title: Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): a randomised, open-label, phase 3 study.
abstract: BACKGROUND
  The results of the addition of gemtuzumab ozogamicin, an anti-CD33 antibody conjugate, to the standard treatment for patients with acute myeloid leukaemia in phase 3 trials were contradictory. We investigated whether the addition of low fractionated-dose gemtuzumab ozogamicin to standard front-line chemotherapy would improve the outcome of patients with this leukaemia without causing excessive toxicity.
  
  
  METHODS
  In a phase 3, open-label study, undertaken in 26 haematology centres in France, patients aged 50-70 years with previously untreated de novo acute myeloid leukaemia were randomly assigned with a computer-generated sequence in a 1:1 ratio with block sizes of four to standard treatment (control group) with or without five doses of intravenous gemtuzumab ozogamicin (3 mg/m(2) on days 1, 4, and 7 during induction and day 1 of each of the two consolidation chemotherapy courses). The primary endpoint was event-free survival (EFS). Secondary endpoints were relapse-free (RFS), overall survival (OS), and safety. Analysis was by intention to treat. This study is registered with EudraCT, number 2007-002933-36.
  
  
  RESULTS
  280 patients were randomly assigned to the control (n=140) and gemtuzumab ozogamicin groups (n=140), and 139 patients were analysed in each group. Complete response with or without incomplete platelet recovery to induction was 104 (75%) in the control group and 113 (81%) in the gemtuzumab ozogamicin group (odds ratio 1·46, 95% CI 0·20-2·59; p=0·25). At 2 years, EFS was estimated as 17·1% (10·8-27·1) in the control group versus 40·8% (32·8-50·8) in the gemtuzumab ozogamicin group (hazard ratio 0·58, 0·43-0·78; p=0·0003), OS 41·9% (33·1-53·1) versus 53·2% (44·6-63·5), respectively (0·69, 0·49-0·98; p=0·0368), and RFS 22·7% (14·5-35·7) versus 50·3% (41·0-61·6), respectively (0·52, 0·36-0·75; p=0·0003). Haematological toxicity, particularly persistent thrombocytopenia, was more common in the gemtuzumab ozogamicin group than in the control group (22 [16%] vs 4 [3%]; p<0·0001), without an increase in the risk of death from toxicity.
  
  
  CONCLUSIONS
  The use of fractionated lower doses of gemtuzumab ozogamicin allows the safe delivery of higher cumulative doses and substantially improves outcomes in patients with acute myeloid leukaemia. The findings warrant reassessment of gemtuzumab ozogamicin as front-line therapy for acute myeloid leukaemia.
  
  
  BACKGROUND
  Wyeth (Pfizer).
authors.affiliation: Hôpital Mignot, Université Versailles-Saint Quentin, Le Chesnay, France. scastaigne@ch-versailles.fr
authors.forename: Sylvie
authors.initials: S
authors.lastname: Castaigne
authors.forename: Cécile
authors.initials: C
authors.lastname: Pautas
authors.forename: Christine
authors.initials: C
authors.lastname: Terré
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Raffoux
authors.forename: Dominique
authors.initials: D
authors.lastname: Bordessoule
authors.forename: Jean-Noel
authors.initials: JN
authors.lastname: Bastie
authors.forename: Ollivier
authors.initials: O
authors.lastname: Legrand
authors.forename: Xavier
authors.initials: X
authors.lastname: Thomas
authors.forename: Pascal
authors.initials: P
authors.lastname: Turlure
authors.forename: Oumedaly
authors.initials: O
authors.lastname: Reman
authors.forename: Thierry
authors.initials: T
authors.lastname: de Revel
authors.forename: Lauris
authors.initials: L
authors.lastname: Gastaud
authors.forename: Noémie
authors.initials: N
authors.lastname: de Gunzburg
authors.forename: Nathalie
authors.initials: N
authors.lastname: Contentin
authors.forename: Estelle
authors.initials: E
authors.lastname: Henry
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Marolleau
authors.forename: Ahmad
authors.initials: A
authors.lastname: Aljijakli
authors.forename: Philippe
authors.initials: P
authors.lastname: Rousselot
authors.forename: Pierre
authors.initials: P
authors.lastname: Fenaux
authors.forename: Claude
authors.initials: C
authors.lastname: Preudhomme
authors.forename: Sylvie
authors.initials: S
authors.lastname: Chevret
authors.forename: Hervé
authors.initials: H
authors.lastname: Dombret
mesh_terms: D000368:Aged; D000617:Aminoglycosides / Q000009:adverse effects / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D018572:Disease-Free Survival; D005260:Female; D000079982:Gemtuzumab; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D015996:Survival Rate
chemical_list: D000617:Aminoglycosides; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000079982:Gemtuzumab