ASCOIn a phase II study, use of dasatinib (Sprycel) as first-line therapy for patients with chronic myelogenous leukemia (CML) in chronic phase led to more and faster cytogenetic responses than seen historically with standard-dose imatinib (Gleevec). "However, with the limited number of patients and short follow-up, the major molecular response rate at 12 months appears similar to imatinib," Ehab L. Atallah, MD, reported at the 43rd Annual Meeting of the American Society of Clinical Oncology (abstract 7005).
Dasatinib is a multi-targeted tyrosine kinase inhibitor that is approximately 300 times more potent against Bcr-Abl than imatinib, said Dr. Atallah, a fellow in the Department of Leukemia at M.D. Anderson Cancer Center. Dasatinib is currently approved for the second-line treatment of imatinib-resistant CML. In this setting, it produces complete cytogenetic remissions (CCyRs) in 75% of imatinib-intolerant and 40% of imatinib-resistant patients. "Thus, we hypothesized that if we treat patients with newly diagnosed CML with dasatinib up front, we would have more and faster responses than with imatinib," Dr. Atallah said. Major molecular response (MMR) at 12 months was chosen as the primary endpoint, since it may correlate with survival.
At ASCO, Dr. Atallah reported on 35 (of a planned 100) patients with previously untreated Philadelphia-chromosome-positive, early chronic-phase CML. Patients were randomized to two different schedules of the same dasatinib dose: 50 mg twice daily or 100 mg once daily. Dose escalation up to 180 mg/d was allowed (but has not been required to date) as was dose reduction to 40 mg/d.
Dr. Atallah reported on 34 evaluable patients with a median follow-up of 9 months (range, 1 to 18 months). All patients achieved a complete hematologic response, he said. The overall cytogenetic response rate for these patients was 94%: complete 85%, partial 6%, and minor 3%. "These responses occurred rapidly," Dr. Atallah said. After 3 months on therapy, 77% had achieved a CCyR, which rose to 92% at 6 months and 95% at 12 months. "Only one patient has failed treatment at this time," he said. There were no major molecular responses at 3 months. At 6 months, 19% of 27 evaluable patients had attained MMR, which rose to 23% of 26 at 9 months and 27% of 22 at 12 months (5% with undetectable Bcr-Abl).
Dasatinib was well tolerated: Most adverse events were grade 1-2, and hematologic toxicity was minimal, he said. The most common toxicities were musculoskeletal pain, fatigue, headache, and skin reaction. Only two patients had grade 3 toxicityone headache and one skin rash. Four patients developed grade 2 pleural effusion, leading to dose interruption in three.
Dose interruptions occurred in 43% of patients (median, 12 days). "Most patients were able to resume the drug at the previous dose," Dr. Atallah said. Dose interruptions were slightly more common with the twice-daily regimen, and the MMR rate at 12 months was slightly higher with the once-daily schedule (33% vs 20%), but these differences were not statistically significant.
Dr. Atallah compared the dasatinib results with those of patients in imatinib studies performed at M.D. Anderson. "Dasatinib appeared to have more CCyRs than imatinib 400 mg/d at all time points (3, 6, and 12 months), and slightly higher CCyR rates than high-dose (800 mg/d) imatinib," he said. Similarly, he said, dasatinib appeared to have more MMRs at 6 and 12 months, compared with standard-dose imatinib. "However," Dr. Atallah said, "the MMR with high-dose imatinib was higher than with dasatinib."