title: Clinical trial of valproic acid and all-trans retinoic acid in patients with poor-risk acute myeloid leukemia.
abstract: BACKGROUND
  Valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, induced in vitro differentiation of primary acute myeloid leukemia (AML) blasts, an effect enhanced by all-trans retinoic acid (ATRA). Clinical responses to VPA were recently observed in patients with myelodysplastic syndrome (MDS). Herein, the authors have described results of a clinical trial with VPA plus ATRA in 26 patients with poor-risk AML.
  
  
  METHODS
  VPA (5-10 mg/kg starting dose) and ATRA (45 mg/m(2)) were administered orally. Low-dose AraC or hydroxyurea were permitted to control leukocytosis. Biologic activity of VPA was confirmed by serial analysis of HDAC2 protein levels in peripheral blood (PB) mononuclear cells.
  
  
  RESULTS
  Nineteen of 26 patients completed at least 4 weeks of VPA/ATRA treatment; 7 patients were withdrawn prematurely because of rapidly progressive disease (n = 3) or unacceptable neurologic and cardiovascular toxicity (n = 4). Additional cytoreductive treatment was required in 58% of patients enrolled. Median treatment duration was 3 months. No patient achieved complete remission, one with de novo AML had a minor response, and two patients with secondary AML arising from myeloproliferative disorder (MPD) achieved a partial remission and clearance of PB blasts, respectively. The latter responses were accompanied by profound granulocytosis and erythrocytosis in both patients, reminiscent of the response pattern known from ATRA treatment of acute promyelocytic leukemia. However, cytogenetic analysis of isolated CD34(+) cells and granulocytes did not reveal terminal differentiation of leukemic blasts.
  
  
  CONCLUSIONS
  Treatment with VPA/ATRA results in transient disease control in a subset of patients with AML that has evolved from a myeloproliferative disorder but not in patients with a primary or MDS-related AML.
authors.affiliation: Department of Internal Medicine II, University Hospital, JW Goethe-University Frankfurt, Germany.
authors.forename: Gesine
authors.initials: G
authors.lastname: Bug
authors.forename: Markus
authors.initials: M
authors.lastname: Ritter
authors.forename: Barbara
authors.initials: B
authors.lastname: Wassmann
authors.forename: Claudia
authors.initials: C
authors.lastname: Schoch
authors.forename: Thorsten
authors.initials: T
authors.lastname: Heinzel
authors.forename: Kerstin
authors.initials: K
authors.lastname: Schwarz
authors.forename: Annette
authors.initials: A
authors.lastname: Romanski
authors.forename: Oliver H
authors.initials: OH
authors.lastname: Kramer
authors.forename: Manuela
authors.initials: M
authors.lastname: Kampfmann
authors.forename: Dieter
authors.initials: D
authors.lastname: Hoelzer
authors.forename: Andreas
authors.initials: A
authors.lastname: Neubauer
authors.forename: Martin
authors.initials: M
authors.lastname: Ruthardt
authors.forename: Oliver G
authors.initials: OG
authors.lastname: Ottmann
mesh_terms: D000284:Administration, Oral; D000368:Aged; D000369:Aged, 80 and over; D015153:Blotting, Western; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D005434:Flow Cytometry; D005500:Follow-Up Studies; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis* / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D011446:Prospective Studies; D018570:Risk Assessment; D012720:Severity of Illness Index; D016019:Survival Analysis; D016896:Treatment Outcome; D014212:Tretinoin / Q000008:administration & dosage* / Q000009:adverse effects; D014635:Valproic Acid / Q000008:administration & dosage* / Q000009:adverse effects
chemical_list: D014212:Tretinoin; D014635:Valproic Acid