Platelet function and bleeding in chronic lymphocytic leukemia and mantle cell lymphoma patients on ibrutinib

2020 ◽  
Vol 18 (10) ◽  
pp. 2672-2684 ◽  
Author(s):  
Elena A. Dmitrieva ◽  
Eugene A. Nikitin ◽  
Anastasia A. Ignatova ◽  
Vladimir I. Vorobyev ◽  
Aleksandr V. Poletaev ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Mantle Cell Lymphoma ◽  
Platelet Function ◽  
Cell Lymphoma ◽  
Lymphocytic Leukemia ◽  
Mantle Cell

Platelet Function Prior to Ibrutinib Treatment Is More Severely Impaired in Chronic Lymphocytic Leukemia Than in Mantle Cell Lymphoma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4917-4917
Author(s):  
Eugene Nikitin ◽  
Anastasia Ignatova ◽  
Vladimir Vorobyev ◽  
Alexander Poletaev ◽  
Dmitrii Polokhov ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Mantle Cell Lymphoma ◽  
Platelet Function ◽  
Functional Activity ◽  
Cell Lymphoma ◽  
Median Number ◽  
Lymphocytic Leukemia ◽  
Bleeding Complications ◽  
Healthy Donors ◽  
Mantle Cell

Abstract INTRODUCTION. Ibrutinib is an oral small-molecule drug that irreversibly inhibits Bruton's tyrosine kinase and thus suppresses proliferation of B cells. Ibrutinib therapy in chronic lymphocytic leukemia (CLL) and in mantle cell lymphoma (MCL) is associated with frequent bleeding complications that were reported to be more severe in CLL. This difference was suggested to be related to differential adenosine diphosphate (ADP) disruption by CD39, expressed by tumor cells. Here we investigate platelet functional activity in CLL and MCL patients before initiation of ibrutinib. MATERIALS. Fifty one adult patients with relapsed and refractory CLL and MCL and 20 healthy donors were included in the study. Platelet functional activity was characterized by flow cytometry before and after activation with SFLLRN plus collagen-related peptide. Levels of CD42b, CD61, CD62P, PAC1, annexin V binding, and mepacrine release were determined. Aggregation with collagen, ADP and ristocetin were measured. RESULTS. Among 36 CLL patients 25 (69%) were men, the median age was 66 (range, 31 to 83 years) and 23 (64%) had a refractory disease. In 34 previously treated patients the median number of prior treatments was 2 (range, 1 - 6). Two CLL patients with del (17p) received ibrutinib as a first line. In a group of MCL patients (n=15) there were 12 men (80%), the median age was 63 years (range, 49-79). Seven (54%) patients had a high MIPI score. The median number of previous chemotherapy lines in MCL patients was 1 (range, 1 - 6). Lymphocyte count before initiation of ibrutinib was significantly higher in CLL group (median 17,5 х 109/L range 0,48 - 189,7) compared to MCL group (median 1,75 х 109/L, range 0,35 - 6,59, p=0,037). Initial platelets count was also different being lower in CLL than in MCL patients (127 х 109/L (15 - 248) versus 186 х 109/L (63 - 311), p=0,005). Platelets of untreated patients with CLL had statistically significant impairments in their responses compared to those with MCL. Specifically, they had decreased integrin activation in response to stimulation (46±19% versus 73±18%; for healthy donors, 100±17%), and relative mepacrine release (2.9±0.9 versus 3.5±0.8; healthy, 4.0±0.7). P-selectin release was impaired milder (77±17% versus 92±14%; healthy, 100±10%), and procogulant platelet formation impairment was not statistically significant (8±6% versus 12±7%; healthy, 12±3%). In control experiments, addition of MeS-AMP and MRS2179, selective inhibitors of ADP receptors, had comparable effects on the healthy donor platelets. Aggregation in response to ADP was dramatically impaired in CLL compared with MCL (24±18% versus 42±16%), as well as that in response to collagen (47±23% versus 72±13%). Upon ibrutinib treatment, further decrease of PAC1 binding and procoagulant platelets formation almost to the level of resting platelets were observed; activation with SFLLRN alone produced a similar result with donor platelets. CONCLUSIONS. Patients with CLL and MCL have initially impaired response of platelets. The defects of platelet function in CLL is much greater suggesting a possible explanation of the different clinical severity. Disclosures Vorobyev: Janssen: Speakers Bureau. Ptushkin:Janssen: Speakers Bureau.

scholarly journals Mantle cell lymphoma and chronic lymphocytic leukemia: report of a rare disease association and review of the literature

2010 ◽  
Vol 3 (2-3) ◽  
pp. 91-99 ◽  
Author(s):  
Joana Perdigão ◽  
Helena Alaiz ◽  
Paulo Lúcio ◽  
Paula Gameiro ◽  
Marta Sebastião ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Mantle Cell Lymphoma ◽  
Rare Disease ◽  
Cell Lymphoma ◽  
Disease Association ◽  
Lymphocytic Leukemia ◽  
Review Of The Literature ◽  
Mantle Cell

scholarly journals Chronic lymphocytic leukemia and mantle cell lymphoma: crossroads of genetic and microenvironment interactions

Blood ◽  
2018 ◽  
Vol 131 (21) ◽  
pp. 2283-2296 ◽  
Author(s):  
Xose S. Puente ◽  
Pedro Jares ◽  
Elias Campo
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
Variable Region ◽  
Lymphocytic Leukemia ◽  
Variable Load ◽  
Genomic Alterations ◽  
Clinical Evolution ◽  
Mantle Cell ◽  
Epidemiological Characteristics

Abstract Chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) are 2 well-defined entities that diverge in their basic pathogenic mechanisms and clinical evolution but they share epidemiological characteristics, cells of origin, molecular alterations, and clinical features that differ from other lymphoid neoplasms. CLL and MCL are classically considered indolent and aggressive neoplasms, respectively. However, the clinical evolution of both tumors is very heterogeneous, with subsets of patients having stable disease for a long time whereas others require immediate intervention. Both CLL and MCL include 2 major molecular subtypes that seem to derive from antigen-experienced CD5+ B cells that retain a naive or memory-like epigenetic signature and carry a variable load of immunoglobulin heavy-chain variable region somatic mutations from truly unmutated to highly mutated, respectively. These 2 subtypes of tumors differ in their molecular pathways, genomic alterations, and clinical behavior, being more aggressive in naive-like than memory-like–derived tumors in both CLL and MCL. The pathogenesis of the 2 entities integrates the relevant influence of B-cell receptor signaling, tumor cell microenvironment interactions, genomic alterations, and epigenome modifications that configure the evolution of the tumors and offer new possibilities for therapeutic intervention. This review will focus on the similarities and differences of these 2 tumors based on recent studies that are enhancing the understanding of their pathogenesis and creating solid bases for new management strategies.

CD5+ B-cell lymphoproliferative disorders: Beyond chronic lymphocytic leukemia and mantle cell lymphoma

2010 ◽  
Vol 34 (9) ◽  
pp. 1235-1238 ◽  
Author(s):  
Dragan Jevremovic ◽  
Roxana S. Dronca ◽  
William G. Morice ◽  
Ellen D. McPhail ◽  
Paul J. Kurtin ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
Lymphoproliferative Disorders ◽  
Lymphocytic Leukemia ◽  
Mantle Cell

Activity of Bendamustine (TREANDA™) in Chronic Lymphocytic Leukemia and Mantle Cell Lymphoma Cells with Alterations in DNA Damage Response Pathway.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2510-2510
Author(s):  
Gaël Roué ◽  
Mónica López-Guerra ◽  
Pierre Milpied ◽  
Patricia Pérez-Galán ◽  
Neus Villamor ◽  
...  
Keyword(s):  
Cell Death ◽  
Chronic Lymphocytic Leukemia ◽  
Mantle Cell Lymphoma ◽  
Tumor Cells ◽  
Cell Lymphoma ◽  
Lymphocytic Leukemia ◽  
Low Grade ◽  
Mantle Cell ◽  
P53 Status

Abstract Mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) are two different types of mature B-cell non-Hodgkin’s lymphoma (NHL). CLL has an indolent natural history and patients are very responsive to frontline chemotherapy. Unfortunately, multiple relapses are inevitable, and ultimately, no regimen or treatment strategy offers a distinct survival benefit over another. In contrast, patients with MCL generally experience a more aggressive course, with rapid disease progression and also without specific therapeutic options. Bendamustine hydrochloride (Treanda™) is a multifunctional, alkylating agent that exhibits single-agent activity in multiple hematologic and solid tumors. Recently, the combination of bendamustine with rituximab has demonstrated to be a highly active regimen in the treatment of low-grade lymphomas and MCL. However, very little is known about its mode of action. The ability of bendamustine to induce apoptosis in vitro in MCL and CLL cells and the mechanisms implicated in bendamustine-evoked cell death signaling were investigated. Bendamustine exerted cytostatic and cytotoxic effects in 11 MCL cell lines and primary tumor cells from 7 MCL patients and 10 CLL patients independent of their p53 status, and other gene alterations. In vitro treatment of cells with bendamustine induced activation of both p53-dependent and -independent signaling pathways that converged in all cases to the activation of the pro-apoptotic protein Noxa, conformational changes of Bax and Bak, and mitochondrial depolarization. These events led to cytosolic release of the mitochondrial apoptogenic factors cytochrome c, Smac/DIABLO and AIF, and activation of both caspase -dependent and -independent cell death. Genotoxic stress and caspase-independent cell death are often associated with the generation of reactive oxygen species (ROS). We observed that ROS production was a key step in the induction of apoptosis by bendamustine, since pre-incubation of tumor cells with ROS scavengers reverted all the typical hallmarks of apoptosis. Furthermore, bendamustine exerted a cytotoxic effect in p53 deleted CLL cases that were resistant to fludarabine treatment. These findings support the use of bendamustine as a therapeutic agent in MCL and CLL cells and also establish the basis for the use of bendamustine in lymphoid malignancies that show resistance to classic genotoxic agents that depend on cellular p53 status.

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