Efficacy of Dasatinib in Patients (pts) with Previously Untreated Chronic Myelogenous Leukemia (CML) in Early Chronic Phase (CML-CP).

Background: Dasatinib (BMS-354825) is a multi-targeted kinase inhibitor of BCR-ABL and SRC. Based on its high level of activity in pts with CML-CP who are resistant to or intolerant of imatinib (IM), we initiated a phase II trial to study the efficacy and safety of dasatinib in pts with previously untreated CML-CP.

Methods: The primary objective was to estimate the proportion of pts attaining major molecular response (BCR-ABL/ABL ratio ≤ 0.05% in our lab) at 12 months (mo). All pts received dasatinib orally 100 mg/day, and were randomized to either a 50 mg-twice-daily (BID) or a 100 mg-once-daily (QD) 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.

Results: Thirty-seven pts have been enrolled between November 2005 and June 2007 (19 on the QD schedule, 18 BID). Median age was 41 years (yrs) (range 18–76 yrs). Nine (24%) of the pts were Sokal intermediate-risk and 3 (8%) were high-risk. Median baseline WBC count was 29.1 x 10⁹/L (range 3.4–300.0). Three pts had clonal evolution at start of therapy. At 3 mo, complete hematologic response (CHR) was achieved in all pts,major cytogenetic response occurred 31/33 (94%), and complete cytogenetic response (CCyR) in 26/33 (79%) evaluable pts. After 6 mo of therapy, 30/32 (94%) evaluable pts had achieved CCyR. This compares favorably with results obtained in historical controls with IM at standard (400 mg) and high-dose (800 mg) at our institution:

At 12 mo, 8/25 (32%) evaluable pts had achieved a major molecular response. Responses are similar in both treatment schedule groups. The most common non-hematologic adverse events (AE) included fatigue (n=22), musculoskeletal pain (n=20), headache (n=19), and dizziness (n=14), and were predominantly grade (grade 1–2). Grade 3–4 non-hematologic toxicity (regardless of causality) included headache, pain, rash, neuropathy and memory impairment (1 each). Pleural effusion occurred in 5 (14%) pts (all grade 1–2). Grade 3–4 hematologic toxicity (transient) included neutropenia in 4 (11%) pts, thrombocytopenia in 4 (11) pts, and anemia in (5%). With a median duration of therapy of 10 mo, 18 (49%) pts required transient treatment interruption, 14 due to non-hematologic toxicities, 3 due to hematologic toxicities, and 1 due to both. Sixteen pts (43%) have required dose reductions. The actual median daily dose for all pts was 100 mg; it was 100 mg for pts treated on the QD schedule, and 90 mg for those in the BID schedule. There is no significant difference in grade 3–4 toxicity by treatment schedule.

Conclusion: Rapid, complete cytogenetic responses to dasatinib 100 mg/day occur in a high percentage of patients with previously untreated CML-CP. Once daily dosing appears to be associated with less toxicity. Accrual to this trial continues.