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A Phase I Study of Bexarotene, a Retinoic X Receptor Agonist, in Non-M3 Acute Myeloid Leukemia

Authors' Affiliations: ¹ Abramson Cancer Center and ² Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania

Requests for reprints: Donald E. Tsai, 16 Penn Tower, 3400 Spruce Street, Philadelphia, PA 19104. Phone: 215-614-0037; Fax: 215-662-4064; E-mail: detsai{at}mail.med.upenn.edu.

Purpose: Bexarotene is a retinoic X receptor agonist that has been shown in vitro to inhibit growth and induce differentiation of myeloid leukemic cell lines. We therefore conducted a phase I dose escalation study to assess the maximum tolerated dose, toxicities, and activity of bexarotene in patients with non-M3 acute myeloid leukemia (AML).

Experimental Design: We enrolled patients with active non-M3 AML who had either relapsed or refractory disease or were not eligible for standard cytotoxic chemotherapy. Cohorts of three to six patients received escalating doses of daily oral bexarotene ranging from 100 to 400 mg/m² until evidence of disease progression or unacceptable adverse events occurred.

Results: Twenty-seven patients, with median age of 69 years (range, 51-82 years), were treated. Twenty-four (89%) patients had undergone prior chemotherapy. At the highest dose level tested (400 mg/m²), three of six patients had to reduce their dose of bexarotene due to grade 3 adverse events. The maximum tolerable dose of bexarotene was determined to be 300 mg/m². Clinical activity was manifested by 4 (15%) patients with reduction in bone marrow blasts to 5%, 11 (41%) patients with improved platelet counts, and 7 (26%) patients with improved neutrophil counts. Three patients with relapsed AML survived >1 year while taking bexarotene. Leukemic blast differentiation was suggested by the presence of the leukemic cytogenetic abnormality in mature circulating granulocytes and the occurrence of differentiation syndrome.

Conclusions: The recommended dose of bexarotene for future studies is 300 mg/m²/d. Bexarotene is well tolerated in patients with non-M3 AML and has evidence of antileukemic activity.

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