BTK Inhibitors in CLL : Second Generation Drugs and Beyond.

BTK inhibitors (BTKi) 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 BTKi have improved selectivity and demonstrate reduced rates of cardiovascular complications in three head-to-head ibrutinib studies. The emergence of BTK C481S mutation led to the development of non-covalent,"reversible" BTKi such as pirtobrutinib which are agnostic to the C481S mutation, but which in turn are associated with resistant mutations outside the C481 hotspot. These variant non-C481 mutations are of great clinical interest as 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. In this review, we review the evolution of therapeutic BTK targeting and discuss future directions for clinical research.