Dasatinib in Imatinib-Resistant Philadelphia Chromosome–Positive Leukemias

摘要: 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 leukemic subclones with imatinib-resistant mutations. We evaluated dasatinib, that targets most BCRABL mutations, patients chronic myelogenous leukemia (CML) or Ph-positive acute lymphoblastic (ALL). Methods Patients various phases CML ALL who could not tolerate were resistant to enrolled phase 1 dose-escalation study. Dasatinib (15 240 mg per day) was administered orally four-week treatment cycles, once twice daily. Results A complete hematologic response achieved 37 40 chronicphase CML, and major responses seen 31 44 accelerated-phase blast crisis, ALL. In these two phases, rates cytogenetic 45 percent 25 percent, respectively. Responses maintained 95 chronic-phase disease 82 disease, median follow-up more than 12 months 5 months, Nearly all lymphoid crisis had within six months. occurred among genotypes, exception T315I mutation, which confers resistance both dasatinib vitro. Myelosuppression common dose-limiting. Conclusions induces cannot are imatinib. (ClinicalTrials.gov number, NCT00064233.)