Efficacy of Dasatinib (SPRYCEL®) in Patients (pts) with Chronic Phase Chronic Myelogenous Leukemia (CP-CML) Resistant to or Intolerant of Imatinib: Updated Results of the CA180013 ‘START-C’ Phase II Study.

Dasatinib (SPRYCEL^®, formerly BMS-354825) is an oral, multi-targeted, kinase inhibitor of BCR-ABL and SRC kinases, approved by the US FDA for the treatment of chronic myelogenous leukemia, including chronic phase, with resistance to or intolerance of prior therapy, including imatinib (im). ‘START-C’ is an open-label phase-II study of dasatinib in imatinib-resistant (im-r) or -intolerant (im-i) pts with CP-CML. Preliminary data previously presented on 186 pts treated showed a complete hematologic response (CHR) rate of 90%, and a major cytogenetic response (MCyR) rate of 45%. With additional recruitment, between February and July 2005, a total of 387 pts (191 male, median age 58 yrs [range 21–85]) were enrolled and treated in 75 centers worldwide. The definition of im-r required progressive disease at a maximal dose of im or the occurrence of BCR-ABL mutations associated with insensitivity to im. Of the 387 pts, 288 were im-r and 99 were im-i. Dasatinib was given at 70 mg twice daily (BID) with dose escalation to 90 mg BID in pts lacking response, and dose reductions to 50 and 40 mg BID for toxicity or intolerance. Complete blood counts were obtained weekly for the first 12 weeks; bone marrow cytology and cytogenetics every 3 months, and molecular monitoring of BCR-ABL transcript levels by real-time qPCR every 4 weeks for the first 12 weeks, then every 12 weeks. The primary endpoint was MCyR rate. Median time from diagnosis of CML was 61 months (range 3–250). Prior therapy included interferon-alpha in 65% and stem cell transplantation in 10% of pts. Fifty five percent of pts had >600 mg of prior im. Fifty three percent of pts received im for >3 yrs. Best response to prior im therapy was a CHR in 82%, and complete (CCyR) and partial (PCyR) cytogenetic responses in 19% and 18% of pts, respectively. Updated analyses with a median follow-up of 13 months (0.1–17 months) show 351 (91%) pts had a CHR, and 225 (58%) a MCyR: 79 (80%) im-i pts, and 146 (51%) im-r pts. CCyR rates were 74% (im-i) and 38% (im-r) giving a total CCyR rate of 47%. Sixty three (41%) pts who never achieved a CyR on im achieved a MCyR with dasatinib. The rate of MCyR was 59% among the 160 (44%) pts with BCR-ABL baseline mutations, and was seen across all mutations with the exception of T315I. Grade 3/4 neutropenia or thrombocytopenia was reported in 49% and 48% of pts, respectively. Dose interruptions occurred in 331 (86%) pts, and dose reductions in 269 (70%) pts, with an average daily dose of 103 mg/day (range 11–169 mg). Non-hematologic toxicity consisted mainly of grade 1/2 diarrhea, headache, rash, and pleural effusion, with 6% grade 3/4 pleural effusion. Dasatinib demonstrated substantial hematologic and cytogenetic activity in im-r and im-i pts with CP-CML. Importantly, the responses rates continue to improve with further follow-up, and 221 of the 225 pts who achieved a MCyR have not progressed or died while on study. The 12 month progression-free survival of all patients is 90%. Updated analyses with at least 15 months of follow-up, in addition to the molecular response data and mutational analysis at time of progression, will be presented.