Practical management of patients with chronic myeloid leukemia who develop tyrosine kinase inhibitor-resistant...

Five BCR-ABL1 tyrosine kinase inhibitors (TKIs), imatinib, nilotinib, dasatinib, bosutinib, and ponatinib, are currently approved for the treatment of chronic myeloid leukemia (CML). Standard treatment of CML with TKIs is highly effective in reducing disease burden, delaying disease progression, and prolonging overall survival of patients; however, resistance to TKI treatment has become an increasingly important cause of treatment failure. The emergence of mutations in the BCR-ABL1 kinase domain is a common mechanism of TKI resistance, and laboratory testing to detect these mutations is currently available for clinical use. Patients who do not respond or have lost their response to TKI therapy should be considered for mutational testing. Despite clinical practice guidelines that recommend testing for BCR-ABL1 mutations in patients with clinical signs of TKI resistance, many oncologists and hematologists managing patients with CML do not perform such testing. This review addresses outstanding questions related to when testing should be conducted, what type of testing should be done, and how testing results should be applied to subsequent therapeutic decisions. It describes how BCR-ABL1 kinase domain mutations confer resistance, outlines the prevalence of mutations in patients with resistance to TKIs, summarizes the common and investigational methods used in mutational testing, and presents an algorithm reflecting a clinical perspective on how and when to conduct mutational testing, and what to do with test results.