Dasatinib (BMS-354825) in Patients with Chronic Myeloid Leukemia (CML) and Philadelphia-Chromosome Positive Acute Lymphoblastic Leukemia (Ph+ ALL) Who Are Resistant or Intolerant to Imatinib: Update of a Phase I Study.

Imatinib mesylate resistance in CML and Ph+ ALL is frequently associated with BCR-ABL mutations that interfere with the ability of imatinib to inhibit BCR-ABL. Dasatinib (BMS-354825) is a novel, oral, multi-targeted kinase inhibitor, which targets BCR-ABL and SRC kinases. Dasatinib is 325-fold more potent versus imatinib in cells transduced with wild-type BCR-ABL, and has demonstrated preclinical activity against 18 of 19 imatinib-resistant BCR-ABL mutants (O’Hare, et al. Cancer Res65(11):4500–5, 2005; Shah et al, Science, 305:399–401, 2004). Here we present an update of a Phase I dose-escalating study, initiated in November 2003, of dasatinib in imatinib-resistant/intolerant patients with CML in late chronic phase (CP) or advanced disease (accelerated phase [AP], myeloid blast crisis [MBC] or lymphoid blast crisis [LBC]) or with Ph+ ALL. Data are available for 84 patients (40 CP, 10 AP, 23 MBC, 11 LBC/Ph+ ALL). As of this writing, 40 CP patients, with 8 years’ median duration of CML (range: 1–17 yrs), have been treated with dasatinib (15–180 mg/day, once-daily [QD] or twice daily [BID]) for a median of 13 months. The rate of complete hematologic response (CHR) in CP is 88% (35/40). Major cytogenetic responses (MCyR) were observed in 40% (16/40), with complete CyR (CCyR) in 33% (13/40). In advanced disease, 44 patients have been treated with dasatinib (70–240 mg/day, BID) for a median of 3–7 months, depending on the cohort (see Table); 2 patients (1 MBC and 1 LBC) are not evaluable for response, but are included in the analysis of time to progression. The rate of major hematologic response (MHR) (bone marrow blasts