The evolving landscape of tyrosine kinase inhibitors in chronic-phase chronic myeloid leukemia: A 25-year journey.

BCR::ABL1 tyrosine kinase inhibitors (TKIs) have transformed the treatment landscape of chronic-phase chronic myeloid leukemia, normalizing life expectancy for most patients. However, potential ABL1 kinase domain mutation-driven treatment resistance and intolerance are perennial clinical challenges. For frontline therapy, generically available first-generation BCR::ABL1 TKI imatinib is a rational and cost-effective approach to optimize survival. Second-line options are more likely to elicit deep molecular responses and treatment-free remission. However, achievement of these milestones has not been associated with improved overall survival as compared with imatinib. The "gatekeeper" T315I ABL1 kinase domain mutation confers resistance to imatinib and all second-generation TKIs. For patients with this mutation and/or resistance or intolerance to prior TKIs, third-generation ponatinib, first-in-class specifically targeting the Abl myristoyl pocket inhibitor asciminib, or (upon regulatory approval) potentially olverembatinib may be appropriate alternatives. Considerable finesse is warranted to tailor a range of efficacious and well-tolerated therapies to the individual needs of patients.