Indeed, BTK is essential for the activation of pathways which promote lymphocyte survival, such as the nuclear factor kappaB (NF-κb) pathway ( 2), and regulates chemokine secretion and B-cell adhesion by activation of phospholipase Cγ2 (PLCγ2) ( 3). BTK inhibitor (BTKi)s block the BCR signaling cascade by binding to the BTK enzyme, hence preventing the proliferation and survival of malignant and normal B cells. Signaling through the B-cell receptor (BCR) is central in CLL and Bruton’s tyrosine kinase (BTK) is a vital component of the BCR signaling pathway ( 1). Indeed, a deeper knowledge on this topic could guide clinicians in the management and prevention of infections in patients with CLL treated with BTKis.Ĭhronic lymphocytic leukemia (CLL) is characterized by the accumulation of mature monoclonal CD5 + B lymphocytes in the secondary lymphoid organs, bone marrow and peripheral blood. Here, we summarize the available knowledge on the impact of BTKis on the immune system and discuss the possible clinical implications. Whether this affects infection susceptibility and vaccination efficacy requires further investigation. Treatment with BTKis potentially impacts on both innate and adaptive immunity. Moreover, the blockade of BCR signaling also indirectly affects the tumor microenvironment in CLL.
Such “off-target” effects are expected to be more limited for second-generation BTKis. 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. Despite having remarkable selectivity for BTK, the first-in-class BTKi ibrutinib can also bind, with various affinities, to other kinases.
At present, three different covalent BTKis, ibrutinib, acalabrutinib and zanubrutinib, are FDA-approved and many new inhibitors are under development. 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. 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.
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