Dasatinib (SPRYCEL®) in Patients (pts) with Previously Untreated Chronic Myelogenous Leukemia (CML) in Chronic Phase (CML-CP).

Dasatinib (SPRYCEL^®, formerly BMS-354825) is a multi-targeted kinase inhibitor of BCR-ABL and SRC. Based on its high level of activity, leading to FDA approval in pts with CML-CP who are resistant to or intolerant of imatinib (im), the present phase II trial was designed to study previously untreated CML-CP pts treated with dasatinib. The primary objective was to estimate the proportion of pts attaining major molecular response (BCR-ABL/ABL ratio ≤0.05% by qPCR) at 12 months (mo). All pts received dasatinib orally 100 mg/day, and were randomized to either a 50 mg-twice-daily or a 100 mg-once-daily schedule. Dose escalation to 140 mg/day and 180 mg/day for poor response or dose reduction to 80 mg/day and 40 mg/day for toxicity, maintaining the same schedule, was allowed. Blood counts were done weekly for the first 4 weeks (wks), every 4–6 wks for the first year, and then every 3–4 mo; bone marrow aspirates with cytogenetics were obtained at baseline and every 3–4 mo during the first year, and then every 6–12 mo; molecular monitoring of BCR-ABL transcript levels by qPCR was done at baseline, every 3-4 mo for the first year, and then every 6–12 mo. Of the first 24 pts enrolled between November 2005 and June 2006, pooled across dosing schedule, 54% were female; median age was 44 years (range 18–76). Nine (38%) of the pts were Sokal intermediate-risk and 1 (4%) was high-risk. Median baseline WBC count was 17.4 x10⁹/L (range 3.7–300.0). At 3 mo, complete hematologic response (CHR) and major cytogenetic response (MCyR) was seen in 17 (89%) of 19 pts who had received at least 3 mo of therapy, and complete cytogenetic response (CCyR) was seen in 15 pts (79%). This compares favorably with a CCyR at 3 mo of 37% with im 400 mg/day and 61% with im 800 mg/day, in historical data of similar patients treated in studies at MD Anderson. qPCR at 3 months was <1% (ie, approximately 2-log reduction) in 5 (26%), and was <10% in 9 (47%) of these 19 pts. The most common non-hematologic adverse events (AE) included dyspnea (8 pts), fatigue (7 pts), muscle pain (6 pts), and headache (5 pts) and were predominantly grade (gr) 1–2. Pleural effusion occurred in 3 pts and was gr 1–2 in all. Hematologic toxicity included anemia in 8 pts (4 gr 3), pancytopenia in 4 pts (3 gr 3, 1 gr 4), and thrombocytopenia in 4 pts (2 gr 3, 2 gr 4). With a median duration of therapy of 5 mo, there were 10 pts who required interruption of treatment, 6 due to non-hematologic toxicities, 2 due to hematologic toxicities, and 2 due to both. Dose reductions occurred in 6 pts, 3 due to non-hematologic toxicity, 1 due to hematologic toxicity, and 2 due to both. Rapid, complete cytogenetic responses to dasatinib 100 mg/day have been observed in a high percentage of patients with previously untreated CML-CP. Accrual to this trial continues, and updated efficacy and safety data will be presented at the meeting.