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.

Findings: 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.

Interpretation: 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.

Funding: None.

Figure 1

Effect of GO on A) Remission and B) 30-day mortality

Figure 1

Effect of GO on A) Remission and B) 30-day mortality

Figure 2

Effect of GO on A) relapse, B) Death in Complete Remission, C) Relapse Free Survival, D) Survival from Remission

Figure 2

Effect of GO on A) relapse, B) Death in Complete Remission, C) Relapse Free Survival, D) Survival from Remission

Figure 2

Effect of GO on A) relapse, B) Death in Complete Remission, C) Relapse Free Survival, D) Survival from Remission

Figure 2

Effect of GO on A) relapse, B) Death in Complete Remission, C) Relapse Free Survival, D) Survival from Remission

Figure 3

Effect of GO on Overall Survival. A) Overall by Trial, B) Survival Curve. Denominators in Figure 3B represent person-years at risk during the time period in question.

Figure 3

Effect of GO on Overall Survival. A) Overall by Trial, B) Survival Curve. Denominators in Figure 3B represent person-years at risk during the time period in question.

Figure 4

Analysis of Overall Survival Stratified by Cytogenetics; A: Overall; B: Favourable (MRC 2009); C: Intermediate (MRC 2009); D: Adverse (MRC 2009). Patients with insufficient karyotype data or <20 metaphases are classified as unknown in the MRC 2009 classification.

Figure 4

Analysis of Overall Survival Stratified by Cytogenetics; A: Overall; B: Favourable (MRC 2009); C: Intermediate (MRC 2009); D: Adverse (MRC 2009). Patients with insufficient karyotype data or <20 metaphases are classified as unknown in the MRC 2009 classification.

Figure 4

Analysis of Overall Survival Stratified by Cytogenetics; A: Overall; B: Favourable (MRC 2009); C: Intermediate (MRC 2009); D: Adverse (MRC 2009). Patients with insufficient karyotype data or <20 metaphases are classified as unknown in the MRC 2009 classification.

Figure 4

Analysis of Overall Survival Stratified by Cytogenetics; A: Overall; B: Favourable (MRC 2009); C: Intermediate (MRC 2009); D: Adverse (MRC 2009). Patients with insufficient karyotype data or <20 metaphases are classified as unknown in the MRC 2009 classification.