Chronic myeloid leukemia: incorporation of recent advances into current treatment algorithms

Several approved and investigational BCR::ABL1 tyrosine kinase inhibitors (TKIs) and STAMP inhibitors are used for the treatment of chronic myeloid leukemia in chronic phase (CML-CP). In the frontline setting, multiple factors affect selection of therapy including the goal of treatment, cost of TKIs, CML risk, and patient's comorbidities. Achieving a complete cytogenetic response (BCR::ABL1 transcripts on the International Scale [IS] <1%) with TKI therapy within the first year is associated with normalization of survival, whereas achieving a deeper molecular response (BCR::ABL1 transcripts < 0.01% [IS]) may allow for treatment discontinuation with the possibility of treatment-free remission. Although standard doses are approved for each TKI, post approval studies have demonstrated that an optimal biologic dose is safer than and as effective as the approved dose. In cases of TKI toxicities, reducing the dose rather than switching TKIs is recommended unless the patient experiences a prohibitive toxicity, in which case the treatment should be changed. In patients experiencing failure of frontline therapy due to resistance or intolerance, multiple second- and third-line options are available, including second-generation TKIs, ponatinib, and asciminib, as well as novel investigational agents, including the ABL1 kinase domain inhibitors olverembatinib and ELVN-001 and the STAMP inhibitors TGRX-678 and TERN-701. In this review, we discuss the recent advances in the treatment of CML-CP and challenge some established management practices.