Valproic acid in combination with all-trans retinoic acid and intensive therapy for acute myeloid leukemia in older patients
Michela Tassara, Konstanze Döhner, Peter Brossart, Gerhard Held, Katharina Götze, Heinz-A Horst, Mark Ringhoffer, Claus-Henning Köhne, Stephan Kremers, Aruna Raghavachar, Gerald Wulf, Heinz Kirchen, David Nachbaur, Hans Günter Derigs, Mohammed Wattad, Elisabeth Koller, Wolfram Brugger, Axel Matzdorff, Richard Greil, Gerhard Heil, Peter Paschka, Verena I Gaidzik, Martin Göttlicher, Hartmut Döhner, Richard F Schlenk, Michela Tassara, Konstanze Döhner, Peter Brossart, Gerhard Held, Katharina Götze, Heinz-A Horst, Mark Ringhoffer, Claus-Henning Köhne, Stephan Kremers, Aruna Raghavachar, Gerald Wulf, Heinz Kirchen, David Nachbaur, Hans Günter Derigs, Mohammed Wattad, Elisabeth Koller, Wolfram Brugger, Axel Matzdorff, Richard Greil, Gerhard Heil, Peter Paschka, Verena I Gaidzik, Martin Göttlicher, Hartmut Döhner, Richard F Schlenk
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.
© 2014 by The American Society of Hematology.
Source: PubMed