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Blood, 1 October 2007, Vol. 110, No. 7, pp. 2302-2308. Prepublished online as a Blood First Edition Paper on June 27, 2007; DOI 10.1182/blood-2007-03-078576. This Article Full Text (PDF) All Versions of this Article: blood-2007-03-078576v1 110/7/2302    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Soriano, A. O. Articles by Garcia-Manero, G. Search for Related Content PubMed PubMed Citation Articles by Soriano, A. O. Articles by Garcia-Manero, G. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted March 9, 2007 Accepted June 18, 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 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, and Guillermo Garcia-Manero* Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX, United States * Corresponding author; email: ggarciam{at}mdanderson.org. 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 I/II 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 x 7. VPA was dose-escalated and given orally daily x 7 concomitantly with 5-AZA. ATRA was given at 45 mg/m2 orally daily x 5, starting on day 3. Fifty three patients were treated. Their median age was 69 years (range 5-84). The maximum tolerated dose of VPA in this combination was 50 mg/kg daily x 7. 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). 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<0.005). In conclusion the combination studied is safe and has significant clinical activity. This clinical trial was registered at www.clinicaltrials.gov as #NCT00326170. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: G. Garcia-Manero, S. Assouline, J. Cortes, Z. Estrov, H. Kantarjian, H. Yang, W. M. Newsome, W. H. Miller Jr, C. Rousseau, A. Kalita, et al. Phase 1 study of the oral isotype specific histone deacetylase inhibitor MGCD0103 in leukemia Blood, August 15, 2008; 112(4): 981 - 989. [Abstract] [Full Text] [PDF] S. D. Nimer Myelodysplastic syndromes Blood, May 15, 2008; 111(10): 4841 - 4851. [Abstract] [Full Text] [PDF] G. Garcia-Manero, H. Yang, C. Bueso-Ramos, A. Ferrajoli, J. Cortes, W. G. Wierda, S. Faderl, C. Koller, G. Morris, G. Rosner, et al. Phase 1 study of the histone deacetylase inhibitor vorinostat (suberoylanilide hydroxamic acid [SAHA]) in patients with advanced leukemias and myelodysplastic syndromes Blood, February 1, 2008; 111(3): 1060 - 1066. [Abstract] [Full Text] [PDF]

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