Hagop M. Kantarjian, MD; Moshe Talpaz, MD; Francis Giles, MD; Susan O'Brien, MD; Jorge Cortes, MD
Grant Support: None.
Potential Financial Conflicts of Interest: Grants received: H.M. Kantarjian (Novartis, Bristol-Myers Squibb), F. Giles (Novartis, Amgen, Merck & Co. Inc.), J. Cortes (Novartis, Bristol-Myers Squibb, Johnson & Johnson, Chemgenex, Breakthrough Therapeutics).
Requests for Single Reprints: Hagop M. Kantarjian, MD, Department of Leukemia, MD Anderson Cancer Center, 1515 Holcombe Boulevard, Box 428, Houston, TX 77030; e-mail, firstname.lastname@example.org.
Current Author Addresses: Drs. Kantarjian, Giles, O'Brien, and Cortes: Department of Leukemia, MD Anderson Cancer Center, 1515 Holcombe Boulevard, Box 428, Houston, TX 77030.
Dr. Talpaz: University of Michigan, Comprehensive Cancer Center, 1500 East Medical Center Drive, CCGC 6-303, Ann Arbor, MI 48109-0944.
Chronic myeloid leukemia (CML) was the first human malignant disease to be linked to a single, acquired genetic abnormality. Identification of the BCR-ABL kinase fusion protein and its central role in the pathogenesis of CML provided new opportunities to develop rational molecular targeted therapies. This review provides an update on the underlying pathophysiologies of disease progression and imatinib mesylate resistance, leading to the development of new targeted tyrosine kinase inhibitors for managing CML. Imatinib, a selective inhibitor of BCR-ABL, represents a major success in the era of target-directed cancer chemotherapy. However, patients with advanced CML have been less sensitive to therapy and responses have been short. In addition, treatment resistance is an emerging problem at all disease stages. Insight into factors involved in imatinib resistance and disease progression has highlighted a role for such BCR-ABL–dependent factors as amplification and overexpression of the BCR-ABL gene and the emergence of mutant isoforms of BCR-ABL. However, BCR-ABL–independent factors, including leukemogenic pathways involving kinases other than BCR-ABL, also play a part. In light of the limitations of imatinib against these factors, newer tyrosine kinase inhibitors, including dasatinib (a multitargeted kinase inhibitor of BCR-ABL and Src family kinases) and nilotinib (AMN107, a selective BCR-ABL inhibitor), may provide promising treatment options for patients with CML.
Hagop M. Kantarjian, Moshe Talpaz, Francis Giles, Susan O'Brien, Jorge Cortes. New Insights into the Pathophysiology of Chronic Myeloid Leukemia and Imatinib Resistance. Ann Intern Med. 2006;145:913–923. doi: 10.7326/0003-4819-145-12-200612190-00008
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Published: Ann Intern Med. 2006;145(12):913-923.
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