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Novel agents for chronic myeloid leukemia: from imatinib to dasatinib and nilotinib: overcoming resistance
Oregon Health and Science University, Center for Hematologic Malignancies, Portland, OR
Patients with chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia express BCR-ABL, a constitutively active tyrosine kinase that is the pharmacologic target of imatinib. The vast majority of newly diagnosed patients in chronic phase CML respond to imatinib, whereas results are less favorable in patients with advanced stages of CML. Similar, relapse after an initial response is relatively rare in early chronic phase but common in accelerated phase or blast crisis. As a rule, acquired resistance to imatinib is associated with reactivation of Bcr-Abl, and kinase domain mutations are the most common mechanism associated with relapse. Therapeutic strategies to overcome acquired drug resistance include combinations with conventional agents; signal transduction inhibitors to block crucial pathways downstream of Bcr-Abl; and, most importantly, alternative Abl kinase inhibitors with activity against imatinib-resistant mutants, such as AMN107 (nilotinib) and BMS-354825 (dasatinib).
| Commun Oncol 2006;3:519–523 | full text |  196 kb |