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Review
. 2022 Jul 22:12:81-98.
doi: 10.2147/BLCTT.S326627. eCollection 2022.

Use of BTK Inhibitors in Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL): A Practical Guidance

Frédérique St-Pierre  1 , Shuo Ma  1   2
Affiliations
Review

Use of BTK Inhibitors in Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL): A Practical Guidance

Frédérique St-Pierre et al. Blood Lymphat Cancer. .

Abstract

The treatment landscape of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) has changed significantly since the development of oral Bruton's tyrosine kinase (BTK) inhibitors. While chemoimmunotherapy was previously the standard of care for first-line treatment, BTK inhibitors have proven to be a highly effective and safe therapeutic option for CLL/SLL, and now constitute one of the preferred first-line options. Ibrutinib, the first approved covalent BTK inhibitor in CLL/SLL, has the most long-term data supporting its efficacy in CLL/SLL treatment although is associated with increased risk of cardiovascular and hemorrhage adverse events due to off-target kinase inhibition. The second-generation covalent BTK inhibitors, including acalabrutinib and zanubrutinib, are more selective to BTK with less off-target effects. Resistance to covalent BTK inhibitors may emerge over time due to mutations in BTK and downstream kinases. Novel non-covalent BTK inhibitors currently being studied are showing promising activities to overcome such resistance. In this review, we discuss the role of BTK inhibitors in treatment of CLL/SLL, review the data that led to approval of BTK inhibitors in CLL/SLL, outline the toxicity profile of each approved BTK inhibitor and management, and give practical guidance on how to select the most appropriate agent for treatment.

Keywords: Bruton’s tyrosine kinase inhibitor; acalabrutinib; chronic lymphocytic leukemia/small lymphocytic lymphoma; ibrutinib; zanubrutinib.

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Conflict of interest statement

Dr. Shuo Ma received research funding from Abbvie, AstraZeneca, BeiGene, Janssen, Juno, Loxo, Pharmacyclics, TG Therapeutics; and honorarium from Abbvie, AstraZeneca, BeiGene, Genentech, Janssen, Pharmacyclics, TG Therapeutics. The authors report no other conflicts of interest in this work.

Figures

Figure 1
Figure 1
BTK structure.
Figure 2
Figure 2
BTK Role in B-Cell Receptor Signalling.
Figure 3
Figure 3
BTK Inhibitor Kinome Map. Figure modified from Kaptein A, de Bruin G, Emmelot-van Hoek M, van de Kar B, de Jong A, Gulrajani M, et al. Potency and Selectivity of BTK Inhibitors in Clinical Development for B-Cell Malignancies. Blood. 2018;132(Supplement 1):1871. Copyright 2018, with permission from Elsevier.
Figure 4
Figure 4
Decision-Making Algorithm for BTK Inhibitor Selection in Previously Untreated CLL/SLL.
See this image and copyright information in PMC

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