scholarly journals Targeting Bruton’s Tyrosine Kinase in CLL

2021 ◽  
Vol 12 ◽  
Author(s):  
Inhye E. Ahn ◽  
Jennifer R. Brown
Keyword(s):  
B Cell ◽  
Covalent Binding ◽  
Variable Region ◽  
Cell Receptor ◽  
Lymphocytic Leukemia ◽  
B Cell Lymphomas ◽  
Region Gene ◽  
Resistant Disease ◽  
B Cell Receptor Signaling ◽  
Combination Regimens

Targeting the B-cell receptor signaling pathway through BTK inhibition proved to be effective for the treatment of chronic lymphocytic leukemia (CLL) and other B-cell lymphomas. Covalent BTK inhibitors (BTKis) led to an unprecedented improvement in outcome in CLL, in particular for high-risk subgroups with TP53 aberration and unmutated immunoglobulin heavy-chain variable-region gene (IGHV). Ibrutinib and acalabrutinib are approved by the US Food and Drug Administration for the treatment of CLL and other B-cell lymphomas, and zanubrutinib, for patients with mantle cell lymphoma. Distinct target selectivity of individual BTKis confer differences in target-mediated as well as off-target adverse effects. Disease progression on covalent BTKis, driven by histologic transformation or selective expansion of BTK and PLCG2 mutated CLL clones, remains a major challenge in the field. Fixed duration combination regimens and reversible BTKis with non-covalent binding chemistry hold promise for the prevention and treatment of BTKi-resistant disease.

scholarly journals An Updated Perspective on Current Prognostic and Predictive Biomarkers in Chronic Lymphocytic Leukemia in the Context of Chemoimmunotherapy and Novel Targeted Therapy

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 894 ◽  
Author(s):  
Jared A. Cohen ◽  
Riccardo Bomben ◽  
Federico Pozzo ◽  
Erika Tissino ◽  
Andrea Härzschel ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Predictive Biomarkers ◽  
Variable Region ◽  
B Cell Lymphoma ◽  
Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Region Gene ◽  
Novel Biomarkers

Chronic lymphocytic leukemia (CLL) is a heterogeneous disease with a variable clinical course. Novel biomarkers discovered over the past 20 years have revolutionized the way clinicians approach prognostication and treatment especially in the chemotherapy-free era. Herein, we review the best established prognostic and predictive biomarkers in the setting of chemoimmunotherapy (CIT) and novel targeted therapy. We propose that TP53 disruption (defined as either TP53 mutation or chromosome 17p deletion), unmutated immunoglobulin heavy chain variable region gene status (UM IGHV), NOTCH1 mutation, and CD49d expression are the strongest prognosticators of disease progression and overall survival in the field of novel biomarkers including recurrent gene mutations. We also highlight the predictive role of TP53 disruption, UM IGHV, and NOTCH1 mutation in the setting of CIT and TP53 disruption and CD49d expression in the setting of novel targeted therapy employing B-cell receptor (BCR) and B-cell lymphoma-2 (BCL2) inhibition. Finally, we discuss future directions in the field of biomarker development to identify those with relapsed/refractory disease at risk for progression despite treatment with novel therapies.

scholarly journals Targeting BCL-2 in B-cell lymphomas

Blood ◽  
2017 ◽  
Vol 130 (9) ◽  
pp. 1081-1088 ◽  
Author(s):  
Matthew S. Davids
Keyword(s):  
B Cell ◽  
Resistance Mechanisms ◽  
Lymphocytic Leukemia ◽  
B Cell Lymphomas ◽  
Non Hodgkin Lymphoma ◽  
Highly Active ◽  
History Of ◽  
B Cell Leukemia ◽  
Selective Therapy ◽  
Combination Regimens

Abstract The B-cell leukemia/lymphoma-2 (BCL-2) family of proteins governs the intrinsic pathway of mitochondrial apoptosis. Dysregulation of BCL-2 has long been known to be a crucial part of the pathophysiology of B-cell lymphomas; however, several early attempts to target this pathway therapeutically were unsuccessful because of toxicity, lack of efficacy, or both. Recently, a highly potent and selective oral BCL-2 antagonist, venetoclax, was approved in chronic lymphocytic leukemia, where it has proven to be highly active, even in patients with high-risk del(17p) disease. Venetoclax has also demonstrated efficacy in other B-cell non-Hodgkin lymphoma subtypes, in particular mantle cell lymphoma and follicular lymphoma. Here, I review the history of targeting BCL-2 in B-cell lymphomas, and I discuss recent data on venetoclax used as monotherapy and in combination with monoclonal antibodies, chemotherapy, and other novel agents. I also discuss how genomic and functional approaches such as BH3 profiling may allow us to prioritize novel-agent combinations for further study in clinical trials. These approaches may also help us to understand resistance mechanisms to BCL-2–selective therapy and how to overcome resistance. Finally, I provide my perspective on how to move BCL-2–directed therapies forward toward a goal of developing well-tolerated, time-limited combination regimens with curative potential for patients with B-cell lymphomas.

Evidence for Autostimulatory Mechanisms in Chronic Lymphocytic Leukemia.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2880-2880
Author(s):  
Martin Trepel ◽  
Fabian Muller ◽  
Mareike Frick ◽  
Janina Rahlff ◽  
Claudia Wehr ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Phage Display ◽  
B Cell ◽  
Conflicts Of Interest ◽  
Specific Binding ◽  
Variable Region ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Fab Fragment

Abstract Abstract 2880 Background: The development and / or course of chronic lymphocytic leukemia (CLL) may be driven by the recognition of antigens through the B cell receptor (BCR). While it has been recognized that the diversity of epitope recognition may be astonishingly confined in CLL, knowledge on antigens recognized by CLL BCRs is still limited. Here, we identified and characterized an epitope recognized by a defined CLL BCR which may broaden our view on potential mechanisms of antigenic drive in CLL. Methods: The B- cell receptor of a random CLL-patient was cloned and expressed as Fab fragment in E.coli. Random phage display reptile litanies we skeletal on the immobilized Fab and landed peptides were tested for specific binding. Specific clones we sequenced and sequences were analyzed for homology to known proteins. Recognition of candidate proteins was verified in brooding assays or recombinant proteins. Results: Screening random phage display peptide libraries, we identified a CLL BCR epitope mimic that displayed a high degree of homology to a conserved peptide string in the variable region of immunoglobulin heavy and light chains. CLL BCR binding to this epitope as well as binding to full length heavy and light immunoglobulin chains was verified by binding assays and a protein array screening. Interestingly, the CLL BCR also interacted with itself, as the identified epitope was also present in its own primary amino acid sequence. Conclusions: These findings suggest the possibility of self-recognition of BCRs within the CLL cell membrane or BCR interactions between neighboring CLL cells. This may potentially result in autostimulation of the leukemic cell independent of “exogenous” antigens and may account for self-sufficient signaling of some CLL-BCRs in driving disease progression. As the peptide mimicking this immunoglobulin epitope is known to be recognized by BCRs of other CLL cases in addition to the index case investigated here, such autostimulatory mechanisms may be relevant to a large number of CLL patients. Disclosures: No relevant conflicts of interest to declare.

scholarly journals The outcome of B-cell receptor signaling in chronic lymphocytic leukemia: proliferation or anergy

Haematologica ◽  
2014 ◽  
Vol 99 (7) ◽  
pp. 1138-1148 ◽  
Author(s):  
G. Packham ◽  
S. Krysov ◽  
A. Allen ◽  
N. Savelyeva ◽  
A. J. Steele ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Receptor Signaling ◽  
B Cell Receptor Signaling ◽  
Cell Receptor Signaling

Genetic analysis of de novo CD5+ diffuse large B-cell lymphomas suggests an origin from a somatically mutated CD5+ progenitor B cell

Blood ◽  
2003 ◽  
Vol 101 (2) ◽  
pp. 699-702 ◽  
Author(s):  
Tiemo Katzenberger ◽  
Andreas Lohr ◽  
Stephan Schwarz ◽  
Martin Dreyling ◽  
Julia Schoof ◽  
...  
Keyword(s):  
B Cell ◽  
Progenitor Cell ◽  
Somatic Mutations ◽  
De Novo ◽  
Variable Region ◽  
Lymphocytic Leukemia ◽  
B Cell Lymphomas ◽  
Cytogenetic Analyses ◽  
Trisomy 3 ◽  
Large B Cell

CD5+ diffuse large B-cell lymphomas (DLBLs) have recently been described as a particular subgroup of DLBLs. Classical banding and interphase cytogenetic analyses targeting ATM, TP53, and P16INK4a genes and theD13S25 locus from 13 CD5+ DLBLs were compared with 55 CD5− DLBLs. Additionally, analysis of somatic mutations of the immunoglobulin heavy chain variable region (IgVH) genes were performed in CD5+ DLBLs. CD5+DLBLs were somatically mutated (7 of 8 cases) and were negative for t(11;14)(q13;q32) and t(14;18)(q32;q21), whereas t(3;14)(q27;q32) was found in only one tumor. Trisomy 3 and gains on chromosomes 16/16p and 18/18q were significantly overrepresented in CD5+DLBLs. No ATM deletions were detected. The prevalence of deletions at the D13S25 locus was significantly higher in CD5+ DLBLs (4 of 12 [33%]) compared with CD5− DLBLs (4 of 42 [10%]), as were p16INK4a deletions (33% versus 8%). On the basis of these findings, CD5+ DLBLs are likely to arise from the same progenitor cell as the mutated variant of CD5+ lymphocytic lymphoma/B-cell chronic lymphocytic leukemia (B-CLL).

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