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

Outcome of AML patients older than 60 years has remained poor due to unfavorable disease characteristics and patient-related factors. The randomized AMLSG 06-04 protocol was designed based on in vitro synergistic effects of valproic acid (VPA) and all-trans retinoic acid (ATRA) with chemotherapy. Between 2004 and 2006, 186 patients were randomized to receive 2 induction cycles with idarubicin, cytarabine and ATRA with VPA (VPA) or without (STANDARD). In all patients consolidation therapy was intended. Complete remission rates after induction tended to be lower in VPA compared to STANDARD (40% vs. 52%; p=0.14) due to a higher early death rate (26% vs. 14%; p=0.06). 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 two arms (p=0.95 and p=0.57, respectively). However, relapse-free-survival was significantly superior in VPA compared to STANDARD (24.4% vs. 6.4% at 5 years, p=0.02). Explorative subset analyses revealed that AML with mutated NPM1 may particularly benefit from VPA. This study was registered at clinicaltrials.gov, identifier: NCT00151255.