Safety and clinical activity of the combination of 5-azacytidine, valproic acid, and all-trans retinoic acid in acute myeloid leukemia and myelodysplastic syndrome.

Abstract

The combination of a DNA hypomethylating agent with a histone deacetylase inhibitor has synergistic antileukemia activity and may restore sensitivity to all-trans retinoic acid (ATRA). We conducted a phase 1/2 study of the combination of 5-azacitidine (5-AZA), valproic acid (VPA), and ATRA in patients with acute myeloid leukemia or high-risk myelodysplastic syndrome. 5-AZA was administered subcutaneously at a fixed dose of 75 mg/m(2) daily for 7 days. VPA was dose-escalated and given orally daily for 7 days concomitantly with 5-AZA. ATRA was given at 45 mg/m(2) orally daily for 5 days, starting on day 3. A total of 53 patients were treated. Their median age was 69 years (range, 5-84 years). The maximum tolerated dose of VPA in this combination was 50 mg/kg daily for 7 days. Dose-limiting toxicity was reversible neurotoxicity. The overall response rate was 42%. In previously untreated older patients, the response rate was 52%. Median number of courses to response was 1 (range, 1-3 courses). Median remission duration was 26 weeks, and median survival has not been reached. A significant decrease in global DNA methylation and induction of histone acetylation were achieved. VPA blood levels were higher in responders (P < .005). In conclusion, the combination studied is safe and has significant clinical activity. This clinical trial was registered at www.clinicaltrials.gov as no. NCT00326170.

• Authors: Andres O Soriano, Hui Yang, Stefan Faderl, Zeev Estrov, Francis Giles, Farhad Ravandi, Jorge Cortes, William G Wierda, Souzanne Ouzounian, Andres Quezada, Sherry Pierce, Elihu H Estey, Jean-Pierre J Issa, Hagop M Kantarjian, Guillermo Garcia-Manero
• Journal: Blood (Blood) Vol. 110 Issue 7 Pg. 2302-8 (Oct 01 2007) ISSN: 0006-4971 [Print] United States
• PMID: 17596541 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Histones
• RNA, Messenger
• Tretinoin
• Valproic Acid
• Azacitidine

Topics

• Acetylation
• Adolescent
• Adult
• Aged
• Aged, 80 and over
• Azacitidine (adverse effects, therapeutic use)
• Child
• Child, Preschool
• DNA Methylation
• Dose-Response Relationship, Drug
• Drug Therapy, Combination
• Drug-Related Side Effects and Adverse Reactions
• Gene Expression Regulation
• Histones (metabolism)
• Humans
• Leukemia, Myeloid, Acute (drug therapy, genetics, metabolism, pathology)
• Middle Aged
• Myelodysplastic Syndromes (drug therapy, genetics, metabolism, pathology)
• RNA, Messenger (genetics)
• Tretinoin (adverse effects, therapeutic use)
• Valproic Acid (adverse effects, therapeutic use)