The clinical challenge of imatinib resistance in chronic myeloid leukemia: Emerging strategies with new targeted agents

Chronic myelogenous leukemia (CML) is a progressive and often fatal hematopoietic neoplasm. The disease is characterized by the presence of the Philadelphia chromosome, which arises following a balanced translocation between chromosomes 9 and 22, creating the BCR-ABL fusion gene. It is often stated that the only proven curative option is allogeneic stem cell transplantation (allo-SCT), which is indicated for only a limited subset of patients. The Bcr-Abl tyrosine kinase inhibitor (TKI) imatinib mesylate (IM) represented a major advance over conventional CML therapy. Following IM treatment, more than 90% of patients obtain complete hematologic response, and 70-80% of patients achieve a complete cytogenetic response. Resistance to IM represents an increasing clinical challenge and is often a result of point mutations causing a conformation change in Bcr-Abl, which impair IM binding. Novel targeted agents designed to overcome IM resistance, including multitargeted TKIs and farnesyl transferase inhibitors, are in various phases of development. Dasatinib, which has recently become available in the clinic, is a Bcr-Abl TKI that also inhibits Src, c-Kit, platelet-derived growth factor receptor, and ephrin A receptor kinases. In a phase II randomized trial in patients resistant or intolerant to IM, patients receiving dasatinib had better hematologic and cytogenetic responses than those on high-dose IM, irrespective of the presence or absence of mutations. Nilotinib has also shown promising activity. Combining IM with conventional chemotherapy, interferon, and targeted agents including TKIs is being actively pursued. Diagnostic testing may enable individualized targeted treatment so that patients receive the most effective agent first-line.