Tam Constantine S, Balendran Shalini, Blombery Piers
Clinical Haematology, Alfred Hospital, Melbourne, VIC, Australia.
Central Clinical School, Monash University, Melbourne, VIC, Australia.
Blood. 2025 Mar 6;145(10):1005-1009. doi: 10.1182/blood.2024026672.
Bruton tyrosine kinase inhibitors (BTKis) are an established standard of care in chronic lymphocytic leukemia. The covalent BTKis ibrutinib, acalabrutinib, and zanubrutinib bind to BTK C481 and are all susceptible to the C481S mutation. Noncovalent 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.
布鲁顿酪氨酸激酶抑制剂（BTKis）是慢性淋巴细胞白血病既定的标准治疗药物。共价BTKis依鲁替尼、阿卡替尼和泽布替尼与BTK C481结合，且均易发生C481S突变。非共价BTKi，包括派罗替尼，可克服C481S耐药性，但与多种变异（非C481）BTK突变相关，包括那些与对阿卡替尼和泽布替尼耐药相关的突变（T474密码子和L528W突变）。我们回顾了关于变异BTK突变的现有知识，讨论了它们的临床意义，并考虑了它们对临床试验的影响。
