Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias - PubMed (original) (raw)
Clinical Trial
. 2006 Jun 15;354(24):2531-41.
doi: 10.1056/NEJMoa055229.
Neil P Shah, Hagop Kantarjian, Nicholas Donato, John Nicoll, Ron Paquette, Jorge Cortes, Susan O'Brien, Claude Nicaise, Eric Bleickardt, M Anne Blackwood-Chirchir, Vishwanath Iyer, Tai-Tsang Chen, Fei Huang, Arthur P Decillis, Charles L Sawyers
Affiliations
- PMID: 16775234
- DOI: 10.1056/NEJMoa055229
Free article
Clinical Trial
Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias
Moshe Talpaz et al. N Engl J Med. 2006.
Free article
Abstract
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 resistance to both dasatinib and imatinib in vitro. Myelosuppression was common but not dose-limiting.
Conclusions: Dasatinib induces hematologic and cytogenetic responses in patients with CML or Ph-positive ALL who cannot tolerate or are resistant to imatinib. (ClinicalTrials.gov number, NCT00064233 [ClinicalTrials.gov].).
Copyright 2006 Massachusetts Medical Society.
Comment in
- Circumventing resistance to kinase-inhibitor therapy.
Druker BJ. Druker BJ. N Engl J Med. 2006 Jun 15;354(24):2594-6. doi: 10.1056/NEJMe068073. N Engl J Med. 2006. PMID: 16775240 No abstract available. - Dasatinib in chronic myelogenous leukemia.
Kathula SK. Kathula SK. N Engl J Med. 2006 Sep 7;355(10):1062; author reply 1063-4. doi: 10.1056/NEJMc061882. N Engl J Med. 2006. PMID: 16957155 No abstract available. - Dasatinib in chronic myelogenous leukemia.
Chu SC, Tang JL, Li CC. Chu SC, et al. N Engl J Med. 2006 Sep 7;355(10):1062-3; author reply 1063-4. N Engl J Med. 2006. PMID: 16960978 No abstract available.
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