BTK inhibitors in CLL: second-generation drugs and beyond
Author(s)
Tam, C; Thompson, PA;
Details
Publication Year 2024-05-14,Volume 8,Issue #9,Page 2300-2309
Journal Title
Blood Advances
Publication Type
Review
Abstract
BTK inhibitors (BTKis) are established standards of care in multiple B-cell malignancies including chronic lymphocytic leukemia, mantle cell lymphoma, and Waldenstrom macroglobulinemia. The first-generation BTKi ibrutinib demonstrated superiority over standard chemoimmunotherapy regimens in multiple randomized trials but is limited by cardiovascular side effects such as atrial fibrillation and hypertension. Second-generation BTKis have improved selectivity and demonstrate reduced rates of cardiovascular complications in 3 head-to-head ibrutinib studies. The emergence of BTK C481S mutation has led to the development of noncovalent, "reversible" BTKis, such as pirtobrutinib, which are agnostic to the C481S mutation. However, these inhibitors are associated with resistant mutations outside the C481 hot spot. These variant non-C481 mutations are of great clinical interest because some are shared among pirtobrutinib, zanubrutinib, and acalabrutinib, with potential implications for cross resistance and treatment sequencing. Finally, BTK protein degraders with in vitro activity against C481 and non-C481 mutations are currently in clinical development. Here, we review the evolution of therapeutic BTK-targeting and discuss future directions for clinical research.
Publisher
American Society of Hematology
Keywords
Humans; *Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors; *Protein Kinase Inhibitors/therapeutic use; *Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy; Mutation; Antineoplastic Agents/therapeutic use/adverse effects; Piperidines/therapeutic use; Adenine/analogs & derivatives/therapeutic use
Department(s)
Clinical Haematology
Open Access at Publisher's Site
https://doi.org/10.1182/bloodadvances.2023012221
Terms of Use/Rights Notice
Refer to copyright notice on published article.


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