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Dasatinib Proves Effective in Resistant CML

Dasatinib Proves Effective in Resistant CML

ATLANTA-First results of four phase II studies of the investigational oral, multitargeted kinase inhibitor dasatinib (BMS-354825) showed significant efficacy in imatinib (Gleevec) resistant and intolerant patients with chronic, accelerated, and blast phase (myeloid and lymphoid) chronic myeloid leukemia (CML). The studies were presented at the 47th Annual Meeting of the American Society of Hematology (ASH).

Dasatinib is several hundred times more active than imatinib and is non-cross-resistant with imatinib, said Francois Guilhot, MD, CHU La Miletrie, Poitiers, France, of the START Trial Study Group. The agent is active against 18 of 19 imatinib-resistant BCR-ABL mutants in vivo, and overcomes resistance conferred by SRC family kinase activation.

The START-A study, reported by Dr. Guilhot (abstract 39), evaluated complete and overall hematologic response rates in 107 Ph+ or BCR-ABL+ patients who progressed to accelerated phase CML on imatinib or who had to discontinue imatinib due to nonhematologic toxicity; 59% had been receiving 600 mg/d or more of ima-tinib. The open-label study was carried out at 39 international centers. Imatinib resistance was found in 93% of patients and mutations in 52%.

The intended dose of dasatinib was 70 mg twice daily, with dose escalations up to 100 mg twice daily allowed for less than optimal response. A complete hematologic response (CHR) was seen in 33% of patients, and no evidence of leukemia (NEL) in 26%, for a major hematologic response rate of 59%. At 2 to 10 months, all responders but one are still on study. A complete cytogenetic response (CCyR) was reported in 21% and a partial cytogenetic response (PCyR) in 9%, for a major cytogenetic response rate of 31%. No patients with the T315I mutation responded.

Grade 3-4 thrombocytopenia occurred in 79% of patients, and grade 3-4 neutropenia in 69%. Higher-grade nonhemato-logic toxicities were infrequent, with diarrhea most common among all grade toxicities (46%).

Dr. Guilhot concluded, "Dasatinib demonstrated significant efficacy in imatinib resistant and intolerant accelerated phase CML patients." He noted further that in patients with compromised bone marrow reserve, hematologic toxicities were "substantial but manageable."

START-B and START-L Trials

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