Valproic acid in combination with all-trans retinoic acid and intensive therapy for acute myeloid leukemia in older patients

Blood. 2014 Jun 26;123(26):4027-36. doi: 10.1182/blood-2013-12-546283. Epub 2014 May 5.

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.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents / administration & dosage*
  • Critical Care / methods*
  • Cytarabine / administration & dosage
  • Cytarabine / agonists
  • Disease-Free Survival
  • Drug Synergism
  • Enzyme Inhibitors / administration & dosage*
  • Female
  • Follow-Up Studies
  • Humans
  • Idarubicin / administration & dosage
  • Idarubicin / agonists
  • Leukemia, Myeloid, Acute / drug therapy*
  • Leukemia, Myeloid, Acute / genetics
  • Leukemia, Myeloid, Acute / mortality*
  • Male
  • Middle Aged
  • Mutation
  • Nuclear Proteins / genetics
  • Survival Rate
  • Tretinoin / administration & dosage*
  • Tretinoin / agonists
  • Valproic Acid / administration & dosage*
  • Valproic Acid / agonists

Substances

  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Nuclear Proteins
  • Cytarabine
  • nucleophosmin
  • Tretinoin
  • Valproic Acid
  • Idarubicin

Associated data

  • ClinicalTrials.gov/NCT00151255