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In a randomized open-label phase II clinical trial (START-R) presented at the 42nd Annual Meeting of the American Society of Clinical Oncology (abstract 6507), the oral multitargeted kinase inhibitor dasatinib achieved major cytogenetic responses in 35% of patients with chronic myeloid leukemia (CML) in chronic phase who had resistance or intolerance to imatinib (Gleevec) (aee also report on page 1 on FDA approval of dasatinib).
ATLANTAIn a randomized open-label phase II clinical trial (START-R) presented at the 42nd Annual Meeting of the American Society of Clinical Oncology (abstract 6507), the oral multitargeted kinase inhibitor dasatinib achieved major cytogenetic responses in 35% of patients with chronic myeloid leukemia (CML) in chronic phase who had resistance or intolerance to imatinib (Gleevec) (aee also report on page 1 on FDA approval of dasatinib). "Imatinib 400 mg daily is certainly frontline medical therapy for chronic phase CML," said Neil P. Shah, MD, PhD. At the time of the study, Dr. Shah was with the UCLA School of Medicine and now is with the University of California, San Francisco.
About 16% of patients with chronic phase CML who receive imatinib as initial therapy have a relapse or progression within 42 months, he said, and roughly 14% of patients do not achieve a major cytogenetic response after taking the drug for a year at the 400 mg daily dose.
"Treatment options for relapse and suboptimally responding patients are reasonably limited," he noted. One strategy has been to escalate the imatinib dose to 800 mg daily. Although this can be effective, he said, responses are not always durable, and some patients cannot tolerate this high dose.
In START-R, patients with imatinib resistance (either primary or acquired) at a dose of 400 to 600 mg/d were randomly assigned in a 2:1 ratio to treatment with dasatinib (70 mg twice daily) or high-dose imatinib (400 mg twice daily). After 12 weeks, patients who did not have a response, progressed, or developed intolerance were allowed to cross over to the other arm. The trial, Dr. Shah noted, was designed to estimate the efficacy of dasatinib and was therefore not powered to detect significant differences.
Analyses were based on 101 patients in the dasatinib arm and 49 patients in the imatinib arm who had follow-up of at least 3 months. At baseline, the median duration of CML was about 5 years. Two-thirds of patients had previously received an imatinib dose of higher than 400 mg/d, and about 40% of patients had taken the drug for more than 3 years. Mutations of Bcr-Abl were more common in the dasatinib group than in the imatinib group (45% vs 22%).
Major Cytogenetic Responses
Twelve weeks after starting therapy, the proportion of patients who had a major cytogenetic response, the study's primary endpoint, was similar in the dasatinib and imatinib arms (35% vs 29%). However, a larger proportion of patients in the dasatinib arm had a complete cytogenetic response (21% vs 8%), Dr. Shah said, noting that deeper responses have been associated with a lower rate of progression in this disease.
In subgroup analyses, the proportion of patients with a major cytogenetic response was higher with dasatinib than with imatinib among patients who had previously received interferon (39% vs 24%) and imatinib at a dose of 600 mg/d (35% vs 21%), and among patients who had never had a cytogenetic response (23% vs 0%).
In patients with P-loop mutations at baseline, 37% of those treated with dasatinib had a major cytogenetic response vs none treated with imatinib. In patients who did not have a Bcr-Abl mutation at baseline, about a third of patients in each treatment group had such a response, but the proportion that had a complete cytogenetic response was higher with dasatinib than with imatinib (25% vs 9%). "This I think maybe speaks to the potency of dasatinib vs imatinib, which may be important in effecting deeper responses, as we would have predicted," Dr. Shah said. None of the patients studied had the highly resistant T315I mutation at baseline, he noted.
Only 15% of dasatinib-treated patients experienced a progression or crossed over because of intolerance, compared with 76% of their imatinib-treated counterparts. Among 19 patients who crossed over from imatinib to dasatinib, 8 (42%) had a major cytogenetic response (half were complete responses); in contrast, among 4 patients who crossed over from dasatinib to imatinib, none had a major cytogenetic response.
The dasatinib patients had higher rates of grade 3-4 neutropenia (58% vs 38%) and thrombocytopenia (54% vs 14%). "In my opinion, in this disease with this drug, this is a reflection of activity of dasatinib essentially eliminating bcr-abl-dependent hematopoiesis," Dr. Shah commented. "Many of these patients probably have very little in the way of bcr-abl-negative hematopoietic progenitors, and as a result, [dasatinib] unmasks cytopenias quite early." He emphasized that there were no individual grade 3-4 nonhematologic drug-related adverse events that occurred in more than 5% of patients in either arm.
"Dasatinib represents an effective alterative to 800 mg of imatinib in patients resistant to 400 to 600 mg of imatinib," Dr. Shah concluded. "Longer follow-up is obviously necessary to allow for a more definitive understanding of the frequency and durability of these responses."