgroups. Using an unsupervised approach, we determined that approximately 600 CLL samples are needed to define the spectrum of diversity in CLL genomic expression. We identified seven genomically-defined CLL subgroups that have distinct biological properties, are associated with specific chromosomal deletions and amplifications, and have marked differences in molecular prognostic markers and clinical outcomes. Our results indicate that investigations focusing on small numbers of patient samples likely provide a biased outlook on CLL biology. These findings may have important implications in identifying patients who should be treated with specific targeted therapies, which could have efficacy against CLL cells that rely on specific biological pathways.

Venetoclax in Patients with Previously Treated Chronic Lymphocytic Leukemia.

PubMed

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

2017-08-15

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

Ibrutinib therapy increases T cell repertoire diversity in patients with chronic lymphocytic leukemia

PubMed Central

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

2017-01-01

The BTK inhibitor ibrutinib is a highly effective, new targeted therapy for chronic lymphocytic leukemia (CLL) that thwarts leukemia cell survival, growth, and tissue homing. The effects of ibrutinib treatment on the T cell compartment, which is clonally expanded and thought to support the growth of the malignant B cells in CLL, are not fully characterized. Using next-generation sequencing technology we characterized the diversity of TCRβ chains in peripheral blood T cells from 15 CLL patients before and after one year of ibrutinib therapy. We noted elevated CD4+ and CD8+ T cell numbers and a restricted TCRβ repertoire in all pretreatment samples. After one year of ibrutinib therapy, elevated PB T cell numbers and T-cell related cytokine levels had normalized and T cell repertoire diversity significantly increased. Dominant TCRβ clones in pretreatment samples declined or became undetectable, and the number of productive unique clones significantly increased during ibrutinib therapy, with the emergence of large numbers of low-frequency TCRβ clones. Importantly, broader TCR repertoire diversity was associated with clinical efficacy and lower rates of infections during ibrutinib therapy. These data demonstrate that ibrutinib therapy increases diversification of the T cell compartment in CLL patients, which contributes to cellular immune reconstitution. PMID:28077600

Mutation Pattern of Paired Immunoglobulin Heavy and Light Variable Domains in Chronic Lymphocytic Leukemia B Cells

PubMed Central

Ghiotto, Fabio; Marcatili, Paolo; Tenca, Claudya; Calevo, Maria Grazia; Yan, Xiao-Jie; Albesiano, Emilia; Bagnara, Davide; Colombo, Monica; Cutrona, Giovanna; Chu, Charles C; Morabito, Fortunato; Bruno, Silvia; Ferrarini, Manlio; Tramontano, Anna; Fais, Franco; Chiorazzi, Nicholas

2011-01-01

B-cell chronic lymphocytic leukemia (CLL) patients display leukemic clones bearing either germline or somatically mutated immunoglobulin heavy variable (IGHV ) genes. Most information on CLL immunoglobulins (Igs), such as the definition of stereotyped B-cell receptors (BCRs), was derived from germline unmutated Igs. In particular, detailed studies on the distribution and nature of mutations in paired heavy- and light-chain domains of CLL clones bearing mutated Igs are lacking. To address the somatic hyper-mutation dynamics of CLL Igs, we analyzed the mutation pattern of paired IGHV–diversity-joining (IGHV-D-J ) and immunoglobulin kappa/lambda variable-joining (IGK/LV-J ) rearrangements of 193 leukemic clones that displayed ≥2% mutations in at least one of the two immunoglobulin variable (IGV ) genes (IGHV and/or IGK/LV ). The relationship between the mutation frequency in IGHV and IGK/LV complementarity determining regions (CDRs) and framework regions (FRs) was evaluated by correlation analysis. Replacement (R) mutation frequency within IGK/LV chain CDRs correlated significantly with mutation frequency of paired IGHV CDRs in λ but not κ isotype CLL clones. CDRs of IGKV-J rearrangements displayed a lower percentage of R mutations than IGHVs. The frequency/pattern of mutations in kappa CLL Igs differed also from that in κ-expressing normal B cells described in the literature. Instead, the mutation frequency within the FRs of IGHV and either IGKV or IGLV was correlated. Notably, the amount of diversity introduced by replaced amino acids was comparable between IGHVs and IGKVs. The data indicate a different mutation pattern between κ and λ isotype CLL clones and suggest an antigenic selection that, in κ samples, operates against CDR variation. PMID:21785810

LPL is the strongest prognostic factor in a comparative analysis of RNA-based markers in early chronic lymphocytic leukemia.

PubMed

Kaderi, Mohd Arifin; Kanduri, Meena; Buhl, Anne Mette; Sevov, Marie; Cahill, Nicola; Gunnarsson, Rebeqa; Jansson, Mattias; Smedby, Karin Ekström; Hjalgrim, Henrik; Jurlander, Jesper; Juliusson, Gunnar; Mansouri, Larry; Rosenquist, Richard

2011-08-01

The expression levels of LPL, ZAP70, TCL1A, CLLU1 and MCL1 have recently been proposed as prognostic factors in chronic lymphocytic leukemia. However, few studies have systematically compared these different RNA-based markers. Using real-time quantitative PCR, we measured the mRNA expression levels of these genes in unsorted samples from 252 newly diagnosed chronic lymphocytic leukemia patients and correlated our data with established prognostic markers (for example Binet stage, CD38, IGHV gene mutational status and genomic aberrations) and clinical outcome. High expression levels of all RNA-based markers, except MCL1, predicted shorter overall survival and time to treatment, with LPL being the most significant. In multivariate analysis including the RNA-based markers, LPL expression was the only independent prognostic marker for overall survival and time to treatment. When studying LPL expression and the established markers, LPL expression retained its independent prognostic strength for overall survival. All of the RNA-based markers, albeit with varying ability, added prognostic information to established markers, with LPL expression giving the most significant results. Notably, high LPL expression predicted a worse outcome in good-prognosis subgroups, such as patients with mutated IGHV genes, Binet stage A, CD38 negativity or favorable cytogenetics. In particular, the combination of LPL expression and CD38 could further stratify Binet stage A patients. LPL expression is the strongest RNA-based prognostic marker in chronic lymphocytic leukemia that could potentially be applied to predict outcome in the clinical setting, particularly in the large group of patients with favorable prognosis.

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

[Expression of Notch Gene and Its Role of Anti-apoptosis and Drug-resistance of Cells in Chronic Lymphocytic Leukemia].

PubMed

Zhang, Jin-Yan; Zhang, Ju-Shun; Xu, Zhen-Shu

2015-08-01

To investigate the expression of Notch gene in chronic lymphocytic leukemia cells and to explore the change of Notch protein after the therapy with cytosine arabinoside or dexmethasone, and the mechanism of Notch mediated anti-apoptosis and drug-resistance in chronic lymphocytic leukemia cells. The mononuclear cells from bone marrow or peripheral blood of chronic lymphocytic leukemia patients (24 cases) and healthy donors (14 cases) were collected, then the expression of Notch gene, BCL-2, as well as NF-κB gene were detected by real-time fluorescent quantitative PCR (qRT-PCR) at the level of transcription. The change of Notch protein in L1210 cell lines after therapy with cytosine arabinoside and dexmethasone was determined by Western blot. mRNA expression levels of Notch1, Notch2, BCL-2 and NF-κB gene in CLL group were significantly higher than those in healthy control group (0.8556 ± 0.8726 vs 0.6731 ± 0.5334, P = 0.0182; 1.2273 ± 0.8207 vs 0.6577 ± 0.6424, P < 0.0001; 8.0960 ± 7.5661 vs 0.5969 ± 0.4976, P < 0.0001; 1.0966 ± 0.6925 vs 0.5373 ± 0.7180, P < 0.0001, respectively), but no significant difference was found between Notch3 and Notch4 gene (1.1914 ± 2.4219 vs 0.8713 ± 0.7937, P = 0.3427; 0.8174 ± 1.0869 vs 0.9752 ± 1.3446, P = 0.2402, respectively). Notch1 protein expression in L1210 cells were significantly decreased after treating with cytosine arabinoside of low and middle concentrations, but increased after treating with cytosine arabinoside of high concentration or prolonging time of cytosine arabinoside of middle con-centration. Notch1 protein expression in L1210 cells dereased after treating with dexamethasone, but did not be changed with the different concentrations and different times of dexmethason. The transcription level of Notch gene in CLL patients significantly higher than that in normal controls. The Notch1 protein expression is down-regulated in process of inhibiting L1210 cell proliferation by Ara-C and dexmethason. Notch

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

PubMed

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

2017-01-26

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

Tanespimycin and Cytarabine in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, Chronic Myelogenous Leukemia, Chronic Myelomonocytic Leukemia, or Myelodysplastic Syndromes

ClinicalTrials.gov

2013-09-27

Accelerated Phase Chronic Myelogenous Leukemia; Adult Acute Basophilic Leukemia; Adult Acute Eosinophilic Leukemia; Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); Adult Acute Monoblastic Leukemia (M5a); Adult Acute Monocytic Leukemia (M5b); Adult Acute Myeloblastic Leukemia With Maturation (M2); Adult Acute Myeloblastic Leukemia Without Maturation (M1); Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Myelomonocytic Leukemia (M4); Adult Erythroleukemia (M6a); Adult Pure Erythroid Leukemia (M6b); Blastic Phase Chronic Myelogenous Leukemia; Chronic Myelomonocytic Leukemia; de Novo Myelodysplastic Syndromes; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Refractory Anemia With Excess Blasts in Transformation; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes

Cutaneous Mucormycosis Following a Bullous Pemphigoid Flare in a Chronic Lymphocytic Leukemia Patient on Ibrutinib.

PubMed

Stein, Matthew K; Karri, Saradasri; Reynolds, Jackson; Owsley, Jeff; Wise, Austin; Martin, Mike G; Zare, Fereshteh

2018-04-01

While the recent development of novel therapeutics in oncology, such as small molecule kinase inhibitors (SMKIs), has enabled our ability to target disease-specific molecular pathways, the prolonged impact of these agents on the immune system and infectious risk remains to be seen. We present a 68-year-old male with refractory chronic lymphocytic leukemia (CLL) on ibrutinib monotherapy for 3 years who developed extensive cutaneous mucormycosis following a severe bullous pemphigoid (BP) flare. He received amphotericin B for 4 weeks and was continued on posaconazole with resolution of his mucormycosis infection. Consistent with a growing evidence of literature identifying opportunistic fungal infections in patients on ibrutinib therapy, providers should be cognizant of medical comorbidities that may predispose to such infections and explore methods of prevention before starting ibrutinib and other SMKIs.

The Next Generation of Targeted Molecules for the Treatment of Chronic Lymphocytic Leukemia.

PubMed

Jeyakumar, Deepa; O'Brien, Susan

2016-11-15

With the recent approval of several new targeted therapies for chronic lymphocytic leukemia (CLL), there are now multiple options for its treatment. Inhibitors of Bruton tyrosine kinase (with ibrutinib being the first-in-class US Food and Drug Administration-approved agent) and phosphoinositide 3-kinase (with idelalisib as the first-in-class approved agent) are promising because they are generally well tolerated and highly effective against this malignancy. These agents may be particularly important in the treatment of older patients who are less able to tolerate the myelosuppression (and subsequent infections) associated with chemoimmunotherapy. As a class of medications, B-cell receptor inhibitors have some unique side effects, including redistribution lymphocytosis. Toxicities associated specifically with ibrutinib include increased risk for bleeding and atrial fibrillation. Idelalisib also has some unique toxicities: transaminitis, colitis, and pneumonitis. Targeted therapies recently approved for use in CLL include the novel anti-CD20 monoclonal antibodies obinutuzumab and ofatumumab, and the B-cell lymphoma 2 inhibitor venetoclax. This article describes the clinical data that led to approval of these B-cell receptor inhibitors for the treatment of CLL, and highlights newer agents in clinical development that target the same kinases as the currently available therapies.

Lenalidomide in the treatment of chronic lymphocytic leukemia.

PubMed

Gentile, Massimo; Recchia, Anna Grazia; Vigna, Ernesto; Mazzone, Carla; Lucia, Eugenio; Gigliotti, Vincenzo; Bossio, Sabrina; Madeo, Antonio; Morabito, Lucio; Servillo, Pasquale; Franzese, Stefania; Caruso, Nadia; De Stefano, Laura; Bisconte, Maria Grazia; Gentile, Carlo; Morabito, Fortunato

2011-02-01

insights into the role of the tumor microenvironment and of immune dysfunction in chronic lymphocytic leukemia (CLL) have opened the way for further augmenting the therapeutic armamentarium for CLL patients. In this respect, lenalidomide represents an exciting drug since it is able to eliminate CLL cells without immunosuppression. mechanism of action and clinical trials of lenalidomide in CLL, and suggestions for its future utilization are reviewed. The most relevant papers and the meeting abstracts published up to July 2010 were used as sources for this review. This review will help readers understand the mechanism of action of lenalidomide and will provide a comprehensive summary regarding efficacy and safety of this drug in CLL patients. lenalidomide shows good activity against CLL. However, the toxicity profile is significant and can result in serious and potentially life-threatening side effects. Definitive data from ongoing trials will aid better definition of its status in CLL therapy. Moreover, clarification of the exact mechanism(s) of action in CLL will allow more precise use of lenalidomide and design of more efficacious combination therapies.

Alterations of mitochondrial biogenesis in chronic lymphocytic leukemia cells with loss of p53

PubMed Central

Ogasawara, Marcia A.; Liu, Jinyun; Pelicano, Helene; Hammoudi, Naima; Croce, Carlo M.; Keating, Michael J.; Huang, Peng

2016-01-01

Deletion of chromosome 17p with a loss of p53 is an unfavorable cytogenetic change in chronic lymphocytic leukemia (CLL) with poor clinical outcome. Since p53 affects mitochondrial function and integrity, we examined possible mitochondrial changes in CLL mice with TCL1-Tg/p53−/− and TCL1-Tg/p53+/+ genotypes and in primary leukemia cells from CLL patients with or without 17p-deletion. Although the expression of mitochondrial COX1, ND2, and ND6 decreased in p53−/−CLL cells, there was an increase in mitochondrial biogenesis as evidenced by higher mitochondrial mass and mtDNA copy number associated with an elevated expression of TFAM and PGC-1α. Surprisingly, the overall mitochondrial respiratory activity and maximum reserved capacity increased in p53−/− CLL cells. Our study suggests that leukemia cells lacking p53 seem able to maintain respiratory function by compensatory increase in mitochondrial biogenesis. PMID:27650502

Ibrutinib as an antitumor immunomodulator in patients with refractory chronic lymphocytic leukemia.

PubMed

Cubillos-Zapata, Carolina; Avendaño-Ortiz, Jose; Córdoba, Raúl; Hernández-Jiménez, Enrique; Toledano, Victor; Pérez de Diego, Rebeca; López-Collazo, Eduardo

2016-01-01

Ibrutinib has emerged as a promising therapy for patients with chronic lymphocytic leukemia (CLL) who are nonresponsive to standard therapies. The refractory state of monocytes and T-cell exhaustion in patients with CLL could explain the morbidity and mortality reported in these patients. We studied the effect of ibrutinib on the immune response of four relapsed patients with CLL during the first treatment cycle. We observed the ability to recover the standard response against bacterial stimulus in CD14 + cells, improving levels of phospho-Erk1/2 and antigen presentation. Meanwhile, ibrutinib drove Th1-selective pressure in T lymphocytes, thus, reducing the PD-1 and PDL-1 expression. Our data suggest the impact of BTK inhibition along with immunomodulation on the innate immune response and a switch to the specific adaptive immune response, which might help to decrease infectious complications. The potential effect of ibrutinib on CLL patient outcomes is worthy of further study, because infections could be reduced with the use of ibrutinib.

Chronic lymphocytic leukemia therapy: new targeted therapies on the way

PubMed Central

Vitale, Candida; Burger, Jan A

2016-01-01

Introduction The critical role of the tissue microenvironment and B cell receptor (BCR) signaling in chronic lymphocytic leukemia (CLL) pathogenesis, and the clinical success of targeted agents that disrupt BCR signaling are currently changing the CLL landscape. Three new drugs were recently approved for CLL therapy, and other agents are in late development. Areas covered In this review, we summarize data on promising new targeted drugs for CLL. The heterogeneous mechanisms of actions of these molecules are described, such as the inhibition of BCR signaling, direct targeting of CD20 molecules on the CLL cell surface, and BCL-2 inhibition. We present preclinical and clinical data from phase I to III studies in order to describe efficacy and side effect profile of these new drugs. Data are derived from peer-reviewed articles indexed in PubMed and from abstracts presented at major international meetings. Expert opinion Ibrutinib and idelalisib are challenging the role of chemo-immunotherapy in CLL therapy in the frontline and relapsed disease settings. High-risk CLL patients particularly benefit from these new agents. Venetoclax and obinutuzumab are other effective agents added to our therapeutic armamentarium. Studies to better define the optimal use of these drugs, alone, or rather in combination or sequenced are underway. PMID:26988407

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

Tetrasomy 8 in a patient with chronic lymphocytic leukemia.

PubMed

de Oliveira, Fábio Morato; Brandão, Renata Amorim; Leite-Cueva, Sabrina Dias; de Paula Careta, Francisco; Simões, Belinda Pinto; Rego, Eduardo Magalhães; Falcão, Roberto Passetto

2010-04-15

We report a case of a 47-year-old man diagnosed with chronic lymphocytic leukemia (CLL) with two extra copies of chromosome 8. Classical cytogenetic analysis by the immunostimulatory combination of DSP30 and interleukin 2 showed tetrasomy of chromosome 8 in 60% of the metaphase cells (48,XY,+8,+8[12]/46,XY[8]). Spectral karyotype analysis confirmed the abnormality previously seen by G banding. Additionally, interphase fluorescence in situ hybridization using an LSI CEP 8 probe performed on peripheral blood cells without any stimulant agent showed tetrasomy of chromosome 8 in 54% of analyzed cells (108 of 200). To our knowledge, tetrasomy 8 as the sole chromosomal abnormality in CLL has not been previously described. The prognostic significance of tetrasomy 8 in CLL remains to be elucidated. However, the patient has been followed up in the outpatient hospital since 2004 without any therapeutic intervention and has so far remained stable. Copyright 2010 Elsevier Inc. All rights reserved.

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

PubMed

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

2009-03-01

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

High-frequency expression of a conserved kappa light-chain variable-region gene in chronic lymphocytic leukemia

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

Kipps, T.J.; Fong, S.; Tomhave, E.

Malignant B lymphocytes from several patients with chronic lymphocytic leukemia (CLL) were examined for reactivity with murine monoclonal antibody 17.109. This antibody, prepared against the rheumatoid factor (RF) paraprotein Sie, recognizes a cross reactive idiotype on 48% of human IgM RF paraproteins, but does not react with IgM paraproteins without RF activity or substantially with normal pooled immunoglobulin. The 17.109-reactive idiotype is a marker for a kappa III variable-region gene, designated V/sub kappa/RF, that is conserved in outbred human populations. In a limited study of 31 CLL patients, the leukemic cells from 5 of 20 patients with kappa light chain-expressingmore » CLL were recognized by the 17.109 monoclonal antibody. Despite having malignant cells specifically reactive with this antibody, patients with 17.109-positive CLL did not have elevated serum levels of circulating antibody bearing 17.109-reactive determinants. Total RNAs isolated from the CLL B lymphocytes, or from hybridomas produced by fusing the CLL cells with the WI-L2-729-HF/sub 2/ cell line, were fractionated electrophoretically and examined by blot hybridization. Under stringent hybridization conditions capable of discerning a single base-pair mismatch, RNA from the 17.109-idiotype-positive CLL cells hybridized to synthetic oligonucleotide probes corresponding to framework and complementary-determining regions in the V/sub kappa/RF gene. The high frequency of the 17.109-associated idiotype and the V/sub kappa/RF gene in CLL suggests that the disease may arise from B lymphocytes that express a restricted set of inherited immunoglobulin variable-region genes with little or no somatic mutation.« less

Clinical and Biological Relevance of Genomic Heterogeneity in Chronic Lymphocytic Leukemia

PubMed Central

Friedman, Daphne R.; Lucas, Joseph E.; Weinberg, J. Brice

2013-01-01

Background Chronic lymphocytic leukemia (CLL) is typically regarded as an indolent B-cell malignancy. However, there is wide variability with regards to need for therapy, time to progressive disease, and treatment response. This clinical variability is due, in part, to biological heterogeneity between individual patients’ leukemias. While much has been learned about this biological variation using genomic approaches, it is unclear whether such efforts have sufficiently evaluated biological and clinical heterogeneity in CLL. Methods To study the extent of genomic variability in CLL and the biological and clinical attributes of genomic classification in CLL, we evaluated 893 unique CLL samples from fifteen publicly available gene expression profiling datasets. We used unsupervised approaches to divide the data into subgroups, evaluated the biological pathways and genetic aberrations that were associated with the subgroups, and compared prognostic and clinical outcome data between the subgroups. Results Using an unsupervised approach, we determined that approximately 600 CLL samples are needed to define the spectrum of diversity in CLL genomic expression. We identified seven genomically-defined CLL subgroups that have distinct biological properties, are associated with specific chromosomal deletions and amplifications, and have marked differences in molecular prognostic markers and clinical outcomes. Conclusions Our results indicate that investigations focusing on small numbers of patient samples likely provide a biased outlook on CLL biology. These findings may have important implications in identifying patients who should be treated with specific targeted therapies, which could have efficacy against CLL cells that rely on specific biological pathways. PMID:23468975

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. ...

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.

Peripheral T-Cell lymphoma manifested as gingival enlargement in a patient with chronic lymphocytic leukemia.

PubMed

Buddula, Aravind; Assad, Daniel

2011-01-01

Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in adults and is associated with increased risk of malignancy. T-cell lymphoma associated with CLL has never been reported. The case report presents a unique case of peripheral T-cell lymphoma on the gingiva of a patient with CLL. A 66-year-old man with a history of CLL was referred to the Mayo Clinic, Department of Dental Specialties, for evaluation of swelling in the upper left posterior sextant. An intraoral examination revealed a soft tissue swelling in the area of teeth number 13 and 15, including the present edentulous ridge between number 13 and 15. An incisional biopsy was performed on the palatal aspect of tooth No. 15 and submitted for histologic evaluation. The histopathology revealed proliferation of large atypical cells beneath the epithelium, positive for antigens CD2, CD3, Beta-F1, TIA-1, and Granzyme B consistent for a diagnosis of a peripheral T-cell lymphoma. A team approach including the hematologist, general dentist and periodontist resulted in timely referrals leading to an early diagnosis and early intervention and treatment.

miR-150 influences B-cell receptor signaling in chronic lymphocytic leukemia by regulating expression of GAB1 and FOXP1

PubMed Central

Mraz, Marek; Chen, Liguang; Rassenti, Laura Z.; Ghia, Emanuela M.; Li, Hongying; Jepsen, Kristen; Smith, Erin N.; Messer, Karen; Frazer, Kelly A.; Kipps, Thomas J.

2014-01-01

We examined the microRNAs (miRNAs) expressed in chronic lymphocytic leukemia (CLL) and identified miR-150 as the most abundant, but with leukemia cell expression levels that varied among patients. CLL cells that expressed ζ-chain–associated protein of 70 kDa (ZAP-70) or that used unmutated immunoglobulin heavy chain variable (IGHV) genes, each had a median expression level of miR-150 that was significantly lower than that of ZAP-70–negative CLL cells or those that used mutated IGHV genes. In samples stratified for expression of miR-150, CLL cells with low-level miR-150 expressed relatively higher levels of forkhead box P1 (FOXP1) and GRB2-associated binding protein 1 (GAB1), genes with 3′ untranslated regions having evolutionary-conserved binding sites for miR-150. High-level expression of miR-150 could repress expression of these genes, which encode proteins that enhance B-cell receptor signaling, a putative CLL-growth/survival signal. Also, high-level expression of miR-150 was a significant independent predictor of longer treatment-free survival or overall survival, whereas an inverse association was observed for high-level expression of GAB1 or FOXP1 for overall survival. This study demonstrates that expression of miR-150 can influence the relative expression of GAB1 and FOXP1 and the signaling potential of the B-cell receptor, thereby possibly accounting for the noted association of expression of miR-150 and disease outcome. PMID:24787006

miR-150 influences B-cell receptor signaling in chronic lymphocytic leukemia by regulating expression of GAB1 and FOXP1.

PubMed

Mraz, Marek; Chen, Liguang; Rassenti, Laura Z; Ghia, Emanuela M; Li, Hongying; Jepsen, Kristen; Smith, Erin N; Messer, Karen; Frazer, Kelly A; Kipps, Thomas J

2014-07-03

We examined the microRNAs (miRNAs) expressed in chronic lymphocytic leukemia (CLL) and identified miR-150 as the most abundant, but with leukemia cell expression levels that varied among patients. CLL cells that expressed ζ-chain-associated protein of 70 kDa (ZAP-70) or that used unmutated immunoglobulin heavy chain variable (IGHV) genes, each had a median expression level of miR-150 that was significantly lower than that of ZAP-70-negative CLL cells or those that used mutated IGHV genes. In samples stratified for expression of miR-150, CLL cells with low-level miR-150 expressed relatively higher levels of forkhead box P1 (FOXP1) and GRB2-associated binding protein 1 (GAB1), genes with 3' untranslated regions having evolutionary-conserved binding sites for miR-150. High-level expression of miR-150 could repress expression of these genes, which encode proteins that enhance B-cell receptor signaling, a putative CLL-growth/survival signal. Also, high-level expression of miR-150 was a significant independent predictor of longer treatment-free survival or overall survival, whereas an inverse association was observed for high-level expression of GAB1 or FOXP1 for overall survival. This study demonstrates that expression of miR-150 can influence the relative expression of GAB1 and FOXP1 and the signaling potential of the B-cell receptor, thereby possibly accounting for the noted association of expression of miR-150 and disease outcome. © 2014 by The American Society of Hematology.

Cytogenetic investigations of chronic lymphocytic leukemia.

PubMed

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

2010-04-15

This study aimed to determine which culture method would yield the highest culture success rate, mitotic index, banding resolution, and abnormality rate in investigation of patients with chronic lymphocytic leukemia (CLL). A range of culture techniques for conventional cytogenetic (CC) analyses was compared: 24-hour unstimulated, 72 hours incubation with additional fetal calf serum, 72 hours stimulation with interleukin 4, 72 hours stimulation with lipopolysaccharide (LPS), 72 hours stimulation with TPA (12-O-tetradecanoylphorbol 13-acetate), and 72 hours stimulation with CpG-oligonucleotide DSP30 + Interleukin-2 (IL-2). CC abnormality rates were also compared to fluorescence in situ hybridization (FISH) results using probes for CLL (LSI D13S319/13q34/CEP 12: LSI ATM/p53). Forty-five samples from 24 patients (consisting of 11 newly diagnosed and 13 previously diagnosed patients) were included. For CC, a 100.0% culture success rate was achieved (n = 45) by means of an EDTA (ethylenediaminetetraacetic acid) peripheral blood sample with an associated 62.5% CC abnormality rate (n = 24). FISH detected an abnormality rate of 75.0% (n = 24). The combined CC and FISH abnormality rate was 87.5% (n = 24). This study demonstrates that CC that uses TPA and DSP30 + IL-2 on EDTA peripheral blood is effective in the investigation of CLL and may be used as a supplement to FISH studies. Copyright 2010 Elsevier Inc. All rights reserved.

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

PubMed

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

2017-02-15

The Bruton's tyrosine kinase inhibitor ibrutinib is a highly effective, new targeted therapy for chronic lymphocytic leukemia (CLL) that thwarts leukemia cell survival, growth, and tissue homing. The effects of ibrutinib treatment on the T cell compartment, which is clonally expanded and thought to support the growth of malignant B cells in CLL, are not fully characterized. Using next-generation sequencing technology, we characterized the diversity of TCRβ-chains in peripheral blood T cells from 15 CLL patients before and after 1 y of ibrutinib therapy. We noted elevated CD4 + and CD8 + T cell numbers and a restricted TCRβ repertoire in all pretreatment samples. After 1 y of ibrutinib therapy, elevated peripheral blood T cell numbers and T cell-related cytokine levels had normalized, and T cell repertoire diversity increased significantly. Dominant TCRβ clones in pretreatment samples declined or became undetectable, and the number of productive unique clones increased significantly during ibrutinib therapy, with the emergence of large numbers of low-frequency TCRβ clones. Importantly, broader TCR repertoire diversity was associated with clinical efficacy and lower rates of infections during ibrutinib therapy. These data demonstrate that ibrutinib therapy increases diversification of the T cell compartment in CLL patients, which contributes to cellular immune reconstitution. Copyright © 2017 by The American Association of Immunologists, Inc.

Comparative sequence analysis of a region on human chromosome 13q14, frequently deleted in B-cell chronic lymphocytic leukemia, and its homologous region on mouse chromosome 14.

PubMed

Kapanadze, B; Makeeva, N; Corcoran, M; Jareborg, N; Hammarsund, M; Baranova, A; Zabarovsky, E; Vorontsova, O; Merup, M; Gahrton, G; Jansson, M; Yankovsky, N; Einhorn, S; Oscier, D; Grandér, D; Sangfelt, O

2000-12-15

Previous studies have indicated the presence of a putative tumor suppressor gene on human chromosome 13q14, commonly deleted in patients with B-cell chronic lymphocytic leukemia (B-CLL). We have recently identified a minimally deleted region encompassing parts of two adjacent genes, termed LEU1 and LEU2 (leukemia-associated genes 1 and 2), and several additional transcripts. In addition, 50 kb centromeric to this region we have identified another gene, LEU5/RFP2. To elucidate further the complex genomic organization of this region, we have identified, mapped, and sequenced the homologous region in the mouse. Fluorescence in situ hybridization analysis demonstrated that the region maps to mouse chromosome 14. The overall organization and gene order in this region were found to be highly conserved in the mouse. Sequence comparison between the human deletion hotspot region and its homologous mouse region revealed a high degree of sequence conservation with an overall score of 74%. However, our data also show that in terms of transcribed sequences, only two of those, human LEU2 and LEU5/RFP2, are clearly conserved, strengthening the case for these genes as putative candidate B-CLL tumor suppressor genes.

Cirmtuzumab inhibits Wnt5a-induced Rac1 activation in chronic lymphocytic leukemia treated with ibrutinib

PubMed Central

Yu, J; Chen, L; Cui, B; Wu, Christina; Choi, M Y; Chen, Y; Zhang, L; Rassenti, L Z; Widhopf II, G F; Kipps, T J

2017-01-01

Signaling via the B cell receptor (BCR) plays an important role in the pathogenesis and progression of chronic lymphocytic leukemia (CLL). This is underscored by the clinical effectiveness of ibrutinib, an inhibitor of Bruton's tyrosine kinase (BTK) that can block BCR-signaling. However, ibrutinib cannot induce complete responses (CR) or durable remissions without continued therapy, suggesting alternative pathways also contribute to CLL growth/survival that are independent of BCR-signaling. ROR1 is a receptor for Wnt5a, which can promote activation of Rac1 to enhance CLL-cell proliferation and survival. In this study, we found that CLL cells of patients treated with ibrutinib had activated Rac1. Moreover, Wnt5a could induce Rac1 activation and enhance proliferation of CLL cells treated with ibrutinib at concentrations that were effective in completely inhibiting BTK and BCR-signaling. Wnt5a-induced Rac1 activation could be blocked by cirmtuzumab (UC-961), an anti-ROR1 mAb. We found that treatment with cirmtuzumab and ibrutinib was significantly more effective than treatment with either agent alone in clearing leukemia cells in vivo. This study indicates that cirmtuzumab may enhance the activity of ibrutinib in the treatment of patients with CLL or other ROR1+ B-cell malignancies. PMID:27904138

Cirmtuzumab inhibits Wnt5a-induced Rac1 activation in chronic lymphocytic leukemia treated with ibrutinib.

PubMed

Yu, J; Chen, L; Cui, B; Wu, Christina; Choi, M Y; Chen, Y; Zhang, L; Rassenti, L Z; Widhopf Ii, G F; Kipps, T J

2017-06-01

Signaling via the B cell receptor (BCR) plays an important role in the pathogenesis and progression of chronic lymphocytic leukemia (CLL). This is underscored by the clinical effectiveness of ibrutinib, an inhibitor of Bruton's tyrosine kinase (BTK) that can block BCR-signaling. However, ibrutinib cannot induce complete responses (CR) or durable remissions without continued therapy, suggesting alternative pathways also contribute to CLL growth/survival that are independent of BCR-signaling. ROR1 is a receptor for Wnt5a, which can promote activation of Rac1 to enhance CLL-cell proliferation and survival. In this study, we found that CLL cells of patients treated with ibrutinib had activated Rac1. Moreover, Wnt5a could induce Rac1 activation and enhance proliferation of CLL cells treated with ibrutinib at concentrations that were effective in completely inhibiting BTK and BCR-signaling. Wnt5a-induced Rac1 activation could be blocked by cirmtuzumab (UC-961), an anti-ROR1 mAb. We found that treatment with cirmtuzumab and ibrutinib was significantly more effective than treatment with either agent alone in clearing leukemia cells in vivo. This study indicates that cirmtuzumab may enhance the activity of ibrutinib in the treatment of patients with CLL or other ROR1 + B-cell malignancies.

Epigenetic deregulation in chronic lymphocytic leukemia: Clinical and biological impact.

PubMed

Mansouri, Larry; Wierzbinska, Justyna Anna; Plass, Christoph; Rosenquist, Richard

2018-02-07

Deregulated transcriptional control caused by aberrant DNA methylation and/or histone modifications is a hallmark of cancer cells. In chronic lymphocytic leukemia (CLL), the most common adult leukemia, the epigenetic 'landscape' has added a new layer of complexity to our understanding of this clinically and biologically heterogeneous disease. Early studies identified aberrant DNA methylation, often based on single gene promoter analysis with both biological and clinical impact. Subsequent genome-wide profiling studies revealed differential DNA methylation between CLLs and controls and in prognostics subgroups of the disease. From these studies, it became apparent that DNA methylation in regions outside of promoters, such as enhancers, is important for the regulation of coding genes as well as for the regulation of non-coding RNAs. Although DNA methylation profiles are reportedly stable over time and in relation to therapy, a higher epigenetic heterogeneity or 'burden' is seen in more aggressive CLL subgroups, albeit as non-recurrent 'passenger' events. More recently, DNA methylation profiles in CLL analyzed in relation to differentiating normal B-cell populations revealed that the majority of the CLL epigenome reflects the epigenomes present in the cell of origin and that only a small fraction of the epigenetic alterations represents truly CLL-specific changes. Furthermore, CLL patients can be grouped into at least three clinically relevant epigenetic subgroups, potentially originating from different cells at various stages of differentiation and associated with distinct outcomes. In this review, we summarize the current understanding of the DNA methylome in CLL, the role of histone modifying enzymes, highlight insights derived from animal models and attempts made to target epigenetic regulators in CLL along with the future directions of this rapidly advancing field. Copyright © 2018 Elsevier Ltd. All rights reserved.

Update of the Grupo Español de Leucemia Linfocítica Crónica clinical guidelines of the management of chronic lymphocytic leukemia.

PubMed

García-Marco, José A; Delgado, Julio; Hernández-Rivas, José A; Ramírez Payer, Ángel; Loscertales Pueyo, Javier; Jarque, Isidro; Abrisqueta, Pau; Giraldo, Pilar; Martínez, Rafael; Yáñez, Lucrecia; Terol, Mª José; González, Marcos; Bosch, Francesc

2017-04-21

The broad therapeutic arsenal and the biological heterogeneity of patients with chronic lymphocytic leukemia (CLL) makes it difficult to standardize treatment for CLL patients with specific clinical settings in routine clinical practice. These considerations prompted us to elaborate the present consensus document, which constitutes an update of the previous version published in 2013, mainly focusing on novel treatment strategies that have been developed over last 5 years, namely B-cell receptor inhibitors (ibrutinib and idelalisib), anti-CD20 monoclonal antibodies (ofatumumab and obinutuzumab), and Bcl-2 inhibitors (venetoclax). A group of experts from the Spanish Chronic Lymphocytic Leukemia Group reviewed all published literature from January 2010 to January 2016, in order to provide recommendations based on clinical evidence. For those areas without strong scientific evidence, the panel of experts established consensus criteria based on their clinical experience. The project has resulted in several practical recommendations that will facilitate the diagnosis, treatment, and follow-up of patients with CLL. There are many controversial issues in the management of CLL with no appropriate studies for making consensus recommendations. Copyright © 2017 Elsevier España, S.L.U. All rights reserved.

Experience with ibrutinib for first-line use in patients with chronic lymphocytic leukemia.

PubMed

Itchaki, Gilad; Brown, Jennifer R

2018-01-01

Ibrutinib is the first in-class, orally administered, Bruton's tyrosine kinase (BTK) inhibitor that abrogates the critical signaling downstream of the B-cell receptor (BCR). This signaling is required for B-cell survival, proliferation and interaction with the microenvironment. Ibrutinib proved active in preclinical models of lymphoproliferative diseases and achieved impressive response rates in heavily pretreated relapsed and refractory (R/R) patients with chronic lymphocytic leukemia (CLL). Ibrutinib prolonged survival compared to standard therapy and mitigated the effect of most poor prognostic factors in CLL, thus becoming the main therapeutic option in high-risk populations. Moreover, compared with standard chemoimmunotherapy (CIT) for adults, ibrutinib causes fewer cytopenias and infections, while having its own unique toxicity profile. Its efficacy in relapsed patients as well as its tolerability have led to its increased use in previously untreated patients, especially in those with poor prognostic markers and/or the elderly. This review elaborates on ibrutinib's unique toxicity profile and the mechanisms of acquired resistance leading to progression on ibrutinib, since both are critical for understanding the obstacles to its first-line use. We will further evaluate the data from ongoing clinical trials in this setting and explore future options for combination therapy.

Safety and activity of BTK inhibitor ibrutinib combined with ofatumumab in chronic lymphocytic leukemia: a phase 1b/2 study

PubMed Central

Jones, Jeffrey A.; Nagar, Veena; Flynn, Joseph M.; Andritsos, Leslie A.; Maddocks, Kami J.; Woyach, Jennifer A.; Blum, Kristie A.; Grever, Michael R.; Smucker, Kelly; Ruppert, Amy S.; Heerema, Nyla A.; Lozanski, Gerard; Stefanos, Mona; Munneke, Brian; West, Jamie-Sue; Neuenburg, Jutta K.; James, Danelle F.; Hall, Nathan; Johnson, Amy J.; Byrd, John C.

2015-01-01

Ibrutinib represents a therapeutic advance in chronic lymphocytic leukemia (CLL) but as monotherapy produces few complete remissions in previously treated patients. Anti-CD20 antibodies have improved response and progression-free survival (PFS) when combined with chemotherapy. We evaluated the safety and activity of adding ofatumumab to ibrutinib in 3 different administration sequences. Patients with CLL/small lymphocytic lymphoma (SLL), prolymphocytic leukemia, or Richter’s transformation who failed ≥2 prior therapies were enrolled. Patients received ibrutinib 420 mg daily and 12 doses of ofatumumab 300/2000 mg in 3 schedules: ibrutinib lead-in (group 1; n = 27), concurrent start (group 2; n = 20), or ofatumumab lead-in (group 3; n = 24). Seventy-one patients were treated; most had high-risk disease including del(17)(p13.1) (44%) or del(11)(q22.3) (31%). The most frequent adverse events (any grade) were diarrhea (70%), infusion-related reaction (45%), and peripheral sensory neuropathy (44%). Overall response rates in CLL/SLL patients (n = 66) were 100%, 79%, and 71% in groups 1, 2, and 3, respectively. Estimated 12-month PFSs for all patients were 89%, 85%, and 75%, respectively. Four patients in group 3 progressed prior to receiving ibrutinib. This study demonstrates the tolerability and clinical activity of this combination with quicker time to best response than single-agent ibrutinib and with durable responses. This trial was registered at www.clinicaltrials.gov as #NCT01217749. PMID:26116658

Safety and activity of BTK inhibitor ibrutinib combined with ofatumumab in chronic lymphocytic leukemia: a phase 1b/2 study.

PubMed

Jaglowski, Samantha M; Jones, Jeffrey A; Nagar, Veena; Flynn, Joseph M; Andritsos, Leslie A; Maddocks, Kami J; Woyach, Jennifer A; Blum, Kristie A; Grever, Michael R; Smucker, Kelly; Ruppert, Amy S; Heerema, Nyla A; Lozanski, Gerard; Stefanos, Mona; Munneke, Brian; West, Jamie-Sue; Neuenburg, Jutta K; James, Danelle F; Hall, Nathan; Johnson, Amy J; Byrd, John C

2015-08-13

Ibrutinib represents a therapeutic advance in chronic lymphocytic leukemia (CLL) but as monotherapy produces few complete remissions in previously treated patients. Anti-CD20 antibodies have improved response and progression-free survival (PFS) when combined with chemotherapy. We evaluated the safety and activity of adding ofatumumab to ibrutinib in 3 different administration sequences. Patients with CLL/small lymphocytic lymphoma (SLL), prolymphocytic leukemia, or Richter's transformation who failed ≥2 prior therapies were enrolled. Patients received ibrutinib 420 mg daily and 12 doses of ofatumumab 300/2000 mg in 3 schedules: ibrutinib lead-in (group 1; n = 27), concurrent start (group 2; n = 20), or ofatumumab lead-in (group 3; n = 24). Seventy-one patients were treated; most had high-risk disease including del(17)(p13.1) (44%) or del(11)(q22.3) (31%). The most frequent adverse events (any grade) were diarrhea (70%), infusion-related reaction (45%), and peripheral sensory neuropathy (44%). Overall response rates in CLL/SLL patients (n = 66) were 100%, 79%, and 71% in groups 1, 2, and 3, respectively. Estimated 12-month PFSs for all patients were 89%, 85%, and 75%, respectively. Four patients in group 3 progressed prior to receiving ibrutinib. This study demonstrates the tolerability and clinical activity of this combination with quicker time to best response than single-agent ibrutinib and with durable responses. This trial was registered at www.clinicaltrials.gov as #NCT01217749. © 2015 by The American Society of Hematology.

Computational Identification Of CDR3 Sequence Archetypes Among Immunoglobulin Sequences in Chronic Lymphocytic Leukemia

PubMed Central

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

2009-01-01

The leukemia cells of unrelated patients with chronic lymphocytic leukemia (CLL) display a restricted repertoire of immunoglobulin (Ig) gene rearrangements with preferential usage of certain Ig gene segments. We developed a computational method to rigorously quantify biases in Ig sequence similarity in large patient databases and to identify groups of patients with unusual levels of sequence similarity. We applied our method to sequences from 1577 CLL patients through the CLL Research Consortium (CRC), and identified 67 similarity groups into which roughly 20% of all patients could be assigned. Immunoglobulin light chain class was highly correlated within all groups and light chain gene usage was similar within sets. Surprisingly, over 40% of the identified groups were composed of somatically mutated genes. This study significantly expands the evidence that antigen selection shapes the Ig repertoire in CLL. PMID:18640719

Inhibition of maternal embryonic leucine zipper kinase with OTSSP167 displays potent anti-leukemic effects in chronic lymphocytic leukemia.

PubMed

Zhang, Ya; Zhou, Xiangxiang; Li, Ying; Xu, Yangyang; Lu, Kang; Li, Peipei; Wang, Xin

2018-06-12

TP53 pathway defects contributed to therapy resistance and adverse clinical outcome in chronic lymphocytic leukemia (CLL), which represents an unmet clinical need with few therapeutic options. Maternal embryonic leucine zipper kinase (MELK) is a novel oncogene, which plays crucial roles in mitotic progression and stem cell maintenance. OTSSP167, an orally administrated inhibitor targeting MELK, is currently in a phase I/II clinical trial in patients with advanced breast cancer and acute myeloid leukemia. Yet, no investigation has been elucidated to date regarding the oncogenic role of MELK and effects of OTSSP167 in chronic lymphocytic leukemia (CLL). Previous studies confirmed MELK inhibition abrogated cancer cell survival via p53 signaling pathway. Thus, we aimed to determine the biological function of MELK and therapeutic potential of OTSSP167 in CLL. Herein, MELK over-expression was observed in CLL cells, and correlated with higher WBC count, advanced stage, elevated LDH, increased β2-MG level, unmutated IGHV, positive ZAP-70, deletion of 17p13 and inferior prognosis of CLL patients. In accordance with functional enrichment analyses in gene expression profiling, CLL cells with depletion or inhibition of MELK exhibited impaired cell proliferation, enhanced fast-onset apoptosis, induced G2/M arrest, attenuated cell chemotaxis and promoted sensitivity to fludarabine and ibrutinib. However, gain-of-function assay showed increased cell proliferation and cell chemotaxis. In addition, OTSSP167 treatment reduced phosphorylation of AKT and ERK1/2. It decreased FoxM1 phosphorylation, expression of FoxM1, cyclin B1 and CDK1, while up-regulating p53 and p21 expression. Taken together, MELK served as a candidate of therapeutic target in CLL. OTSSP167 exhibits potent anti-tumor activities in CLL cells, highlighting a novel molecule-based strategy for leukemic interventions.

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

Targeting BTK through microRNA in chronic lymphocytic leukemia

PubMed Central

Bottoni, Arianna; Rizzotto, Lara; Lai, Tzung-Huei; Liu, Chaomei; Smith, Lisa L.; Mantel, Rose; Reiff, Sean; El-Gamal, Dalia; Larkin, Karilyn; Johnson, Amy J.; Lapalombella, Rosa; Lehman, Amy; Plunkett, William; Byrd, John C.; Blachly, James S.; Woyach, Jennifer A.

2016-01-01

Bruton’s tyrosine kinase (BTK) is a critical mediator of survival in B-cell neoplasms. Although BTK inhibitors have transformed therapy in chronic lymphocytic leukemia (CLL), patients with high-risk genetics are at risk for relapse and have a poor prognosis. Identification of novel therapeutic strategies for this group of patients is an urgent unmet clinical need, and therapies that target BTK via alternative mechanisms may fill this niche. Herein, we identify a set of microRNAs (miRs) that target BTK in primary CLL cells and show that the histone deacetylase (HDAC) repressor complex is recruited to these miR promoters to silence their expression. Targeting the HDACs by using either RNA interference against HDAC1 in CLL or a small molecule inhibitor (HDACi) in CLL and mantle cell lymphoma restored the expression of the BTK-targeting miRs with loss of BTK protein and downstream signaling and consequent cell death. We have also made the novel and clinically relevant discovery that inhibition of HDAC induces the BTK-targeting miRs in ibrutinib-sensitive and resistant CLL to effectively reduce both wild-type and C481S-mutant BTK. This finding identifies a novel strategy that may be promising as a therapeutic modality to eliminate the C481S-mutant BTK clone that drives resistance to ibrutinib and provides the rationale for a combination strategy that includes ibrutinib to dually target BTK to suppress its prosurvival signaling. PMID:27756747

Targeting BTK through microRNA in chronic lymphocytic leukemia.

PubMed

Bottoni, Arianna; Rizzotto, Lara; Lai, Tzung-Huei; Liu, Chaomei; Smith, Lisa L; Mantel, Rose; Reiff, Sean; El-Gamal, Dalia; Larkin, Karilyn; Johnson, Amy J; Lapalombella, Rosa; Lehman, Amy; Plunkett, William; Byrd, John C; Blachly, James S; Woyach, Jennifer A; Sampath, Deepa

2016-12-29

Bruton's tyrosine kinase (BTK) is a critical mediator of survival in B-cell neoplasms. Although BTK inhibitors have transformed therapy in chronic lymphocytic leukemia (CLL), patients with high-risk genetics are at risk for relapse and have a poor prognosis. Identification of novel therapeutic strategies for this group of patients is an urgent unmet clinical need, and therapies that target BTK via alternative mechanisms may fill this niche. Herein, we identify a set of microRNAs (miRs) that target BTK in primary CLL cells and show that the histone deacetylase (HDAC) repressor complex is recruited to these miR promoters to silence their expression. Targeting the HDACs by using either RNA interference against HDAC1 in CLL or a small molecule inhibitor (HDACi) in CLL and mantle cell lymphoma restored the expression of the BTK-targeting miRs with loss of BTK protein and downstream signaling and consequent cell death. We have also made the novel and clinically relevant discovery that inhibition of HDAC induces the BTK-targeting miRs in ibrutinib-sensitive and resistant CLL to effectively reduce both wild-type and C481S-mutant BTK. This finding identifies a novel strategy that may be promising as a therapeutic modality to eliminate the C481S-mutant BTK clone that drives resistance to ibrutinib and provides the rationale for a combination strategy that includes ibrutinib to dually target BTK to suppress its prosurvival signaling. © 2016 by The American Society of Hematology.

Hematopoietic stem cell transplantation for chronic lymphocytic leukemia.

PubMed

Gladstone, Douglas E; Fuchs, Ephraim

2012-03-01

Although hematopoietic stem cell transplantation (HSCT) is the treatment of choice for many aggressive hematologic malignancies, the role of HSCT in chronic lymphocytic leukemia (CLL) has remained controversial. Now in the era of improved conventional treatment and better prognostication of long-term outcome, a review of autologous and allogeneic HSCT in CLL treatment is warranted. Despite an improved disease-free survival in some patients, multiple, prospective, randomized autologous HSCT CLL trials fail to demonstrate an overall survival benefit as compared to conventional therapy. Allogeneic bone marrow transplantation, although limited by donor availability, can successfully eradicate CLL with adverse prognostic features. In the older CLL patients, nonmyeloablative allogeneic transplants are better tolerated than myeloablative transplants. Nonmyeloablative allogeneic transplants are less effective in heavily diseased burdened patients. Outside of a clinical protocol, autologous HSCT for CLL cannot be justified. Nonmyeloablative allogeneic transplantation should be considered in high-risk populations early in the disease process, when disease burden is most easily controlled. Alternative donor selection using haploidentical donors and posttransplantation cyclophosphamide has the potential to vastly increase the availability of curative therapy in CLL while retaining a low treatment-related toxicity.

Phase I Trial: Cirmtuzumab Inhibits ROR1 Signaling and Stemness Signatures in Patients with Chronic Lymphocytic Leukemia.

PubMed

Choi, Michael Y; Widhopf, George F; Ghia, Emanuela M; Kidwell, Reilly L; Hasan, Md Kamrul; Yu, Jian; Rassenti, Laura Z; Chen, Liguang; Chen, Yun; Pittman, Emily; Pu, Minya; Messer, Karen; Prussak, Charles E; Castro, Januario E; Jamieson, Catriona; Kipps, Thomas J

2018-06-01

Cirmtuzumab is a humanized monoclonal antibody (mAb) that targets ROR1, an oncoembryonic orphan receptor for Wnt5a found on cancer stem cells (CSCs). Aberrant expression of ROR1 is seen in many malignancies and has been linked to Rho-GTPase activation and cancer stem cell self-renewal. For patients with chronic lymphocytic leukemia (CLL), self-renewing, neoplastic B cells express ROR1 in 95% of cases. High-level leukemia cell expression of ROR1 is associated with an unfavorable prognosis. We conducted a phase 1 study involving 26 patients with progressive, relapsed, or refractory CLL. Patients received four biweekly infusions, with doses ranging from 0.015 to 20 mg/kg. Cirmtuzumab had a long plasma half-life and did not have dose-limiting toxicity. Inhibition of ROR1 signaling was observed, including decreased activation of RhoA and HS1. Transcriptome analyses showed that therapy inhibited CLL stemness gene expression signatures in vivo. Cirmtuzumab is safe and effective at inhibiting tumor cell ROR1 signaling in patients with CLL. Copyright © 2018. Published by Elsevier Inc.

Allogeneic stem cell transplantation for acute myeloid leukemia with del(7q) following untreated chronic lymphocytic leukemia.

PubMed

DeFilipp, Zachariah; Huynh, Donny V; Fazal, Salman; Sahovic, Entezam

2012-01-01

The development of hematologic malignancy in the presence of chronic lymphocytic leukemia (CLL) is rare. We present a case of acute myeloid leukemia (AML) with del(7q) occurring in a patient with a 4-year history of untreated CLL. Application of flow cytometry and immunohistochemistry allowed for characterization of two distinct coexisting malignant cell populations. After undergoing induction and consolidation chemotherapy, the patient achieved complete remission of AML with the persistence of CLL. Allogeneic transplantation was pursued given his unfavorable cytogenetics. Subsequent matched unrelated donor allogeneic stem cell transplantation resulted in full engraftment and complete remission, with no evidence of AML or CLL. Due to a scarcity of reported cases, insight into treatment and prognosis in cases of concurrent AML and CLL is limited. However, prognosis seems dependent on the chemosensitivity of AML. CLL did not have a detrimental effect on treatment or transplant outcome in our case. This is the first reported case of concomitant de novo AML and CLL to undergo allogeneic transplantation. The patient remained in complete hematologic and cytogenetic remission of both malignancies over a year after transplantation.

Comparison of Rai and Binet Classifications in Chronic Lymphocytic Leukemia.

PubMed

Zengin, N; Kars, A; Kansu, E; Özdemir, O; Barişta, İ; Güllü, İ; Güler, N; Özişik, Y; Dündar, S; Firat, D

1997-01-01

Staging systems are essential for understanding disease, in predicting the outcome, and therapeutic decision making in any tumor as well as chronic lymphocytic leukemia (CLL). In this study, we compared the clinical correlation of the Rai and Binet classification systems in 133 CLL patients. The distribution of 133 patients according to the Rai system was as follows, stage 0:17, I:13, II:45, III:30, IV:28, and in the Binet system stage A:35, B:40, C:58 patients. Median survival of patients according to the Rai staging system was >67.0, >91.0, 63.8, 20.9 and 9.8 months, and >91.0, 63.4, 16.0 months according to Binet, respectively. Although no difference was found between Rai stages 0, I, II (p > 0.05) in terms of median survival, the difference between these stages and stages III and IV was statistically significant (p < 0.05). In the Binet staging system statistically significant survival difference was found between all stages (p < 0.05). We concluded that although both systems are comparable in terms of staging and predicting the outcome of patients with CLL, the Rai staging system appears to have an advantage over the Binet system by defining a subset of patients with excellent prognosis (stage 0) which is included within stage A of the latter.

Pim kinase inhibitor, SGI-1776, induces apoptosis in chronic lymphocytic leukemia cells.

PubMed

Chen, Lisa S; Redkar, Sanjeev; Bearss, David; Wierda, William G; Gandhi, Varsha

2009-11-05

Pim kinases are involved in B-cell development and are overexpressed in B-cell chronic lymphocytic leukemia (CLL). We hypothesized that Pim kinase inhibition would affect B-cell survival. Identified from a screen of imidazo[1,2-b]pyridazine compounds, SGI-1776 inhibits Pim-1, Pim-2, and Pim-3. Treatment of CLL cells with SGI-1776 results in a concentration-dependent induction of apoptosis. To elucidate its mechanism of action, we evaluated the effect of SGI-1776 on Pim kinase function. Unlike in replicating cells, phosphorylation of traditional Pim-1 kinase targets, phospho-Bad (Ser112) and histone H3 (Ser10), and cell-cycle proteins were unaffected by SGI-1776, suggesting an alternative mechanism in CLL. Protein levels of total c-Myc as well as phospho-c-Myc(Ser62), a Pim-1 target site, were decreased after SGI-1776 treatment. Levels of antiapoptotic proteins Bcl-2, Bcl-X(L), XIAP, and proapoptotic Bak and Bax were unchanged; however, a significant reduction in Mcl-1 was observed that was not caused by caspase-mediated cleavage of Mcl-1 protein. The mechanism of decline in Mcl-1 was at the RNA level and was correlated with inhibition of global RNA synthesis. Consistent with a decline in new RNA synthesis, MCL-1 transcript levels were decreased after treatment with SGI-1776. These data suggest that SGI-1776 induces apoptosis in CLL and that the mechanism involves Mcl-1 reduction.

Pim kinase inhibitor, SGI-1776, induces apoptosis in chronic lymphocytic leukemia cells

PubMed Central

Chen, Lisa S.; Redkar, Sanjeev; Bearss, David; Wierda, William G.

2009-01-01

Pim kinases are involved in B-cell development and are overexpressed in B-cell chronic lymphocytic leukemia (CLL). We hypothesized that Pim kinase inhibition would affect B-cell survival. Identified from a screen of imidazo[1,2-b]pyridazine compounds, SGI-1776 inhibits Pim-1, Pim-2, and Pim-3. Treatment of CLL cells with SGI-1776 results in a concentration-dependent induction of apoptosis. To elucidate its mechanism of action, we evaluated the effect of SGI-1776 on Pim kinase function. Unlike in replicating cells, phosphorylation of traditional Pim-1 kinase targets, phospho-Bad (Ser112) and histone H3 (Ser10), and cell-cycle proteins were unaffected by SGI-1776, suggesting an alternative mechanism in CLL. Protein levels of total c-Myc as well as phospho-c-Myc(Ser62), a Pim-1 target site, were decreased after SGI-1776 treatment. Levels of antiapoptotic proteins Bcl-2, Bcl-XL, XIAP, and proapoptotic Bak and Bax were unchanged; however, a significant reduction in Mcl-1 was observed that was not caused by caspase-mediated cleavage of Mcl-1 protein. The mechanism of decline in Mcl-1 was at the RNA level and was correlated with inhibition of global RNA synthesis. Consistent with a decline in new RNA synthesis, MCL-1 transcript levels were decreased after treatment with SGI-1776. These data suggest that SGI-1776 induces apoptosis in CLL and that the mechanism involves Mcl-1 reduction. PMID:19734450

Duvelisib treatment is associated with altered expression of apoptotic regulators that helps in sensitization of chronic lymphocytic leukemia cells to venetoclax (ABT-199).

PubMed

Patel, V M; Balakrishnan, K; Douglas, M; Tibbitts, T; Xu, E Y; Kutok, J L; Ayers, M; Sarkar, A; Guerrieri, R; Wierda, W G; O'Brien, S; Jain, N; Stern, H M; Gandhi, V

2017-09-01

Duvelisib, an oral dual inhibitor of PI3K-δ and PI3K-γ, is in phase III trials for the treatment of chronic lymphocytic leukemia (CLL) and indolent non-Hodgkin's lymphoma. In CLL, duvelisib monotherapy is associated with high iwCLL (International Workshop on Chronic Lymphocytic Leukemia) and nodal response rates, but complete remissions are rare. To characterize the molecular effect of duvelisib, we obtained samples from CLL patients on the duvelisib phase I trial. Gene expression studies (RNAseq, Nanostring, Affymetrix array and real-time RT-PCR) demonstrated increased expression of BCL2 along with several BH3-only pro-apoptotic genes. In concert with induction of transcript levels, reverse phase protein arrays and immunoblots confirmed increase at the protein level. The BCL2 inhibitor venetoclax induced greater apoptosis in ex vivo-cultured CLL cells obtained from patients on duvelisib compared with pre-treatment CLL cells from the same patients. In vitro combination of duvelisib and venetoclax resulted in enhanced apoptosis even in CLL cells cultured under conditions that simulate the tumor microenvironment. These data provide a mechanistic rationale for testing the combination of duvelisib and venetoclax in the clinic. Such combination regimen (NCT02640833) is being evaluated for patients with B-cell malignancies including CLL.

"Surgical" abdomen in a patient with chronic lymphocytic leukemia: a case of acquired angioedema.

PubMed

Jung, Moonjung; Rice, Lawrence

2011-12-01

Acquired angioedema (AAE), an acquired deficiency of C1esterase inhibitor, is a medically treatable condition which can cause severe abdominal pain mimicking an acute surgical abdomen. This disorder is strongly associated with chronic lymphocytic leukemia (CLL) and other indolent lymphoplasmacytic disorders. We describe a patient with known CLL who developed incapacitating, recurrent severe abdominal pains, culminating in partial bowel resection. Signs, symptoms, laboratory and pathologic findings demonstrated AAE. Wider appreciation of the possibility of AAE, particularly in patients with lymphoproliferative disorders, could lead to preventive therapy and spare unnecessary surgery. This is more important now that more effective medical therapies are available.

NOTCH1 Is Aberrantly Activated in Chronic Lymphocytic Leukemia Hematopoietic Stem Cells.

PubMed

Di Ianni, Mauro; Baldoni, Stefano; Del Papa, Beatrice; Aureli, Patrizia; Dorillo, Erica; De Falco, Filomena; Albi, Elisa; Varasano, Emanuela; Di Tommaso, Ambra; Giancola, Raffaella; Accorsi, Patrizia; Rotta, Gianluca; Rompietti, Chiara; Silva Barcelos, Estevão Carlos; Campese, Antonio Francesco; Di Bartolomeo, Paolo; Screpanti, Isabella; Rosati, Emanuela; Falzetti, Franca; Sportoletti, Paolo

2018-01-01

To investigate chronic lymphocytic leukemia (CLL)-initiating cells, we assessed NOTCH1 mutation/expression in hematopoietic stem cells (HSCs). In NOTCH1- mutated CLL, we detected subclonal mutations in 57% CD34+/CD38- HSCs. NOTCH1 mutation was present in 66% CD34+/CD38+ progenitor cells displaying an increased mutational burden compared to HSCs. Flow cytometric analysis revealed significantly higher NOTCH1 activation in CD34+/CD38- and CD34+/CD38+ cells from CLL patients, regardless NOTCH1 mutation compared to healthy donors. Activated NOTCH1 resulted in overexpression of the NOTCH1 target c-MYC. We conclude that activated NOTCH1 is an early event in CLL that may contribute to aberrant HSCs in this disease.

MALT1 Inhibition Is Efficacious in Both Naïve and Ibrutinib-Resistant Chronic Lymphocytic Leukemia.

PubMed

Saba, Nakhle S; Wong, Deanna H; Tanios, Georges; Iyer, Jessica R; Lobelle-Rich, Patricia; Dadashian, Eman L; Liu, Delong; Fontan, Lorena; Flemington, Erik K; Nichols, Cydney M; Underbayev, Chingiz; Safah, Hana; Melnick, Ari; Wiestner, Adrian; Herman, Sarah E M

2017-12-15

The clinical efficacy displayed by ibrutinib in chronic lymphocytic leukemia (CLL) has been challenged by the frequent emergence of resistant clones. The ibrutinib target, Bruton's tyrosine kinase (BTK), is essential for B-cell receptor signaling, and most resistant cases carry mutations in BTK or PLCG2 , a downstream effector target of BTK. Recent findings show that MI-2, a small molecule inhibitor of the para-caspase MALT1, is effective in preclinical models of another type of BCR pathway-dependent lymphoma. We therefore studied the activity of MI-2 against CLL and ibrutinib-resistant CLL. Treatment of CLL cells in vitro with MI-2 inhibited MALT1 proteolytic activity reduced BCR and NF-κB signaling, inhibited nuclear translocation of RelB and p50, and decreased Bcl-xL levels. MI-2 selectively induced dose and time-dependent apoptosis in CLL cells, sparing normal B lymphocytes. Furthermore, MI-2 abrogated survival signals provided by stromal cells and BCR cross-linking and was effective against CLL cells harboring features associated with poor outcomes, including 17p deletion and unmutated IGHV Notably, MI-2 was effective against CLL cells collected from patients harboring mutations conferring resistance to ibrutinib. Overall, our findings provide a preclinical rationale for the clinical development of MALT1 inhibitors in CLL, in particular for ibrutinib-resistant forms of this disease. Cancer Res; 77(24); 7038-48. ©2017 AACR . ©2017 American Association for Cancer Research.

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

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

PubMed

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

2016-04-01

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

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

PubMed Central

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

2014-01-01

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 TCL1tg 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. PMID:24668151

Multidimensional Single-Cell Analysis of BCR Signaling Reveals Proximal Activation Defect As a Hallmark of Chronic Lymphocytic Leukemia B Cells

PubMed Central

Palomba, M. Lia; Piersanti, Kelly; Ziegler, Carly G. K.; Decker, Hugo; Cotari, Jesse W.; Bantilan, Kurt; Rijo, Ivelise; Gardner, Jeff R.; Heaney, Mark; Bemis, Debra; Balderas, Robert; Malek, Sami N.; Seymour, Erlene; Zelenetz, Andrew D.

2014-01-01

Purpose Chronic Lymphocytic Leukemia (CLL) is defined by a perturbed B-cell receptor-mediated signaling machinery. We aimed to model differential signaling behavior between B cells from CLL and healthy individuals to pinpoint modes of dysregulation. Experimental Design We developed an experimental methodology combining immunophenotyping, multiplexed phosphospecific flow cytometry, and multifactorial statistical modeling. Utilizing patterns of signaling network covariance, we modeled BCR signaling in 67 CLL patients using Partial Least Squares Regression (PLSR). Results from multidimensional modeling were validated using an independent test cohort of 38 patients. Results We identified a dynamic and variable imbalance between proximal (pSYK, pBTK) and distal (pPLCγ2, pBLNK, ppERK) phosphoresponses. PLSR identified the relationship between upstream tyrosine kinase SYK and its target, PLCγ2, as maximally predictive and sufficient to distinguish CLL from healthy samples, pointing to this juncture in the signaling pathway as a hallmark of CLL B cells. Specific BCR pathway signaling signatures that correlate with the disease and its degree of aggressiveness were identified. Heterogeneity in the PLSR response variable within the B cell population is both a characteristic mark of healthy samples and predictive of disease aggressiveness. Conclusion Single-cell multidimensional analysis of BCR signaling permitted focused analysis of the variability and heterogeneity of signaling behavior from patient-to-patient, and from cell-to-cell. Disruption of the pSYK/pPLCγ2 relationship is uncovered as a robust hallmark of CLL B cell signaling behavior. Together, these observations implicate novel elements of the BCR signal transduction as potential therapeutic targets. PMID:24489640

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

PubMed Central

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

2008-01-01

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

Overexpressed BAG3 is a potential therapeutic target in chronic lymphocytic leukemia.

PubMed

Zhu, Huayuan; Wu, Wei; Fu, Yuan; Shen, Wenyi; Miao, Kourong; Hong, Min; Xu, Wei; Young, Ken H; Liu, Peng; Li, Jianyong

2014-03-01

Bcl-2-associated athanogene 3 (BAG3), a member of BAG family, is shown to sustain cell survival and underlie resistance to chemotherapy in human neoplastic cells. We aimed to determine the exact role and underlying mechanisms of BAG3 in human chronic lymphocytic leukemia (CLL). One hundred human CLL samples and 20 normal B-cell samples from healthy controls were collected. We measured the BAG3 expression in these cells and explored its relationship with known prognostic factors for CLL. The roles of BAG3 in cell apoptosis and migration were evaluated by small interfering RNA-mediated knockdown of BAG3 in primary CLL cells. We showed that BAG3 expression level was increased in CLL cells compared with normal B cells. Moreover, BAG3 expression was particularly upregulated in CD38 positive, unmutated immunoglobulin heavy-chain patients and those with lymphadenopathy and/or splenomegaly. Importantly, patients with increased BAG3 expression level have poor overall survival in subgroups with positive ZAP-70 or those without any "p53 abnormality". In addition, knocking down of BAG3 expression resulted in increased apoptotic ratio and decreased migration in primary CLL cells. Our data indicate that BAG3 is a marker of poor prognostic in specific subgroups of CLL patients and may be a potential therapeutic target for this disease.

Pharmacokinetic and Pharmacodynamic Considerations in the Treatment of Chronic Lymphocytic Leukemia: Ibrutinib, Idelalisib, and Venetoclax.

PubMed

Waldron, Madeline; Winter, Allison; Hill, Brian T

2017-11-01

Management of chronic lymphocytic leukemia has changed markedly over the last several years with the emergence of several novel oral agents targeting B-cell receptor and Bcl-2 signaling pathways. For patients requiring treatment, ibrutinib, idelalisib, and venetoclax offer unique clinical benefits with a different set of therapeutic considerations compared with traditional parenteral therapy. Despite the conveniences afforded by oral therapy, these agents also carry unique logistical obstacles. Drug interactions with agents that are metabolized via the cytochrome P450 3A4 pathway are possible with all three agents. Unique treatment-related adverse events including bleeding and atrial fibrillation with ibrutinib, hepatotoxicity with idelalisib, and tumor lysis syndrome with venetoclax can be severe and dose limiting. Furthermore, dose adjustments for organ dysfunction may also be warranted. Here, we review the available literature on the pharmacokinetic and pharmacodynamic properties of these novel agents to guide the reader in the appropriate use of ibrutinib, idelalisib, and venetoclax.

Antibody persistence after pneumococcal conjugate vaccination in patients with chronic lymphocytic leukemia.

PubMed

Lindström, Vesa; Aittoniemi, Janne; Salmenniemi, Urpu; Käyhty, Helena; Huhtala, Heini; Itälä-Remes, Maija; Sinisalo, Marjatta

2018-02-08

Patients with chronic lymphocytic leukemia (CLL) are at a high risk for infections caused by Streptococcus pneumoniae. A pneumococcal conjugate vaccine (PCV) can induce a significant antibody response for some CLL patients. In this study we investigated antibody persistence after PCV7 in patients with CLL. The study material comprised 24 patients with CLL and 8 immunocompetent controls. The median antibody concentrations five years after PCV7 were lower for six pneumococcal serotypes in patients with CLL compared to controls, but the difference was not statistically significant. Depending on the serotype, the percentage of the CLL patients with antibody levels suggested to provide protection against invasive pneumococcal disease (IPD) varied from 29 to 71% five years after vaccination. This data suggests that PCV could result in antibody persistence at least five years in CLL patients.

Current Treatment of Chronic Lymphocytic Leukemia.

PubMed

Jamroziak, Krzysztof; Puła, Bartosz; Walewski, Jan

2017-01-01

A number of new treatment options have recently emerged for chronic lymphocytic leukemia (CLL) patients, including the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib, phosphatidylinositol-3-kinase (PI3K) delta isoform inhibitor idelalisib combined with rituximab, the Bcl-2 antagonist venetoclax, and the new anti-CD20 antibodies obinutuzumab and ofatumumab. Most of these agents are already included into treatment algorithms defined by international practice guidelines, but more clinical investigations are needed to answer still remaining questions. Ibrutinib was proven as a primary choice for patients with the TP53 gene deletion/mutation, who otherwise have no active treatment available. Idelalisib with rituximab is also an active therapy, but due to increased risk of serious infections, its use in first-line treatment is limited to patients for whom ibrutinib is not an option. A new indication for ibrutinib was recently approved for older patients with comorbidities, as an alternative to the already existing indication for chlorambucil with obinutuzumab. The use of kinase inhibitors is already well established in recurrent/refractory disease. Immunochemotherapy with fludarabine, cyclophosphamide, rituximab (FCR) remains a major first-line option for many CLL patients without the TP53 gene deletion/mutation, and who have no significant comorbidities or history of infections, and is particularly effective in patients with favorable features including mutated IGHV status. There are a number of issues regarding novel therapies for CLL that need further investigation such as optimum duration of treatment with kinase inhibitors, appropriate sequencing of novel agents, mechanisms of resistance to inhibitors and response to class switching after treatment failure, along with the potential role of combinations of targeted agents.

Prevalence of ZAP-70 and CD 38 in Indian chronic lymphocytic leukemia patients.

PubMed

Gogia, A; Sharma, A; Raina, V; Kumar, L; Gupta, R; Kumar, R

2013-01-01

Chronic lymphocytic leukemia (CLL) is the most common chronic lympho-proliferative disorder. This study was undertaken to know the prevalence of ZAP-70 and CD 38 in the treatment naive patients of CLL seen at a tertiary care centre of north India. ZAP-70 and CD 38 were tested by flow cytometry on peripheral blood samples. ZAP-70 positive and CD 38 positivity was defined as positive expression on 20% and 30% of CLL cells, respectively. Clinico-hematological profile and its correlation with ZAP-70 and CD 38 were assessed in consecutive 80 CLL patients. There were 64 males and median age of the group was 58 years. Sixteen patients (20%) were asymptomatic and diagnosed incidentally. Median total lymphocyte count (TLC) at presentation was 62 × 10 9 /L. Rai stage distribution was: Stage 0-6, stage I-20, stage II-36, stage III-5, and stage IV-13. ZAP-70 and CD 38 positivity were detected in 20 patients (25%) and 29 patients (36%), respectively. Eleven patients were positive and 34 were negative for both ZAP-70 and CD 38 yielding a concordance rate of 56%. There was no statistically significant difference between ZAP-70 and CD 38 positivity and negativity with regard to age, sex, Lymphocyte count, lymphadenopathy, organomegaly, and Rai staging. ZAP-70 and CD 38 positivity were detected 25% and 36%, respectively, with concordance rate of 56%, which is higher than Western literature. There was no correlation of ZAP-70 and CD 38 positivity with age, sex, lymphadenopathy, organomegaly, and Rai staging.

Human Lyb-2 homolog CD72 is a marker for progenitor B-cell leukemias.

PubMed

Schwarting, R; Castello, R; Moldenhauer, G; Pezzutto, A; von Hoegen, I; Ludwig, W D; Parnes, J R; Dörken, B

1992-11-01

S-HCL 2 is the prototype antibody of the recently defined CD72 cluster (human Lyb-2). Under nonreducing conditions, S-HCL 2 monoclonal antibody (mAb) precipitates a glycoprotein of 80-86 kDa. Under reducing conditions, a dimer of 43 and 39 kDa, with core proteins of 40 and 36 kDa, is precipitated. CD72 expression in normal and malignant tissues is different from expression of all other previously described human B-cell antigens. In peripheral blood and bone marrow, the antigen appears to be present on all B lymphocytes, with the exception of plasma cells. In tissue, immunohistochemical staining revealed positivity for all known B-cell compartments; however, pulpa macrophages of the spleen and von Kupffer cells exhibited distinct positivity for CD72 also. Among 83 malignant non-Hodgkin's lymphomas examined by immunohistochemistry (alkaline phosphatase anti-alkaline phosphatase technique), all 54 B-cell lymphomas, including precursor B-cell lymphomas, Burkitt's lymphomas, germinal center lymphomas, chronic lymphocytic leukemias, and hairy cell leukemias, were CD72 positive, but no T-cell lymphomas were. Flow cytometry study of more than 80 mainly acute leukemias (52 B-cell leukemias) showed reactivity with S-HCL 2 mAb over the full range of B-cell differentiation. In particular, very early B cells in cytoplasmic Ig (cIg)-negative, CD19-positive pre-pre-B-cell leukemias and hybrid leukemias (mixed myeloid and B-cell type) were consistently positive for CD72 on the cell surface. Therefore, CD72 may become an important marker for progenitor B-cell leukemias.

Targeting BCL2 With BH3 Mimetics: Basic Science and Clinical Application of Venetoclax in Chronic Lymphocytic Leukemia and Related B Cell Malignancies.

PubMed

Roberts, A W; Huang, Dcs

2017-01-01

The intracellular protein B-cell-lymphoma-2 (BCL2) has been considered an attractive target for cancer therapy since the discovery of its function as a major promoter of cell survival (an anti-apoptotic) in the late 1980s. However, the challenges of targeting a protein-protein interaction delayed the discovery of fit-for-purpose molecules until the mid-2000s. Since then, a series of high affinity small organic molecules that inhibits the interaction of BCL2 with the apoptotic machinery, the so-called BH3-mimetics, have been developed. Venetoclax (formerly ABT-199) is the first to achieve US Food and Drug Administration approval, with an indication for treatment of patients with previously treated chronic lymphocytic leukemia (CLL) bearing deletion of the long arm of chromosome 17. Here, we review key aspects of the science underpinning the clinical application of BCL2 inhibitors and explore both our current knowledge and unresolved questions about its clinical utility, both in CLL and in other B-cell malignancies that highly express BCL2. © 2016 The Authors Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

Comparable Efficacy of Idelalisib Plus Rituximab and Ibrutinib in Relapsed/refractory Chronic Lymphocytic Leukemia: A Retrospective Case Matched Study of the Polish Adult Leukemia Group (PALG).

PubMed

Puła, Bartosz; Budziszewska, Bożena Katarzyna; Rybka, Justyna; Gil, Lidia; Subocz, Edyta; Długosz-Danecka, Monika; Zawirska, Daria; Waszczuk-Gajda, Anna; Iskierka-Jażdżewska, Elżbieta; Kopacz, Agnieszka; Szymczyk, Agnieszka; Czyż, Jarosław; Lech-Marańda, Ewa; Warzocha, Krzysztof; Jamroziak, Krzysztof

2018-05-01

There is limited amount of data available on the comparative efficacy of ibrutinib and idelalisib, the B-cell receptor inhibitors (BCRi) newly approved for relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (r/r CLL/SLL) treatment. The aim of our study was to analyze and compare the outcomes of real-world r/r CLL/SLL patients treated with these two BCRi in outside clinical trials. A comparative case matched 1:2 analysis was performed on idelalisib combined with rituximab and ibrutinib efficacy in 102 patients with r/r CLL/SLL from two observational studies of the Polish Adult Leukemia Group (PALG). Both therapies produced similar overall response rates (idelalisib plus rituximab 76.4% and ibrutinib 72.1%). Median progression-free survival (PFS) and overall survival (OS) in both groups were not reached. Furthermore, no significant difference was observed between both BCRi regimens in regard to PFS (HR=0.75, 95% CI=0.30-1.86, p=0.55) and OS (HR=0.65, 95%CI=0.26-1.68, p=0.39). In summary, the results of this retrospective analysis suggest that idelalisib combined with rituximab and ibrutinib therapies have comparable activity in r/r CLL/SLL in daily clinical practice. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

VpreB gene expression in hematopoietic malignancies: a lineage- and stage-restricted marker for B-cell precursor leukemias.

PubMed

Bauer, S R; Kubagawa, H; Maclennan, I; Melchers, F

1991-09-15

We show here that analysis of VpreB gene transcription can be a specific way to identify acute leukemias of cells at very early stages of B-cell development. Northern blot analysis of RNAs from 63 leukemia samples showed that VpreB RNA was present in malignancies of precursor B cells, the expression being a feature of both common acute lymphoblastic leukemia (ALL) (CD10+) and null ALL (CD10-). It was absent from malignancies of mature B cells (surface Ig positive), from acute leukemias of the T-cell lineage and granulocyte-macrophage lineages, and from normal tonsil B and T lymphocytes. Chronic myeloid leukemia blast crises of the B-precursor-cell type expressed the VpreB gene while myeloid blast crises did not. VpreB RNA was also expressed in the neoplastic cells of one of three patients with acute undifferentiated leukemias. These data show that VpreB RNA expression is a marker of the malignant forms of precursor B cells, and that it appears at least as early as cytoplasmic CD22 and CD19 in tumors of the B-cell lineage.

Bruton's tyrosine kinase (BTK) function is important to the development and expansion of chronic lymphocytic leukemia (CLL).

PubMed

Woyach, Jennifer A; Bojnik, Engin; Ruppert, Amy S; Stefanovski, Matthew R; Goettl, Virginia M; Smucker, Kelly A; Smith, Lisa L; Dubovsky, Jason A; Towns, William H; MacMurray, Jessica; Harrington, Bonnie K; Davis, Melanie E; Gobessi, Stefania; Laurenti, Luca; Chang, Betty Y; Buggy, Joseph J; Efremov, Dimitar G; Byrd, John C; Johnson, Amy J

2014-02-20

Chronic lymphocytic leukemia (CLL) is characterized by constitutive activation of the B-cell receptor (BCR) signaling pathway, but variable responsiveness of the BCR to antigen ligation. Bruton's tyrosine kinase (BTK) shows constitutive activity in CLL and is the target of irreversible inhibition by ibrutinib, an orally bioavailable kinase inhibitor that has shown outstanding activity in CLL. Early clinical results in CLL with other reversible and irreversible BTK inhibitors have been less promising, however, raising the question of whether BTK kinase activity is an important target of ibrutinib and also in CLL. To determine the role of BTK in CLL, we used patient samples and the Eμ-TCL1 (TCL1) transgenic mouse model of CLL, which results in spontaneous leukemia development. Inhibition of BTK in primary human CLL cells by small interfering RNA promotes apoptosis. Inhibition of BTK kinase activity through either targeted genetic inactivation or ibrutinib in the TCL1 mouse significantly delays the development of CLL, demonstrating that BTK is a critical kinase for CLL development and expansion and thus an important target of ibrutinib. Collectively, our data confirm the importance of kinase-functional BTK in CLL.

Molecular genetics of chronic neutrophilic leukemia, chronic myelomonocytic leukemia and atypical chronic myeloid leukemia.

PubMed

Li, Bing; Gale, Robert Peter; Xiao, Zhijian

2014-12-12

According to the 2008 World Health Organization classification, chronic neutrophilic leukemia, chronic myelomonocytic leukemia and atypical chronic myeloid leukemia are rare diseases. The remarkable progress in our understanding of the molecular genetics of myeloproliferative neoplasms and myelodysplastic/myeloproliferative neoplasms has made it clear that there are some specific genetic abnormalities in these 3 rare diseases. At the same time, there is considerable overlap among these disorders at the molecular level. The various combinations of genetic abnormalities indicate a multi-step pathogenesis, which likely contributes to the marked clinical heterogeneity of these disorders. This review focuses on the current knowledge and challenges related to the molecular pathogenesis of chronic neutrophilic leukemia, chronic myelomonocytic leukemia and atypical chronic myeloid leukemia and relationships between molecular findings, clinical features and prognosis.

Treatment of Relapsed and/or Chemotherapy Refractory B-cell Malignancy by CART19

ClinicalTrials.gov

2016-01-26

Hematopoietic/Lymphoid Cancer; Adult Acute Lymphoblastic Leukemia in Remission; B-cell Adult Acute Lymphoblastic Leukemia; B-cell Chronic Lymphocytic Leukemia; Prolymphocytic Leukemia; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Refractory Chronic Lymphocytic Leukemia; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Chronic Lymphocytic Leukemia; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Chronic Lymphocytic Leukemia; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma

DNA repair polymorphisms in B-cell chronic lymphocytic leukemia in sufferers of Chernobyl Nuclear Power Plant accident.

PubMed

Abramenko, Iryna; Bilous, Nadiia; Chumak, Anatolyi; Kostin, Alexey; Martina, Zoya; Dyagil, Iryna

2012-01-01

An association between DNA repair gene polymorphisms, environmental factors, and development of some types of cancer has been suggested by several studies. Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in the clean-up workers of the Chernobyl Nuclear Power Plant (NPP) accident and it has some specific features. Therefore, we have studied the possible differences in DNA repair gene polymorphisms in CLL patients depending on ionizing radiation (IR) exposure history and their clinical characterictics. Arg399Gln XRCC1, Thr241Met XRCC3, and Lys751Gln XPD polymorphisms were studied in 64 CLL patients, exposed to IR due to the Chernobyl NPP accident, 114 IR-non-exposed CLL patients, and 103 sex- and age-matched IR-exposed controls using polymerase chain reaction-restriction fragment-length polymorphism analysis. All investigated polymorphisms were equally distributed between two groups of CLL patients and IR-exposed controls, except that that there was a significant reduction of the common homozygous Lys/Lys XPD genotype among IR-exposed CLL patients (23.7%) compared with IR-exposed controls (45.6%), OR = 0.37; 95% CI = 0.18-0.75; (P = 0.005). The number of IR-non-exposed CLL patients (37.4%) with the Lys/Lys XPD genotype was also decreased compared to IR-exposed controls, although this difference was not significant (P = 0.223). These preliminary data suggest a possible modifying role of Lys751Gln XPD polymorphism for the development of CLL, expecially in radiation-exposed persons.

FTY720, a new alternative for treating blast crisis chronic myelogenous leukemia and Philadelphia chromosome–positive acute lymphocytic leukemia

PubMed Central

Neviani, Paolo; Santhanam, Ramasamy; Oaks, Joshua J.; Eiring, Anna M.; Notari, Mario; Blaser, Bradley W.; Liu, Shujun; Trotta, Rossana; Muthusamy, Natarajan; Gambacorti-Passerini, Carlo; Druker, Brian J.; Cortes, Jorge; Marcucci, Guido; Chen, Ching-Shih; Verrills, Nicole M.; Roy, Denis C.; Caligiuri, Michael A.; Bloomfield, Clara D.; Byrd, John C.; Perrotti, Danilo

2007-01-01

Blast crisis chronic myelogenous leukemia (CML-BC) and Philadelphia chromosome–positive (Ph1-positive) acute lymphocytic leukemia (ALL) are 2 fatal BCR/ABL-driven leukemias against which Abl kinase inhibitors fail to induce a long-term response. We recently reported that functional loss of protein phosphatase 2A (PP2A) activity is important for CML blastic transformation. We assessed the therapeutic potential of the PP2A activator FTY720 (2-amino-2-[2-(4-octylphenyl)ethyl]-1,3-propanediol hydrochloride), an immunomodulator in Phase III trials for patients with multiple sclerosis or undergoing organ transplantation, in CML-BC and Ph1 ALL patient cells and in in vitro and in vivo models of these BCR/ABL+ leukemias. Our data indicate that FTY720 induces apoptosis and impairs clonogenicity of imatinib/dasatinib-sensitive and -resistant p210/p190BCR/ABL myeloid and lymphoid cell lines and CML-BCCD34+ and Ph1 ALLCD34+/CD19+ progenitors but not of normal CD34+ and CD34+/CD19+ bone marrow cells. Furthermore, pharmacologic doses of FTY720 remarkably suppress in vivo p210/p190BCR/ABL-driven [including p210/p190BCR/ABL (T315I)] leukemogenesis without exerting any toxicity. Altogether, these results highlight the therapeutic relevance of rescuing PP2A tumor suppressor activity in Ph1 leukemias and strongly support the introduction of the PP2A activator FTY720 in the treatment of CML-BC and Ph1 ALL patients. PMID:17717597

Diagnosis of Richter transformation in chronic lymphocytic leukemia: histology tips the scales.

PubMed

Federmann, Birgit; Mueller, Martin R; Steinhilber, Julia; Horger, Marius S; Fend, Falko

2018-06-12

Development of diffuse large B-cell lymphoma in chronic lymphocytic leukemia, so-called Richter transformation (RT), occurs in 2-5% of patients and is associated with poor outcome. The clinical features of RT are fairly non-specific and unable to discriminate transformation from other mimics. In case of clinically suspected RT, a CT/MRT is recommended, and FDG-PET/CT may help to select the site of biopsy. Radiological features suggestive of RT have been defined, but there are only limited data about their predictive value, and histological confirmation is still considered the gold standard for RT diagnosis. We retrospectively analyzed 34 patients with clinically suspected RT and available radiological and histological data. A histopathological diagnosis of RT with concordant clinical and radiological findings was obtained in 13 patients. In 18 patients, CT did not show features of transformation, concordant with lack of RT in the biopsy. Of interest, a distinct lymphoma other than DLBCL was identified in two of these cases. A false-positive radiological diagnosis of RT was rendered in two patients, including a case of Herpes simplex virus lymphadenitis. In conclusion, our findings confirm the central role of tissue biopsy in the diagnostic work up in case of clinically suspected RT.

Ibrutinib modifies the function of monocyte/macrophage population in chronic lymphocytic leukemia

PubMed Central

Audrito, Valentina; Martinelli, Silvia; Hacken, Elisa ten; Zucchini, Patrizia; Grisendi, Giulia; Potenza, Leonardo; Luppi, Mario; Burger, Jan A.; Deaglio, Silvia; Marasca, Roberto

2016-01-01

In lymphoid organs, nurse-like cells (NLCs) show properties of tumor-associated macrophages, playing a crucial role in chronic lymphocytic leukemia (CLL) cell survival. Ibrutinib, a potent inhibitor of Bruton's tyrosine kinase (BTK), is able to counteract pro-survival signals in CLL cells. Since the effects on CLL cells have been studied in the last years, less is known about the influence of ibrutinib on NLCs properties. We sought to determine how ibrutinib modifies NLCs functions focusing on the balance between immunosuppressive and inflammatory features. Our data show that ibrutinib targets BTK expressed by NLCs modifying their phenotype and function. Treatment with ibrutinib reduces the phagocytic ability and increases the immunosuppressive profile of NLCs exacerbating the expression of M2 markers. Accordingly, ibrutinib hampers LPS-mediated signaling, decreasing STAT1 phosphorylation, while allows IL-4-mediated STAT6 phosphorylation. In addition, NLCs treated with ibrutinib are able to protect CLL cells from drug-induced apoptosis partially through the secretion of IL-10. Results from patient samples obtained prior and after 1 month of treatment with ibrutinib show an accentuation of CD206, CD11b and Tie2 in the monocytic population in the peripheral blood. Our study provides new insights into the immunomodulatory action of ibrutinib on monocyte/macrophage population in CLL. PMID:27602755

Ibrutinib modifies the function of monocyte/macrophage population in chronic lymphocytic leukemia.

PubMed

Fiorcari, Stefania; Maffei, Rossana; Audrito, Valentina; Martinelli, Silvia; Ten Hacken, Elisa; Zucchini, Patrizia; Grisendi, Giulia; Potenza, Leonardo; Luppi, Mario; Burger, Jan A; Deaglio, Silvia; Marasca, Roberto

2016-10-04

In lymphoid organs, nurse-like cells (NLCs) show properties of tumor-associated macrophages, playing a crucial role in chronic lymphocytic leukemia (CLL) cell survival. Ibrutinib, a potent inhibitor of Bruton's tyrosine kinase (BTK), is able to counteract pro-survival signals in CLL cells. Since the effects on CLL cells have been studied in the last years, less is known about the influence of ibrutinib on NLCs properties. We sought to determine how ibrutinib modifies NLCs functions focusing on the balance between immunosuppressive and inflammatory features. Our data show that ibrutinib targets BTK expressed by NLCs modifying their phenotype and function. Treatment with ibrutinib reduces the phagocytic ability and increases the immunosuppressive profile of NLCs exacerbating the expression of M2 markers. Accordingly, ibrutinib hampers LPS-mediated signaling, decreasing STAT1 phosphorylation, while allows IL-4-mediated STAT6 phosphorylation. In addition, NLCs treated with ibrutinib are able to protect CLL cells from drug-induced apoptosis partially through the secretion of IL-10. Results from patient samples obtained prior and after 1 month of treatment with ibrutinib show an accentuation of CD206, CD11b and Tie2 in the monocytic population in the peripheral blood. Our study provides new insights into the immunomodulatory action of ibrutinib on monocyte/macrophage population in CLL.

Massive oral bleeding after full-mouth extraction in a patient with B-cell lymphocytic leukemia/small lymphocytic lymphoma reversed with recombinant activated factor VII.

PubMed

Sprenker, Collin; Omar, Hesham R; Powless, R Andrew; Mangar, Devanand; Camporesi, Enrico

2016-02-01

Full-mouth extraction can be associated with intraoral bleeding, which usually is controlled with local hemostatic measures. Recombinant activated factor VII (rFVIIa) occasionally is used to stop bleeding in a variety of off-label indications, with the main argument curtailing its use being thrombotic events. The authors describe the use of rFVIIa for bleeding after full-mouth extraction in a patient with undiagnosed B-cell lymphocytic leukemia/small lymphocytic lymphoma. A 72-year-old man underwent full-mouth extraction (18 teeth). The next day, the patient experienced massive oral bleeding. The authors administered tranexamic acid, aminocaproic acid, and a total of 12 units of packed red blood cells in addition to local hemostatic measures without control of bleeding. On postoperative day 10, the authors administered 5,000 micrograms of rFVIIa, and within 2 hours oral the bleeding ceased. The authors performed flow cytometry and diagnosed B-cell lymphocytic leukemia/small lymphocytic lymphoma. Unexplained massive oral bleeding despite adequate local hemostatic measures should prompt further investigations for underlying bleeding or coagulation disorders. The authors describe the successful use of rFVIIa in massive oral bleeding. Further studies are mandatory to study the effectiveness of this drug for this off-label indication. Copyright © 2016 American Dental Association. Published by Elsevier Inc. All rights reserved.

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

PubMed Central

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

2016-01-01

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

Diagnosis and treatment of chronic lymphocytic leukemia in a bat-eared fox (Otocyon megalotis).

PubMed

Nevitt, Benjamin N; Langan, Jennifer N; Adkesson, Michael J; Landolfi, Jennifer A; Wilson, Rand

2014-12-15

Severe lymphocytosis and leukocytosis were detected during examination of a 10-year-old sexually intact male bat-eared fox (Otocyon megalotis) with regionally extensive alopecia. A CBC revealed severe leukocytosis (39,100 leukocytes/μL) and marked lymphocytosis (90%). A blood smear consisted predominantly of intermediate-sized lymphocytes and few large lymphocytes, with mild to moderate nuclear atypia. These findings were highly suggestive of chronic lymphocytic leukemia (CLL). Cytologic evaluation of bone marrow aspirates revealed no evidence of overt malignancy, with 10% of all cells identified as small to intermediate-sized mature lymphocytes. Treatment with chlorambucil and prednisone administered orally over a 1.8-year period decreased the leukocyte and lymphocyte counts to within reference intervals with no adverse effects. Although repeated flow cytometry revealed evidence of residual disease, the fox remained free of clinical disease, and WBC counts were within reference intervals for this species. At 22 months after initial evaluation, the fox was euthanized because of debilitating arthritis. No evidence of CLL was detected grossly or histologically during necropsy. To the authors' knowledge, this was the first report of CLL in a bat-eared fox and first successful treatment in a nondomestic carnivore. Treatment in accordance with a chemotherapeutic protocol successfully resolved the leukocytosis and lymphocytosis with no serious adverse effects. Description of this fox and the treatment protocol should provide a valuable reference for future cases in this and other nondomestic canine species.

Phase 1 Study of Terameprocol (EM-1421) in Patients With Leukemia

ClinicalTrials.gov

2016-02-20

Leukemias; Acute Myeloid Leukemia (AML); Acute Lymphocytic Leukemia (ALL); Adult T Cell Leukemia (ATL); Chronic Myeloid Leukemia (CML-BP); Chronic Lymphocytic Leukemia (CLL); Myelodysplastic Syndrome (MDS); Chronic Myelomonocytic Leukemia (CMML)

Acute Lymphocytic Leukemia

MedlinePlus

... radiation. People exposed to very high levels of radiation, such as survivors of a nuclear reactor accident, have an increased risk of developing acute lymphocytic leukemia. Genetic disorders. Certain genetic disorders, such as Down syndrome, are associated with an increased risk of acute ...

County level incidence rates of chronic lymphocytic leukemia are associated with residential radon levels.

PubMed

Oancea, S Cristina; Rundquist, Bradley C; Simon, Isaac; Swartz, Sami; Zheng, Yun; Zhou, Xudong; Sens, Mary Ann; Schwartz, Gary G

2017-09-01

We previously reported that incidence rates for chronic lymphocytic leukemia (CLL) among US states are significantly correlated with levels of residential radon (RR). Because these correlations could be influenced by confounding and/or misclassification among large geographic units, we reinvestigated them using smaller geographic units that better reflect exposure and disease at the individual level. We examined the relationships between CLL and RR per county in 478 counties with publicly-available data. After adjustment for ultraviolet radiation, a possible risk factor for CLL, county rates for CLL and RR were significantly correlated among males and females both together and separately (p < 0.0001). CLL is significantly associated with RR at the county level.

Coming full circle: 70 years of chronic lymphocytic leukemia cell redistribution, from glucocorticoids to inhibitors of B-cell receptor signaling

PubMed Central

Montserrat, Emili

2013-01-01

Chronic lymphocytic leukemia (CLL) cells proliferate in pseudofollicles within the lymphatic tissues, where signals from the microenvironment and BCR signaling drive the expansion of the CLL clone. Mobilization of tissue-resident cells into the blood removes CLL cells from this nurturing milieu and sensitizes them to cytotoxic drugs. This concept recently gained momentum after the clinical activity of kinase inhibitors that target BCR signaling (spleen tyrosine kinase, Bruton tyrosine kinase, PI3Kδ inhibitors) was established. Besides antiproliferative activity, these drugs cause CLL cell redistribution with rapid lymph node shrinkage, along with a transient surge in lymphocytosis, before inducing objective remissions. Inactivation of critical CLL homing mechanism (chemokine receptors, adhesion molecules), thwarting tissue retention and recirculation into the tissues, appears to be the basis for this striking clinical activity. This effect of BCR-signaling inhibitors resembles redistribution of CLL cells after glucocorticoids, described as early as in the 1940s. As such, we are witnessing a renaissance of the concept of leukemia cell redistribution in modern CLL therapy. Here, we review the molecular basis of CLL cell trafficking, homing, and redistribution and similarities between old and new drugs affecting these processes. In addition, we outline how these discoveries are changing our understanding of CLL biology and therapy. PMID:23264597

[National guidelines for the management of patients with chronic lymphocytic leukemia. Sociedad Espan˜ola de Hematologı´a y Hemoterapia and Grupo Espan˜ol de Leucemia Linfocı´tica Cro´ nica].

PubMed

García Marco, José A; Giraldo Castellano, Pilar; López Jiménez, Javier; Ríos Herranz, Eduardo; Sastre Moral, José Luis; Terol Casterá, M José; Bosch Albareda, Francesc

2013-08-17

Chronic lymphocytic leukemia is the most common chronic lymphoproliferative disorder in Spain. The clinical management of this entity varies widely. Currently, in Spain, there are no national consensus guidelines, such as those published in other countries, to guide the diagnosis and treatment of this malignancy and the use of prognostic scores. This article reviews the current scientific literature and addresses issues on the diagnosis of chronic lymphocytic leukemia, the spread of the disease, the presence of comorbidities, the classification of prognostic scores, the common treatment regimens stratified by risk factors, and the management of complications associated with both the disease and its treatment, as well as the various controversies related to this entity. This document was drafted with the collaboration of national experts and aims to establish practical guidelines with their corresponding levels of evidence and grades of recommendation to guide the diagnosis, treatment and follow-up of patients with chronic lymphocytic leukemia. Copyright © 2013 Elsevier España, S.L. All rights reserved.

Targeted Axl Inhibition Primes Chronic Lymphocytic Leukemia B Cells to Apoptosis and Shows Synergistic/Additive Effects in Combination with BTK Inhibitors.

PubMed

Sinha, Sutapa; Boysen, Justin; Nelson, Michael; Secreto, Charla; Warner, Steven L; Bearss, David J; Lesnick, Connie; Shanafelt, Tait D; Kay, Neil E; Ghosh, Asish K

2015-05-01

B-cell chronic lymphocytic leukemia (CLL) is an incurable disease despite aggressive therapeutic approaches. We previously found that Axl receptor tyrosine kinase (RTK) plays a critical role in CLL B-cell survival. Here, we explored the possibility of using a high-affinity Axl inhibitor as a single agent or in combination with Bruton's tyrosine kinase (BTK) inhibitors for future clinical trial to treat patients with CLL. Expression/activation status of other members of the TAM (e.g., Tyro3, Axl, and MER) family of RTKs in CLL B cells was evaluated. Cells were treated with a high-affinity orally bioavailable Axl inhibitor TP-0903 with or without the presence of CLL bone marrow stromal cells (BMSCs). Inhibitory effects of TP-0903 on the Axl signaling pathway were also evaluated in CLL B cells. Finally, cells were exposed to TP-0903 in combination with BTK inhibitors to determine any synergistic/additive effects of the combination. CLL B cells overexpress Tyro3, but not MER. Of interest, Tyro3 remains as constitutively phosphorylated and forms a complex with Axl in CLL B cells. TP-0903 induces massive apoptosis in CLL B cells with LD50 values of nanomolar ranges. Importantly, CLL BMSCs could not protect the leukemic B cells from TP-0903-induced apoptosis. A marked reduction of the antiapoptotic proteins Mcl-1, Bcl-2, and XIAP and upregulation of the proapoptotic protein BIM in CLL B cells was detected as a result of Axl inhibition. Finally, combination of TP-0903 with BTK inhibitors augments CLL B-cell apoptosis. Administration of TP-0903 either as a single agent or in combination with BTK inhibitors may be effective in treating patients with CLL. ©2015 American Association for Cancer Research.

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.

Chronic lymphocytic leukemia-associated chromosomal abnormalities and miRNA deregulation.

PubMed

Kiefer, Yvonne; Schulte, Christoph; Tiemann, Markus; Bullerdiek, Joern

2012-01-01

Chronic lymphocytic leukemia is the most common leukemia in adults. By cytogenetic investigations major subgroups of the disease can be identified that reflect different routes of tumor development. Of these chromosomal deviations, trisomy 12 and deletions of parts of either the long arm of chromosome 13, the long arm of chromosome 11, or the short arm of chromosome 17 are most commonly detected. In some of these aberrations the molecular target has been identified as eg, ataxia telangiectasia mutated (ATM) in case of deletions of chromosomal region 11q22~23 and the genes encoding microRNAs miR-15a/16-1 as likely targets of deletions of chromosomal band 13q14.3. Of note, these aberrations do not characterize independent subgroups but often coexist within the metaphases of one tumor. Generally, complex aberrations are associated with a worse prognosis than simple karyotypic alterations. Due to smaller sizes of the missing segment the detection of recurrent deletions is not always possible by means of classical cytogenetics but requires more advanced techniques as in particular fluorescence in situ hybridization (FISH). Nevertheless, at this time it is not recommended to replace classical cytogenetics by FISH because this would miss additional information given by complex or secondary karyotypic alterations. However, the results of cytogenetic analyses allow the stratification of prognostic and predictive groups of the disease. Of these, the group characterized by deletions involving TP53 is clinically most relevant. In the future refined methods as eg, array-based comparative genomic hybridization will supplement the existing techniques to characterize CLL.

Glutathione-S-transferases pi, alpha, mu and mdr1 mRNA expression in normal lymphocytes and chronic lymphocytic leukemia.

PubMed

Marie, J P; Simonin, G; Legrand, O; Delmer, A; Faussat, A M; Lewis, A D; Sikic, B I; Zittoun, R

1995-10-01

Chronic B cell lymphoproliferative disorders are frequently sensitive to alkylating agents. To assess the glutathione-S-transferases (GSTs) gene expression in B tumoral lymphocytes, possibly responsible for this sensitivity, we developed a sensitive RT-PCR assay for the three isoenzymes GST pi, GST mu and GST alpha mRNA. Normal B and T lymphocytes from 11 blood donors were separated by magnetic beads and tested with this assay. The GST pi was the most abundant transferase, and was detected in all B and T cell samples. GST mu was undetectable ('null' phenotype) in 6/11 normal donors, either in B or T cells. GST alpha was very stable from donor to donor, and was highly correlated between B and T cells of the same individual (P < 0.0001). There is no correlation between the three isoenzymes, and between each isoenzyme and mdr1 gene expression. Twenty-three B lymphoproliferative disorders (20 B-CLL, 3 CD5- chronic lymphoproliferative syndromes) were tested with the same technique. An average decrease of 57% of the GST pi expression was noted in the mononuclear cells of these patients (P < 0.02), with no differences between the untreated and treated cases. The GST alpha and mdr1 mRNA levels did not differ from normal B lymphocytes, but the proportion of patients with no detectable expression of GST mu is lower than in the control (13%). Interestingly, the low content of GST pi in B-CLL could explain the frequent sensitivity of this disease to alkylating agents.

Different frequencies and effects of ABCB1 T3435C polymorphism on clinical and laboratory features of B cell chronic lymphocytic leukemia in Kurdish patients.

PubMed

Maroofi, Farzad; Amini, Sabrieh; Roshani, Daem; Ghaderi, Bayazid; Abdi, Mohammad

2015-04-01

Finding the effects of gene polymorphism on cancer pathogenesis is very desirable. The ATP-binding cassette is involved in drug metabolism, and the polymorphism of this gene may be an important risk factor in B cell chronic lymphocytic leukemia (B-CLL) or progression and/or response to chemotherapy agents. For the first time, the present study was aimed to evaluate the probable effects of ABCB1 T3435C polymorphism on clinical and laboratory features of Kurdish patients with B-CLL. This descriptive analytical case-control study was performed on 50 B-CLL patients and 100 healthy subjects. Serum levels of beta-2-microglobulin (B2M) and lactate dehydrogenase (LDH) and blood WBC, RBC, Plt and ESR were measured. The T3435C polymorphism of the ABCB1 gene was determined by PCR-RFLP. Concentration of serum and blood markers was significantly higher in the malignant group than in the benign subjects. The CC genotype had the highest frequency (66%) in the patient groups. There are no significant differences between the genotypes and type of treatment. Our results demonstrate the high frequency of C allele of ABCB1 T3435C in B-CLL patients with Kurdish ethnicity. We also show that this polymorphism has a significant risk factor in B-CLL. However, the effect of this polymorphism on clinical and laboratory characteristics of B-CLL patients was not significant.

[Chromosome banding analysis of peripheral blood lymphocytes stimulated with IL2 and CpG oligonucleotide DSP30 in patients with chronic lymphocytic leukemia].

PubMed

Stěpanovská, K; Vaňková, G; Némethová, V; Tomášiková, L; Smuhařová, P; Divíšková, E; Vallová, V; Kuglík, P; Plevová, K; Oltová, A; Doubek, M; Pospíšilová, S; Mayer, J

2013-01-01

Chromosomal aberrations play an important role as prognostic factors in chronic lymphocytic leukemia (CLL). These aberrations are mostly detected by fluorescent in situ hybridization (FISH), as chromosomal banding analysis has been scarce due to low proliferative activity of malignant B-lymphocytes in vitro. In 2006, a new method using stimulation with IL-2 and CpG oligonucleotide DSP30 for metaphase generation in CLL was published [1]. The objective of our study was to verify the efficacy of stimulation and to evaluate if the method is suitable for routine diagnostics. In total, peripheral blood samples of 369 CLL patients were analyzed in parallel by chromosomal banding analysis and by FISH probes for 13q14, 11q22-23, CEP12 and 17p13. Out of 369 patients, 307 (83%) were successfully stimulated for metaphase generation. Chromosomal aberrations were detected in 243 (79%) out of 307 patients evaluated by chromosomal banding analysis. Other aberrations that are not included into standard FISH panel were detected in patients karyotypes, e.g. del(6q), del(14q), t(14;18)(q32;q21), t(11;14)(q13;q32) and t(18;22)(q21;q11). One hundred and three (42%) patients showed complex aberrant karyotype not detected by FISH analysis. Stimulation with IL-2 and oligonucleotide DSP30 is an efficient method how to induce proliferation of malignant B-lymphocytes and allows detection of a substantial number of chromosomal aberrations in addition to those detected by standard FISH panel. Using this method in routine diagnostics is helpful particularly in identification of patients with complex aberrant karyotype.

Familial chronic lymphocytic leukemia in Israel: A disproportionate distribution among Ashkenazi Jews.

PubMed

Zada, Mor; Lerner, Daniele; Piltz, Yuval; Perry, Chava; Avivi, Irit; Herishanu, Yair

2017-07-01

Relatives of patients with chronic lymphocytic leukemia (CLL) are at increased risk of developing CLL. Familial CLL is defined as more than one case of CLL among blood relatives, a phenomenon reported in approximately 5%-10% of all CLL patients. Given the known predisposition of CLL among Ashkenazi Jews, we studied the features of familial CLL in an Israeli population. This is a retrospective study, in which we reviewed the demographics, clinical characteristics, and outcomes of a total of 332 patients with CLL/small lymphocytic lymphoma. Familial CLL was recorded in 41 cases (12.3%) of the patients. The age at diagnosis was younger in patients with familial CLL (by almost 3.5 years). Familial CLL was strongly associated with Ashkenazi Jewish origin. Patients with familial CLL more commonly presented with higher hemoglobin and lower serum β-2-microglobulin levels. No significant differences were detected between sporadic and familial CLL in disease stage, time to treatment, second cancers, or overall survival. Familial cases of CLL in an Israeli population show a disproportionate ethnic distribution toward Jews of Ashkenazi origin. The clinical characteristics and the overall outcome are not substantially different from sporadic cases. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Ibrutinib: a new frontier in the treatment of chronic lymphocytic leukemia by Bruton's tyrosine kinase inhibition.

PubMed

Dias, Ajoy Lawrence; Jain, Dharamvir

2013-12-01

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

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

PubMed

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

2016-12-22

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

Flavopiridol in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, or Chronic Myelogenous Leukemia

ClinicalTrials.gov

2013-06-03

Adult Acute Basophilic Leukemia; Adult Acute Eosinophilic Leukemia; Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); Adult Acute Monoblastic Leukemia (M5a); Adult Acute Monocytic Leukemia (M5b); Adult Acute Myeloblastic Leukemia With Maturation (M2); Adult Acute Myeloblastic Leukemia Without Maturation (M1); Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Myelomonocytic Leukemia (M4); Adult Erythroleukemia (M6a); Adult Pure Erythroid Leukemia (M6b); Blastic Phase Chronic Myelogenous Leukemia; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Relapsing Chronic Myelogenous Leukemia

A human monoclonal antibody drug and target discovery platform for B-cell chronic lymphocytic leukemia based on allogeneic hematopoietic stem cell transplantation and phage display.

PubMed

Baskar, Sivasubramanian; Suschak, Jessica M; Samija, Ivan; Srinivasan, Ramaprasad; Childs, Richard W; Pavletic, Steven Z; Bishop, Michael R; Rader, Christoph

2009-11-12

Allogeneic hematopoietic stem cell transplantation (alloHSCT) is the only potentially curative treatment available for patients with B-cell chronic lymphocytic leukemia (B-CLL). Here, we show that post-alloHSCT antibody repertoires can be mined for the discovery of fully human monoclonal antibodies to B-CLL cell-surface antigens. Sera collected from B-CLL patients at defined times after alloHSCT showed selective binding to primary B-CLL cells. Pre-alloHSCT sera, donor sera, and control sera were negative. To identify post-alloHSCT serum antibodies and subsequently B-CLL cell-surface antigens they recognize, we generated a human antibody-binding fragment (Fab) library from post-alloHSCT peripheral blood mononuclear cells and selected it on primary B-CLL cells by phage display. A panel of Fab with B-CLL cell-surface reactivity was strongly enriched. Selection was dominated by highly homologous Fab predicted to bind the same antigen. One Fab was converted to immunoglobulin G1 and analyzed for reactivity with peripheral blood mononuclear cells from B-CLL patients and healthy volunteers. Cell-surface antigen expression was restricted to primary B cells and up-regulated in primary B-CLL cells. Mining post-alloHSCT antibody repertoires offers a novel route to discover fully human monoclonal antibodies and identify antigens of potential therapeutic relevance to B-CLL and possibly other cancers. Trials described herein were registered at www.clinicaltrials.gov as nos. NCT00055744 and NCT00003838.

Automated array-based genomic profiling in chronic lymphocytic leukemia: Development of a clinical tool and discovery of recurrent genomic alterations

PubMed Central

Schwaenen, Carsten; Nessling, Michelle; Wessendorf, Swen; Salvi, Tatjana; Wrobel, Gunnar; Radlwimmer, Bernhard; Kestler, Hans A.; Haslinger, Christian; Stilgenbauer, Stephan; Döhner, Hartmut; Bentz, Martin; Lichter, Peter

2004-01-01

B cell chronic lymphocytic leukemia (B-CLL) is characterized by a highly variable clinical course. Recurrent chromosomal imbalances provide significant prognostic markers. Risk-adapted therapy based on genomic alterations has become an option that is currently being tested in clinical trials. To supply a robust tool for such large scale studies, we developed a comprehensive DNA microarray dedicated to the automated analysis of recurrent genomic imbalances in B-CLL by array-based comparative genomic hybridization (matrix–CGH). Validation of this chip in a series of 106 B-CLL cases revealed a high specificity and sensitivity that fulfils the criteria for application in clinical oncology. This chip is immediately applicable within clinical B-CLL treatment trials that evaluate whether B-CLL cases with distinct chromosomal abnormalities should be treated with chemotherapy of different intensities and/or stem cell transplantation. Through the control set of DNA fragments equally distributed over the genome, recurrent genomic imbalances were discovered: trisomy of chromosome 19 and gain of the MYCN oncogene correlating with an elevation of MYCN mRNA expression. PMID:14730057

Rapid and efficient nonviral gene delivery of CD154 to primary chronic lymphocytic leukemia cells.

PubMed

Li, L H; Biagi, E; Allen, C; Shivakumar, R; Weiss, J M; Feller, S; Yvon, E; Fratantoni, J C; Liu, L N

2006-02-01

Interactions between CD40 and CD40 ligand (CD154) are essential in the regulation of both humoral and cellular immune responses. Forced expression of human CD154 in B chronic lymphocytic leukemia (B-CLL) cells can upregulate costimulatory and adhesion molecules and restore antigen-presenting capacity. Unfortunately, B-CLL cells are resistant to direct gene manipulation with most currently available gene transfer systems. In this report, we describe the use of a nonviral, clinical-grade, electroporation-based gene delivery system and a standard plasmid carrying CD154 cDNA, which achieved efficient (64+/-15%) and rapid (within 3 h) transfection of primary B-CLL cells. Consistent results were obtained from multiple human donors. Transfection of CD154 was functional in that it led to upregulated expression of CD80, CD86, ICAM-I and MHC class II (HLA-DR) on the B-CLL cells and induction of allogeneic immune responses in MLR assays. Furthermore, sustained transgene expression was demonstrated in long-term cryopreserved transfected cells. This simple and rapid gene delivery technology has been validated under the current Good Manufacturing Practice conditions, and multiple doses of CD154-expressing cells were prepared for CLL patients from one DNA transfection. Vaccination strategies using autologous tumor cells manipulated ex vivo for patients with B-CLL and perhaps with other hematopoietic malignancies could be practically implemented using this rapid and efficient nonviral gene delivery system.

Ibrutinib as Initial Therapy for Patients with Chronic Lymphocytic Leukemia

PubMed Central

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

2016-01-01

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

Ibrutinib as Initial Therapy for Patients with Chronic Lymphocytic Leukemia.

PubMed

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

2015-12-17

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

Polymer-coated surface enhanced Raman scattering (SERS) gold nanoparticles for multiplexed labeling of chronic lymphocytic leukemia cells

NASA Astrophysics Data System (ADS)

MacLaughlin, Christina M.; Parker, Edward P. K.; Walker, Gilbert C.; Wang, Chen

2012-01-01

The ease and flexibility of functionalization and inherent light scattering properties of plasmonic nanoparticles make them suitable contrast agents for measurement of cell surface markers. Immunophenotyping of lymphoproliferative disorders is traditionally undertaken using fluorescence detection methods which have a number of limitations. Herein, surface-enhanced Raman scattering (SERS) gold nanoparticles conjugated to monoclonal antibodies are used for the selective targeting of CD molecules on the surface of chronic lymphocytic leukemia (CLL) cells. Raman-active reporters were physisorbed on to the surface of 60 nm spherical Au nanoparticles, the particles were coated with 5kDa polyethylene glycol (PEG) including functionalities for conjugation to monoclonal IgG1 antibodies. A novel method for quantifying the number of antibodies bound to SERS probes on an individual basis as opposed to obtaining averages from solution was demonstrated using metal dots in transmission electron microscopy (TEM). The specificity of the interaction between SERS probes and surface CD molecules of CLL cells was assessed using Raman spectroscopy and dark field microscopy. An in-depth study of SERS probe targeting to B lymphocyte marker CD20 was undertaken, and proof-of-concept targeting using different SERS nanoparticle dyes specific for cell surface CD19, CD45 and CD5 demonstrated using SERS spectroscopy.

Arsenic Trioxide in Treating Patients With Relapsed or Refractory Lymphoma or Leukemia

ClinicalTrials.gov

2013-01-31

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

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

ClinicalTrials.gov

2018-04-02

Glioma; Lymphoma; Metastatic Malignant Solid Neoplasm; Neuroendocrine Neoplasm; Recurrent Adult Soft Tissue Sarcoma; Recurrent Bladder Carcinoma; Recurrent Breast Carcinoma; Recurrent Chronic Lymphocytic Leukemia; Recurrent Colorectal Carcinoma; Recurrent Head and Neck Carcinoma; Recurrent Lung Carcinoma; Recurrent Malignant Solid Neoplasm; Recurrent Melanoma; Recurrent Pancreatic Carcinoma; Recurrent Primary Cutaneous T-Cell Non-Hodgkin Lymphoma; Recurrent Prostate Carcinoma; Recurrent Renal Cell Carcinoma; Recurrent Thyroid Gland Carcinoma; Refractory Chronic Lymphocytic Leukemia; Refractory Mature T-Cell and NK-Cell Non-Hodgkin Lymphoma; Refractory Primary Cutaneous T-Cell Non-Hodgkin Lymphoma; Stage III Breast Cancer AJCC v7; Stage III Colorectal Cancer AJCC v7; Stage III Cutaneous Melanoma AJCC v7; Stage III Lung Cancer AJCC v7; Stage III Pancreatic Cancer AJCC v6 and v7; Stage III Prostate Cancer AJCC v7; Stage III Renal Cell Cancer AJCC v7; Stage III Soft Tissue Sarcoma AJCC v7; Stage IIIA Breast Cancer AJCC v7; Stage IIIA Colorectal Cancer AJCC v7; Stage IIIA Cutaneous Melanoma AJCC v7; Stage IIIB Breast Cancer AJCC v7; Stage IIIB Colorectal Cancer AJCC v7; Stage IIIB Cutaneous Melanoma AJCC v7; Stage IIIC Breast Cancer AJCC v7; Stage IIIC Colorectal Cancer AJCC v7; Stage IIIC Cutaneous Melanoma AJCC v7; Stage IV Breast Cancer AJCC v6 and v7; Stage IV Colorectal Cancer AJCC v7; Stage IV Cutaneous Melanoma AJCC v6 and v7; Stage IV Lung Cancer AJCC v7; Stage IV Pancreatic Cancer AJCC v6 and v7; Stage IV Prostate Cancer AJCC v7; Stage IV Renal Cell Cancer AJCC v7; Stage IV Soft Tissue Sarcoma AJCC v7; Stage IVA Colorectal Cancer AJCC v7; Stage IVB Colorectal Cancer AJCC v7; Unresectable Solid Neoplasm

Impact of Venetoclax Exposure on Clinical Efficacy and Safety in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia.

PubMed

Freise, Kevin J; Jones, Aksana K; Eckert, Doerthe; Mensing, Sven; Wong, Shekman L; Humerickhouse, Rod A; Awni, Walid M; Salem, Ahmed Hamed

2017-05-01

Venetoclax is a selective, potent, first-in-class B-cell lymphoma-2 inhibitor that restores apoptosis in cancer cells and has demonstrated efficacy in a variety of hematological malignancies. The objective of this research was to characterize the relationship between venetoclax exposures and efficacy and safety in patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). A total of 272 and 338 patients from four clinical studies were pooled for the exposure-efficacy and exposure-safety analyses, respectively. Demographics, baseline disease characteristics, and select co-medications were evaluated for their impact on efficacy (lymphocytes, tumor size, objective response [OR]) and safety (neutropenia and infection). Higher venetoclax concentrations led to a more rapid decrease in lymphocyte counts and tumor size, which translated into patients more rapidly achieving OR. The 17p deletion somatic mutation was not identified, in any of the analyses, to affect the responsiveness of patients to venetoclax. Model-based simulations of lymphocyte counts and tumor size estimated an OR rate (ORR) of 84.8 % (95 % confidence interval 81.5-88.0 %) at a venetoclax dosage of 400 mg daily, with minimal increase in ORR at higher doses. The safety analyses of the adverse events (grade 3 or higher) of neutropenia and infection indicated that higher average venetoclax concentrations were not associated with an increase in adverse events. The exposure-response analyses indicated that a venetoclax dosage regimen of 400 mg daily results in a high (>80 %) probability of achieving OR in R/R CLL/SLL patients, with minimal probability of increasing neutropenia or infection with higher exposures.

Overexpression of nucleolin in chronic lymphocytic leukemia cells induces stabilization of bcl2 mRNA

PubMed Central

Otake, Yoko; Soundararajan, Sridharan; Sengupta, Tapas K.; Kio, Ebenezer A.; Smith, James C.; Pineda-Roman, Mauricio; Stuart, Robert K.; Spicer, Eleanor K.

2007-01-01

B-cell chronic lymphocytic leukemia (CLL) is characterized by the accumulation of clonal B cells that are resistant to apoptosis as a result of bcl2 oncogene overexpression. Studies were done to determine the mechanism for the up-regulation of bcl-2 protein observed in CD19+ CLL cells compared with CD19+ B cells from healthy volunteers. The 11-fold higher level of bcl-2 protein in CLL cells was positively correlated with a 26-fold elevation in the cytosolic level of nucleolin, a bcl2 mRNA–stabilizing protein. Measurements of the bcl2 heterogeneous nuclear/bcl2 mRNA (hnRNA)/mRNA ratios and the rates of bcl2 mRNA decay in cell extracts indicated that the 3-fold higher steady-state level of bcl2 mRNA in CLL cells was the result of increased bcl2 mRNA stability. Nucleolin was present throughout the nucleus and cytoplasm of CLL cells, whereas in normal B cells nucleolin was only detected in the nucleus. The addition of recombinant human nucleolin to extracts of normal B cells markedly slowed the rate of bcl2 mRNA decay. SiRNA knockdown of nucleolin in MCF-7 cells resulted in decreased levels of bcl2 mRNA and protein but no change in β-actin. These results indicate that bcl-2 overexpression in CLL cells is related to stabilization of bcl2 mRNA by nucleolin. PMID:17179226

Study of the quantitative, functional, cytogenetic, and immunoregulatory properties of bone marrow mesenchymal stem cells in patients with B-cell chronic lymphocytic leukemia.

PubMed

Pontikoglou, Charalampos; Kastrinaki, Maria-Christina; Klaus, Mirjam; Kalpadakis, Christina; Katonis, Pavlos; Alpantaki, Kalliopi; Pangalis, Gerassimos A; Papadaki, Helen A

2013-05-01

The bone marrow (BM) microenvironment has clearly been implicated in the pathogenesis of B-cell chronic lymphocytic leukemia (B-CLL). However, the potential involvement of BM stromal progenitors, the mesenchymal stem cells (MSCs), in the pathophysiology of the disease has not been extensively investigated. We expanded in vitro BM-MSCs from B-CLL patients (n=11) and healthy individuals (n=16) and comparatively assessed their reserves, proliferative potential, differentiation capacity, and immunoregulatory effects on T- and B-cells. We also evaluated the anti-apoptotic effect of patient-derived MSCs on leukemic cells and studied their cytogenetic characteristics in comparison to BM hematopoietic cells. B-CLL-derived BM MSCs exhibit a similar phenotype, differentiation potential, and ability to suppress T-cell proliferative responses as compared with MSCs from normal controls. Furthermore, they do not carry the cytogenetic abnormalities of the leukemic clone, and they exert a similar anti-apoptotic effect on leukemic cells and healthy donor-derived B-cells, as their normal counterparts. On the other hand, MSCs from B-CLL patients significantly promote normal B-cell proliferation and IgG production, in contrast to healthy-donor-derived MSCs. Furthermore, they have impaired reserves, defective cellular growth due to increased apoptotic cell death and exhibit aberrant production of stromal cell-derived factor 1, B-cell activating factor, a proliferation inducing ligand, and transforming growth factor β1, cytokines that are crucial for the survival/nourishing of the leukemic cells. We conclude that ex vivo expanded B-CLL-derived MSCs harbor intrinsic qualitative and quantitative abnormalities that may be implicated in disease development and/or progression.

Cryptococcal infections in two patients receiving ibrutinib therapy for chronic lymphocytic leukemia.

PubMed

Stankowicz, Matthew; Banaszynski, Megan; Crawford, Russell

2018-01-01

Cryptococcal infections are responsible for significant morbidity and mortality in immunocompromised patients. Reports of these infections in patients on small molecular kinase inhibitors have not been widely reported in clinical trials. We describe one case of cryptococcal meningoencephalitis and one case of cryptococcal pneumonia in two patients who were receiving ibrutinib for chronic lymphocytic leukemia. Despite different sites of cryptococcal infection, both patients had similar presentations of acute illness. Patient 1 was worked up for health care-associated pneumonia, as well as acute sinusitis prior to the diagnosis of cryptococcal meningoencephalitis. He also had a more complex past medical history than patient 2. Patient 2 developed atrial fibrillation from ibrutinib prior to admission for presumed health care-associated pneumonia. Cryptococcal antigen testing was done sooner in this patient due to patient receiving high-dose steroids for the treatment of underlying hemolytic anemia. We conclude that patients who develop acute illness while receiving ibrutinib should be considered for cryptococcal antigen testing.

STAT3-activated CD36 facilitates fatty acid uptake in chronic lymphocytic leukemia cells

PubMed Central

Rozovski, Uri; Harris, David M.; Li, Ping; Liu, Zhiming; Jain, Preetesh; Ferrajoli, Alessandra; Burger, Jan; Thompson, Phillip; Jain, Nitin; Wierda, William; Keating, Michael J.; Estrov, Zeev

2018-01-01

Although several studies established that unlike normal B cells chronic lymphocytic leukemia (CLL) cells metabolize fatty acids (FA), how CLL cells internalize FA is poorly understood. Because in various cell types CD36 facilitates FA uptake, we wondered whether a similar mechanism is operative CLL. We found that CD36 levels are higher in CLL cells than in normal B cells, and that small interfering RNA, CD36 neutralizing antibodies or sulfosuccinimidyl oleate (SSO) that inhibits CD36 significantly reduced the oxygen consumption of CLL cells incubated with FA. Because CD36 is oeverexpressed and STAT3 is constitutively activated in CLL cells, we wondered whether STAT3 induces CD36 expression. Sequence analysis identified putative STAT3 binding sites in the CD36 gene promoter. Chromatin immunoprecipitation and an electrophoretic mobility shift assay revealed that STAT3 binds to the CD36 gene promoter. A luciferase assay and STAT3-small hairpin RNA, that significantly decreased the levels of CD36 in CLL cells, established that STAT3 activates the transcription of the CD36 gene. Furthermore, SSO induced a dose-dependent apoptosis of CLL cells. Taken together, our data suggest that STAT3 activates CD36 and that CD36 facilitates FA uptake in CLL cells. Whether CD36 inhibition would provide clinical benefits in CLL remains to be determined. PMID:29765537

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

PubMed Central

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

2011-01-01

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

Three newly approved drugs for chronic lymphocytic leukemia (CLL): Incorporating ibrutinib, idelalisib and obinutuzumab into clinical practice

PubMed Central

Sanford, David; Wierda, William G.; Burger, Jan A.; Keating, Michael J.; O’Brien, Susan M.

2016-01-01

Three agents have received FDA approval for treatment of chronic lymphocytic leukemia (CLL) within the last year. Ibrutinib and idelalisib block B-cell receptor signaling through inhibition of BTK and PI3Kδ molecules respectively, interfering with several pathways required for leukemia cell survival. Idelalisib has shown efficacy in in the relapsed setting and is currently approved for use in combination with rituximab. Ibrutinib has been studied in patients with relapsed CLL and as frontline therapy. In the relapsed setting, these agents produce durable remissions, and may be preferable to retreatment with chemoimmunotherapy for many patients. Ibrutinib is also effective treatment for patients with deletion 17p and is approved as frontline therapy in this patient group, although it does not appear to completely abrogate this adverse prognostic factor. These agents have a unique side effect profile and longer follow-up is required to further understand tolerability and rare adverse effects. Obinutuzumab is a type-2 monoclonal anti-CD20 antibody which results in direct and antibody-dependent cell-mediated cytotoxicity of leukemia cells. It is approved in combination with chlorambucil, and has shown efficacy in the frontline setting in patients unfit for more intensive chemoimmunotherapy. It produces increased response rates and minimal residual disease (MRD) negativity in comparison with chlorambucil/rituximab and is associated with an advantage in progression free survival but not yet overall survival. These agents underscore our advancement in the understanding of the biology of CLL and will improve outcomes for many patients with CLL. PMID:25817936

Treatment of Relapsed and/or Chemotherapy Refractory B-cell Malignancy by Tandem CAR T Cells Targeting CD19 and CD20

ClinicalTrials.gov

2017-03-26

Hematopoietic/Lymphoid Cancer; Adult Acute Lymphoblastic Leukemia in Remission; B-cell Adult Acute Lymphoblastic Leukemia; B-cell Chronic Lymphocytic Leukemia; Prolymphocytic Leukemia; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Refractory Chronic Lymphocytic Leukemia; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Chronic Lymphocytic Leukemia; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Chronic Lymphocytic Leukemia; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma

Treatment of Relapsed and/or Chemotherapy Refractory B-cell Malignancy by Tandem CAR T Cells Targeting CD19 and CD22

ClinicalTrials.gov

2017-06-10

Hematopoietic/Lymphoid Cancer; Adult Acute Lymphoblastic Leukemia in Remission; B-cell Adult Acute Lymphoblastic Leukemia; B-Cell Chronic Lymphocytic Leukemia in Relapse (Diagnosis); Prolymphocytic Leukemia; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Refractory Chronic Lymphocytic Leukemia; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Chronic Lymphocytic Leukemia; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Chronic Lymphocytic Leukemia; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma

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

PubMed Central

Dias, Ajoy Lawrence; Jain, Dharamvir

2013-01-01

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

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

Assessment of Impact of HLA Type on Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation for Chronic Lymphocytic Leukemia.

PubMed

Hill, Brian T; Ahn, Kwang Woo; Hu, Zhen-Huan; Aljurf, Mahmoud; Beitinjaneh, Amer; Cahn, Jean-Yves; Cerny, Jan; Kharfan-Dabaja, Mohamed A; Ganguly, Siddhartha; Ghosh, Nilanjan; Grunwald, Michael R; Inamoto, Yoshihiro; Kindwall-Keller, Tamila; Nishihori, Taiga; Olsson, Richard F; Saad, Ayman; Seftel, Matthew; Seo, Sachiko; Szer, Jeffrey; Tallman, Martin; Ustun, Celalettin; Wiernik, Peter H; Maziarz, Richard T; Kalaycio, Matt; Alyea, Edwin; Popat, Uday; Sobecks, Ronald; Saber, Wael

2018-03-01

Chronic lymphocytic leukemia (CLL) is a common hematologic malignancy with many highly effective therapies. Chemorefractory disease, often characterized by deletion of chromosome 17p, has historically been associated with very poor outcomes, leading to the application of allogeneic hematopoietic stem cell transplantation (allo-HCT) for medically fit patients. Although the use of allo-HCT has declined since the introduction of novel targeted therapy for the treatment of CLL, there remains significant interest in understanding factors that may influence the efficacy of allo-HCT, the only known curative treatment for CLL. The potential benefit of transplantation is most likely due to the presence of alloreactive donor T cells that mediate the graft-versus-leukemia (GVL) effect. The recognition of potentially tumor-specific antigens in the context of class I and II major histocompatibility complex on malignant B lymphocytes by donor T cells may be influenced by subtle differences in the highly polymorphic HLA locus. Given previous reports of specific HLA alleles impacting the incidence of CLL and the clinical outcomes of allo-HCT for CLL, we sought to study the overall survival and progression-free survival of a large cohort of patients with CLL who underwent allo-HCT from fully HLA-matched related and unrelated donors at Center for International Blood and Marrow Transplant Research transplantation centers. We found no statistically significant association of allo-HCT outcomes in CLL based on previously reported HLA combinations. Additional study is needed to further define the immunologic features that portend a more favorable GVL effect after allo-HCT for CLL. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

The dual Syk/JAK inhibitor cerdulatinib antagonises B-cell receptor and microenvironmental signaling in chronic lymphocytic leukemia

PubMed Central

Blunt, Matthew D; Koehrer, Stefan; Dobson, Rachel; Larrayoz, Marta; Wilmore, Sarah; Hayman, Alice; Parnell, Jack; Smith, Lindsay; Davies, Andrew; Johnson, Peter W; Conley, Pamela B; Pandey, Anjali; Strefford, Jon C; Stevenson, Freda K; Packham, Graham; Forconi, Francesco; Coffey, Greg; Burger, Jan A; Steele, Andrew J

2017-01-01

Purpose B-cell receptor (BCR)-associated kinase inhibitors such as ibrutinib have revolutionised the treatment of chronic lymphocytic leukemia (CLL). However, these agents are not curative and resistance is already emerging in a proportion of patients. Interleukin-4 (IL-4), expressed in CLL lymph nodes, can augment BCR-signalling and reduce the effectiveness of BCR-kinase inhibitors. Therefore simultaneous targeting of the IL-4- and BCR-signalling pathways by cerdulatinib, a novel dual Syk/JAK inhibitor currently in clinical trials (NCT01994382), may improve treatment responses in patients. Experimental Design PBMCs from CLL patients were treated with cerdulatinib alone or in combination with venetoclax. Cell death, chemokine and cell signalling assay were performed and analysed by flow cytometry, immunoblotting, Q-PCR and ELISA as indicated. Results At concentrations achievable in patients, cerdulatinib inhibited BCR- and IL-4-induced downstream signalling in CLL cells using multiple read-outs and prevented anti-IgM- and nurse-like cell (NLC)-mediated CCL3/CCL4 production. Cerdulatinib induced apoptosis of CLL cells, in a time- and concentration-dependent manner, and particularly in IGHV unmutated samples with greater BCR-signalling capacity and response to IL-4, or samples expressing higher levels of sIgM, CD49d+ or ZAP70+. Cerdulatinib overcame anti-IgM, IL-4/CD40L or NLC-mediated protection by preventing upregulation of MCL-1- and BCL-XL, however BCL-2 expression was unaffected. Furthermore in samples treated with IL-4/CD40L, cerdulatinib synergised with venetoclax in vitro to induce greater apoptosis than either drug alone. Conclusion Cerdulatinib is a promising therapeutic for the treatment of CLL either alone or in combination with venetoclax, with the potential to target critical survival pathways in this currently incurable disease. PMID:27697994

Association of polygenic risk score with the risk of chronic lymphocytic leukemia and monoclonal B-cell lymphocytosis.

PubMed

Kleinstern, Geffen; Camp, Nicola J; Goldin, Lynn R; Vachon, Celine M; Vajdic, Claire M; de Sanjose, Silvia; Weinberg, J Brice; Benavente, Yolanda; Casabonne, Delphine; Liebow, Mark; Nieters, Alexandra; Hjalgrim, Henrik; Melbye, Mads; Glimelius, Bengt; Adami, Hans-Olov; Boffetta, Paolo; Brennan, Paul; Maynadie, Marc; McKay, James; Cocco, Pier Luigi; Shanafelt, Tait D; Call, Timothy G; Norman, Aaron D; Hanson, Curtis; Robinson, Dennis; Chaffee, Kari G; Brooks-Wilson, Angela R; Monnereau, Alain; Clavel, Jacqueline; Glenn, Martha; Curtin, Karen; Conde, Lucia; Bracci, Paige M; Morton, Lindsay M; Cozen, Wendy; Severson, Richard K; Chanock, Stephen J; Spinelli, John J; Johnston, James B; Rothman, Nathaniel; Skibola, Christine F; Leis, Jose F; Kay, Neil E; Smedby, Karin E; Berndt, Sonja I; Cerhan, James R; Caporaso, Neil; Slager, Susan L

2018-06-07

Inherited loci have been found to be associated with risk of chronic lymphocytic leukemia (CLL). A combined polygenic risk score (PRS) of representative single nucleotide polymorphisms (SNPs) from these loci may improve risk prediction over individual SNPs. Herein, we evaluated the association of a PRS with CLL risk and its precursor, monoclonal B-cell lymphocytosis (MBL). We assessed its validity and discriminative ability in an independent sample and evaluated effect modification and confounding by family history (FH) of hematological cancers. For discovery, we pooled genotype data on 41 representative SNPs from 1499 CLL and 2459 controls from the InterLymph Consortium. For validation, we used data from 1267 controls from Mayo Clinic and 201 CLL, 95 MBL, and 144 controls with a FH of CLL from the Genetic Epidemiology of CLL Consortium. We used odds ratios (ORs) to estimate disease associations with PRS and c-statistics to assess discriminatory accuracy. In InterLymph, the continuous PRS was strongly associated with CLL risk (OR, 2.49; P = 4.4 × 10 -94 ). We replicated these findings in the Genetic Epidemiology of CLL Consortium and Mayo controls (OR, 3.02; P = 7.8 × 10 -30 ) and observed high discrimination (c-statistic = 0.78). When jointly modeled with FH, PRS retained its significance, along with FH status. Finally, we found a highly significant association of the continuous PRS with MBL risk (OR, 2.81; P = 9.8 × 10 -16 ). In conclusion, our validated PRS was strongly associated with CLL risk, adding information beyond FH. The PRS provides a means of identifying those individuals at greater risk for CLL as well as those at increased risk of MBL, a condition that has potential clinical impact beyond CLL.

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.

Serum level of CD26 predicts time to first treatment in early B-chronic lymphocytic leukemia.

PubMed

Molica, Stefano; Digiesi, Giovanna; Mirabelli, Rosanna; Cutrona, Giovanna; Antenucci, Anna; Molica, Matteo; Giannarelli, Diana; Sperduti, Isabella; Morabito, Fortunato; Neri, Antonino; Baldini, Luca; Ferrarini, Manlio

2009-09-01

We analyzed the correlation between well-established biological parameters of prognostic relevance in B-cell chronic lymphocytic leukemia (CLL) [i.e. mutational status of the immunoglobulin heavy chain variable region (IgV(H)), ZAP-70- and CD38-expression] and serum levels of CD26 (dipeptidyl peptidase IV, DPP IV) by evaluating the impact of these variables on the time to first treatment (TFT) in a series of 69 previously untreated Binet stage A B-cell CLL patients. By using a commercial ELISA we found that with exception of a borderline significance for ZAP-70 (P = 0.07) and CD38 (P = 0.08), circulating levels of CD26 did not correlate with either Rai substages (P = 0.520) or other biomarker [beta2-microglobulin (P = 0.933), LDH (P = 0.101), mutational status of IgV(H) (P = 0.320)]. Maximally selected log-rank statistic plots identified a CD26 serum concentration of 371 ng/mL as the best cut-off. This threshold allowed the identification of two subsets of patients with CD26 serum levels higher and lower that 371 ng/mL respectively, whose clinical outcome was different with respect to TFT (i.e. 46% and 71% at 5 yr respectively; P = 0.005). Along with higher serum levels of CD26, the univariate Cox proportional hazard model identified absence of mutation in IgV(H) (P < 0.0001) as predictor of shorter TFT. As in multivariate analysis all these parameters maintained their discriminating power (mutational status of IgV(H,)P < 0.0001; soluble CD26, P = 0.02) their combined effect on clinical outcome was assessed. When three groups were considered: (1) Low-risk group (n = 31), patients with concordant IgVH(mut) and low level of soluble CD26; (2) intermediate risk group (n = 26), patients with discordant pattern; (3) high-risk group (n = 12), patients with concordant IgVH(unmut) and high level of soluble CD26, differences in the TFT were statistically significant, with a TFT at 5 yr of respectively 88%, 51% and 43% (P < 0.0001). Our results indicate that in early B

Improved detection rate of cytogenetic abnormalities in chronic lymphocytic leukemia and other mature B-cell neoplasms with use of CpG-oligonucleotide DSP30 and interleukin 2 stimulation.

PubMed

Shi, Min; Cipollini, Matthew J; Crowley-Bish, Patricia A; Higgins, Anne W; Yu, Hongbo; Miron, Patricia M

2013-05-01

Detection of cytogenetic abnormalities requires successful culture of the clonal population to obtain metaphase chromosomes for study, and as such, has been hampered by low mitotic indices of mature B cells in culture. Our study presents data on the improved abnormality detection rate with the use of a CpG-oligonucleotide/interleukin 2 (OL/IL-2) culture protocol for mature B-cell neoplasms, including chronic lymphocytic leukemia (CLL) and non-CLL specimens. The increased detection rate of abnormalities, compared with unstimulated culture and traditional pokeweed mitogen culture, was statistically significant for both CLL and non-CLL neoplasms. For CLL specimens, our data also showed that for cytogenetically visible aberrations, OL/IL-2 was as, if not more, sensitive than detection with interphase fluorescence in situ hybridization (iFISH). Use of OL/IL-2 allowed a number of abnormalities to be detected, which were not covered by specific iFISH panels, especially balanced translocations. Therefore, OL/IL-2 stimulation improves diagnostic sensitivity and increases discovery rate of novel prognostic findings.

ARResT/AssignSubsets: a novel application for robust subclassification of chronic lymphocytic leukemia based on B cell receptor IG stereotypy.

PubMed

Bystry, Vojtech; Agathangelidis, Andreas; Bikos, Vasilis; Sutton, Lesley Ann; Baliakas, Panagiotis; Hadzidimitriou, Anastasia; Stamatopoulos, Kostas; Darzentas, Nikos

2015-12-01

An ever-increasing body of evidence supports the importance of B cell receptor immunoglobulin (BcR IG) sequence restriction, alias stereotypy, in chronic lymphocytic leukemia (CLL). This phenomenon accounts for ∼30% of studied cases, one in eight of which belong to major subsets, and extends beyond restricted sequence patterns to shared biologic and clinical characteristics and, generally, outcome. Thus, the robust assignment of new cases to major CLL subsets is a critical, and yet unmet, requirement. We introduce a novel application, ARResT/AssignSubsets, which enables the robust assignment of BcR IG sequences from CLL patients to major stereotyped subsets. ARResT/AssignSubsets uniquely combines expert immunogenetic sequence annotation from IMGT/V-QUEST with curation to safeguard quality, statistical modeling of sequence features from more than 7500 CLL patients, and results from multiple perspectives to allow for both objective and subjective assessment. We validated our approach on the learning set, and evaluated its real-world applicability on a new representative dataset comprising 459 sequences from a single institution. ARResT/AssignSubsets is freely available on the web at http://bat.infspire.org/arrest/assignsubsets/ nikos.darzentas@gmail.com. Supplementary data are available at Bioinformatics online. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Incidence rates of chronic lymphocytic leukemia in US states are associated with residential radon levels.

PubMed

Schwartz, Gary G; Klug, Marilyn G

2016-01-01

Environmental risk factors for chronic lymphocytic leukemia (CLL) have not been consistently identified. An etiologic role for ionizing radiation in CLL is controversial. Because most of the ionizing radiation to which individuals are exposed comes from radon at home, we examined CLL incidence rates in relation to residential radon levels. We used population-based rates for CLL for US states from 2007 to 2011 and measurements of residential radon made by the US Environmental Protection Agency. Incidence rates for CLL were significantly correlated with residential radon levels among whites (both genders together and each gender separately; p < 0.005) and among blacks (p < 0.05). We speculate that radon increases CLL risk and that the mechanisms may be similar to those by which radon causes lung cancer.

Adult advanced chronic lymphocytic leukemia: computational analysis of whole-body CT documents a bone structure alteration.

PubMed

Fiz, Francesco; Marini, Cecilia; Piva, Roberta; Miglino, Maurizio; Massollo, Michela; Bongioanni, Francesca; Morbelli, Silvia; Bottoni, Gianluca; Campi, Cristina; Bacigalupo, Andrea; Bruzzi, Paolo; Frassoni, Francesco; Piana, Michele; Sambuceti, Gianmario

2014-06-01

To assess the presence of alteration of bone structure and bone marrow metabolism in adult patients who were suspected of having advanced chronic lymphocytic leukemia (ACLL) by using a computational prognostic model that was based on computational analysis of positron emission tomography (PET)/computed tomography (CT) images. In this retrospective study, all patients signed written informed consent as a requisite to undergo PET/CT examination. However, due to its observational nature, approval from the ethical committee was not deemed necessary. Twenty-two previously untreated chronic lymphocytic leukemia patients underwent PET/CT for disease progression. PET/CT images were analyzed by using dedicated software, capable of recognizing an external 2-pixel bone ring whose Hounsfield coefficient served as cutoff to recognize trabecular and compact bone. PET/CT data from 22 age- and sex-matched control subjects were used as comparison. All data are reported as means ± standard deviations. The Student t test, log-rank, or Cox proportional hazards model were used as appropriate, considering a difference with a P value of less than .05 as significant. Trabecular bone was expanded in ACLL patients and occupied a larger fraction of the skeleton with respect to control subjects (mean, 39% ± 5 [standard deviation] vs 31% ± 7; ie, 32 of 81 mL/kg of ideal body weight vs 27 of 86 mL/kg of ideal body weight, respectively; P < .001). After stratification according to median value, patients with a ratio of trabecular to skeletal bone volume of more than 37.3% showed an actuarial 2-year survival of 18%, compared with 82% for those with a ratio of less than 37.3% (P < .001), independent from age, sex, biological markers, and disease duration. These data suggest that computational assessment of skeletal alterations might represent a new window for prediction of the clinical course of the disease.

Venetoclax for the treatment of patients with chronic lymphocytic leukemia.

PubMed

Crombie, Jennifer; Davids, Matthew S

2017-06-01

Venetoclax is a potent, selective inhibitor of BCL-2, a key regulator of the intrinsic pathway of apoptosis. In preclinical studies, venetoclax bound to BCL-2 with high affinity and rapidly induced apoptosis in chronic lymphocytic leukemia (CLL) cells. In early-phase clinical trials in CLL, venetoclax treatment led to tumor lysis syndrome in some patients with a large tumor burden, but this risk was subsequently mitigated by a revised study design that included lower initial dosing with intrapatient dose ramp up and close tumor lysis syndrome monitoring and prophylaxis. Other toxicities, such as neutropenia and gastrointestinal adverse events, were manageable. Venetoclax monotherapy resulted in durable and deep responses in patients with relapsed, refractory CLL, including for those with deletion 17p, leading to the approval of venetoclax by the US FDA for relapsed or refractory deletion 17p CLL, and recently to additional approvals in Europe and Canada. Trials also suggest that venetoclax induces deeper and more durable responses when used in combination with rituximab, and combination studies with other agents are ongoing. Phase III trials are also underway, and will provide data on the efficacy and safety of venetoclax in combination with monoclonal antibodies and targeted therapies in larger patient populations.

Rituximab plus bendamustine or chlorambucil for chronic lymphocytic leukemia: primary analysis of the randomized, open-label MABLE study

PubMed Central

Michallet, Anne-Sophie; Aktan, Melih; Hiddemann, Wolfgang; Ilhan, Osman; Johansson, Peter; Laribi, Kamel; Meddeb, Balkis; Moreno, Carol; Raposo, João; Schuh, Anna; Ünal, Ali; Widenius, Tom; Bernhardt, Alf; Kellershohn, Kerstin; Messeri, Dimitri; Osborne, Stuart; Leblond, Véronique

2018-01-01

MABLE investigated the efficacy and safety of rituximab plus bendamustine or rituximab plus chlorambucil in fludarabine-ineligible patients with chronic lymphocytic leukemia. Patients received rituximab plus bendamustine or rituximab plus chlorambucil every four weeks for six cycles. Rituximab plus chlorambucil-treated patients without a complete response after Cycle 6 received chlorambucil monotherapy for at least six additional cycles or until complete response. The primary endpoint was complete response rate (confirmed by bone marrow biopsy) after Cycle 6 in first-line patients. Secondary endpoints included progression-free survival, overall survival, minimal residual disease, and safety. Overall, 357 patients were randomized (rituximab plus bendamustine, n=178; rituximab plus chlorambucil, n=179; intent-to-treat population), including 241 first-line patients (n=121 and n=120, respectively); 355 patients received treatment (n=177 and n=178, respectively; safety population). In first-line patients, complete response rate after Cycle 6 (rituximab plus bendamustine, 24%; rituximab plus chlorambucil, 9%; P=0.002) and median progression-free survival (rituximab plus bendamustine, 40 months; rituximab plus chlorambucil, 30 months; P=0.003) were higher with rituximab plus bendamustine than rituximab plus chlorambucil. Overall response rate and overall survival were not different. In first-line patients with a complete response, minimal residual disease-negativity was higher with rituximab plus bendamustine than rituximab plus chlorambucil (66% vs. 36%). Overall adverse event incidence was similar (rituximab plus bendamustine, 98%; rituximab plus chlorambucil, 97%). Rituximab plus bendamustine may be a valuable first-line option for fludarabine-ineligible patients with chronic lymphocytic leukemia. PMID:29419437

Prognostic Factors for Complete Response to Ibrutinib in Patients With Chronic Lymphocytic Leukemia: A Pooled Analysis of 2 Clinical Trials.

PubMed

O'Brien, Susan M; Jaglowski, Samantha; Byrd, John C; Bannerji, Rajat; Blum, Kristie A; Fox, Christopher P; Furman, Richard R; Hillmen, Peter; Kipps, Thomas J; Montillo, Marco; Sharman, Jeff; Suzuki, Sam; James, Danelle F; Chu, Alvina D; Coutre, Steven E

2018-05-01

Ibrutinib, a first-in-class Bruton tyrosine kinase inhibitor taken once daily, is approved in the United States for patients with chronic lymphocytic leukemia/small lymphocytic lymphoma and allows for treatment without chemotherapy. Extended treatment with ibrutinib has demonstrated increased complete response (CR) rates over time. To analyze baseline factors that predict CR in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma treated with ibrutinib. Univariate and multivariate analyses of pooled data from 2 clinical trials were used to assess the prognostic value of baseline factors associated with CR in 327 patients from the PCYC-1102 and PCYC-1112 studies treated with single-agent ibrutinib. Participants were followed up in academic and community medical centers in the United States, the United Kingdom, Australia, France, Italy, Ireland, Poland, Spain, and Austria. Odds ratio (OR) of CR rate. The 327 patients included in this analysis had a median age of 67 years (range, 30-86 years) and 227 (69.4%) were male. At baseline, 185 patients (56.6%) had bulky disease (lymph node ≥5 cm), 184 (56.3%) had advanced-stage disease, and 182 (55.7%) had an Eastern Cooperative Oncology Group performance status of 1 or higher. Thirty-one patients (9.5%) were in the first-line setting; 38 (11.6%) had undergone 1 previous therapy, 81 (24.8%) had undergone 2, and 177 (54.1%) had undergone 3 or more; patients with relapsed/refractory disease had undergone a median of 3 (range, 0-12) previous therapies. Median time on study was 26.4 months (range, 0.3-55.6 months). Thirty-two of the 327 patients (9.8%) treated with ibrutinib had a CR (PCYC-1102: relapsed/refractory, 12 of 101 [11.9%]; treatment-naive, 8 of 31 [25.8%]; and PCYC-1112: 12 of 195 [6.2%]). The median time to CR for these patients was 14.7 months (range, 4.6-47.1 months). Univariate analysis of baseline factors showed that bulky disease, clinical stage, number of previous therapies, and β2

CD200 is a useful diagnostic marker for identifying atypical chronic lymphocytic leukemia by flow cytometry.

PubMed

Ting, Y S; Smith, S A B C; Brown, D A; Dodds, A J; Fay, K C; Ma, D D F; Milliken, S; Moore, J J; Sewell, W A

2018-05-27

Immunophenotyping by flow cytometry is routinely employed in distinguishing between chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). Inclusion of CD200 has been reported to contribute to more reliable differentiation between CLL and MCL. We investigated the value of CD200 in assessment of atypical CLL cases. CD200 expression on mature B cell neoplasms was studied by eight-color flow cytometry in combination with a conventional panel of flow cytometry markers. The study included 70 control samples, 63 samples with CLL or atypical CLL phenotype, 6 MCL samples, and 40 samples of other mature B cell neoplasms. All CLL samples were positive for CD200, whereas MCL samples were dim or negative for CD200. Of the CLL samples, 7 were atypical by conventional flow cytometry, with Matutes scores ≤3. These cases were tested for evidence of a t(11;14) translocation, characteristic of MCL, and all were negative, consistent with their classification as atypical CLL. All these atypical CLL samples were strongly positive for CD200. CD200 proved to be a useful marker for differentiation between CLL and MCL by flow cytometry. In particular, CD200 was useful in distinguishing CLL samples with atypical immunophenotypes from MCL. © 2018 John Wiley & Sons Ltd.

[Advances in the treatment of chronic lymphocytic leukaemia].

PubMed

Mozas, Pablo; Delgado, Julio

2016-11-18

Chronic lymphocytic leukemia (CLL), a proliferation of mature B cells, is one of the most prevalent haematological malignancies. Progress has been made in its treatment during the last few decades, and chemoimmunotherapy based on fludarabine, cyclophosphamide and rituximab is considered the treatment of choice for patients with standard-risk CLL and good performance status. However, due to the characterization of high-risk biological subgroups and its presentation in elderly patients and/or with comorbidities, targeted therapies, such as B-cell receptor inhibitors, have been developed and approved during the last few years. The current review examines traditional therapeutic strategies and focuses on new small molecules that already represent promising elements of the CLL treatment landscape. Copyright © 2016 Elsevier España, S.L.U. All rights reserved.

Chronic myelogenous leukemia (CML)

MedlinePlus

CML; Chronic myeloid leukemia; CGL; Chronic granulocytic leukemia; Leukemia - chronic granulocytic ... nuclear disaster. It takes many years to develop leukemia from radiation exposure. Most people treated for cancer ...

High incidence of chronic graft-versus-host disease after myeloablative allogeneic stem cell transplantation for chronic lymphocytic leukemia in Sweden: graft-versus-leukemia effect protects against relapse.

PubMed

Machaczka, Maciej; Johansson, Jan-Erik; Remberger, Mats; Hallböök, Helene; Lazarevic, Vladimir Lj; Wahlin, Björn Engelbrekt; Omar, Hamdy; Wahlin, Anders; Juliusson, Gunnar; Kimby, Eva; Hägglund, Hans

2013-12-01

Allogeneic hematopoietic stem cell transplantation (allo-SCT) is a potentially curative treatment option for eligible patients with chronic lymphocytic leukemia (CLL). However, it is known that cure of CLL is only possible if a graft-versus-leukemia effect is present. Between 1994 and 2007, 48 adults underwent allo-SCT for poor-risk CLL in Sweden. Of these, ten (21%) patients aged 24-53 years (median: 46 years) received myeloablative conditioning (MAC), based on TBI and cyclophosphamide. All MAC patients had refractory, poorly controlled CLL before allo-SCT (partial remission in 9/10 patients and progressive disease in one). The cumulative incidence of acute graft-versus-host disease (GVHD) grades II-IV was 30%. Nine patients developed chronic GVHD; extensive in four. Rates of nonrelapse mortality at 1, 3 and 10 years were 0, 10 and 20%, respectively. Two patients relapsed 36 and 53 months after transplantation. Six patients were still alive after a median follow-up time of 11.5 years (range 5.9-13.7). The probabilities of relapse-free and overall survival from 1, 3 and 5 years after transplantation were 100, 90 and 70%, and 100, 90 and 80%, respectively. Nevertheless, our analysis of long-term outcome after MAC allo-SCT for CLL suggests that younger patients with poorly controlled CLL may benefit from MAC allo-SCT.

Ibrutinib as initial therapy for elderly patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma: an open-label, multicentre, phase 1b/2 trial.

PubMed

O'Brien, Susan; Furman, Richard R; Coutre, Steven E; Sharman, Jeff P; Burger, Jan A; Blum, Kristie A; Grant, Barbara; Richards, Donald A; Coleman, Morton; Wierda, William G; Jones, Jeffrey A; Zhao, Weiqiang; Heerema, Nyla A; Johnson, Amy J; Izumi, Raquel; Hamdy, Ahmed; Chang, Betty Y; Graef, Thorsten; Clow, Fong; Buggy, Joseph J; James, Danelle F; Byrd, John C

2014-01-01

Chemoimmunotherapy has led to improved numbers of patients achieving disease response, and longer overall survival in young patients with chronic lymphocytic leukaemia; however, its application in elderly patients has been restricted by substantial myelosuppression and infection. We aimed to assess safety and activity of ibrutinib, an orally administered covalent inhibitor of Bruton tyrosine kinase (BTK), in treatment-naive patients aged 65 years and older with chronic lymphocytic leukaemia. In our open-label phase 1b/2 trial, we enrolled previously untreated patients at clinical sites in the USA. Eligible patients were aged at least 65 years, and had symptomatic chronic lymphocytic leukaemia or small lymphocytic lymphoma requiring therapy. Patients received 28 day cycles of once-daily ibrutinib 420 mg or ibrutinib 840 mg. The 840 mg dose was discontinued after enrolment had begun because comparable activity of the doses has been shown. The primary endpoint was the safety of the dose-fixed regimen in terms of frequency and severity of adverse events for all patients who received treatment. This study is registered with ClinicalTrials.gov, number NCT01105247. Between May 20, 2010, and Dec 18, 2012, we enrolled 29 patients with chronic lymphocytic leukaemia and two patients with small lymphocytic lymphoma. Median age was 71 years (range 65-84), and 23 (74%) patients were at least 70 years old. Toxicity was mainly of mild-to-moderate severity (grade 1-2). 21 (68%) patients had diarrhoea (grade 1 in 14 [45%] patients, grade 2 in three [10%] patients, and grade 3 in four [13%] patients). 15 (48%) patients developed nausea (grade 1 in 12 [39%] patients and grade 2 in three [10%] patients). Ten (32%) patients developed fatigue (grade 1 in five [16%] patients, grade 2 in four [13%] patients, and grade 3 in one [3%] patient). Three (10%) patients developed grade 3 infections, although no grade 4 or 5 infections occurred. One patient developed grade 3 neutropenia, and one

Ibrutinib as initial therapy for elderly patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma: an open-label, multicentre, phase 1b/2 trial

PubMed Central

O’Brien, Susan; Furman, Richard R; Coutre, Steven E; Sharman, Jeff P; Burger, Jan A; Blum, Kristie A; Grant, Barbara; Richards, Donald A; Coleman, Morton; Wierda, William G; Jones, Jeffrey A; Zhao, Weiqiang; Heerema, Nyla A; Johnson, Amy J; Izumi, Raquel; Hamdy, Ahmed; Chang, Betty Y; Graef, Thorsten; Clow, Fong; Buggy, Joseph J; James, Danelle F; Byrd, John C

2014-01-01

Summary Background Chemoimmunotherapy has led to improved numbers of patients achieving disease response, and longer overall survival in young patients with chronic lymphocytic leukaemia; however, its application in elderly patients has been restricted by substantial myelosuppression and infection. We aimed to assess safety and activity of ibrutinib, an orally administered covalent inhibitor of Bruton tyrosine kinase (BTK), in treatment-naive patients aged 65 years and older with chronic lymphocytic leukaemia. Methods In our open-label phase 1b/2 trial, we enrolled previously untreated patients at clinical sites in the USA. Eligible patients were aged at least 65 years, and had symptomatic chronic lymphocytic leukaemia or small lymphocytic lymphoma requiring therapy. Patients received 28 day cycles of once-daily ibrutinib 420 mg or ibrutinib 840 mg. The 840 mg dose was discontinued after enrolment had begun because comparable activity of the doses has been shown. The primary endpoint was the safety of the dose-fixed regimen in terms of frequency and severity of adverse events for all patients who received treatment. This study is registered with ClinicalTrials.gov, number NCT01105247. Findings Between May 20, 2010, and Dec 18, 2012, we enrolled 29 patients with chronic lymphocytic leukaemia and two patients with small lymphocytic lymphoma. Median age was 71 years (range 65–84), and 23 (74%) patients were at least 70 years old. Toxicity was mainly of mild-to-moderate severity (grade 1–2). 21 (68%) patients had diarrhoea (grade 1 in 14 [45%] patients, grade 2 in three [10%] patients, and grade 3 in four [13%] patients). 15 (48%) patients developed nausea (grade 1 in 12 [39%] patients and grade 2 in three [10%] patients). Ten (32%) patients developed fatigue (grade 1 in five [16%] patients, grade 2 in four [13%] patients, and grade 3 in one [3%] patient). Three (10%) patients developed grade 3 infections, although no grade 4 or 5 infections occurred. One patient

LDOC1 mRNA is differentially expressed in chronic lymphocytic leukemia and predicts overall survival in untreated patients

PubMed Central

Duzkale, Hatice; Schweighofer, Carmen D.; Coombes, Kevin R.; Barron, Lynn L.; Ferrajoli, Alessandra; O'Brien, Susan; Wierda, William G.; Pfeifer, John; Majewski, Tadeusz; Czerniak, Bogdan A.; Jorgensen, Jeffrey L.; Medeiros, L. Jeffrey; Freireich, Emil J; Keating, Michael J.

2011-01-01

We previously identified LDOC1 as one of the most significantly differentially expressed genes in untreated chronic lymphocytic leukemia (CLL) patients with respect to the somatic mutation status of the immunoglobulin heavy-chain variable region genes. However, little is known about the normal function of LDOC1, its contribution to the pathophysiology of CLL, or its prognostic significance. In this study, we have investigated LDOC1 mRNA expression in a large cohort of untreated CLL patients, as well as in normal peripheral blood B-cell (NBC) subsets and primary B-cell lymphoma samples. We have confirmed that LDOC1 is dramatically down-regulated in mutated CLL cases compared with unmutated cases, and have identified a new splice variant, LDOC1S. We show that LDOC1 is expressed in NBC subsets (naive > memory), suggesting that it may play a role in normal B-cell development. It is also expressed in primary B-cell lymphoma samples, in which its expression is associated with somatic mutation status. In CLL, we show that high levels of LDOC1 correlate with biomarkers of poor prognosis, including cytogenetic markers, unmutated somatic mutation status, and ZAP70 expression. Finally, we demonstrate that LDOC1 mRNA expression is an excellent predictor of overall survival in untreated CLL patients. PMID:21310924

A Phase 1/2 Study To Evaluate ASN002 In Relapsed/Refractory Lymphoma And Advanced Solid Tumors

ClinicalTrials.gov

2018-04-30

Lymphoma, Large B-Cell, Diffuse; Lymphoma, Mantle-Cell; Lymphoma, Follicular; Cancer; Neoplasm; Tumor; Lymphoma, Malignant; Lymphoma, B-cell; Lymphoma, Non-Hodgkin; B-Cell Chronic Lymphocytic Leukemia; B-Cell Leukemia, Chronic; B-Lymphocytic Leukemia, Chronic; Chronic Lymphocytic Leukemia; Leukemia, Lymphocytic, Chronic; Leukemia, Lymphocytic, Chronic, B Cell; Myelofibrosis; Chronic Idiopathic Myelofibrosis; Idiopathic Myelofibrosis; Lymphoma, T Cell, Peripheral; Peripheral T-Cell Lymphoma; T-Cell Lymphoma, Peripheral

Chimeric Antigen Receptor–Modified T Cells in Chronic Lymphoid Leukemia

PubMed Central

Porter, David L.; Levine, Bruce L.; Kalos, Michael; Bagg, Adam; June, Carl H.

2012-01-01

SUMMARY We designed a lentiviral vector expressing a chimeric antigen receptor with specificity for the B-cell antigen CD19, coupled with CD137 (a costimulatory receptor in T cells [4-1BB]) and CD3-zeta (a signal-transduction component of the T-cell antigen receptor) signaling domains. A low dose (approximately 1.5×105 cells per kilogram of body weight) of autologous chimeric antigen receptor–modified T cells reinfused into a patient with refractory chronic lymphocytic leukemia (CLL) expanded to a level that was more than 1000 times as high as the initial engraftment level in vivo, with delayed development of the tumor lysis syndrome and with complete remission. Apart from the tumor lysis syndrome, the only other grade 3/4 toxic effect related to chimeric antigen receptor T cells was lymphopenia. Engineered cells persisted at high levels for 6 months in the blood and bone marrow and continued to express the chimeric antigen receptor. A specific immune response was detected in the bone marrow, accompanied by loss of normal B cells and leukemia cells that express CD19. Remission was ongoing 10 months after treatment. Hypogammaglobulinemia was an expected chronic toxic effect. PMID:21830940

Pharmacovigilance during ibrutinib therapy for chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) in routine clinical practice.

PubMed

Finnes, Heidi D; Chaffee, Kari G; Call, Timothy G; Ding, Wei; Kenderian, Saad S; Bowen, Deborah A; Conte, Michael; McCullough, Kristen B; Merten, Julianna A; Bartoo, Gabriel T; Smith, Matthew D; Leis, Jose; Chanan-Khan, Asher; Schwager, Susan M; Slager, Susan L; Kay, Neil E; Shanafelt, Tait D; Parikh, Sameer A

2017-06-01

Due to Cytochrome P450 3A (CYP3A) metabolism, clinical trials of ibrutinib-treated chronic lymphocytic leukemia (CLL) patients prohibited concurrent medications metabolized by CYP3A. We evaluated concomitant medication use in 118 ibrutinib-treated CLL patients outside the context of clinical trials. Seventy-five (64%) patients were on medications that could increase ibrutinib toxicity and 4 (3%) were on drugs that could decrease ibrutinib efficacy. Nineteen (16%) patients were on concomitant CYP3A inhibitors (11 moderate, 8 strong), and 4 (3%) were on CYP3A inducers (two patients were on both CYP3A inhibitors and inducers). Although the ibrutinib starting dose was changed in 18 patients on CYP3A interacting medications, no difference in 18-month progression-free survival or rate of ibrutinib discontinuation was observed in patients who were not. In routine clinical practice, 2 of 3 CLL patients commencing ibrutinib are on a concomitant medication with potential to influence ibrutinib metabolism. Formal medication review by a pharmacist should be considered in all patients initiating ibrutinib.

miRNA deregulation by epigenetic silencing disrupts suppression of the oncogene PLAG1 in chronic lymphocytic leukemia.

PubMed

Pallasch, Christian Philipp; Patz, Michaela; Park, Yoon Jung; Hagist, Susanne; Eggle, Daniela; Claus, Rainer; Debey-Pascher, Svenja; Schulz, Alexandra; Frenzel, Lukas P; Claasen, Julia; Kutsch, Nadine; Krause, Günter; Mayr, Christine; Rosenwald, Andreas; Plass, Christoph; Schultze, Joachim L; Hallek, Michael; Wendtner, Clemens-Martin

2009-10-08

MicroRNAs (miRNA) play a key role in cellular regulation and, if deregulated, in the development of neoplastic disorders including chronic lymphocytic leukemia (CLL). RNAs from primary cells of 50 treatment-naive CLL patients and peripheral B cells of 14 healthy donors were applied to miRNA expression profiling using bead chip technology. In CLL cells, a set of 7 up- and 19 down-regulated miRNAs was identified. Among the miRNAs down-regulated in CLL cells, 6 of 10 miRNA promoters examined showed gain of methylation compared with normal B-cell controls. Subsequent target prediction of deregulated miRNAs revealed a highly significant binding prediction at the 3' untranslated region of the pleomorphic adenoma gene 1 (PLAG1) oncogene. Luciferase reporter assays including site-directed mutagenesis of binding sites revealed a significant regulation of PLAG1 by miR-181a, miR-181b, miR-107, and miR-424. Although expression of PLAG1 mRNA was not affected, PLAG1 protein expression was shown to be significantly elevated in CLL cells compared with the levels in healthy donor B cells. In summary, we could demonstrate disruption of miRNA-mediated translational control, partly due to epigenetic transcriptional silencing of miRNAs, with subsequent overexpression of the oncogenic transcription factor PLAG1 as a putative novel mechanism of CLL pathogenesis.

miRNA deregulation by epigenetic silencing disrupts suppression of the oncogene PLAG1 in chronic lymphocytic leukemia

PubMed Central

Pallasch, Christian Philipp; Patz, Michaela; Park, Yoon Jung; Hagist, Susanne; Eggle, Daniela; Claus, Rainer; Debey-Pascher, Svenja; Schulz, Alexandra; Frenzel, Lukas P.; Claasen, Julia; Kutsch, Nadine; Krause, Günter; Mayr, Christine; Rosenwald, Andreas; Plass, Christoph; Schultze, Joachim L.; Hallek, Michael

2009-01-01

MicroRNAs (miRNA) play a key role in cellular regulation and, if deregulated, in the development of neoplastic disorders including chronic lymphocytic leukemia (CLL). RNAs from primary cells of 50 treatment-naive CLL patients and peripheral B cells of 14 healthy donors were applied to miRNA expression profiling using bead chip technology. In CLL cells, a set of 7 up- and 19 down-regulated miRNAs was identified. Among the miRNAs down-regulated in CLL cells, 6 of 10 miRNA promoters examined showed gain of methylation compared with normal B-cell controls. Subsequent target prediction of deregulated miRNAs revealed a highly significant binding prediction at the 3′ untranslated region of the pleomorphic adenoma gene 1 (PLAG1) oncogene. Luciferase reporter assays including site-directed mutagenesis of binding sites revealed a significant regulation of PLAG1 by miR-181a, miR-181b, miR-107, and miR-424. Although expression of PLAG1 mRNA was not affected, PLAG1 protein expression was shown to be significantly elevated in CLL cells compared with the levels in healthy donor B cells. In summary, we could demonstrate disruption of miRNA-mediated translational control, partly due to epigenetic transcriptional silencing of miRNAs, with subsequent overexpression of the oncogenic transcription factor PLAG1 as a putative novel mechanism of CLL pathogenesis. PMID:19692702

Childhood Leukemia--A Look at the Past, the Present and the Future.

ERIC Educational Resources Information Center

Findeisen, Regina; Barber, William H.

1997-01-01

Provides an overview of childhood leukemia. The causes, the survival period, different types (acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, and hairy cell leukemia), symptoms, treatment, side effects of treatment (including learning problems), and the expected future direction of…

Selinexor is effective in acquired resistance to ibrutinib and synergizes with ibrutinib in chronic lymphocytic leukemia.

PubMed

Hing, Zachary A; Mantel, Rose; Beckwith, Kyle A; Guinn, Daphne; Williams, Erich; Smith, Lisa L; Williams, Katie; Johnson, Amy J; Lehman, Amy M; Byrd, John C; Woyach, Jennifer A; Lapalombella, Rosa

2015-05-14

Despite the therapeutic efficacy of ibrutinib in chronic lymphocytic leukemia (CLL), complete responses are infrequent, and acquired resistance to Bruton agammaglobulinemia tyrosine kinase (BTK) inhibition is being observed in an increasing number of patients. Combination regimens that increase frequency of complete remissions, accelerate time to remission, and overcome single agent resistance are of considerable interest. We previously showed that the XPO1 inhibitor selinexor is proapoptotic in CLL cells and disrupts B-cell receptor signaling via BTK depletion. Herein we show the combination of selinexor and ibrutinib elicits a synergistic cytotoxic effect in primary CLL cells and increases overall survival compared with ibrutinib alone in a mouse model of CLL. Selinexor is effective in cells isolated from patients with prolonged lymphocytosis following ibrutinib therapy. Finally, selinexor is effective in ibrutinib-refractory mice and in a cell line harboring the BTK C481S mutation. This is the first report describing the combined activity of ibrutinib and selinexor in CLL, which represents a new treatment paradigm and warrants further evaluation in clinical trials of CLL patients including those with acquired ibrutinib resistance. © 2015 by The American Society of Hematology.

Prognostic significance of signal transducer and activator of transcription 5 and 5b expression in Epstein-Barr virus-positive patients with chronic lymphocytic leukemia.

PubMed

Diamantopoulos, Panagiotis T; Sofotasiou, Maria; Georgoussi, Zafiroula; Giannakopoulou, Nefeli; Papadopoulou, Vasiliki; Galanopoulos, Athanasios; Kontandreopoulou, Elina; Zervakis, Panagiotis; Pallaki, Paschalina; Kalala, Fani; Kyrtsonis, Marie-Christine; Dimitrakopoulou, Aglaia; Vassilakopoulos, Theodoros; Angelopoulou, Maria; Spanakis, Nikolaos; Viniou, Nora-Athina

2016-09-01

Signal transducer and activator of transcription (STAT) proteins have been intensively studied in hematologic malignancies, and the efficacy of agents against STATs in lymphomas is already under research. We investigated the expression of total STAT5 and STAT5b in peripheral blood samples of patients with chronic lymphocytic leukemia (CLL) in correlation with the presence of Epstein-Barr Virus (EBV) and its major oncoprotein (latent membrane protein 1, LMP1). The EBV load was measured in the peripheral blood by real-time PCR for the BXLF1 gene and the levels of LMP1 by PCR and ELISA. Western blotting was performed for total STAT5 and STAT5b in protein extracts. STAT5b was only expressed in patients (not in healthy subjects) and STAT5 but particularly STAT5b expression was correlated with the presence of the virus (77.3% vs. 51.2%, P = 0.006 for STAT5b) and to the expression of LMP1 (58.3% vs. 21.6%, P = 0.011 for STAT5b). Moreover, the expression of STAT5b and the presence of EBV and LMP1 were strongly negatively correlated with the overall survival of the patients (log-rank test P = 0.011, 0.015, 0.006, respectively). Double positive (for EBV and STAT5b) patients had the lowest overall survival (log-rank test P = 0.013). This is the first report of a survival disadvantage of EBV+ patients with CLL, and the first time that STAT5b expression is correlated with survival. The correlation of STAT5 expression with the presence of the virus, along with our survival correlations defines a subgroup of patients with CLL that may benefit from anti-STAT agents. © 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

SB-715992 in Treating Patients With Acute Leukemia, Chronic Myelogenous Leukemia, or Advanced Myelodysplastic Syndromes

ClinicalTrials.gov

2013-01-10

Acute Undifferentiated Leukemia; Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); Adult Acute Monoblastic Leukemia (M5a); Adult Acute Monocytic Leukemia (M5b); Adult Acute Myeloblastic Leukemia With Maturation (M2); Adult Acute Myeloblastic Leukemia Without Maturation (M1); Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Myelomonocytic Leukemia (M4); Adult Acute Promyelocytic Leukemia (M3); Adult Erythroleukemia (M6a); Adult Pure Erythroid Leukemia (M6b); Blastic Phase Chronic Myelogenous Leukemia; de Novo Myelodysplastic Syndromes; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Refractory Anemia With Excess Blasts; Refractory Anemia With Excess Blasts in Transformation; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes; Untreated Adult Acute Myeloid Leukemia

Detection of chromosomal changes in chronic lymphocytic leukemia using classical cytogenetic methods and FISH: application of rich mitogen mixtures for lymphocyte cultures.

PubMed

Koczkodaj, Dorota; Popek, Sylwia; Zmorzyński, Szymon; Wąsik-Szczepanek, Ewa; Filip, Agata A

2016-04-01

One of the research methods of prognostic value in chronic lymphocytic leukemia (CLL) is cytogenetic analysis. This method requires the presence of appropriate B-cell mitogens in cultures in order to obtain a high mitotic index. The aim of our research was to determine the most effective methods of in vitro B-cell stimulation to maximize the number of metaphases from peripheral blood cells of patients with CLL for classical cytogenetic examination, and then to correlate the results with those obtained using fluorescence in situ hybridization (FISH). The study group involved 50 consecutive patients with CLL. Cell cultures were maintained with the basic composition of culture medium and addition of respective stimulators. We used the following stimulators: Pokeweed Mitogen (PWM), 12-O-tetradecanoylphorbol 13-acetate (TPA), ionophore, lipopolysaccharide (LPS), and CpG-oligonucleotide DSP30. We received the highest mitotic index when using the mixture of PWM+TPA+I+DSP30. With classical cytogenetic tests using banding techniques, numerical and structural aberrations of chromosomes were detected in 46 patients, and no change was found in only four patients. Test results clearly confirmed the legitimacy of using cell cultures enriched with the mixture of cell stimulators and combining classical cytogenetic techniques with the FISH technique in later patient diagnosing. Copyright © 2016 American Federation for Medical Research.

The Bruton tyrosine kinase inhibitor ibrutinib with chemoimmunotherapy in patients with chronic lymphocytic leukemia

PubMed Central

Barrientos, Jacqueline C.; Barr, Paul M.; Flinn, Ian W.; Burger, Jan A.; Tran, Anh; Clow, Fong; James, Danelle F.; Graef, Thorsten; Friedberg, Jonathan W.; Rai, Kanti; O’Brien, Susan

2015-01-01

The safety and efficacy of ibrutinib, an oral inhibitor of Bruton tyrosine kinase, were evaluated with chemoimmunotherapy (CIT) in a multicenter phase 1b study. Patients with relapsed/refractory chronic lymphocytic leukemia received bendamustine and rituximab (BR) or fludarabine, cyclophosphamide, and rituximab (FCR) for up to 6 cycles with daily ibrutinib (420 mg) until progressive disease or unacceptable toxicity. Enrollment to FCR-ibrutinib closed early due to a lack of fludarabine-naïve previously treated patients. No patients treated with BR-ibrutinib (n = 30) or FCR-ibrutinib (n = 3) experienced prolonged hematologic toxicity in cycle 1 (primary end point). Tolerability was as expected with either CIT or single-agent ibrutinib. The overall response rate (ORR) with BR-ibrutinib was 93.3%, including 16.7% complete responses (CRs) initially, which increased to 40% with the extension period. Including 1 patient with partial response with lymphocytosis, the best ORR was 96.7%. Sixteen of 21 patients with baseline cytopenias had sustained hematologic improvement. At 12 and 36 months, 86.3% and 70.3% remained progression-free, respectively. All 3 patients treated with ibrutinib-FCR achieved CR. Ibrutinib may enhance CIT efficacy without additive toxicities, providing the rationale for studying this combination in an ongoing phase 3 trial. The study is registered to www.clinicaltrials.gov as #NCT01292135. PMID:25755291

The Bruton tyrosine kinase inhibitor ibrutinib with chemoimmunotherapy in patients with chronic lymphocytic leukemia.

PubMed

Brown, Jennifer R; Barrientos, Jacqueline C; Barr, Paul M; Flinn, Ian W; Burger, Jan A; Tran, Anh; Clow, Fong; James, Danelle F; Graef, Thorsten; Friedberg, Jonathan W; Rai, Kanti; O'Brien, Susan

2015-05-07

The safety and efficacy of ibrutinib, an oral inhibitor of Bruton tyrosine kinase, were evaluated with chemoimmunotherapy (CIT) in a multicenter phase 1b study. Patients with relapsed/refractory chronic lymphocytic leukemia received bendamustine and rituximab (BR) or fludarabine, cyclophosphamide, and rituximab (FCR) for up to 6 cycles with daily ibrutinib (420 mg) until progressive disease or unacceptable toxicity. Enrollment to FCR-ibrutinib closed early due to a lack of fludarabine-naïve previously treated patients. No patients treated with BR-ibrutinib (n = 30) or FCR-ibrutinib (n = 3) experienced prolonged hematologic toxicity in cycle 1 (primary end point). Tolerability was as expected with either CIT or single-agent ibrutinib. The overall response rate (ORR) with BR-ibrutinib was 93.3%, including 16.7% complete responses (CRs) initially, which increased to 40% with the extension period. Including 1 patient with partial response with lymphocytosis, the best ORR was 96.7%. Sixteen of 21 patients with baseline cytopenias had sustained hematologic improvement. At 12 and 36 months, 86.3% and 70.3% remained progression-free, respectively. All 3 patients treated with ibrutinib-FCR achieved CR. Ibrutinib may enhance CIT efficacy without additive toxicities, providing the rationale for studying this combination in an ongoing phase 3 trial. The study is registered to www.clinicaltrials.gov as #NCT01292135. © 2015 by The American Society of Hematology.

Non-codingRNA sequence variations in human chronic lymphocytic leukemia and colorectal cancer.

PubMed

Wojcik, Sylwia E; Rossi, Simona; Shimizu, Masayoshi; Nicoloso, Milena S; Cimmino, Amelia; Alder, Hansjuerg; Herlea, Vlad; Rassenti, Laura Z; Rai, Kanti R; Kipps, Thomas J; Keating, Michael J; Croce, Carlo M; Calin, George A

2010-02-01

Cancer is a genetic disease in which the interplay between alterations in protein-coding genes and non-coding RNAs (ncRNAs) plays a fundamental role. In recent years, the full coding component of the human genome was sequenced in various cancers, whereas such attempts related to ncRNAs are still fragmentary. We screened genomic DNAs for sequence variations in 148 microRNAs (miRNAs) and ultraconserved regions (UCRs) loci in patients with chronic lymphocytic leukemia (CLL) or colorectal cancer (CRC) by Sanger technique and further tried to elucidate the functional consequences of some of these variations. We found sequence variations in miRNAs in both sporadic and familial CLL cases, mutations of UCRs in CLLs and CRCs and, in certain instances, detected functional effects of these variations. Furthermore, by integrating our data with previously published data on miRNA sequence variations, we have created a catalog of DNA sequence variations in miRNAs/ultraconserved genes in human cancers. These findings argue that ncRNAs are targeted by both germ line and somatic mutations as well as by single-nucleotide polymorphisms with functional significance for human tumorigenesis. Sequence variations in ncRNA loci are frequent and some have functional and biological significance. Such information can be exploited to further investigate on a genome-wide scale the frequency of genetic variations in ncRNAs and their functional meaning, as well as for the development of new diagnostic and prognostic markers for leukemias and carcinomas.

Non-codingRNA sequence variations in human chronic lymphocytic leukemia and colorectal cancer

PubMed Central

Wojcik, Sylwia E.; Rossi, Simona; Shimizu, Masayoshi; Nicoloso, Milena S.; Cimmino, Amelia; Alder, Hansjuerg; Herlea, Vlad; Rassenti, Laura Z.; Rai, Kanti R.; Kipps, Thomas J.; Keating, Michael J.

2010-01-01

Cancer is a genetic disease in which the interplay between alterations in protein-coding genes and non-coding RNAs (ncRNAs) plays a fundamental role. In recent years, the full coding component of the human genome was sequenced in various cancers, whereas such attempts related to ncRNAs are still fragmentary. We screened genomic DNAs for sequence variations in 148 microRNAs (miRNAs) and ultraconserved regions (UCRs) loci in patients with chronic lymphocytic leukemia (CLL) or colorectal cancer (CRC) by Sanger technique and further tried to elucidate the functional consequences of some of these variations. We found sequence variations in miRNAs in both sporadic and familial CLL cases, mutations of UCRs in CLLs and CRCs and, in certain instances, detected functional effects of these variations. Furthermore, by integrating our data with previously published data on miRNA sequence variations, we have created a catalog of DNA sequence variations in miRNAs/ultraconserved genes in human cancers. These findings argue that ncRNAs are targeted by both germ line and somatic mutations as well as by single-nucleotide polymorphisms with functional significance for human tumorigenesis. Sequence variations in ncRNA loci are frequent and some have functional and biological significance. Such information can be exploited to further investigate on a genome-wide scale the frequency of genetic variations in ncRNAs and their functional meaning, as well as for the development of new diagnostic and prognostic markers for leukemias and carcinomas. PMID:19926640

[CpG-oligodeoxynucleotide stimulation improves the success for karyotypic analysis of chronic lymphocytic leukemia cells].

PubMed

Liu, Qiong; Xu, Wei; Qiu, Hai-rong; Wang, Rong; Yu, Hui; Fan, Lei; Miao, Kou-rong; Li, Jian-yong

2009-09-01

To explore the effect of CpG-oligodeoxynucleotides (ODN) in chromosome study of chronic lymphocytic leukemia (CLL). Blood or bone marrow cells of 70 CLL patients were cultured for 72 h with PHA, CpG-ODN and CpG-ODN combined with IL-2, respectively. Routine karyotype analysis with R banding technique and interphase fluorescence in situ hybridization (FISH) were performed. The metaphase number>or=20 was considered as successful stimulation, which in PHA, CpG-ODN and CpG-ODN combined IL-2 groups were 90.0%, 68.6% and 68.6%, respectively, and the detection rates of chromosome aberrations were 3.2%, 43.6% and 43.6%, respectively. The aberrations rates detected by interphase FISH with a panel of probes was 64.3%. CpG-ODN DSP30 can effectively raise the detection rate of chromosome aberrations in CLL patients.

Analysis of the risk of infection in patients with chronic lymphocytic leukemia in the era of novel therapies.

PubMed

Williams, AnnaLynn M; Baran, Andrea M; Meacham, Philip J; Feldman, Megan M; Valencia, Hugo E; Newsom-Stewart, Catherine; Gupta, Nealansh; Janelsins, Michelle C; Barr, Paul M; Zent, Clive S

2018-03-01

We studied the risk of infections in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL). Major infections were defined as requiring hospital admission or intravenous antimicrobial treatment. Incidence rate (IR) ratios (IRR) were used to compare infection rates. Of 263 CLL patients followed for 936.9 person-years, 60% required treatment for progressive CLL (66 received ibrutinib). Infections occurred in 71.9% patients (IR 92.4/100 person-years) with 31.9% having major infections (IR 20.3/100 person-years) and infections causing 37.5% of deaths. CLL treatment was associated with significantly higher risk of major (IRR 3.31, 95% CI 2.10, 5.21) and minor (IRR 1.78, 95% CI 1.43, 2.22) infections. Compared to their previous chemoimmunotherapy patients receiving salvage ibrutinib therapy (n = 47) had a significantly increased risk of a major infection (IRR 2.35 95% CI 1.27, 4.34). The risk of infection in CLL patients remains high even with use of less immunosuppressive therapies.

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

PubMed

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

2016-06-01

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

Graft-versus-leukemia effects of transplantation and donor lymphocytes.

PubMed

Kolb, Hans-Jochem

2008-12-01

Allogeneic transplantation of hematopoietic cells is an effective treatment of leukemia, even in advanced stages. Allogeneic lymphocytes produce a strong graft-versus-leukemia (GVL) effect, but the beneficial effect is limited by graft-versus-host disease (GVHD). Depletion of T cells abrogates GVHD and GVL effects. Delayed transfusion of donor lymphocytes into chimeras after T cell-depleted stem cell transplantation produces a GVL effect without necessarily producing GVHD. Chimerism and tolerance provide a platform for immunotherapy using donor lymphocytes. The allogeneic GVL effects vary from one disease to another, the stage of the disease, donor histocompatibility, the degree of chimerism, and additional treatment. Immunosuppressive therapy before donor lymphocyte transfusions may augment the effect as well as concomitant cytokine treatment. Possible target antigens are histocompatibility antigens and tumor-associated antigens. Immune escape of tumor cells and changes in the reactivity of T cells are to be considered. Durable responses may be the result of the elimination of leukemia stem cells or the establishment of a durable immune control on their progeny. Recently, we have learned from adoptive immunotherapy of viral diseases and HLA-haploidentical stem cell transplantation that T-cell memory may be essential for the effective treatment of leukemia and other malignancies.

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

PubMed

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

2011-02-10

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

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

PubMed

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

2013-01-08

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

Where does allogeneic stem cell transplantation fit in the treatment of chronic lymphocytic leukemia?

PubMed

Dreger, Peter; Montserrat, Emili

2015-03-01

Allogeneic hematopoietic stem cell transplantation (alloHSCT) has been considered as the treatment of choice for patients with high-risk chronic lymphocytic leukemia (CLL) (i.e., refractory to purine analogs, short response (<24 months) to intensive treatments, and/or presence of 17p/TP53 abnormalities). Currently, new and highly effective therapeutic agents targeting BCR-mediated intracellular signal transduction have been incorporated into the CLL treatment armamentarium. These signal transduction inhibitors (STI) will change the algorithms of high-risk CLL (HR-CLL) management. Despite the limited body of evidence, there is sufficient rationale for withholding alloHSCT in patients with 17p-/TP53mut CLL in first remission. In contrast, the perspectives of patients with relapsed 17p-/TP53mut CLL remain uncertain even if responding to STI. The same accounts for patients with HR-CLL progressing under STI. In both scenarios, it is reasonable to consider alloHSCT, ideally after response to alternative STI regimens.

Integrated single-cell genetic and transcriptional analysis suggests novel drivers of chronic lymphocytic leukemia

PubMed Central

Wang, Lili; Fan, Jean; Francis, Joshua M.; Georghiou, George; Hergert, Sarah; Li, Shuqiang; Gambe, Rutendo; Zhou, Chensheng W.; Yang, Chunxiao; Xiao, Sheng; Cin, Paola Dal; Bowden, Michaela; Kotliar, Dylan; Shukla, Sachet A.; Brown, Jennifer R.; Neuberg, Donna; Alessi, Dario R.; Zhang, Cheng-Zhong; Kharchenko, Peter V.; Livak, Kenneth J.; Wu, Catherine J.

2017-01-01

Intra-tumoral genetic heterogeneity has been characterized across cancers by genome sequencing of bulk tumors, including chronic lymphocytic leukemia (CLL). In order to more accurately identify subclones, define phylogenetic relationships, and probe genotype–phenotype relationships, we developed methods for targeted mutation detection in DNA and RNA isolated from thousands of single cells from five CLL samples. By clearly resolving phylogenic relationships, we uncovered mutated LCP1 and WNK1 as novel CLL drivers, supported by functional evidence demonstrating their impact on CLL pathways. Integrative analysis of somatic mutations with transcriptional states prompts the idea that convergent evolution generates phenotypically similar cells in distinct genetic branches, thus creating a cohesive expression profile in each CLL sample despite the presence of genetic heterogeneity. Our study highlights the potential for single-cell RNA-based targeted analysis to sensitively determine transcriptional and mutational profiles of individual cancer cells, leading to increased understanding of driving events in malignancy. PMID:28679620

Attenuation of CXCR4 responses by CCL18 in acute lymphocytic leukemia B cells.

PubMed

Catusse, J; Wollner, S; Leick, M; Schröttner, P; Schraufstätter, I; Burger, M

2010-11-01

CCL18 and CXCL12 are homeostatic chemokines with high constitutive concentrations in serum. Elevated levels of CCL18 have been described in various diseases including childhood acute lymphocytic leukemia (ALL) but its functions remain poorly characterized. Its receptor has not been identified, but functional cellular responses like lymphocyte chemotaxis have been described. CXCL12 is a pivotal chemokine for hematopoiesis and B cell homing processes. We demonstrate that CCL18 interferes with CXCL12-mediated pre-B ALL cell activation. CXCL12-induced calcium mobilization, chemotaxis, pseudo-emperipolesis and cellular proliferation could be significantly reduced by CCL18 in pre-B ALL cell lines. The results could be observed in primary cells from patients suffering from pre-B ALL, but not in cells from patients suffering from common ALL. Direct effects of CCL18 on the receptor for CXCL12, CXCR4, could be excluded. Moreover, we found that CCL18 modulations of CXCL12-induced responses are mediated through the chemokine-like receptor GPR30. CCL18 bound to GPR30 expressing cells, and antibodies against GPR30 abolished this binding as well as CCL18-mediated functional effects. We also observed that, CCL18 interferes with the activation of GPR30 by previously identified ligands (17β-estradiol and chemical agonists). We therefore suggest that CCL18 is an important modulator of CXCR4-dependent responses in pre-B ALL cells via interactions with GPR30. © 2010 Wiley-Liss, Inc.

Cell-Intrinsic Determinants of Ibrutinib-Induced Apoptosis in Chronic Lymphocytic Leukemia.

PubMed

Amin, Nisar A; Balasubramanian, Sriram; Saiya-Cork, Kamlai; Shedden, Kerby; Hu, Nan; Malek, Sami N

2017-02-15

Purpose: Ibrutinib, a Bruton tyrosine kinase (BTK) inhibitor, is approved for the treatment of relapsed chronic lymphocytic leukemia (CLL) and CLL with del17p. Mechanistically, ibrutinib interferes with B-cell receptor (BCR) signaling as well as multiple CLL cell-to-microenvironment interactions. Given the importance of ibrutinib in the management of CLL, a deeper understanding of factors governing sensitivity and resistance is warranted. Experimental Design: We studied 48 longitudinally sampled paired CLL samples, 42 of which were procured before and after standard CLL chemotherapies, and characterized them for well-studied CLL molecular traits as well as by whole-exome sequencing and SNP 6.0 array profiling. We exposed these samples to 0.25 to 5 μmol/L of ibrutinib ex vivo and measured apoptosis fractions as well as BCR signaling by immunoblotting. We disrupted TP53 in HG3, PGA1, and PG-EBV cell lines and measured BCR signaling and ibrutinib responses. Results: CLL samples demonstrated a surprisingly wide range of ex vivo sensitivities to ibrutinib, with IC 50 values ranging from 0.4 to 9.7 μmol/L. Unmutated IGVH status, elevated ZAP70 expression, and trisomy 12 were associated with heightened sensitivity to ibrutinib treatment. Five CLL samples were substantially more resistant to ibrutinib following relapse from chemotherapy; of these, three had acquired a del17p/ TP53 -mutated status. A validation sample of 15 CLL carrying TP53 mutations, of which 13 carried both del17p and a TP53 mutation, confirmed substantially less sensitivity to ibrutinib-induced apoptosis. Conclusions: This study identifies that CLL harboring del17p/ TP53 -mutated cells are substantially less sensitive to ibrutinib-induced apoptosis than del17p/ TP53 wild-type cells. Clin Cancer Res; 23(4); 1049-59. ©2016 AACR . ©2016 American Association for Cancer Research.

Clinical effect of stereotyped B-cell receptor immunoglobulins in chronic lymphocytic leukaemia: a retrospective multicentre study.

PubMed

Baliakas, Panagiotis; Hadzidimitriou, Anastasia; Sutton, Lesley-Ann; Minga, Eva; Agathangelidis, Andreas; Nichelatti, Michele; 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; 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; Rosenquist, Richard; Ghia, Paolo; Stamatopoulos, Kostas

2014-11-01

cases of CLL and represent both U-CLL and M-CLL, constituted separate clinical entities, ranging from very indolent (subset 4) to aggressive disease (subsets 1 and 2). The molecular classification of chronic lymphocytic leukaemia based on B-cell receptor immunoglobulin stereotypy improves the Döhner hierarchical model and refines prognostication beyond immunoglobulin mutational status, with potential implications for clinical decision making, especially within prospective clinical trials. European Union; General Secretariat for Research and Technology of Greece; AIRC; Italian Ministry of Health; AIRC Regional Project with Fondazione CARIPARO and CARIVERONA; Regione Veneto on Chronic Lymphocytic Leukemia; Nordic Cancer Union; Swedish Cancer Society; Swedish Research Council; and National Cancer Institute (NIH). Copyright © 2014 Elsevier Ltd. All rights reserved.

Characterizing patients with multiple chromosomal aberrations detected by FISH in chronic lymphocytic leukemia.

PubMed

González-Gascón Y Marín, Isabel; Hernández-Sanchez, María; Rodríguez-Vicente, Ana Eugenia; Puiggros, Anna; Collado, Rosa; Luño, Elisa; González, Teresa; Ruiz-Xivillé, Neus; Ortega, Margarita; Gimeno, Eva; Muñoz, Carolina; Infante, Maria Stefania; Delgado, Julio; Vargas, María Teresa; González, Marcos; Bosch, Francesc; Espinet, Blanca; Hernández-Rivas, Jesús María; Hernández, José Ángel

2018-03-01

We analyzed the features of chronic lymphocytic leukemia (CLL) with multiple abnormalities (MA) detected by FISH. A local database including 2095 CLL cases was used and 323 with MA (15.4%) were selected. MA was defined by the presence of two or more alterations (deletions of 13q14 (13q-), 11q22 (11q-), 17p13 (17p-) or trisomy 12 (+12)). The combination of 13q- with 11q- and 13q- with 17p-, accounted for 58.2% of the series, in contrast to 11q- with 17p- (3.7%). Patients carrying MA since diagnosis presented a short time to first therapy(TTFT) (27 months) and overall survival (OS) (76 months). The combinations including 17p- had a shorter OS (58 months) than the ones without 17p- (not reached, p = .002). Patients with a complex-FISH were the ones with worse OS (34 months). MA imply poor prognosis when they emerge at diagnosis, probably due to the high incidence of bad prognosis markers, which may be a reflection of a more complex karyotype.

The CD94/NKG2C-expressing NK cell subset is augmented in chronic lymphocytic leukemia patients with positive human cytomegalovirus serostatus.

PubMed

Petersen, Line; Roug, Anne S; Skovbo, Anni; Thysen, Anna H; Eskelund, Christian W; Hokland, Marianne E

2009-10-01

Human cytomegalovirus (HCMV) manipulates the host immune system in various ways. Allegedly, HCMV infection is associated with increased percentages of a particular natural killer (NK) cell subset expressing the activating receptor CD94/NKG2C in both healthy individuals and in patients infected with human immunodeficiency virus (HIV). Whether the HCMV-mediated induction of this specific NK cell subset is also apparent for other diseases characterized by abnormal immune responses, such as malignant blood diseases, is unknown. By comparing the fractions of CD94/NKG2C(+) NK cells in B-cell chronic lymphocytic leukemia (B-CLL) patients having either positive or negative HCMV serostatus, a proportional increase of this cell subset was obvious in the HCMV-seropositive subjects. Therapeutic intervention in the patients with positive HCMV serostatus did not seem to reduce the percentage of CD94/NKG2C-expressing NK cells. Thus, HCMV infection seemingly shapes the NK cell system in healthy individuals, HIV patients, and B-CLL patients in a uniform manner, even though these involve different immunological challenges.

Efficacy and Safety of Bendamustine and Ibrutinib in Previously Untreated Patients With Chronic Lymphocytic Leukemia: Indirect Comparison.

PubMed

Andrasiak, Iga; Rybka, Justyna; Knopinska-Posluszny, Wanda; Wrobel, Tomasz

2017-05-01

Bendamustine and ibrutinib are commonly used in the treatment of patients suffering from chronic lymphocytic leukemia (CLL). In this study we compare efficacy and safety bendamustine versus ibrutinib therapy in previously untreated patients with CLL. Because there are no head-to-head comparisons between bendamustine and ibrutinib, we performed indirect comparison using Bucher method. A systematic literature review was performed and 2 studies published before June 2016 were taken into analysis. Treatment with ibrutinib significantly improves PFS determined by investigator (HR of 0.3; P = .01) and OS (HR of 0.21; P < .001. Our study indicates that ibrutinib therapy improves PFS, OS and is superior in terms of safety comparing with bendamustine therapy in CLL patients. Copyright © 2017 Elsevier Inc. All rights reserved.

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

ClinicalTrials.gov

2017-05-25

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

Pharmacokinetics of venetoclax in patients with 17p deletion chronic lymphocytic leukemia.

PubMed

Salem, Ahmed Hamed; Dunbar, Martin; Agarwal, Suresh K

2017-09-01

Venetoclax is a first-in-class orally available, B-cell lymphoma (BCL)-2 inhibitor indicated for the treatment of patients with relapsed/refractory chronic lymphocytic leukemia (CLL) harboring the 17p deletion. We used a novel approach for evaluating venetoclax pharmacokinetics using only sparse sampling in 155 patients enrolled in a phase 2, multicenter, open-label study in CLL patients with the 17p deletion. Patients received venetoclax doses within 30 min after the completion of breakfast or the first meal of the day, with no specific recommendations for the fat content in the meal. Blood samples for venetoclax assay were collected during the ramp-up period and on day 1 of weeks 8, 12, 16, 24, and every 12 weeks thereafter. The mean postdose (8 h) plasma venetoclax concentrations increased with increasing weekly venetoclax dose during the ramp-up period to reach 1.89 µg/ml on week 5 day 1 at the 400 mg dose. The mean predose concentration at the 400 mg dose ranged between 0.69 and 0.99 µg/ml across visits between weeks 8 and 120. Repeated-measures analysis detected no statistical significance (P≥0.05) for the mean predose concentrations at any of the times tested from weeks 8 to 24. The study shows that the pharmacokinetic profile of venetoclax in CLL patients with the 17p deletion is comparable to the overall CLL as well as non-Hodgkin's lymphoma patient populations. Furthermore, no specific recommendation in terms of fat content in the meal is needed for the intake of venetoclax in patients with CLL.

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

Nilotinib and Combination Chemotherapy in Treating Patients With Newly Diagnosed Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia or Blastic Phase Chronic Myelogenous Leukemia

ClinicalTrials.gov

2015-10-29

B-cell Adult Acute Lymphoblastic Leukemia; Blastic Phase Chronic Myelogenous Leukemia; Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Philadelphia Chromosome Positive Adult Precursor Acute Lymphoblastic Leukemia; Untreated Adult Acute Lymphoblastic Leukemia

Genomic characterization of chronic lymphocytic leukemia (CLL) in radiation-exposed Chornobyl cleanup workers.

PubMed

Ojha, Juhi; Dyagil, Iryna; Finch, Stuart C; Reiss, Robert F; de Smith, Adam J; Gonseth, Semira; Zhou, Mi; Hansen, Helen M; Sherborne, Amy L; Nakamura, Jean; Bracci, Paige M; Gudzenko, Nataliya; Hatch, Maureen; Babkina, Nataliya; Little, Mark P; Chumak, Vadim V; Walsh, Kyle M; Bazyka, Dimitry; Wiemels, Joseph L; Zablotska, Lydia B

2018-05-02

Chronic lymphocytic leukemia (CLL) was the predominant leukemia in a recent study of Chornobyl cleanup workers from Ukraine exposed to radiation (UR-CLL). Radiation risks of CLL significantly increased with increasing bone marrow radiation doses. Current analysis aimed to clarify whether the increased risks were due to radiation or to genetic mutations in the Ukrainian population. A detailed characterization of the genomic landscape was performed in a unique sample of 16 UR-CLL patients and age- and sex-matched unexposed general population Ukrainian-CLL (UN-CLL) and Western-CLL (W-CLL) patients (n = 28 and 100, respectively). Mutations in telomere-maintenance pathway genes POT1 and ATM were more frequent in UR-CLL compared to UN-CLL and W-CLL (both p < 0.05). No significant enrichment in copy-number abnormalities at del13q14, del11q, del17p or trisomy12 was identified in UR-CLL compared to other groups. Type of work performed in the Chornobyl zone, age at exposure and at diagnosis, calendar time, and Rai stage were significant predictors of total genetic lesions (all p < 0.05). Tumor telomere length was significantly longer in UR-CLL than in UN-CLL (p = 0.009) and was associated with the POT1 mutation and survival. No significant enrichment in copy-number abnormalities at CLL-associated genes was identified in UR-CLL compared to other groups. The novel associations between radiation exposure, telomere maintenance and CLL prognosis identified in this unique case series provide suggestive, though limited data and merit further investigation.

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.

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

Pharmacological and Protein Profiling Suggests Venetoclax (ABT-199) as Optimal Partner with Ibrutinib in Chronic Lymphocytic Leukemia.

PubMed

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

2015-08-15

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. 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. 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 in high 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 antiapoptotic proteins that are overexpressed in CLL, levels of MCL-1 and BCL-XL were decreased after ibrutinib while ABT-199 selectively antagonizes BCL-2. Our biologic and molecular results suggest that ibrutinib and ABT-199 combination should be tested clinically against CLL. ©2015 American Association for Cancer Research.

Partial reconstitution of humoral immunity and fewer infections in patients with chronic lymphocytic leukemia treated with ibrutinib.

PubMed

Sun, Clare; Tian, Xin; Lee, Yuh Shan; Gunti, Sreenivasulu; Lipsky, Andrew; Herman, Sarah E M; Salem, Dalia; Stetler-Stevenson, Maryalice; Yuan, Constance; Kardava, Lela; Moir, Susan; Maric, Irina; Valdez, Janet; Soto, Susan; Marti, Gerald E; Farooqui, Mohammed Z; Notkins, Abner L; Wiestner, Adrian; Aue, Georg

2015-11-05

Chronic lymphocytic leukemia (CLL) is characterized by immune dysregulation, often including hypogammaglobulinemia, which contributes to a high rate of infections and morbidity. Ibrutinib, a covalent inhibitor of Bruton tyrosine kinase (BTK), inhibits B-cell receptor signaling and is an effective, US Food and Drug Administration (FDA)-approved treatment of CLL. Inactivating germline mutations in BTK cause a severe B-cell defect and agammaglobulinemia. Therefore, we assessed the impact of ibrutinib on immunoglobulin levels, normal B cells, and infection rate in patients with CLL treated with single-agent ibrutinib on a phase 2 investigator-initiated trial. Consistent with previous reports, immunoglobulin G (IgG) levels remained stable during the first 6 months on treatment, but decreased thereafter. In contrast, there were a transient increase in IgM and a sustained increase in IgA (median increase 45% at 12 months, P < .0001). To distinguish the effects on clonal B cells from normal B cells, we measured serum free light chains (FLCs). In κ-clonal CLL cases, clonal (κ) FLCs were elevated at baseline and normalized by 6 months. Nonclonal (λ) FLCs, which were often depressed at baseline, increased, suggesting the recovery of normal B cells. Consistently, we observed normal B-cell precursors in the bone marrow and an increase in normal B-cell numbers in the peripheral blood. Patients with superior immune reconstitution, as defined by an increase in serum IgA of ≥50% from baseline to 12 months, had a significantly lower rate of infections (P = .03). These data indicate that ibrutinib allows for a clinically meaningful recovery of humoral immune function in patients with CLL. This trial was registered at www.clinicaltrials.gov as #NCT015007330.

Tipifarnib in Treating Patients With Chronic Myeloid Leukemia, Chronic Myelomonocytic Leukemia, or Undifferentiated Myeloproliferative Disorders

ClinicalTrials.gov

2018-05-31

Accelerated Phase of Disease; Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative; Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Chronic Myelomonocytic Leukemia; Chronic Phase of Disease; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Recurrent Disease

Venetoclax for patients with chronic lymphocytic leukemia who progressed during or after idelalisib therapy

PubMed Central

Choi, Michael; Furman, Richard R.; Eradat, Herbert; Heffner, Leonard; Jones, Jeffrey A.; Chyla, Brenda; Zhou, Lang; Agarwal, Suresh; Waskiewicz, Tina; Verdugo, Maria; Humerickhouse, Rod A.; Potluri, Jalaja; Wierda, William G.; Davids, Matthew S.

2018-01-01

B-cell receptor pathway inhibitors (BCRis) have transformed treatment of chronic lymphocytic leukemia (CLL); however, the efficacy of therapies for patients whose disease is refractory to/relapses after (R/R) BCRis is unknown. Venetoclax is a selective, orally bioavailable BCL-2 inhibitor with activity in patients with CLL, including those who are heavily pretreated or have 17p deletion. This phase 2 study prospectively evaluated venetoclax in patients with R/R CLL after ibrutinib or idelalisib; here we report on patients who received idelalisib as the last BCRi before enrollment. Venetoclax was initiated at 20 mg daily, followed by intrapatient ramp-up to 400 mg daily. Primary objectives included efficacy (objective response rate [ORR]) and safety of venetoclax. The study enrolled 36 patients who previously received idelalisib (ORR, 67% [24/36]); 2 patients achieved complete remission, and 1 had complete remission with incomplete bone marrow recovery. Median progression-free survival (PFS) has not yet been reached; estimated 12-month PFS was 79%. The most common adverse events (AEs; all grades) were neutropenia (56%), diarrhea (42%), upper respiratory tract infection (39%), thrombocytopenia (36%), nausea (31%), fatigue (28%), cough (22%), rash (22%), and anemia (22%). Grade 3 or 4 AEs were primarily hematologic (neutropenia [50%], thrombocytopenia [25%], and anemia [17%]). No patients experienced tumor lysis syndrome. Venetoclax demonstrated promising clinical activity and favorable tolerability in patients with CLL whose disease progressed during or after idelalisib therapy. This trial was registered at www.clinicaltrials.gov as #NCT02141282. PMID:29305552

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

PubMed

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

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

PubMed Central

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

2018-01-01

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

Pembrolizumab in Untreated B-Cell Non-Hodgkin Lymphoproliferative Diseases

ClinicalTrials.gov

2018-04-06

B-Cell Non-Hodgkin Lymphoma; Waldenstrom Macroglobulinemia; Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma; Lymphoplasmacytic Lymphoma; Follicular Lymphoma; Indolent Non-Hodgkin Lymphoma; Marginal Zone Lymphoma

Venetoclax for Patients With Chronic Lymphocytic Leukemia With 17p Deletion: Results From the Full Population of a Phase II Pivotal Trial.

PubMed

Stilgenbauer, Stephan; Eichhorst, Barbara; Schetelig, Johannes; Hillmen, Peter; Seymour, John F; Coutre, Steven; Jurczak, Wojciech; Mulligan, Stephen P; Schuh, Anna; Assouline, Sarit; Wendtner, Clemens-Martin; Roberts, Andrew W; Davids, Matthew S; Bloehdorn, Johannes; Munir, Talha; Böttcher, Sebastian; Zhou, Lang; Salem, Ahmed Hamed; Desai, Monali; Chyla, Brenda; Arzt, Jennifer; Kim, Su Young; Verdugo, Maria; Gordon, Gary; Hallek, Michael; Wierda, William G

2018-07-01

Purpose Venetoclax is an orally bioavailable B-cell lymphoma 2 inhibitor. US Food and Drug Administration and European Medicines Agency approval for patients with 17p deleted relapsed/refractory chronic lymphocytic leukemia [del(17p) CLL] was based on results from 107 patients. An additional 51 patients were enrolled in a safety expansion cohort. Extended analysis of all enrolled patients, including the effect of minimal residual disease (MRD) negativity on outcome, is now reported. Patients and Methods Overall, 158 patients with relapsed/refractory or previously untreated (n = 5) del(17p) CLL received venetoclax 400 mg per day after an initial dose ramp up. Responses were based on 2008 International Workshop on Chronic Lymphocytic Leukemia criteria, with monthly physical exams and blood counts. Computed tomography scan was mandatory at week 36, after which assessment made was by clinical evaluation. Marrow biopsy was performed when complete remission was suspected. MRD was assessed by flow cytometry. Results Patients had a median of two prior therapies (range, zero to 10 therapies), 71% had TP53 mutation, and 48% had nodes that were ≥ 5 cm. Median time on venetoclax was 23.1 months (range, 0 to 44.2 months) and median time on study was 26.6 months (range, 0 to 44.2 months). For all patients, investigator-assessed objective response rate was 77% (122 of 158 patients; 20% complete remission) and estimated progression-free survival at 24 months was 54% (95% CI, 45% to 62%). For 16 patients who received prior kinase inhibitors, objective response rate was 63% (10 of 16 patients) and 24-month progression-free survival estimate was 50% (95% CI, 25% to 71%). By intent-to-treat analysis, 48 (30%) of 158 patients achieved MRD below the cutoff of 10 -4 in blood. Common grade 3 and 4 adverse events were hematologic and managed with supportive care and/or dose adjustments. Conclusion Venetoclax achieves durable responses and was well tolerated in patients with del(17p) CLL

Outpatient-Based Therapy of Oral Fludarabine and Subcutaneous Alemtuzumab for Asian Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia

PubMed Central

Hwang, William Y. K.; Dearden, Claire; Loh, Yvonne S. M.; Linn, Yeh C.; Tien, Sim L.; Teoh, Gerrard K. H.; How, Gee F.; Heng, Kee K.; Goh, Yeow T.; Lee, Lai H.

2009-01-01

Background. Intravenous alemtuzumab and fludarabine are effective in combination for the treatment of chronic lymphocytic leukemia (CLL), but require hospital visits for intravenous injection. We performed a pilot study to assess the safety and efficacy of outpatient-based oral fludarabine with subcutaneous alemtuzumab (OFSA) for the treatment of relapsed/refractory CLL. Results. Depending on their response, patients were given two to six 28-day cycles of subcutaneous alemtuzumab 30 mg on days 1,3, and 5 and oral fludarabine 40 mg/m2/day for 5 days. Median patient age was 74. The lymphocyte counts of all five patients fell after the 1st cycle of treatment and reached normal/low levels on completion of 2 to 6 cycles of therapy. Platelet counts and hemoglobin were unaffected. All five patients achieved complete hematological remission, while two attained minimal residual disease negativity on 4-color flow cytometry. Conclusions. Our OFSA regimen was effective in elderly Asian patients with relapsed/refractory CLL, and it should be investigated further. PMID:19960058

Positive regulation of deoxycytidine kinase activity by phosphorylation of Ser-74 in B-cell chronic lymphocytic leukaemia lymphocytes.

PubMed

Smal, Caroline; Van Den Neste, Eric; Maerevoet, Marie; Poiré, Xavier; Théate, Ivan; Bontemps, Françoise

2007-08-08

Deoxycytidine kinase (dCK) activates several antileukaemic nucleoside analogues. We have recently reported that the activity of dCK, overexpressed in HEK 293T cells, correlates with its phosphorylation level on Ser-74. Here, we show that dCK from B-cell chronic lymphocytic leukaemia (B-CLL) lymphocytes can be detected by an anti-phospho-Ser-74 antibody and that interindividual variability in dCK activity is related to its phosphorylation level on Ser-74. Moreover, pharmacological intervention modified Ser-74 phosphorylation, in close parallel with changes in dCK activity. These results suggest that activation of dCK via phosphorylation of Ser-74 might constitute a new therapeutic strategy to enhance activation and efficacy of nucleoside analogues.

14q deletions are associated with trisomy 12, NOTCH1 mutations and unmutated IGHV genes in chronic lymphocytic leukemia and small lymphocytic lymphoma.

PubMed

Cosson, Adrien; Chapiro, Elise; Belhouachi, Nabila; Cung, Hong-Anh; Keren, Boris; Damm, Frederik; Algrin, Caroline; Lefebvre, Christine; Fert-Ferrer, Sandra; Luquet, Isabelle; Gachard, Nathalie; Mugneret, Francine; Terre, Christine; Collonge-Rame, Marie-Agnes; Michaux, Lucienne; Rafdord-Weiss, Isabelle; Talmant, Pascaline; Veronese, Lauren; Nadal, Nathalie; Struski, Stephanie; Barin, Carole; Helias, Catherine; Lafage, Marina; Lippert, Eric; Auger, Nathalie; Eclache, Virginie; Roos-Weil, Damien; Leblond, Veronique; Settegrana, Catherine; Maloum, Karim; Davi, Frederic; Merle-Beral, Helene; Lesty, Claude; Nguyen-Khac, Florence

2014-08-01

Deletions of the long arm of chromosome 14 [del(14q)] are rare but recurrently observed in mature B-cell neoplasms, particularly in chronic lymphocytic leukemia (CLL). To further characterize this aberration, we studied 81 cases with del(14q): 54 of CLL and 27 of small lymphocytic lymphoma (SLL), the largest reported series to date. Using karyotype and fluorescence in situ hybridization (FISH), the most frequent additional abnormality was trisomy 12 (tri12), observed in 28/79 (35%) cases, followed by del13q14 (12/79, 15%), delTP53 (11/80, 14%) delATM (5/79, 6%), and del6q21 (3/76, 4%). IGHV genes were unmutated in 41/53 (77%) patients, with a high frequency of IGHV1-69 (21/52, 40%). NOTCH1 gene was mutated in 14/45 (31%) patients. There was no significant difference in cytogenetic and molecular abnormalities between CLL and SLL. Investigations using FISH and SNP-array demonstrated the heterogeneous size of the 14q deletions. However, a group with the same del(14)(q24.1q32.33) was identified in 48% of cases. In this group, tri12 (P = 0.004) and NOTCH1 mutations (P = 0.02) were significantly more frequent than in the other patients. In CLL patients with del(14q), median treatment-free survival (TFS) was 27 months. In conclusion, del(14q) is associated with tri12 and with pejorative prognostic factors: unmutated IGHV genes (with over-representation of the IGHV1-69 repertoire), NOTCH1 mutations, and a short TFS. © 2014 Wiley Periodicals, Inc.

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

ClinicalTrials.gov

2015-08-18

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

Functional and clinical relevance of VLA-4 (CD49d/CD29) in ibrutinib-treated chronic lymphocytic leukemia.

PubMed

Tissino, Erika; Benedetti, Dania; Herman, Sarah E M; Ten Hacken, Elisa; Ahn, Inhye E; Chaffee, Kari G; Rossi, Francesca Maria; Dal Bo, Michele; Bulian, Pietro; Bomben, Riccardo; Bayer, Elisabeth; Härzschel, Andrea; Gutjahr, Julia Christine; Postorino, Massimiliano; Santinelli, Enrico; Ayed, Ayed; Zaja, Francesco; Chiarenza, Annalisa; Pozzato, Gabriele; Chigaev, Alexandre; Sklar, Larry A; Burger, Jan A; Ferrajoli, Alessandra; Shanafelt, Tait D; Wiestner, Adrian; Del Poeta, Giovanni; Hartmann, Tanja Nicole; Gattei, Valter; Zucchetto, Antonella

2018-02-05

The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib, which antagonizes B cell receptor (BCR) signals, demonstrates remarkable clinical activity in chronic lymphocytic leukemia (CLL). The lymphocytosis experienced by most patients under ibrutinib has previously been attributed to inhibition of BTK-dependent integrin and chemokine cues operating to retain the tumor cells in nodal compartments. Here, we show that the VLA-4 integrin, as expressed by CD49d-positive CLL, can be inside-out activated upon BCR triggering, thus reinforcing the adhesive capacities of CLL cells. In vitro and in vivo ibrutinib treatment, although reducing the constitutive VLA-4 activation and cell adhesion, can be overcome by exogenous BCR triggering in a BTK-independent manner involving PI3K. Clinically, in three independent ibrutinib-treated CLL cohorts, CD49d expression identifies cases with reduced lymphocytosis and inferior nodal response and behaves as independent predictor of shorter progression-free survival, suggesting the retention of CD49d-expressing CLL cells in tissue sites via activated VLA-4. Evaluation of CD49d expression should be incorporated in the characterization of CLL undergoing therapy with BCR inhibitors. © 2018 Tissino et al.

Functional and clinical relevance of VLA-4 (CD49d/CD29) in ibrutinib-treated chronic lymphocytic leukemia

PubMed Central

Tissino, Erika; Benedetti, Dania; Herman, Sarah E.M.; ten Hacken, Elisa; Rossi, Francesca Maria; Dal Bo, Michele; Bulian, Pietro; Bomben, Riccardo; Bayer, Elisabeth; Härzschel, Andrea; Gutjahr, Julia Christine; Postorino, Massimiliano; Santinelli, Enrico; Zaja, Francesco; Pozzato, Gabriele; Chigaev, Alexandre; Sklar, Larry A.; Burger, Jan A.; Ferrajoli, Alessandra; Shanafelt, Tait D.; Wiestner, Adrian; Del Poeta, Giovanni; Hartmann, Tanja Nicole

2018-01-01

The Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib, which antagonizes B cell receptor (BCR) signals, demonstrates remarkable clinical activity in chronic lymphocytic leukemia (CLL). The lymphocytosis experienced by most patients under ibrutinib has previously been attributed to inhibition of BTK-dependent integrin and chemokine cues operating to retain the tumor cells in nodal compartments. Here, we show that the VLA-4 integrin, as expressed by CD49d-positive CLL, can be inside-out activated upon BCR triggering, thus reinforcing the adhesive capacities of CLL cells. In vitro and in vivo ibrutinib treatment, although reducing the constitutive VLA-4 activation and cell adhesion, can be overcome by exogenous BCR triggering in a BTK-independent manner involving PI3K. Clinically, in three independent ibrutinib-treated CLL cohorts, CD49d expression identifies cases with reduced lymphocytosis and inferior nodal response and behaves as independent predictor of shorter progression-free survival, suggesting the retention of CD49d-expressing CLL cells in tissue sites via activated VLA-4. Evaluation of CD49d expression should be incorporated in the characterization of CLL undergoing therapy with BCR inhibitors. PMID:29301866

New insights into hematopoietic stem cell transplantation for chronic lymphocytic leukemia: a 2015 perspective.

PubMed

McClanahan, Fabienne; Gribben, John

2015-09-01

A considerable body of evidence demonstrates that allogeneic hematopoietic stem cell transplantation (HSCT) offers the only potentially curative treatment option for patients with chronic lymphocytic leukemia (CLL). However, this approach is suitable for only a minority of CLL patients, owing to its significant treatment-related mortality and morbidity. Until recently, internationally accepted guidelines suggested that HSCT should be considered in physically fit CLL patients who carry poor-risk features, such as TP53 abnormalities, or who had a short response to previous immunochemotherapy. However, several new agents and alternative treatment strategies are available that demonstrate impressive and durable responses, even in CLL patients who previously might have been candidates for transplant. The decision about which patients merit HSCT therefore remains important, and HSCT must now be considered in light of other less toxic therapies. Until data on the long-term efficacy of novel treatment approaches mature, the choice of HSCT vs alternative strategies must be assessed on a patient-by-patient basis, and treatment in the setting of randomized clinical trials should be pursued whenever possible.

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

PubMed

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

2015-07-01

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