title: Phase 1/2 study of the combination of 5-aza-2'-deoxycytidine with valproic acid in patients with leukemia.
abstract: We conducted a phase 1/2 study of the combination of 5-aza-2'-deoxycytidine (decitabine) and the histone deacetylase inhibitor valproic acid (VPA) in patients with advanced leukemia, including older untreated patients. A group of 54 patients were treated with a fixed dose of decitabine (15 mg/m(2) by IV daily for 10 days) administered concomitantly with escalating doses of VPA orally for 10 days. A 50 mg/kg daily dose of VPA was found to be safe. Twelve (22%) patients had objective response, including 10 (19%) complete remissions (CRs), and 2 (3%) CRs with incomplete platelet recovery (CRp). Among 10 elderly patients with acute myelogenous leukemia or myelodysplastic syndrome, 5 (50%) had a response (4CRs, 1CRp's). Induction mortality was observed in 1 (2%) patient. Major cytogenetic response was documented in 6 of 8 responders. Remission duration was 7.2 months (range, 1.3-12.6+ months). Overall survival was 15.3 months (range, 4.6-20.2+ months) in responders. Transient DNA hypomethylation and global histone H3 and H4 acetylation were induced, and were associated with p15 reactivation. Patients with lower pretreatment levels of p15 methylation had a significantly higher response rate. In summary, this combination of epigenetic therapy in leukemia was safe and active, and was associated with transient reversal of aberrant epigenetic marks.
authors.affiliation: Department of Leukemia, Box 428, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA. ggarciam@mdanderson.org
authors.forename: Guillermo
authors.initials: G
authors.lastname: Garcia-Manero
authors.forename: Hagop M
authors.initials: HM
authors.lastname: Kantarjian
authors.forename: Blanca
authors.initials: B
authors.lastname: Sanchez-Gonzalez
authors.forename: Hui
authors.initials: H
authors.lastname: Yang
authors.forename: Gary
authors.initials: G
authors.lastname: Rosner
authors.forename: Srdan
authors.initials: S
authors.lastname: Verstovsek
authors.forename: Michael
authors.initials: M
authors.lastname: Rytting
authors.forename: William G
authors.initials: WG
authors.lastname: Wierda
authors.forename: Farhad
authors.initials: F
authors.lastname: Ravandi
authors.forename: Charles
authors.initials: C
authors.lastname: Koller
authors.forename: Lianchun
authors.initials: L
authors.lastname: Xiao
authors.forename: Stefan
authors.initials: S
authors.lastname: Faderl
authors.forename: Zeev
authors.initials: Z
authors.lastname: Estrov
authors.forename: Jorge
authors.initials: J
authors.lastname: Cortes
authors.forename: Susan
authors.initials: S
authors.lastname: O'brien
authors.forename: Elihu
authors.initials: E
authors.lastname: Estey
authors.forename: Carlos
authors.initials: C
authors.lastname: Bueso-Ramos
authors.forename: Jackie
authors.initials: J
authors.lastname: Fiorentino
authors.forename: Elias
authors.initials: E
authors.lastname: Jabbour
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Issa
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001374:Azacitidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D002648:Child; D002675:Child, Preschool; D019175:DNA Methylation / Q000187:drug effects; D000077209:Decitabine; D044127:Epigenesis, Genetic / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000378:metabolism; D006801:Humans; D007938:Leukemia / Q000150:complications / Q000188:drug therapy* / Q000401:mortality; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000188:drug therapy; D012074:Remission Induction / Q000379:methods; D016019:Survival Analysis; D014635:Valproic Acid / Q000008:administration & dosage* / Q000494:pharmacology
chemical_list: D056572:Histone Deacetylase Inhibitors; D006657:Histones; D014635:Valproic Acid; D000077209:Decitabine; D001374:Azacitidine