title: Feasibility of azacitidine added to standard chemotherapy in older patients with acute myeloid leukemia--a randomised SAL pilot study.
abstract: BACKGROUND
  Older patients with acute myeloid leukemia (AML) experience short survival despite intensive chemotherapy. Azacitidine has promising activity in patients with low proliferating AML. The aim of this dose-finding part of this trial was to evaluate feasibility and safety of azacitidine combined with a cytarabine- and daunorubicin-based chemotherapy in older patients with AML.
  
  
  METHODS
  Prospective, randomised, open, phase II trial with parallel group design and fixed sample size.
  
  
  METHODS
  Patients aged 61 years or older, with untreated acute myeloid leukemia with a leukocyte count of <20,000/µl at the time of study entry and adequate organ function were eligible. Patients were randomised to receive azacitidine either 37.5 (dose level 1) or 75 mg/sqm (dose level 2) for five days before each cycle of induction (7+3 cytarabine plus daunorubicine) and consolidation (intermediate-dose cytarabine) therapy. Dose-limiting toxicity was the primary endpoint.
  
  
  RESULTS
  Six patients each were randomised into each dose level and evaluable for analysis. No dose-limiting toxicity occurred in either dose level. Nine serious adverse events occurred in five patients (three in the 37.5 mg, two in the 75 mg arm) with two fatal outcomes. Two patients at the 37.5 mg/sqm dose level and four patients at the 75 mg/sqm level achieved a complete remission after induction therapy. Median overall survival was 266 days and median event-free survival 215 days after a median follow up of 616 days.
  
  
  CONCLUSIONS
  The combination of azacitidine 75 mg/sqm with standard induction therapy is feasible in older patients with AML and was selected as an investigational arm in the randomised controlled part of this phase-II study, which is currently halted due to an increased cardiac toxicity observed in the experimental arm.
  
  
  BACKGROUND
  This trial is registered at clinical trials.gov (identifier: NCT00915252).
authors.affiliation: Department of Medicine A, University Hospital, Muenster, Germany.
authors.forename: Utz
authors.initials: U
authors.lastname: Krug
authors.forename: Anja
authors.initials: A
authors.lastname: Koschmieder
authors.forename: Daniela
authors.initials: D
authors.lastname: Schwammbach
authors.forename: Joachim
authors.initials: J
authors.lastname: Gerss
authors.forename: Nicola
authors.initials: N
authors.lastname: Tidow
authors.forename: Björn
authors.initials: B
authors.lastname: Steffen
authors.forename: Gesine
authors.initials: G
authors.lastname: Bug
authors.forename: Christian H
authors.initials: CH
authors.lastname: Brandts
authors.forename: Markus
authors.initials: M
authors.lastname: Schaich
authors.forename: Christoph
authors.initials: C
authors.lastname: Röllig
authors.forename: Christian
authors.initials: C
authors.lastname: Thiede
authors.forename: Richard
authors.initials: R
authors.lastname: Noppeney
authors.forename: Matthias
authors.initials: M
authors.lastname: Stelljes
authors.forename: Thomas
authors.initials: T
authors.lastname: Büchner
authors.forename: Steffen
authors.initials: S
authors.lastname: Koschmieder
authors.forename: Ulrich
authors.initials: U
authors.lastname: Dührsen
authors.forename: Hubert
authors.initials: H
authors.lastname: Serve
authors.forename: Gerhard
authors.initials: G
authors.lastname: Ehninger
authors.forename: Wolfgang E
authors.initials: WE
authors.lastname: Berdel
authors.forename: Carsten
authors.initials: C
authors.lastname: Müller-Tidow
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use* / Q000633:toxicity; D001374:Azacitidine / Q000008:administration & dosage; D060830:Consolidation Chemotherapy; D003561:Cytarabine / Q000008:administration & dosage; D003630:Daunorubicin / Q000008:administration & dosage; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D060828:Induction Chemotherapy; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D010865:Pilot Projects; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D003561:Cytarabine; D001374:Azacitidine; D003630:Daunorubicin