title: Addition of gemtuzumab ozogamicin to induction chemotherapy in adult patients with acute myeloid leukaemia: a meta-analysis of individual patient data from randomised controlled trials.
abstract: BACKGROUND
  Gemtuzumab ozogamicin was the first example of antibody-directed chemotherapy in cancer, and was developed for acute myeloid leukaemia. However, randomised trials in which it was combined with standard induction chemotherapy in adults have produced conflicting results. We did a meta-analysis of individual patient data to assess the efficacy of adding gemtuzumab ozogamicin to induction chemotherapy in adult patients with acute myeloid leukaemia.
  
  
  METHODS
  We searched PubMed for reports of randomised controlled trials published in any language up to May 1, 2013, that included an assessment of gemtuzumab ozogamicin given to adults (aged 15 years and older) in conjunction with the first course of intensive induction chemotherapy for acute myeloid leukaemia (excluding acute promyelocytic leukaemia) compared with chemotherapy alone. Published data were supplemented with additional data obtained by contacting individual trialists. The primary endpoint of interest was overall survival. We used standard meta-analytic techniques, with an assumption-free (or fixed-effect) method. We also did exploratory stratified analyses to investigate whether any baseline features predicted a greater or lesser benefit from gemtuzumab ozogamicin.
  
  
  RESULTS
  We obtained data from five randomised controlled trials (3325 patients); all trials were centrally randomised and open label, with overall survival as the primary endpoint. The addition of gemtuzumab ozogamicin did not increase the proportion of patients achieving complete remission with or without complete peripheral count recovery (odds ratio [OR] 0·91, 95% CI 0·77-1·07; p=0·3). However, the addition of gemtuzumab ozogamicin significantly reduced the risk of relapse (OR 0·81, 0·73-0·90; p=0·0001), and improved overall survival at 5 years (OR 0·90, 0·82-0·98; p=0·01). At 6 years, the absolute survival benefit was especially apparent in patients with favourable cytogenetic characteristics (20·7%; OR 0·47, 0·31-0·73; p=0·0006), but was also seen in those with intermediate characteristics (5·7%; OR 0·84, 0·75-0·95; p=0·005). Patients with adverse cytogenetic characteristics did not benefit (2·2%; OR 0·99, 0·83-1·18; p=0·9). Doses of 3 mg/m(2) were associated with fewer early deaths than doses of 6 mg/m(2), with equal efficacy.
  
  
  CONCLUSIONS
  Gemtuzumab ozogamicin can be safely added to conventional induction therapy and provides a significant survival benefit for patients without adverse cytogenetic characteristics. These data suggest that the use of gemtuzumab ozogamicin should be reassessed and its licence status might need to be reviewed.
  
  
  BACKGROUND
  None.
authors.affiliation: School of Medicine, Cardiff University, Cardiff, UK.
authors.forename: Robert K
authors.initials: RK
authors.lastname: Hills
authors.affiliation: Centre Hospitalier de Versailles, Université de Versailles Saint Quentin, Le Chesnay, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Castaigne
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Frederick R
authors.initials: FR
authors.lastname: Appelbaum
authors.affiliation: Service D'Hématologie Clinique, CHU Hotel Dieu, Nantes, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Delaunay
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Petersdorf
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Megan
authors.initials: M
authors.lastname: Othus
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Elihu H
authors.initials: EH
authors.lastname: Estey
authors.affiliation: Hôpital Saint-Louis, University Paris Diderot, Paris, France.
authors.forename: Hervé
authors.initials: H
authors.lastname: Dombret
authors.affiliation: Centre Hospitalier de Versailles, Université de Versailles Saint Quentin, Le Chesnay, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Chevret
authors.affiliation: Service des Maladies du Sang and Inserm U892/CNRS6299, CHU d'Angers, Angers, France.
authors.forename: Norbert
authors.initials: N
authors.lastname: Ifrah
authors.affiliation: Department of Haematology, University Hospital, Grenoble, France.
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Cahn
authors.affiliation: Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer Toulouse Oncopole, Toulouse, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Récher
authors.affiliation: Leukaemia Research Cytogenetics Group, Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Lucy
authors.initials: L
authors.lastname: Chilton
authors.affiliation: Leukaemia Research Cytogenetics Group, Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Anthony V
authors.initials: AV
authors.lastname: Moorman
authors.affiliation: School of Medicine, Cardiff University, Cardiff, UK. Electronic address: BurnettAK@cardiff.ac.uk.
authors.forename: Alan K
authors.initials: AK
authors.lastname: Burnett
mesh_terms: D000328:Adult; D000617:Aminoglycosides / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D016001:Confidence Intervals; D003561:Cytarabine / Q000627:therapeutic use; D003630:Daunorubicin / Q000627:therapeutic use; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D000079982:Gemtuzumab; D006801:Humans; D007262:Infusions, Intravenous; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis / Q000188:drug therapy* / Q000401:mortality*; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D011379:Prognosis; D016032:Randomized Controlled Trials as Topic; D012074:Remission Induction / Q000379:methods; D018570:Risk Assessment; D015996:Survival Rate; D016896:Treatment Outcome
chemical_list: D000617:Aminoglycosides; D061067:Antibodies, Monoclonal, Humanized; D003561:Cytarabine; D000079982:Gemtuzumab; D003630:Daunorubicin