title: Valproic acid in combination with all-trans retinoic acid and intensive therapy for acute myeloid leukemia in older patients.
abstract: The outcome of patients with acute myeloid leukemia who are older than 60 years has remained poor because of unfavorable disease characteristics and patient-related factors. The randomized German-Austrian AML Study Group 06-04 protocol was designed on the basis of in vitro synergistic effects of valproic acid (VPA) and all-trans retinoic acid with chemotherapy. Between 2004 and 2006, 186 patients were randomly assigned to receive 2 induction cycles with idarubicin, cytarabine, and all-trans retinoic acid either with VPA or without (STANDARD). In all patients, consolidation therapy was intended. Complete remission rates after induction tended to be lower in VPA compared with STANDARD (40% vs 52%; P = .14) as a result of a higher early death rate (26% vs 14%; P = .06). The main toxicities attributed to VPA were delayed hematologic recovery and grade 3/4 infections, observed predominantly during the second induction cycle. After restricting VPA to the first induction cycle and reducing the dose of idarubicin, these toxicities dropped to rates observed in STANDARD. After a median follow-up time of 84 months, event-free and overall survival were not different between the 2 groups (P = .95 and P = .57, respectively). However, relapse-free-survival was significantly superior in VPA compared with STANDARD (24.4% vs 6.4% at 5 years; P = .02). Explorative subset analyses revealed that AML with mutated Nucleophosmin 1 (NPM1) may particularly benefit from VPA. This trial was registered at www.clinicaltrials.gov as #NCT00151255.
authors.affiliation: Department of Internal Medicine III, University of Ulm, Ulm, Germany; Istituto di Ricovero e Cura a Carattere Scientifico Ospedale San Raffaele, Milano, Italy;
authors.forename: Michela
authors.initials: M
authors.lastname: Tassara
authors.affiliation: Department of Internal Medicine III, University of Ulm, Ulm, Germany;
authors.forename: Konstanze
authors.initials: K
authors.lastname: Döhner
authors.affiliation: Department of Internal Medicine III, University Hospital of Bonn, Bonn, Germany;
authors.forename: Peter
authors.initials: P
authors.lastname: Brossart
authors.affiliation: Department of Internal Medicine, University of Saarland, Homburg, Germany;
authors.forename: Gerhard
authors.initials: G
authors.lastname: Held
authors.affiliation: Department of Internal Medicine III, University of Munich, Munich, Germany;
authors.forename: Katharina
authors.initials: K
authors.lastname: Götze
authors.affiliation: Department of Internal Medicine II, University Hospital Schleswig-Holstein Kiel, Kiel, Germany;
authors.forename: Heinz-A
authors.initials: HA
authors.lastname: Horst
authors.affiliation: Department of Internal Medicine III, Städtisches Klinikum Karlsruhe, Karlsruhe, Germany;
authors.forename: Mark
authors.initials: M
authors.lastname: Ringhoffer
authors.affiliation: Department of Oncology and Hematology, University Clinic Oldenburg, Oldenburg, Germany;
authors.forename: Claus-Henning
authors.initials: CH
authors.lastname: Köhne
authors.affiliation: Department of Internal Medicine, Caritas-Krankenhaus, Lebach, Germany;
authors.forename: Stephan
authors.initials: S
authors.lastname: Kremers
authors.affiliation: Department of Internal Medicine I, HELIOS Klinikum Wuppertal, Wuppertal, Germany;
authors.forename: Aruna
authors.initials: A
authors.lastname: Raghavachar
authors.affiliation: Department of Hematology and Oncology, University Hospital of Göttingen, Göttingen, Germany;
authors.forename: Gerald
authors.initials: G
authors.lastname: Wulf
authors.affiliation: Department of Internal Medicine I, Krankenhaus der Barmherzigen Brüder, Trier, Germany;
authors.forename: Heinz
authors.initials: H
authors.lastname: Kirchen
authors.affiliation: Department of Internal Medicine V, University Hospital Innsbruck, Innsbruck, Austria;
authors.forename: David
authors.initials: D
authors.lastname: Nachbaur
authors.affiliation: Departmant of Internal Medicine III, Klinikum Frankfurt Höchst, Frankfurt, Germany;
authors.forename: Hans Günter
authors.initials: HG
authors.lastname: Derigs
authors.affiliation: Department of Hematology and Oncology, Kliniken Essen Süd, Essen, Germany;
authors.forename: Mohammed
authors.initials: M
authors.lastname: Wattad
authors.affiliation: Department of Internal Medicine III, Hanuschkrankenhaus, Vienna, Austria;
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Koller
authors.affiliation: Department of Internal Medicine II, Schwarzwald-Baar Klinikum, Villingen-Schwenningen, Germany;
authors.forename: Wolfram
authors.initials: W
authors.lastname: Brugger
authors.affiliation: Department of Hematology/Oncology, Caritasklinikum Saarbrücken, St. Theresia, Germany;
authors.forename: Axel
authors.initials: A
authors.lastname: Matzdorff
authors.affiliation: Department of Internal Medicine III, University Hospital Salzburg, Austria;
authors.forename: Richard
authors.initials: R
authors.lastname: Greil
authors.affiliation: Department of Hematology/Oncology, Klinikum Lüdenscheid, Lüdenscheid, Germany; and.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Heil
authors.affiliation: Department of Internal Medicine III, University of Ulm, Ulm, Germany;
authors.forename: Peter
authors.initials: P
authors.lastname: Paschka
authors.affiliation: Department of Internal Medicine III, University of Ulm, Ulm, Germany;
authors.forename: Verena I
authors.initials: VI
authors.lastname: Gaidzik
authors.affiliation: Department of Toxicology, Helmholtz-Zentrum, München, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Göttlicher
authors.affiliation: Department of Internal Medicine III, University of Ulm, Ulm, Germany;
authors.forename: Hartmut
authors.initials: H
authors.lastname: Döhner
authors.affiliation: Department of Internal Medicine III, University of Ulm, Ulm, Germany;
authors.forename: Richard F
authors.identifier: http://orcid.org/0000-0002-5298-3120
authors.initials: RF
authors.lastname: Schlenk
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D003422:Critical Care / Q000379:methods*; D003561:Cytarabine / Q000008:administration & dosage / Q000819:agonists; D018572:Disease-Free Survival; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015255:Idarubicin / Q000008:administration & dosage / Q000819:agonists; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics; D000090243:Nucleophosmin; D015996:Survival Rate; D014212:Tretinoin / Q000008:administration & dosage* / Q000819:agonists; D014635:Valproic Acid / Q000008:administration & dosage* / Q000819:agonists
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D003561:Cytarabine; D000090243:Nucleophosmin; D014212:Tretinoin; D014635:Valproic Acid; D015255:Idarubicin