title: The histone deacetylase (HDAC) inhibitor valproic acid as monotherapy or in combination with all-trans retinoic acid in patients with acute myeloid leukemia.
abstract: BACKGROUND
  Valproic acid (VPA) inhibits histone deacetylase activity and, synergizing with all-trans retinoic acid (ATRA), achieves differentiation induction of myeloid blast cells in vitro.
  
  
  METHODS
  We used VPA in 58 patients with acute myeloid leukemia (AML) who were too old and/or medically unfit to receive intensive chemotherapy (32 AML secondary to myelodysplastic syndrome [MDS], 22 de novo AML, 4 AML secondary to myeloproliferative syndrome). VPA serum concentrations were 50-100 mug/mL. Thirty-one patients received VPA monotherapy. ATRA was added later in 13 patients who did not respond or who relapsed. Another 27 patients received VPA plus ATRA from the start. Median treatment duration was 93 days for VPA and 88 days for ATRA.
  
  
  RESULTS
  The response rate was only 5% according to International Working Group (IWG) criteria for AML but was 16% when IWG response criteria for MDS were used, which capture hematologic improvement and stabilization of the disease. These endpoints, which are not necessarily correlated with diminishing blast counts, are relevant for the patients' quality of life. Among 23 patients with a peripheral blast count > 5%, 6 (26%) showed a diminishing blast count, and 5 of these had a complete peripheral blast clearance.
  
  
  CONCLUSIONS
  Future trials should combine VPA with chemotherapy or demethylating agents.
authors.affiliation: Department of Hematology, Oncology, and Clinical Immunology, Heinrich-Heine-University, Dusseldorf, Germany. kuendgen@med.uni-duesseldorf.de
authors.forename: Andrea
authors.initials: A
authors.lastname: Kuendgen
authors.forename: Mathias
authors.initials: M
authors.lastname: Schmid
authors.forename: Richard
authors.initials: R
authors.lastname: Schlenk
authors.forename: Sabine
authors.initials: S
authors.lastname: Knipp
authors.forename: Barbara
authors.initials: B
authors.lastname: Hildebrandt
authors.forename: Christian
authors.initials: C
authors.lastname: Steidl
authors.forename: Ulrich
authors.initials: U
authors.lastname: Germing
authors.forename: Rainer
authors.initials: R
authors.lastname: Haas
authors.forename: Hartmut
authors.initials: H
authors.lastname: Dohner
authors.forename: Norbert
authors.initials: N
authors.lastname: Gattermann
mesh_terms: D000208:Acute Disease; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D005260:Female; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome; D014212:Tretinoin / Q000008:administration & dosage / Q000627:therapeutic use*; D014635:Valproic Acid / Q000008:administration & dosage / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D014212:Tretinoin; D014635:Valproic Acid