Dasatinib in Imatinib-Resistant Philadelphia Chromosome–Positive Leukemias

作者：Moshe Talpaz, Neil P. Shah, Hagop M. Kantarjian, Nicholas J. Donato, John M. Nicoll, Ron L. Paquette, Jörge E. Cortes, Susan Mary O'Brien, Claude Nicaise, Eric W. Bleickardt, M. Anne Blackwood-Chirchir, Vishwanath R. Iyer, Tai‐Tsang Chen, Fei Huang, Arthur P. DeCillis, Charles L. Sawyers · 发表于：New England Journal of Medicine · 年份：2006 · DOI：10.1056/nejmoa055229 · 被引用次数：1788 · 研究领域：Chronic Myeloid Leukemia Treatments、Eosinophilic Disorders and Syndromes、Myeloproliferative Neoplasms: Diagnosis and Treatment

BACKGROUND: The BCR-ABL tyrosine kinase inhibitor imatinib is effective in Philadelphia chromosome-positive (Ph-positive) leukemias, but relapse occurs, mainly as a result of the outgrowth of leukemic subclones with imatinib-resistant BCR-ABL mutations. We evaluated dasatinib, a BCR-ABL inhibitor that targets most imatinib-resistant BCR-ABL mutations, in patients with chronic myelogenous leukemia (CML) or Ph-positive acute lymphoblastic leukemia (ALL). METHODS: Patients with various phases of CML or with Ph-positive ALL who could not tolerate or were resistant to imatinib were enrolled in a phase 1 dose-escalation study. Dasatinib (15 to 240 mg per day) was administered orally in four-week treatment cycles, once or twice daily. RESULTS: A complete hematologic response was achieved in 37 of 40 patients with chronic-phase CML, and major hematologic responses were seen in 31 of 44 patients with accelerated-phase CML, CML with blast crisis, or Ph-positive ALL. In these two phases, the rates of major cytogenetic response were 45 percent and 25 percent, respectively. Responses were maintained in 95 percent of patients with chronic-phase disease and in 82 percent of patients with accelerated-phase disease, with a median follow-up more than 12 months and 5 months, respectively. Nearly all patients with lymphoid blast crisis and Ph-positive ALL had a relapse within six months. Responses occurred among all BCR-ABL genotypes, with the exception of the T315I mutation, which confers resis...