Resistance to Bruton Tyrosine Kinase Inhibitors.

Targeting Bruton tyrosine kinase (BTK) has revolutionized the therapy for chronic lymphocytic leukemia. As patients remain on therapy, however, resistance develops progressively over time. The most common mechanism of resistance to covalent BTK inhibitors is mutation of the C481 target residue to serine, abrogating covalent binding. Other less common mutations are C481Y/R/F after ibrutinib, T474I after acalabrutinib, and L528W after zanubrutinib. The first-in-class noncovalent inhibitor pirtobrutinib has activity against C481 mutations, but resistance develops through alternative site BTK mutations. About one-third of BTK inhibitor resistance, both covalent and noncovalent, is not related to BTK mutations and remains poorly understood.