Efficacy of various doses and schedules of second-generation tyrosine kinase inhibitors.
Imatinib is one of the most potent cancer therapeutic agents identified to date. Before the introduction of this tyrosine kinase inhibitor (TKI), 5-year survival in chronic myeloid leukemia (CML) was approximately 40%-60%, but since the introduction of imatinib, overall survival has increased to approximately 90% for patients with chronic-phase disease. However, nearly one fifth of patients are intolerant or resistant to imatinib, resulting in patients with persistent or progressive disease. Recent research has identified a number of additional compounds that more efficiently inhibit the Abl tyrosine kinase and additional kinases that potentially play a role in imatinib resistance. The advent of dasatinib and nilotinib has provided additional options for patients with progressive disease. A number of phase II clinical trials have recently demonstrated that these second-generation TKIs are well tolerated and effective in patients with Philadelphia chromosome-positive (Ph+) leukemias. Recent clinical trial developments raise questions regarding the proper dosage and schedule of these newer agents as well as the timing of their use in the treatment of patients with CML. Additionally, the development of nonoverlapping resistance patterns with sequential drug exposure argues for the possibility of a drug selection scheme that might limit the development of resistant disease. As the era of personalized medicine has begun to take shape in the 21st century, the addition of newer TKIs might facilitate this trend in the treatment of Ph+ leukemias.