Current and Future Clinical Strategies in the Management of Chronic Myeloid Leukemia

Abstract

Rational design of tyrosine kinase inhibitors, such as imatinib, against leukemogenic Bcr‐Abl kinase has resulted in unprecedented responses and survival rates in patients with chronic myeloid leukemia (CML). Although these responses are sustained for years in the majority of patients, a fraction of the patients either fail or respond suboptimally to imatinib therapy, or are intolerant to the drug. Biologic insights into the mechanisms of imatinib resistance led to the development of several strategies, including dose escalation and second‐generation tyrosine kinase inhibitors. Dasatinib and nilotinib are second‐generation tyrosine kinase inhibitors that are approved as second‐line treatment for imatinib‐resistant patients based on their activity in these patients and their favorable toxicity profiles. Dasatinib and nilotinib have demonstrated promising activity as front‐line therapy and are being directly compared with imatinib therapy in this setting. Salvage treatment options are evolving for patients with CML, with several novel agents showing promising activity, even in patients with the noted T315I mutation. The role of stem cell transplantation for patients with CML is being redefined in the context of significant transplantation‐related morbidity and mortality and the availability of effective alternate therapies. In this context, practical considerations such as guidelines for monitoring responses to imatinib therapy, criteria for choice of second‐line therapy, management of the adverse events of tyrosine kinase inhibitors, and quality‐of‐life issues are of particular importance. This review summarizes recent advances in the treatment of CML over the past decade, with an emphasis on tyrosine kinase inhibitor therapy.