Novel tyrosine kinase inhibitors for patients with inadequate response in chronic myeloid leukemia.

PURPOSE OF REVIEW: The purpose of this review is to summarize treatment expectations and response milestones, to conceptualize the approach to defining inadequate response to therapy and critically appraise current available strategies, as well to highlight novel agents under development to address unmet needs in chronic myeloid leukemia (CML) therapy.

RECENT FINDINGS: Given excess risk with currently available highly potent ABL1 (Abelson murine leukemia viral oncogene homolog 1) inhibitors, a number of alternate, highly potent compounds have entered the clinic to address select resistance such as the T315I mutation with the promise of greater selectivity and better adverse event profile. In addition, alternate approaches to ABL1 inhibition, targeting the myristoyl pocket of ABL1, are showing promising early results and are moving into later phase trials.

SUMMARY: CML is a highly treatable form of leukemia with multiple orally available small molecule inhibitors of the activated BCR-ABL1 (breakpoint cluster region-ABL1) kinase. Despite such an array of therapy options, inadequate response to therapy remains a challenge with a substantial minority of patients facing tyrosine kinase inhibitor (TKI) resistance, intolerance, or both. Unmet needs in Ph+ leukemia include highly selective resistant disease, multi-TKI resistant CML, and advanced phase disease.