New targeted approaches in chronic myeloid leukemia.

The treatment of chronic myeloid leukemia has changed dramatically in the last few years. Stem-cell transplantation and the use of interferon alfa had already offered the possibility of complete and durable cytogenetic responses, improving the survival over that expected with conventional chemotherapy. The introduction of imatinib mesylate has started the era of molecular therapy with remarkable results including complete cytogenetic responses in up to 90% of patients and major molecular responses in most. However, some patients, particularly those treated in the advanced stages, may develop resistance to imatinib. Thus there has been interest in developing new agents that would not only help patients for whom imatinib is ineffective or intolerable, but that could also be combined with the intention of eliminating all evidence of disease. Several approaches are being pursued. These include new and more potent tyrosine kinase inhibitors that may not be affected by the most common mutations seen in the clinic. Some of these agents also inhibit Src-related kinases that may play a role in the development of resistance to imatinib. Other agents are directed at downstream or alternative pathways in leukemic cells, exploring potential synergy with imatinib. Another approach is to pursue an immune modulation that might eliminate small amounts of residual disease. Many of these agents are already showing promising results in the clinic. This manuscript reviews some of these agents, particularly those for which clinical data are already available.