Understanding the Role of Mutations in Therapeutic Decision Making for Chronic Myeloid Leukemia

In patients with chronic myeloid leukemia (CML) resistant to imatinib, resistance is commonly associated with mutations in the BCR-ABL protein. Approximately 85% to 90% of resistance-associated mutations occur within the ABL kinase domain, and confer resistance either directly, by blocking imatinib binding, or indirectly, by altering the conformation of BCR-ABL. The degree of resistance depends on the mutation, with some remaining sensitive to imatinib. Imatinib dose escalation may overcome resistance in some of these patients or therapy can be switched to the second-generation tyrosine kinase inhibitors (TKIs) nilotinib or dasatinib. The long-term efficacy of second-generation TKIs may also be related to specific BCR-ABL mutations, with the T315I mutant remaining resistant to all currently available TKIs. Other treatments, including investigational agents, may be options for patients with this mutation. The choice of therapy should be guided by multiple factors, including mutational analysis, disease phase, patient characteristics, and the safety profile of the agents.