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Dasatinib Superior to High-Dose Imatinib in Resistant CML

Dasatinib Superior to High-Dose Imatinib in Resistant CML

ORLANDO—When patients with chronic phase chronic myeloid leukemia (CP-CML) receiving imatinib (Gleevec) progress to accelerated phase (AP) or blast phase (BP), their prognosis is poor. In a clinical trial (START-R) involving CP-CML patients with disease resistant to doses of imatinib up to 600 mg/d, progression-free survival (PFS), using a broad definition of progression, was greater for those switching to dasatinib (Sprycel), compared with those receiving imatinib dose escalation (800 mg/d).

Neil Shah, MD, PhD, of the Division of Hematology/Oncology, University of California, San Francisco, Comprehensive Cancer Center, reported the results at the 48th Annual Meeting of the American Society of Hematology (abstract 167). The report updated the 3-month results presented at ASCO 2006. Dasatinib is an approved oral multi-targeted kinase inhibitor that blocks Bcr-Abl in vitro about 300-fold more powerfully than imatinib, he said.

Dr. Shah noted that, based on experience from the IRIS trial, 31% of CP-CML patients discontinue imatinib therapy within 5 years. He said that about 16% of CP patients lose an established response or progress to AP or BP after 42 months. Fifteen percent of CP patients fail to achieve a major cytogenetic response (MCyR) after 12 months of imatinib therapy, and have a significantly increased risk of disease progression. While increasing Bcr-Abl inhibition by escalating the imatinib dose to 800 mg can be effective in some patients with resistant disease, intolerance to the higher dose can occur, and, typically, clinical responses are not durable.

150 CP-CML Patients

In Dr. Shah's international, randomized, open-label, phase II trial, 150 CP-CML patients (median age, 51 years) who were resistant to imatinib at doses of 400 to 600 mg/d were randomized 2:1 to dasatinib 70 mg twice daily or imatinib 400 mg twice daily.

Dasatinib dose escalations to 90 mg twice daily were allowed at 12 weeks with disease progression, and dose reductions to 50 or 40 mg twice daily were allowed with toxicity, Dr. Shah said. Imatinib doses could be reduced to 600 mg/d among patients who experienced toxicity at 800 mg/d and had not previously received 600 mg/d.

Crossovers were allowed for disease progression, failure to achieve major cytogenetic response, or intolerance. The median follow-up was 15 months. The median average daily doses for the dasatinib and imatinib groups, respectively, were 103 mg and 796 mg.

A higher percentage of dasatinib-treated patients achieved and maintained MCyR, compared with imatinib, according to analyses at both 3 and 15 months. At 3 months, 36% of the dasatinib group had achieved MCyR, which increased to 53% at 15 months. In the high-dose imatinib group, 29% had achieved MCyR at 3 months, which increased to 33% at 15 months.

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