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Dasatinib Responses Durable in Chronic‐Phase CML Patients Resistant or Intolerant to Imatinib

sponses induced by the secondgeneration tyrosine kinase inhibitor dasatinib remain durable in patients with chronic-phase chronic myelogenous leukemia (CML) resistant or intolerant to imatinib, according to data reported here at the ASH Annual Meeting. “Dasatinib is the stepchild of the important discovery of imatinib, which has led to a tremendous change in the treatment of CML,” said Richard M. Stone, MD, Clinical Director of the Adult Leukemia Program at DanaFarber Cancer Institute, who presented the data at an oral session. However, the most recent percentages show that about 5% to 7% of CML patients are intolerant to imatinib, and about 10% are resistant to the drug. “Imatinib resistance and intolerance in chronic-phase CML are of increasing clinical relevance. About one-third—31 percent—of patients in the IRIS [International Randomized Study of Interferon vs STI-571 (imatinib)] trial discontinued imatinib within five years, and more than half of these discontinuations were due to resistance or intolerance,” he said. Dasatinib is the most potent BCRABL inhibitor—325 times more potent than imatinib and 16 times more potent in vitro than nilotinib—and binds to BCR-ABL in both inactive and active oncogenic conformations. Dr. Stone reported the extended follow-up of the START-C trial, a 75center, international study of dasatinib in 387 patients—288 resistant to imatinib and 99 intolerant to imatinib. Dasatinib was administered on a 70mg BID regimen; dose escalation to 90 mg twice-daily was allowed for lack of response or reductions to 50 or 40 mg BID due to toxicity. The median time from diagnosis was 61 months. Prior therapy included interferon in 65% of patients and stem-cell transplantation in 10%; 55% had received prior imatinib doses of more than 600 mg and 53% had been treated with imatinib for more than three years. The best response to prior imatinib was complete hematologic response in 82% of patients, major cytogenetic response in 37% of patients, complete cytogenetic response in 19% of patients, and partial cytogenetic response in 18% of patients. After a median follow-up of 24 months, a major cytogenetic response was attained in 62% of patients (55% imatinib-resistant, 78% imatinib-intolerant) and a complete cytogenetic response in 53% of patients (45% imatinib-resistant; 78% imatinib-intolerant). For patients with no prior major cytogenetic response to imatinib, 85% achieved a major cytogenetic response with dasatinib. A major cytogenetic response rate of 52% was recorded for patients with baseline BCR-ABL mutations, and responses were seen across all mutations with the exception of T315I. Dr. Stone said the major cytogenetic responses were durable, with 88% of patients without a loss of response at 24 months. “There were few relapses, (continued on page 18) Dasatinib Responses Durable in Chronic-Phase CML Patients Resistant or Intolerant to Imatinib