Novel Mechanisms of Resistance in CLL: Variant BTK Mutations in Second-Generation and Noncovalent BTK Inhibitors

BTK inhibitors (BTKi) are an established standard of care in CLL. The covalent BTKi ibrutinib, acalabrutinib and zanubrutinib bind to BTK C481 and are all susceptible to the C481S mutation. Non-covalent BTKi including pirtobrutinib overcome C481S resistance but are associated with multiple variant (non-C481) BTK mutations, including those associated with resistance to acalabrutinib and zanubrutinib (T474 codon and L528W mutations). We review the current knowledge on variant BTK mutations, discuss their clinical implications and consider their impact on clinical trials.