Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias

Moshe Talpaz, 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

Research output: Contribution to journalArticle

1342 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2531-2541
Number of pages11
JournalNew England Journal of Medicine
Volume354
Issue number24
DOIs
StatePublished - Jun 15 2006
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)

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    Talpaz, M., Shah, N. P., Kantarjian, H., Donato, N., Nicoll, J., Paquette, R., Cortes, J., O'Brien, S., Nicaise, C., Bleickardt, E., Blackwood-Chirchir, M. A., Iyer, V., Chen, T. T., Huang, F., Decillis, A. P., & Sawyers, C. L. (2006). Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. New England Journal of Medicine, 354(24), 2531-2541. https://doi.org/10.1056/NEJMoa055229