title: 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.affiliation: Department of Leukemia, University of Texas M D Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Andres O
authors.initials: AO
authors.lastname: Soriano
authors.forename: Hui
authors.initials: H
authors.lastname: Yang
authors.forename: Stefan
authors.initials: S
authors.lastname: Faderl
authors.forename: Zeev
authors.initials: Z
authors.lastname: Estrov
authors.forename: Francis
authors.initials: F
authors.lastname: Giles
authors.forename: Farhad
authors.initials: F
authors.lastname: Ravandi
authors.forename: Jorge
authors.initials: J
authors.lastname: Cortes
authors.forename: William G
authors.initials: WG
authors.lastname: Wierda
authors.forename: Souzanne
authors.initials: S
authors.lastname: Ouzounian
authors.forename: Andres
authors.initials: A
authors.lastname: Quezada
authors.forename: Sherry
authors.initials: S
authors.lastname: Pierce
authors.forename: Elihu H
authors.initials: EH
authors.lastname: Estey
authors.forename: Jean-Pierre J
authors.initials: JP
authors.lastname: Issa
authors.forename: Hagop M
authors.initials: HM
authors.lastname: Kantarjian
authors.forename: Guillermo
authors.initials: G
authors.lastname: Garcia-Manero
mesh_terms: D000107:Acetylation; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001374:Azacitidine / Q000009:adverse effects / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D019175:DNA Methylation; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D064420:Drug-Related Side Effects and Adverse Reactions; D005786:Gene Expression Regulation; D006657:Histones / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D014212:Tretinoin / Q000009:adverse effects / Q000627:therapeutic use*; D014635:Valproic Acid / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D006657:Histones; D012333:RNA, Messenger; D014212:Tretinoin; D014635:Valproic Acid; D001374:Azacitidine