BTK Inhibitors in Chronic Lymphocytic Leukemia: Biological Activity and Immune Effects
Open Access
- 1 July 2021
- journal article
- review article
- Published by Frontiers Media SA in Frontiers in Immunology
Abstract
Bruton´s tyrosine kinase (BTK) inhibitor (BTKi)s block the B-cell receptor (BCR) signaling cascade by binding to the BTK enzyme preventing the proliferation and survival of malignant and normal B cells. During the past decade, the clinical use of BTKis for the treatment of B-cell malignancies has exponentially grown, changing the treatment landscape for chronic lymphocytic leukemia (CLL) in particular. At present, three different covalent BTKis, ibrutinib, acalabrutinib and zanubrutinib, are FDA-approved and many new inhibitors are under development. Despite having remarkable selectivity for BTK, the first-in-class BTKi ibrutinib can also bind, with various affinities, to other kinases. The combined inhibition of BTK (“on-target” effect) and other kinases (“off-target” effect) can have additive or synergistic anti-tumor effects but also induce undesired side effects which might be treatment-limiting. Such “off-target” effects are expected to be more limited for second-generation BTKis. Moreover, the blockade of BCR signaling also indirectly affects the tumor microenvironment in CLL. Treatment with BTKis potentially impacts on both innate and adaptive immunity. Whether this affects infection susceptibility and vaccination efficacy requires further investigation. Here, we summarize the available knowledge on the impact of BTKis on the immune system and discuss the possible clinical implications. Indeed, a deeper knowledge on this topic could guide clinicians in the management and prevention of infections in patients with CLL treated with BTKis.This publication has 90 references indexed in Scilit:
- The clinically active BTK inhibitor PCI-32765 targets B-cell receptor– and chemokine-controlled adhesion and migration in chronic lymphocytic leukemiaBlood, 2012
- A Novel Role for Bruton's Tyrosine Kinase in Hepatocyte Growth Factor-mediated Immunoregulation of Dendritic CellsOnline Journal of Public Health Informatics, 2011
- Absence of Tec Family Kinases Interleukin-2 Inducible T cell Kinase (Itk) and Bruton's Tyrosine Kinase (Btk) Severely Impairs FcϵRI-dependent Mast Cell ResponsesOnline Journal of Public Health Informatics, 2011
- Neutrophil development and function critically depend on Bruton tyrosine kinase in a mouse model of X-linked agammaglobulinemiaBlood, 2011
- The lymph node microenvironment promotes B-cell receptor signaling, NF-κB activation, and tumor proliferation in chronic lymphocytic leukemiaBlood, 2011
- The Bruton tyrosine kinase inhibitor PCI-32765 ameliorates autoimmune arthritis by inhibition of multiple effector cellsArthritis Research & Therapy, 2011
- Repeated vaccination is required to optimize seroprotection against H1N1 in the immunocompromised hostHaematologica, 2010
- Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute–Working Group 1996 guidelinesBlood, 2008
- Bruton's Tyrosine Kinase Is Required for Activation of Iκb Kinase and Nuclear Factor κb in Response to B Cell Receptor EngagementThe Journal of Experimental Medicine, 2000
- Interleukin 4 protects chronic lymphocytic leukemic B cells from death by apoptosis and upregulates Bcl-2 expression.The Journal of Experimental Medicine, 1992