Dasatinib (SPRYCEL®) Efficacy and Safety in Patients (pts) with Chronic Myelogenous Leukemia in Lymphoid (CML-LB) or Myeloid Blast (CML-MB) Phase Who Are Imatinib-Resistant (Im-r) or -Intolerant (Im-i).

Pts with CML-LB or CML-MB have a poor prognosis with survival from onset of blast crisis of 3–6 months. Dasatinib (SPRYCEL^®, formerly BMS-354825) is a multi-targeted kinase inhibitor of BCR-ABL and SRC, which results in complete hematologic and cytogenetic responses in pts with CML-LB or CML-MB who are Im-i, or who have disease that is Im-r. Between January and June 2005, 48 CML-LB pts were enrolled in the START-L trial, and 109 CML-MB pts in the START-B trial both of which were open label, multi-center, global phase II studies. As previously reported, with a minimum of 6-months follow up in the combined blast-phase pts, the major hematologic response (MHR) rate was 32% including 26% complete hematologic responses (CHR) and the major cytogenic response (MCyR) rate was 38%, including 31% complete cytogenetic responses (CCyR). The median duration of MHR had not been reached and the median progression-free survival (PFS) was 4.3 months (mo). In both studies, dasatinib was given orally, 70 mg twice daily (BID) with escalation to 100 mg BID for poor response or reductions to 50 mg and 40 mg BID for toxicity. Pts had weekly blood counts and monthly bone marrow exams, including cytogenetics. Mutation analysis was conducted at baseline and at end of study. Quantitative PCR was carried out at pretreatment and at the time of CCyR. Overall, among all blast-crisis pts in both studies, 90% were Im-r. Due to the small number of Im-i pts, data for all pts is presented. Among the 157 pts, 56% were male, with a median age of 54 years (range 17–81). The median time from diagnosis of CML was 45 mo (range 2–216). Prior therapy included Im >600 mg/d in 50%, with Im for >3 years in 36% and stem cell transplantation in 19% of the pts. At baseline, 57% of pts had WBC <20,000/mm³, 69% had platelets <100,000/mm³, and 17% had extramedullary disease outside of the spleen. In the 149 pts with baseline mutation data, Im-resistant BCR-ABL mutations were observed in 50%. With a minimum of 9 mo follow up on all pts, 19% pts remained on treatment with disease progression as the most common reason for discontinuation. Overall, doses were reduced in 33% of pts and interrupted in 59%, most commonly due to non-hematologic toxicities. Dasatinib dose was escalated in 43% of pts. The median duration of therapy was 3.4 mo (0.03–18) in all pts and was 14 mo (6–18) in pts still on treatment. The MHR rate was 34% including 27% CHR; the MCyR was 38% including 31% CCyR. Of the 73 pts with baseline mutations, the MHR rate was 32%. The median duration of MHR still has not been reached and the median PFS was 4.3 mo. Among all pts, grade 3–4 thrombocytopenia occurred in 17% and 68%, respectively and grade 3–4 neutropenia was observed in 17% and 63%, respectively. Most frequent non-hematologic toxicities included diarrhea in 37% (grade 3–4, 5%), pleural effusion in 27% (grade 3–4, 11%), vomiting in 22% (grade 3–4, 3%), nausea in 20% (grade 3–4, 3%), and fatigue in 21% (grade 3–4, 3%) of pts. Dasatinib has efficacy in pts with blast phase CML including some with substantial duration of response and PFS. Updated efficacy (including molecular response), safety, and mutational analysis data will be presented at the meeting.