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.

The updated study results also showed that the percentage of patients achieving a complete cytogenetic remission (CCyR) in the dasatinib treatment arm increased from 22% at 3 months to 40% at 15 months, whereas the CCyR rate in the patients treated with high-dose imatinib was 8% at 3 months and 16% at 15 months.

Major molecular remission was reported in 16% of the dasatinib group vs 4% of the high-dose imatinib group. For dasatinib, the median duration of response was 13.7 months vs 3.1 months with imatinib.

Dr. Shah noted that CCyRs with dasatinib occurred in a substantial proportion of patients, irrespective of prior cytogenetic response, whereas CCyRs with imatinib were most common in patients who had previously had a cytogenetic response on imatinib.

MCyRs achieved on dasatinib were highly durable, Dr. Shah said. While 10 of 49 patients progressed in the imatinib group, only 6 of 101 progressed in the dasatinib group (P < .0001). Progression was defined as the development of AP or BP disease, loss of a complete hematologic response or MCyR, or increasing leukocytosis.

Although grade 3-4 nonhematologic side effects were similar for both groups, grade 3-4 cytopenias were more common with dasatinib. Neutropenia was reported in 59% and 39% for dasatinib and imatinib, respectively, and thrombocytopenia in 55% and 14%, respectively. Low rates of grade 3-4 pleural effusion and pulmonary edema were observed in the dasatinib group only.

Dr. Shah concluded, "Dasatinib is superior to imatinib 800 mg in terms of progression-free survival . . . and the overall benefit-risk assessment favors dasatinib relative to imatinib 800 mg in this patient population." The safety profile of dasatinib, he said, was acceptable and consistent with prior studies.