Lymphocytic Leukemia

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Clinical Implications of Novel Genomic Discoveries in Chronic Lymphocytic Leukemia

Clinical Implications of Novel Genomic Discoveries in Chronic Lymphocytic Leukemia

J Clin Oncol 35:984-993. © 2017 by American Society of Clinical Oncology Chronic lymphocytic leukemia (CLL) is char- acterized by the accumulation and proliferation of clonal B cells in the blood, marrow, and lymph nodes. The clinical course of CLL is remarkably variable among patients, with median overall survival (OS) ranging from less than 3 years, despite the use of effective combination chemotherapy regimens, to more than 10 years without need of therapeutic intervention. 1 , 2 Genetic features underlying this var- iability in clinical course have been long identified. Conventional karyotype banding and fluorescent in situ hybridization (FISH) analysis are the bases of the existing widely used hierarchic prognostic model. 3 The recent advent of transformative next-generation sequencing (NGS) has uncovered many novel putative disease-driving somatic alterations and accurately quantified intrasample heterogeneity. With the recent US Food and Drug Administration approval of in- hibitors targeting CLL pathways, 4 - 6 the identification of the connections between each therapy and po- tentially vulnerable genomically defined disease sub- populations has become a priority in CLL.
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State-of-the-art for CAR T-cell therapy for chronic lymphocytic leukemia in 2019

State-of-the-art for CAR T-cell therapy for chronic lymphocytic leukemia in 2019

Keywords: CLL, CAR T cells, Ibrutinib Introduction Chronic lymphocytic leukemia (CLL) is the most common lymphoid hemopathy (estimated incidence of 2 to 4 cases per 100,000 inhabitants/year). It is diagnosed at a median age of 72 years, and therefore mostly in patients with comorbid conditions [ 1 ]. It is a B lymphoid hemopathy characterized by invasion of the bone marrow, blood, and secondary lymphoid organs (spleen and/or lymph nodes). Prognosis is evaluated essentially on the basis of cytogenetic and molecular biology analyses. The two most unfavor- able elements associated with a poor prognosis are:
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Concomitant heterochromatinisation and down-regulation of gene expression unveils epigenetic silencing of RELB in an aggressive subset of chronic lymphocytic leukemia in males.

Concomitant heterochromatinisation and down-regulation of gene expression unveils epigenetic silencing of RELB in an aggressive subset of chronic lymphocytic leukemia in males.

Background: The sensitivity of chronic lymphocytic leukemia (CLL) cells to current treatments, both in vitro and in vivo, relies on their ability to activate apoptotic death. CLL cells resistant to DNA damage-induced apoptosis display deregulation of a specific set of genes. Methods: Microarray hybridization (Human GeneChip, Affymetrix), immunofluorescent in situ labeling coupled with video-microscopy recording/analyses, chromatin-immunoprecipitation (ChIP), polymerase chain reactions (PCR), real- time quantitative PCR (RT-QPCR) and bisulfite genome sequencing were the main methods applied. Statistical analyses were performed by applying GCRMA and SAM analysis (microarray data) and Student’s t-test or Mann & Whitney’s U-test.
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CD47 Agonist Peptides Induce Programmed Cell Death in Refractory Chronic Lymphocytic Leukemia B Cells via PLCγ1 Activation: Evidence from Mice and Humans

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

Editors’ Summary Background Chronic lymphocytic leukemia (CLL) is the most common type of adult leukemia (cancer of the white blood cells). It accounts for about a third of all adult leukemias, and about one in 200 people will develop CLL during their lifetime, usually in old age. White blood cells (including T and B lymphocytes) are made by the bone marrow (the soft center of certain bones in the body) and help the body fight infections. Leukemia begins when a bone mar- row cell acquires genetic changes (mutations and chromosomal abnormalities) that make it grow and develop abnormally. Over time, the abnormal cells accumulate in the bone marrow, blood, and lymphoid organs (lymph nodes and spleen) (malignant B lympho- cytes accumulate in the case of CLL) and stop the marrow producing healthy blood cells. CLL does not usually cause any symptoms during its early stages and is often diagnosed as a result of a routine blood test. Some patients, however, develop painless swellings in the lymph nodes in the neck, armpit, or groin. Other symptoms of CLL include tiredness, fre- quent infections, and weight loss. Treatments for CLL, which are not given unless symp- toms develop, include chemotherapy, immunotherapy, and targeted therapies, which attack cancer cells without harming normal cells.
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Activation of Interferon Signaling in Chronic Lymphocytic Leukemia Cells Contributes to Apoptosis Resistance via a JAK-Src/STAT3/Mcl-1 Signaling Pathway

Activation of Interferon Signaling in Chronic Lymphocytic Leukemia Cells Contributes to Apoptosis Resistance via a JAK-Src/STAT3/Mcl-1 Signaling Pathway

Chronic lymphocytic leukemia (CLL) is a very heterogeneous disease characterized by a peripheral accumulation of abnormal CD5 + B lymphocytes in the blood, bone marrow and lymphoid tissues [ 15 ]. The leukemic cells (which are mostly quiescent) mainly accumu- late because they are unable to develop a cell death program—even though proliferating pools are found in the bone marrow and lymph nodes [ 15 ]. Treatment of CLL remains a challenge in the clinic because ~15–25% of patients either are refractory to today’s front-line therapies or relapse after treatment [ 16 ]. The drugs currently prescribed are a combination of fludarabine-cyclophosphamide-rituximab (FCR), signaling inhibitors targeting B cell receptor (BCR)-associated kinases (i.e., Bruton’s tyrosine kinase (BTK) inhibitors such as ibrutinib) or the antagonist of the B-cell lymphoma-2 (Bcl-2) anti-apoptotic protein (venetoclax) [ 16 ]. Venetoclax has been initially approved for relapsed or refractory CLL patients [ 17 ], and today may be prescribed in first-line treatment of untreated CLL pa- tients [ 18 , 19 ]. Unfortunately, these therapies are often accompanied by adverse effects or favored mutations associated to drug resistance [ 20 – 22 ]. Therefore, novel therapies are needed to overcome resistance to these drugs, and the identification of new therapeutic possibilities in CLL therapy is of general interest.
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“Double-hit” chronic lymphocytic leukemia: An aggressive subgroup with 17p deletion and 8q24 gain

“Double-hit” chronic lymphocytic leukemia: An aggressive subgroup with 17p deletion and 8q24 gain

20. Collado R, Puiggros A, Lopez-Guerrero JA, et al. Chronic lymphocytic leukemia with isochromosome 17q: An aggressive subgroup associated with TP53 mutations and complex karyotypes. Cancer letters 2017. 21. Shanafelt TD, Witzig TE, Fink SR, et al. Prospective evaluation of clonal evolution during long- term follow-up of patients with untreated early-stage chronic lymphocytic leukemia. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2006;24:4634-4641. 22. Stilgenbauer S, Sander S, Bullinger L, et al. Clonal evolution in chronic lymphocytic leukemia: acquisition of high-risk genomic aberrations associated with unmutated VH, resistance to therapy, and short survival. Haematologica 2007;92:1242-1245.
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Study of chronic lymphocytic leukemia cells by FT-IR spectroscopy and cluster analysis

Study of chronic lymphocytic leukemia cells by FT-IR spectroscopy and cluster analysis

Abstract-The peripheral mononuclear cells from 23 normal individuals and the purified B cells from 38 patients with chronic lymphocytic leukemia (CLL) were examined[r]

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CD49d promotes disease progression in chronic lymphocytic leukemia : new insights from CD49d bimodal expression

CD49d promotes disease progression in chronic lymphocytic leukemia : new insights from CD49d bimodal expression

CD49d is a remarkable prognostic biomarker of chronic lymphocytic leukemia (CLL). The cutoff value for the extensively validated 30% of positive CLL cells is able to separate CLL patients into 2 subgroups with different prognoses, but it does not consider the pattern of CD49d expression. In the present study, we analyzed a cohort of 1630 CLL samples and identified the presence of ∼20% of CLL cases (n 5 313) characterized by a bimodal ex- pression of CD49d, that is, concomitant presence of a CD49d 1 subpopulation and a CD49d 2 subpopulation. At variance with the highly stable CD49d expression observed in CLL patients with a homogeneous pattern of CD49d expression, CD49d bimodal CLL showed a higher level of variability in sequential samples, and an increase in the CD49d 1 sub- population over time after therapy. The CD49d 1 subpopulation from CD49d bimodal CLL displayed higher levels of proliferation compared with the CD49d 2 cells; and was more highly represented in the bone marrow compared with peripheral blood (PB), and in PB CLL subsets expressing the CXCR4 dim /CD5 bright phenotype, known to be enriched in proliferative cells. From a clinical standpoint, CLL patients with CD49d bimodal expression, regardless of whether the CD49d 1 subpopulation exceeded the 30% cutoff or not, experienced clinical behavior similar to CD49d 1 CLL, both in chemoimmunotherapy (n 5 1522) and in ibrutinib (n 5 158) settings. Altogether, these results suggest that CD49d can drive disease progression in CLL, and that the pattern of CD49d expression should also be considered to improve the prognostic impact of this biomarker in CLL. (Blood. 2020;135(15):1244-1254)
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Activated Allogeneic NK Cells Preferentially Kill Poor Prognosis B-Cell Chronic Lymphocytic Leukemia Cells

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

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 machin- ery. 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.
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Ibrutinib in very elderly patients with relapsed/refractory chronic lymphocytic leukemia: A real-world experience of 71 patients treated in France: A study from the French Innovative Leukemia Organization (FILO) group

Ibrutinib in very elderly patients with relapsed/refractory chronic lymphocytic leukemia: A real-world experience of 71 patients treated in France: A study from the French Innovative Leukemia Organization (FILO) group

French Innovative Leukemia Organization (FILO) group To the Editor: In first-line therapy, 20% of patient with chronic lymphocytic leukemia (CLL) are even 80 years old or over, rendering therapeutic decisions often challenging. Due to the common comorbidity burden and fre- quency of adverse cytogenetics associated with this elderly population,

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Identification of a 20-gene expression-based risk score as a predictor of clinical outcome in chronic lymphocytic leukemia patients.

Identification of a 20-gene expression-based risk score as a predictor of clinical outcome in chronic lymphocytic leukemia patients.

Copyright © 2014 Elias Bou Samra et al. his is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Despite the improvement in treatment options, chronic lymphocytic leukemia (CLL) remains an incurable disease and patients show a heterogeneous clinical course requiring therapy for many of them. In the current work, we have built a 20-gene expression (GE)-based risk score predictive for patients overall survival and improving risk classiication using microarray gene expression data. GE-based risk score allowed identifying a high-risk group associated with a signiicant shorter overall survival (OS) and time
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Obinutuzumab plus fludarabine and cyclophosphamide in previously untreated, fit patients with chronic lymphocytic leukemia: a subgroup analysis of the GREEN study

Obinutuzumab plus fludarabine and cyclophosphamide in previously untreated, fit patients with chronic lymphocytic leukemia: a subgroup analysis of the GREEN study

Received: 28 March 2019 / Revised: 21 June 2019 / Accepted: 4 July 2019 / Published online: 27 August 2019 © The Author(s) 2019. This article is published with open access Abstract GREEN (NCT01905943) is a nonrandomized, open-label, single-arm, phase 3b study investigating the safety and ef ficacy of obinutuzumab alone or in combination with chemotherapy in chronic lymphocytic leukemia (CLL). We report the preplanned subgroup analysis of 140 previously untreated, fit CLL patients who received obinutuzumab plus fludarabine and cyclophosphamide (G-FC). The primary endpoint was safety and tolerability. Ef ficacy was the secondary endpoint. Obinutuzumab 1000 mg was administered intravenously on Day (D)1 (dose split D1 ‒2), D8 and D15 of Cycle (C)1, and D1 of C2 –6 (28-day cycles). Standard intravenous/oral doses of fludarabine and cyclophosphamide were administered on D1–3 of C1 –6. Overall, 87.1% of patients experienced grade ≥ 3 adverse events (AEs), including neutropenia (67.1%) and thrombocytopenia (17.1%). Serious AEs were experienced by 42.1% of patients. Rates of grade ≥ 3 infusion-related reactions and infections were 19.3% and 15.7%, respectively. Overall response rate was observed in 90.0%, with 46.4% of patients achieving complete response (CR; including CR with incomplete marrow recovery). Minimal residual disease negativity rates were 64.3% in peripheral blood and 35.7% in bone marrow (intent-to-treat analysis). After a median observation time of 25.6 months, 2 year progression-free survival was 91%. Frontline G-FC represents a promising treatment option for fit patients with CLL.
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Evaluation of Caspase-9b and PP2Acα2 as potential biomarkers for chronic lymphocytic leukemia

Evaluation of Caspase-9b and PP2Acα2 as potential biomarkers for chronic lymphocytic leukemia

Keywords: Caspase-9, Caspase-9b, PP2Ac α, PP2Acα2, Chronic lymphocytic leukemia, Alternative splicing, Biomarker Introduction Chronic lymphocytic leukemia (CLL) is the most common B-cell malignancy in Caucasian aging adults, rarely younger than 50 years old [1]. Disruption of alternative splicing in many apoptotic factors is related to hematological malig- nancies and cancer, as CLL [2–6]. Abnormally expressed splicing factors in tumor cells induce the production of mRNA isoforms that are nonexistent or less abundant in normal cells, thus contributing to cancer development, tumor progression, different response to therapy and che- morefractoriness [7, 8].
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en fr Analysis of immunoregulatory CD5⁺CD19⁺ subpopulations in chronic lymphocytic leukemia and of the impact of ibrutinib therapy on these subpopulations Analyse des sous-populations lymphocytaires B dans la leucémie lymphoïde chronique et de l'Impact de l'ibrutinib sur ces sous-populations

Letter to Editor: Chronic Lymphocytic Leukemia (CLL) is a mature CD5 + B cells neoplasm that accumulates in the peripheral blood and other tissues, including bone marrow, spleen and lymph nodes [1]. By interfering with other blood cells and/or altering the architecture of several invaded tissues, malignant B lymphocytes alter the immune system from CLL patients [2-7]. Indeed, increased regulatory T cells (Treg) number in CLL cases contributes to immune-suppression that facilitates disease progression [8, 9]. Human and mouse CLL B cell subpopulations produce the immune-regulatory factor, IL-10, and the IL-10 producing tumor B cells not only support Treg differentiation but also suppress monocyte/macrophage function as well as Helper T cell proliferation and differentiation ([10-14] and submitted manuscript). The B cell production of IL-10 is regulated by various pathways [15, 16], including Toll like receptors and the B Cell Receptor (BCR) mediated signaling; the latter playing a crucial role in CLL pathogenesis and progression [16, 17]. In CLL, ibrutinib, an efficient present therapy triggers this pathway by targeting Btk [18]. IL-10 production is also dependent on the interaction between B and T lymphocytes, as ex-vivo stimulation with CD40L enhances the ability of B cells to produce the interleukin in various murine and human models [15]. To date, the impact of IL10 production by CLL B cells in disease progression remains unclear, especially regarding IGHV mutational status, a well-accepted prognostic factor in CLL [10, 11]. In this work, we gained insight on characterizing IL-10 producing CLL B cells in untreated patients and followed their frequency among indolent, progressive and Ibrutinib- treated CLL patients.
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Prognosis of chronic lymphocytic leukemia from infrared spectra of lymphocytes

Prognosis of chronic lymphocytic leukemia from infrared spectra of lymphocytes

Peripheral mononuclear cells obtained from blood of normal individuals and from patients with chronic lymphocytic leukemia (CLL) were investigated by infrared spectr[r]

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International prognostic score for asymptomatic early-stage chronic lymphocytic leukemia

International prognostic score for asymptomatic early-stage chronic lymphocytic leukemia

We consecutively performed both uni- and multivariable anal- yses using the full data set of the training cohort (UEP). Sub- sequently, we analyzed the external validation data sets to confirm the findings from the full-analysis data set. The study end point was time to first treatment (TTFT), defined as the time between presentation and start of first treatment of CLL because of progression to symptomatic disease according to the National Cancer Institute-Working Group/International Workshop on Chronic Lymphocytic Leukemia guidelines (patients without a documented event were censored at the date of last observation or death). 3,4 Nineteen baseline biomarkers, assessed within 1 month from initial presentation, were initially considered as
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Nurse-like cells impact on disease progression in chronic lymphocytic leukemia

Nurse-like cells impact on disease progression in chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) is one of the most common B-cell malignancies in adults, characterized by an accumulation of monoclonal CD5 + mature B cells in lymphoid tissues and peripheral blood. 1 The complex interplay between malignant CLL cells and their surrounding bystander tumor microenviron- ment (TME) 2 is critical for their survival and facilitates both their resistance to drug therapy and their orchestration of an immunosubversive milieu. 3 CLL cells proliferate in distinct microanatomical tissue sites, termed proliferation centers, that allow intimate interactions with TME components notably nurse-like cells (NLC). 4 These cells represent a leukemia-associated counterpart of tissue-associated macrophages, expressing high level of CD68 and CD163 5,6 and mediating chemoresistance particularly to ibrutinib, dexamethasone and chlorambucil. 7 Even if these cells was well studied by in vitro approaches, the in vivo clinical impact of NLC outgrowth in the TME has not been de finitively addressed to date in CLL, as described for the tumor- associated macrophages (TAMs) in solid tumors. If high TAM in filtration has been associated with a worse outcome in several solid cancers as well as in hematological malignancies including diffuse large B-cell lymphoma, 8 in CLL studies were focused on
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Expression and role of RIP140/NRIP1 in chronic lymphocytic leukemia

Expression and role of RIP140/NRIP1 in chronic lymphocytic leukemia

Abstract RIP140 is a transcriptional coregulator, (also known as NRIP1), which finely tunes the activity of various transcription factors and plays very important physiological roles. Noticeably, the RIP140 gene has been implicated in the control of energy expenditure, behavior, cognition, mammary gland development and intestinal homeostasis. RIP140 is also involved in the regulation of various oncogenic signaling pathways and participates in the development and progression of solid tumors. During the past years, several papers have reported evidences linking RIP140 to hematologic malignancies. Among them, two recent studies with correlative data suggested that gene expression signatures including RIP140 can predict survival in chronic lymphocytic leukemia (CLL). This review aims to summarize the literature dealing with the expression of RIP140 in CLL and to explore the potential impact of this factor on transcription pathways which play key roles in this pathology.
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Expanded and activated allogeneic NK cells are cytotoxic against B-chronic lymphocytic leukemia (B-CLL) cells with sporadic cases of resistance

Expanded and activated allogeneic NK cells are cytotoxic against B-chronic lymphocytic leukemia (B-CLL) cells with sporadic cases of resistance

recently, phase I/II clinical studies have been performed using NK cells expanded through different approaches, on multiple myeloma and acute myeloid leukemia (AML), including pediatric patients 15 – 18 . Other pertinent clinical trials are currently ongoing 19 . The importance of KIR mismatch in expanded NK cells is yet unknown. B-cell chronic lymphocytic leukemia (B-CLL) is the most common leukemia in adults in the Western world and is characterized by the accumulation of mature B-lymphocytes in peripheral blood, bone marrow and secondary lymphoid organs. The leukemia cells express a variety of proteins of the Bcl-2 family that favor the inhibition of apoptosis, which, together with the interaction with the cellular microenvironment and the release of cytokines, results in the accumulation of B-CLL cells in several organs 20 . Alkylating drug-based therapies,
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Biological and clinical implications of BIRC3 mutations in chronic lymphocytic leukemia

Biological and clinical implications of BIRC3 mutations in chronic lymphocytic leukemia

Introduction Nuclear factor- κB (NF-κB) signaling is a key component of the development and evolution of chronic lymphocytic leukemia (CLL). 1 Two NF- κB pathways exist, namely the canonical and non-canonical pathways. 2 The former is triggered by B-cell receptor signaling via Bruton tyrosine kinase (BTK), while the latter is activated by members of the tumor necrosis factor (TNF) cytokine family. 3 Upon receptor binding, the TRAF3/MAP3K14-TRAF2/BIRC3 negative regulatory complex of non-canonical NF- κB sig- naling is disrupted, MAP3K14 (also known as NIK), the central activating kinase of the pathway, is released and activated to induce the phosphorylation and proteasomal processing of p100, thereby leading to the formation of p52-containing NF-κB dimers. The p52 protein dimerizes with RelB to translocate into the nucleus, where it regu- lates gene transcription. BIRC3 (Baculoviral IAP Repeat Containing 3) is a negative regulator of non-canonical NF- κB. Physiologically, BIRC3 (also known as cIAP2) cat- alyzes MAP3K14 protein ubiquitination in a manner that is dependent on the E3 ubiquitinine ligase activity of its C- terminal RING domain. MAP3K14 ubiquitination results in its proteasomal degradation. 4
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