Journal
CLINICAL CANCER RESEARCH
Volume 14, Issue 24, Pages 8295-8301Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-08-0999
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Purpose: The outcome of patients with refractory leukemia and myelodysplasia is poor, and new therapies are needed. The antiapoptotic proteins of the Bcl-2 family are overexpressed in these malignancies and are potential therapeutic targets. Therefore, we conducted a phase I clinical trial of the small-molecule pan-Bcl-2 inhibitor, obatoclax mesylate, in patients with refractory leukemia and myelodysplasia to assess its safety and define its optimal dose. Experimental Design: Forty-four patients with refractory leukemia or myelodysplasia were treated with obatoclax mesylate by continuous intravenous infusion at increasing doses and frequencies. Results: A total of 306 infusions of obatoclax mesylate were administered with a median of 5 infusions per patient. The study drug was well tolerated up to the highest dose planned without dose-limiting toxicity. Grade 1/2 central nervous system symptoms were the most common adverse events attributable to the study drug. One patient with acute myeloid leukemia with mixed lineage leukemia t(9;11) rearrangement achieved a complete remission, which lasted 8 months. Three of 14 patients with myelodysplasia showed hematologic improvement with RBC or platelet transfusion independence. Conclusions: Obatoclax mesylate is well tolerated and these results support its further investigation in patients with leukemia and myelodysplasia.
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