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Dasatinib Shows Greater Efficacy Than Very High-Dose Imatinib for Imatinib-Resistant Chronic-Phase Myelogenous Leukemia (CML) Patients: Presented at ASCO

By Bruce Sylvester

ATLANTA, G.A. -- June 5, 2006 -- Interim data from a randomized, phase 2 study of dasatinib (140 mg/day) shows higher response rates versus imatinib (Gleevec) 800 mg/day in patients with chronic-phase myelogenous leukemia (CML) resistant to imatinib at doses of 600 mg/day or greater.

The data were presented in an oral session here on June 3^rd at the American Society of Clinical Oncology 2006 Annual Meeting (ASCO).

The FDA approved the 400-mg/day dose of imatinib for CML.

Lead investigator and presenter Neil Shah, MD, PhD, assistant professor of hematology and oncology, University of California at San Francisco, San Francisco, California, reported the comparison study on June 4^th.

"Dasatinib is an effective alternative to 800-mg daily imatinib in patients who do not respond to 400- to 600-mg daily dosing of imatinib," he said. "Notably, the percentage of patients showing a complete cytogenetic response to dasatinib was 21% compared to 8% for higher-dose imatinib."

For this multicenter trial, investigators enrolled 150 patients with chronic-phase CML that was resistant to imatinib. They were randomized in a 2:1 ratio to dasatinib 140 mg/day (n = 101) or imatinib 800 mg/day (n = 49).

The primary endpoint of the study was major cytogenetic response at 12 weeks, defined both as a complete cytogenic response (no signs of Philadelphia-chromosome positive cells in the bone marrow) and a partial cytogenic response of < 35% of Ph+ cells in bone marrow.

Results show that 35% of subjects on dasatinib achieved a major cytogenetic response (21% complete) compared with 29% of subjects on high-dose imatinib (8% complete).

In the event of disease progression or intolerable toxicity, the design of the trial permitted subjects to continue on their initial drug treatment or crossover to the other drug at week 12. The researchers reported that 6% of dasatinib-treated patients and 73% of imatinib-treated patients crossed over to the opposite treatment arm.

At the time of the interim analysis of data, 19 of the patients who crossed over from imatinib to dasatinib were evaluable. The researchers reported that 8 of these patients had achieved a major cytogenetic response (4 were complete responders) and none of the 4 evaluable patients who had switched from dasatinib to imatinib achieved a major cytogenetic response.

Nonhematologic adverse effects in the dasatinib arm included diarrhea (26%), fluid retention (25%), nausea (21%), bleeding (17%), and vomiting (6%). In the imatinib arm these were fluid retention (43%), nausea (31%), diarrhea (29%), vomiting (22%), and bleeding (8%).

Grade 3 or 4 cytopenia in the dasatinib arm included low absolute neutrophil white blood cells (58%), platelets (54%), and hemoglobin (9%). In the imatinib group grade 3 or 4 cytopenia included low absolute neutrophil white blood cells (38%), platelets (14%), and hemoglobin (8%).

In a presentation on June 2^nd during the ASCO meeting, the Food and Drug Administration (FDA)'s Oncologic Drugs Advisory Committee (ODEC) recommended approval of dasatinib for the treatment of adults in all phases of chronic myeloid leukemia (accelerated, lymphoid blast, and myeloid blast) with resistance or intolerance to prior therapy, including Gleevec.

The committee also recommended full approval of dasatinib for the treatment of adults with Philadelphia chromosome-positive acute lymphoblastic leukemia with resistance or intolerance to imatinib.

The recommendation will now go to the FDA for final approval. Previously, the FDA granted a priority review to dasatinib. Based on the priority review timeline, the FDA's action date for the new drug application (NDA) is June 28, 2006.

The research was supported by Bristol-Myers Squibb.


[Presentation title: Dasatinib (D) vs High Dose Imatinib (IM) in Patients (pts) With Chronic Phase Chronic Myeloid Leukemia (CP-CML) Resistant to Imatinib. Results of CA180017 START-R Randomized Trial. Abstract 6507]

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