Chronic Myeloid Leukemia Therapy: Focus on Second-Generation Tyrosine Kinase Inhibitors

Background: Chronic myeloid leukemia, the most common adult leukemia, is characterized by the Ph+ chromosome produced by the fusion of the BCR gene from chromosome 22 and the ABL gene from chromosome 9. Inhibition of the deleterious effects of this potent oncogene by the tyrosine kinase inhibitor (TKI) imatinib has revolutionized care of this disease, but intolerance and resistance does occur. Methods: The authors have reviewed both the preclinical and the clinical data concerning second-generation TKIs intended to circumvent or ameliorate issues with imatinib intolerance or resistance. Results: Two second-generation TKIs, dasatinib and nilotinib, are currently approved by the US Food and Drug Administration. Both have shown significant clinical activity in patients with chronic myeloid leukemia (CML) and Ph+ acute lymphoblastic leukemia (ALL) who are resistant or intolerant to imatinib or other therapies. Conclusions: The TKIs are a superb example of an effective targeted approach for a malignant disease. As more clinical data become available and additional novel agents are developed, specific therapy and dosing strategies for individuals with CML will depend on the status of their disease, the anticipated side effects, and concurrent drug therapy.