Targeting the BCR::ABL1 Kinase: Advances Beyond Imatinib in Chronic Myeloid Leukemia.

PURPOSE OF REVIEW: Despite the success of tyrosine kinase inhibitors (TKIs) in the treatment of chronic myeloid leukemia (CML), resistance and disease progression remain significant challenges. In this review, we summarize current understanding of BCR::ABL1 dependent and independent mechanisms of resistance, including BCR::ABL1 mutations and additional genetic abnormalities. We also discuss the current and emerging therapeutic strategies aimed at overcoming treatment failure. RECENT FINDINGS: Recent findings have highlighted the heterogeneity of resistance in CML, suggesting that distinct BCR::ABL1 mutations confer variable sensitivity to TKIs, including mutations affecting the myristoyl binding pocket. In parallel, the acquisition of additional genetic abnormalities such as ASXL1 and RUNX1 has been increasingly linked to disease progression and poor outcomes. Together, these findings have driven the development of novel therapeutic agents such as TERN-701, ELVN-001 and Olverembatinib, as well as growing interest in combination therapy such as asciminib plus ATP-binding site TKIs. Early studies indicate that these novel agents and combination approaches show promising activity against resistant CML. Resistance in CML can be BCR::ABL1 dependent or independent, emphasising the need for molecular profiling to guide treatment decisions. Continued development of mutation-specific therapies, and combination BCR::ABL1-targeted approaches may improve outcomes for patients who develop resistance or experience disease progression. This represents an important focus for future investigations.