PHASE-I CLINICAL-TRIAL OF 13-CIS-RETINOIC ACID IN MYELODYSPLASTIC SYNDROMES

Abstract

13-cis-Retinoic acid (13-cRA) induces maturation and differentiation of neoplastic myeloid cell lines in vitro. A phase I clinical trial of 13-cRA in patients with myelodysplastic syndromes (MDS) was conducted using a single daily oral dose schedule. Seventeen patients with MDS and one each with acute nonlymphoblastic leukemia and chronic myelogenous leukemia in blast crisis were treated with 13-cRA at doses ranging from 20-125 mg/m2 per day. Hepatotoxicity was dose-limiting and was manifested by hyperbilirubinemia and increased SGOT [serum glutamic oxalacetic transaminase] levels. This effect was seen only at the highest dose level of 125 mg/m2 per day and was completely reversible upon cessation of the drug. Other toxic effects were mild, and included cheilosis, hyperkeratosis, stomatitis and elevation of serum triglyceride levels. Fifteen patients with MDS were evaluable for therapeutic response. Five patients showed improvement in hematologic parameters. These responses included normalization of bone marrow blast count and increases in leukocyte count, platelet count, and/or Hb concentration. Responses were generally not seen until at least 3 wk of therapy were completed. Further study of 13-cRA in myelodysplastic syndromes is warranted and it is recommended that future studies utilize a starting dose of 100 mg/m2.