title: Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study.
abstract: BACKGROUND
  Drug treatments for patients with high-risk myelodysplastic syndromes provide no survival advantage. In this trial, we aimed to assess the effect of azacitidine on overall survival compared with the three commonest conventional care regimens.
  
  
  METHODS
  In a phase III, international, multicentre, controlled, parallel-group, open-label trial, patients with higher-risk myelodysplastic syndromes were randomly assigned one-to-one to receive azacitidine (75 mg/m(2) per day for 7 days every 28 days) or conventional care (best supportive care, low-dose cytarabine, or intensive chemotherapy as selected by investigators before randomisation). Patients were stratified by French-American-British and international prognostic scoring system classifications; randomisation was done with a block size of four. The primary endpoint was overall survival. Efficacy analyses were by intention to treat for all patients assigned to receive treatment. This study is registered with ClinicalTrials.gov, number NCT00071799.
  
  
  RESULTS
  Between Feb 13, 2004, and Aug 7, 2006, 358 patients were randomly assigned to receive azacitidine (n=179) or conventional care regimens (n=179). Four patients in the azacitidine and 14 in the conventional care groups received no study drugs but were included in the intention-to-treat efficacy analysis. After a median follow-up of 21.1 months (IQR 15.1-26.9), median overall survival was 24.5 months (9.9-not reached) for the azacitidine group versus 15.0 months (5.6-24.1) for the conventional care group (hazard ratio 0.58; 95% CI 0.43-0.77; stratified log-rank p=0.0001). At last follow-up, 82 patients in the azacitidine group had died compared with 113 in the conventional care group. At 2 years, on the basis of Kaplan-Meier estimates, 50.8% (95% CI 42.1-58.8) of patients in the azacitidine group were alive compared with 26.2% (18.7-34.3) in the conventional care group (p<0.0001). Peripheral cytopenias were the most common grade 3-4 adverse events for all treatments.
  
  
  CONCLUSIONS
  Treatment with azacitidine increases overall survival in patients with higher-risk myelodysplastic syndromes relative to conventional care.
authors.affiliation: Hôpital Avicenne, Université Paris XIII, Bobigny, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Fenaux
authors.forename: Ghulam J
authors.initials: GJ
authors.lastname: Mufti
authors.forename: Eva
authors.initials: E
authors.lastname: Hellstrom-Lindberg
authors.forename: Valeria
authors.initials: V
authors.lastname: Santini
authors.forename: Carlo
authors.initials: C
authors.lastname: Finelli
authors.forename: Aristoteles
authors.initials: A
authors.lastname: Giagounidis
authors.forename: Robert
authors.initials: R
authors.lastname: Schoch
authors.forename: Norbert
authors.initials: N
authors.lastname: Gattermann
authors.forename: Guillermo
authors.initials: G
authors.lastname: Sanz
authors.forename: Alan
authors.initials: A
authors.lastname: List
authors.forename: Steven D
authors.initials: SD
authors.lastname: Gore
authors.forename: John F
authors.initials: JF
authors.lastname: Seymour
authors.forename: John M
authors.initials: JM
authors.lastname: Bennett
authors.forename: John
authors.initials: J
authors.lastname: Byrd
authors.forename: Jay
authors.initials: J
authors.lastname: Backstrom
authors.forename: Linda
authors.initials: L
authors.lastname: Zimmerman
authors.forename: David
authors.initials: D
authors.lastname: McKenzie
authors.forename: Cl
authors.initials: C
authors.lastname: Beach
authors.forename: Lewis R
authors.initials: LR
authors.lastname: Silverman
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D001374:Azacitidine / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000188:drug therapy* / Q000401:mortality; D016016:Proportional Hazards Models
chemical_list: D000964:Antimetabolites, Antineoplastic; D001374:Azacitidine