OncoMatch/Leukemia — Chronic Myeloid (CML)/BCR-ABL1 kinase domain mutation

Leukemia — Chronic Myeloid (CML)BCR-ABL1 kinase domain mutation Clinical Trials

BCR-ABL1 kinase domain mutations are a major clinically actionable mechanism of targeted-therapy resistance in CML, shifting which tyrosine kinase inhibitor remains active and making mutation-specific TKI selection central to later-line trials — though resistance can also be BCR-ABL1-independent, from pharmacokinetics, adherence, or clonal evolution. The T315I gatekeeper mutation matters most: it resists the ATP-competitive inhibitors imatinib, dasatinib, nilotinib, and bosutinib, and in US practice usually directs selection toward ponatinib or asciminib, the STAMP inhibitor that binds the myristoyl pocket rather than the ATP site (olverembatinib is a further T315I-active option outside the US). Other recurrent variants steer therapy too — F317L toward dasatinib resistance, Y253H and E255K/V and F359V toward nilotinib resistance — while compound mutations, especially T315I-containing ones, can defeat even ponatinib or asciminib. Trials investigate mutation-specific treatment sequencing, asciminib combinations, and novel allosteric ABL1 inhibitors.