scholarly journals Bruton tyrosine kinase inhibitors for the frontline treatment of chronic lymphocytic leukemia

2020 ◽  
Vol 27 (6) ◽  
Author(s):  
V. Banerji ◽  
A. Aw ◽  
S. Robinson ◽  
S. Doucette ◽  
A. Christofides ◽  
...  
Keyword(s):  
High Risk ◽  
Chronic Lymphocytic Leukemia ◽  
Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Variable Region ◽  
Tp53 Gene ◽  
Cell Receptor ◽  
Response To Therapy ◽  
Lymphocytic Leukemia ◽  
Btk Inhibitors

Chronic lymphocytic leukemia (CLL) is the most commonly diagnosed adult leukemia in Canada. Biologic heterogeneity of CLL can be observed between patients which results in variable disease trajectory and response to therapy. Notably, patients with high-risk features such as the presence of deletions in chromosome 17p, aberrations in the TP53 gene, or unmutated immunoglobulin heavy chain variable region genes have inferior outcomes and response to standard chemoimmunotherapy compared to patients without these features. Novel agents which target the B cell receptor signalling pathway, such as Bruton’s tyrosine kinase (BTK) inhibitors have demonstrated clinical efficacy and safety in patients with treatment-naïve CLL, particularly in those with high-risk features. However, due to the current lack of head-to-head trials comparing BTK inhibitors, selection of the optimal BTK inhibitor for patients with CLL is unclear and requires the consideration of multiple factors. This review focuses on the efficacy, safety, and pharmacological features of the BTK inhibitors that are approved or are under clinical development and discusses the practical considerations for the use of these agents in the Canadian treatment landscape.

scholarly journals A Review of the Bruton Tyrosine Kinase Inhibitors in B-Cell Malignancies

2021 ◽  
Vol 12 (4) ◽  
Author(s):  
Donald C. Moore, PharmD, BCPS, BCOP, DPLA ◽  
Daniel Thompson, PharmD
Keyword(s):  
Tyrosine Kinase ◽  
B Cell ◽  
Kinase Inhibitors ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Lymphocytic Leukemia ◽  
B Cell Malignancies ◽  
Bruton Tyrosine Kinase ◽  
Integral Role ◽  
Btk Inhibitors

The B-cell receptor signaling pathway plays an integral role in the proliferation and survival of malignant B cells. Targeting the B-cell receptor pathway via the inhibition of Bruton tyrosine kinase (BTK) has evolved the treatment of a variety of B-cell malignancies, including chronic lymphocytic leukemia, mantle cell lymphoma, marginal zone lymphoma, and Waldenström macroglobulinemia. Currently, there are three BTK inhibitors approved by the U.S. Food and Drug Administration: ibrutinib, acalabrutinib, and zanubrutinib. This article reviews the pharmacology, clinical efficacy, safety, dosing, drug-drug interactions, and implications for advanced practitioners of BTK inhibitors in the treatment of B-cell malignancies.

ZAP-70 Expression in Chronic Lymphocytic Leukemia Is Associated with Altered Signal Transduction.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4702-4702
Author(s):  
Kristy L. Wolniak ◽  
James Marvin ◽  
Charles Goolsby
Keyword(s):  
Signal Transduction ◽  
Chronic Lymphocytic Leukemia ◽  
Tyrosine Kinase ◽  
B Cell ◽  
Kinase Inhibitors ◽  
Cell Receptor ◽  
Prognostic Indicator ◽  
Lymphocytic Leukemia ◽  
Prognostic Information

Abstract B-cell chronic lymphocytic leukemia (CLL) is a malignancy of mature B-cells with a variable clinical course. Given the heterogeneity of disease course, identification of prognostic factors is imperative. One recently identified negative prognostic indicator in CLL is the T-cell tyrosine kinase ZAP70. ZAP70 is analogous to, and can functionally substitute for, the B-cell tyrosine kinase Syk and is activated following B cell receptor (BCR) crosslinking in CLL cells. However, the role of ZAP70 expression in CLL remains elusive. Utilizing flow cytometric analyses of signal transduction molecules, this study examined if ZAP70 expression affects signal transduction in CLL. Peripheral blood samples from ZAP70+ and ZAP70− CLL patients were analyzed. The levels of phosphorylated ERK, STAT5, and S6 (p-ERK, p-STAT5, p-S6) were measured by flow cytometry with and without BCR stimulation. Kinase inhibitors were used to verify the measured phosphorlyated protein levels. Increased constitutive levels of p-ERK, p-STAT5, and p-S6 were seen in ZAP70+ CLL cells as compared to ZAP70− CLL cells. BCR crosslinking gave variable responses in both ZAP70+ and ZAP70− CLL. The majority of ZAP70− cases showed no significant activation or a predominant activation of ERK with rare p-S6 activation. ZAP70+ cells showed activation of either, or both, ERK and S6 pathways and fewer showing no activation. In summary, though the role of ZAP70 in B cell signaling is poorly understood, expression of ZAP70 in CLL correlates with a constitutively active phenotype. Additionally, differential response in ZAP70+ versus ZAP70− cases following BCR crosslinking suggests a possible modulatory role of the BCR pathway. Current studies are underway to determine if these measures carry prognostic information and if the varying signal responses to BCR stimulation correlate with reported differences in apoptotic versus proliferative response.

scholarly journals The Role of Bruton’s Kinase Inhibitors in Chronic Lymphocytic Leukemia: Current Status and Future Directions

2021 ◽  
Author(s):  
Tadeusz Robak ◽  
Magda Witkowska ◽  
Piotr Smolewski
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Adverse Effects ◽  
Kinase Inhibitors ◽  
Clinical History ◽  
Lymphocytic Leukemia ◽  
Current Status ◽  
Covalent Inhibitors ◽  
History Of ◽  
Reduced Toxicity ◽  
Btk Inhibitors

The use of the Bruton’s tyrosine kinase (BTK) inhibitors has changed the management and clinical history of patients with chronic lymphocytic leukemia (CLL). BTK is a critical molecule that interconnects B-cell antigen receptor (BCR) signaling. BTKIs are classified into two categories: irreversible (covalent) inhibitors and reversible (non-covalent) inhibitors. Ibrutinib is the first irreversible BTK inhibitor approved by the U.S. Food and Drug Administration in 2013 as a breakthrough therapy in CLL patients. Subsequently, several studies evaluated the efficacy and safety of new agents with reduced toxicity when compared with ibrutinib. Two other irreversible, second-generation BTK inhibitors, acalabrutinib and zanubrutinib, were developed to reduce ibrutinib-mediated adverse effects. Additionally, new reversible BTK inhibitors are currently under development in an early phase studies to improve their activity and to diminish adverse effects. This review summarizes the pharmacology, clinical efficacy, safety, dosing, drug-drug interactions associated with the treatment of CLL with BTK inhibitors, and examines its further implications.

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.

Nurture versus Nature: The Microenvironment in Chronic Lymphocytic Leukemia

Hematology ◽  
2011 ◽  
Vol 2011 (1) ◽  
pp. 96-103 ◽  
Author(s):  
Jan A. Burger
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Tyrosine Kinase ◽  
B Cell ◽  
Disease Progression ◽  
Drug Testing ◽  
Cell Receptor ◽  
Lymphocytic Leukemia ◽  
In Vivo Models

Abstract Intrinsic factors such as genetic lesions, anti-apoptotic proteins, and aberrant signaling networks within leukemia cells have long been the main focus of chronic lymphocytic leukemia (CLL) research. However, over the past decade, it became increasingly clear that external signals from the leukemia microenvironment make pivotal contributions to disease progression in CLL and other B-cell malignancies. Consequently, increasing emphasis is now placed on exploring and targeting the CLL microenvironment. This review highlights critical cellular and molecular pathways of CLL-microenvironment cross-talk. In vitro and in vivo models for studying the CLL microenvironment are discussed, along with their use in searching for therapeutic targets and in drug testing. Clinically, CXCR4 antagonists and small-molecule antagonists of B cell receptor (BCR)-associated kinases (spleen tyrosine kinase [Syk], Bruton's tyrosine kinase [Btk], and PI3Kδ) are the most advanced drugs for targeting specific interactions between CLL cells and the miocroenvironment. Preclinical and first clinical evidence suggests that high-risk CLL patients can particularly benefit from these alternative agents. These findings indicate that interplay between leukemia-inherent and environmental factors, nature and nurture determines disease progression in CLL.

Additional Genetic High-Risk Features Such As 11q Deletion, 17p Deletion, and V3-21 Usage Characterize Discordance of ZAP-70 and VH Mutation Status in Chronic Lymphocytic Leukemia

2006 ◽  
Vol 24 (6) ◽  
pp. 969-975 ◽  
Author(s):  
Alexander Kröber ◽  
Johannes Bloehdorn ◽  
Sebastian Hafner ◽  
Andreas Bühler ◽  
Till Seiler ◽  
...  
Keyword(s):  
High Risk ◽  
Chronic Lymphocytic Leukemia ◽  
Variable Region ◽  
Multivariate Regression Analysis ◽  
Lymphocytic Leukemia ◽  
Prognostic Impact ◽  
Mutation Status ◽  
Characteristic Modes ◽  
Genomic Aberrations ◽  
Vh Gene

Purpose Immunoglobulin heavy chain variable-region (VH) gene mutation status and zeta-associated protein 70 (ZAP-70) expression are correlated in chronic lymphocytic leukemia (CLL), but their concordance is variable. The goal of this study was to elucidate additional factors potentially characterizing their discordance. Patients and Methods We evaluated ZAP-70 expression by flow cytometry, VH status by DNA sequencing, and genomic aberrations by fluorescence in situ hybridization in 148 CLL patients. The parameters were analyzed for their associations and their individual prognostic impact. Results ZAP-70 expression and VH mutation status were strongly associated in CLL without additional genetic high-risk-features as defined by the absence of 11q or 17p deletion and V3-21 usage (concordance 84%). In contrast, the proportion of discordant cases was significantly higher (39%), if such additional genetic high-risk features were present. Discordant cases with V3-21 usage were almost exclusively ZAP-70 positive and VH mutated (89%), whereas all but one of the discordant cases with high-risk aberrations were ZAP-70 negative and VH unmutated (92%). By multivariate regression analysis, two models were developed, which both include high-risk genomic aberrations and, alternatively, VH mutation status and V3-21 usage or ZAP-70 expression as independent outcome predictors. Conclusion There were characteristic modes of discordance between ZAP-70 and VH mutation status depending on the presence or absence of additional genetic high-risk features such as 11q and 17p deletion or V3-21 usage. Although the biologic background for these findings is yet to be determined, these data have biologic and clinical implications regarding ZAP-70 as a pathogenic factor and outcome predictor, respectively.

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.

Novel Tyrosine Kinase Inhibitors Trigger Drug Sensitivity of Primary CLL Cells by Controlling Glucosylation of Ceramides

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3905-3905
Author(s):  
Janine Schwamb ◽  
Valeska Feldhaus ◽  
Michael Baumann ◽  
Michaela Patz ◽  
Susanne Brodesser ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Conflicts Of Interest ◽  
Treatment Options ◽  
Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Published Data ◽  
The Novel ◽  
Apoptosis Resistance

Abstract Abstract 3905 Background: Apoptosis resistance of chronic lymphocytic leukemia (CLL) cells is mediated by several pro-survival stimuli. In particular, engagement of the B-cell receptor (BCR), CD40-CD40 ligand (CD40L) interaction or stimulation by interleukin-(IL)-4 were identified as major factors to regulate chemoresistance. Sphingolipids are known to be involved in several metabolic pathways involved in chemoresitance. Therefore, we focused on ceramide as pro-apoptotic molecule and its counterpart glucosylceramide, which rather contributes to proliferation and survival. Methods and Results: Applying liquid chromatography electrospray ionization tandem mass spectrometry, we revealed a significant decrease of pro-apoptotic ceramide in BCR/IL-4/CD40L-stimulated primary CLL cells compared to untreated controls (p=0.0258, p=0.0478, p=0.0114). Anti-apoptotic glucosylceramide levels were significantly increased after BCR cross-linking (p=0.0435) while other stimuli caused no relevant change in glucosylceramide expression. We identified BCR engagement to catalyze the crucial modification of ceramide to glucosylceramide via the enzyme UDP-glucose ceramide glucosyltransferase (UGCG) (p=0.0001). Besides specific UGCG inhibitors, we could show for the first time that IgM-mediated UGCG expression was significantly inhibited by the novel and highly effective PI3Kδ and BTK inhibitors CAL-101 and PCI-32765, which were able to revert IgM-induced apoptosis resistance of CLL cells. Recently published data revealed sphingolipids to be essential for mediation of apoptosis via mitochondria. Therefore, we chose ABT-737 – a well-known and also mitochondria-targeting drug – as candidate partner for PI3Kδ and BTK inhibition. When combining each tyrosine kinase inhibitor with ABT-737, a synergistic apoptotic effect could be documented, even under protection by BCR stimulation. Conclusion: In summary, we could demonstrate that sphingolipids are critically involved in CLL pathogenesis. UGCG could be identified as drugable target by the novel kinase inhibitors CAL-101 and PCI-32765 resulting in even synergistic apoptosis following additional application of ABT-737. Sphingolipids seem to offer further targets providing novel treatment options in CLL. C.M.W. and L.P.F. contributed equally to this work. Disclosures: No relevant conflicts of interest to declare.

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