Dasatinib (SPRYCEL®) in Patients (pts) with Chronic Myelogenous Leukemia in Accelerated Phase (AP-CML) That Is Imatinib-Resistant (im-r) or -Intolerant (im-i): Updated Results of the CA180–005 ’START-A’ Phase II Study.

Dasatinib (SPRYCEL®, formerly BMS-354825) is a novel, oral, multi-targeted kinase inhibitor that induces complete hematologic and cytogenetic remissions in pts in all phases of im-r or im-i CML. START-A is an open-label study of dasatinib in pts with im-r or im-i AP-CML. Preliminary results with early follow-up suggested significant activity. The present report updates the results of this study with a minimum of 9 months of follow-up. Dasatinib was given orally at 70 mg twice daily (BID). Dose escalation to 100 mg BID was allowed for inadequate initial response and reduction to 50 or 40 mg BID for persistent toxicity.

Evaluation included weekly blood counts and monthly bone marrow including cytogenetics. Molecular evaluation of BCR-ABL transcript levels by real-time qPCR was performed at baseline and upon documentation of complete cytogenetic response. A total of 174 pts (161 im-r and 13 im-i) were enrolled between December 2004 and July 2005 in 39 centers worldwide. There were 96 (55%) males; median age was 57 years (range 22–86); median time from original diagnosis of CML was 82 months.

Prior therapy included im in all pts (>600 mg/day in 91 (52%), im for >3 years in 103 (59%) pts, interferon in 126 (72%) pts, stem cell transplantation in 23 (13%) pts. Major cytogenetic response (MCyR) to prior im had been seen in 57 (33%) pts. The average daily dose (median across all pts) was 130 mg/day (range 44–199). Major hematologic response (MaHR) was documented in 110 (63%) pts with complete hematologic response in 75 (43%) and no evidence of leukemia in 35 (20%). At 9 months, 85% of pts have maintained their MaHR. MCyR was documented in 65 (37%) pts, complete in 49 (28%), partial in 16 (9%). Median progression-free survival (PFS) has not been reached; estimated PFS at 9 months is 70%. In the 94 pts with BCR-ABL mutations at baseline the MaHR rate was 69%. Generally, response rates were similar in the im-i and im-r groups. Cytopenias were significant with grade 3–4 thrombocytopenia and neutropenia in 82% and 76% of pts, respectively. Non-hematologic toxicities were generally mild to moderate. The most frequent (% any grade, % grade 3–4) were diarrhea (51%, 8%), headache (29%, 1%), fatigue (26%, 4%), fever (25%, 3%) and pleural effusion (25%, 3%). Pleural effusions were optimally managed with dose interruption and diuretics and/or pulse steroids. Dasatinib is highly effective in pts with im-r or im-i AP-CML with high rates of durable MaHR and MCyR. An updated analysis with at least 12 months of follow-up, including molecular response data and mutational analysis at time of progression, will be presented.