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

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

Research output: Contribution to journalArticle

332 Scopus citations

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/m2 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/m2 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.

Original languageEnglish (US)
Pages (from-to)2302-2308
Number of pages7
JournalBlood
Volume110
Issue number7
DOIs
StatePublished - Oct 1 2007
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Soriano, A. O., Yang, H., Faderl, S., Estrov, Z., Giles, F., Ravandi, F., Cortes, J., Wierda, W. G., Ouzounian, S., Quezada, A., Pierce, S., Estey, E. H., Issa, J. P. J., Kantarjian, H. M., & Garcia-Manero, G. (2007). Safety and clinical activity of the combination of 5-azacytidine, valproic acid, and all-trans retinoic acid in acute myeloid leukemia and myelodysplastic syndrome. Blood, 110(7), 2302-2308. https://doi.org/10.1182/blood-2007-03-078576