Elsevier

The Lancet Oncology

Volume 15, Issue 9, August 2014, Pages 986-996
The Lancet Oncology

Articles
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

https://doi.org/10.1016/S1470-2045(14)70281-5Get rights and content

Summary

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/m2 were associated with fewer early deaths than doses of 6 mg/m2, 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.

Introduction

Very few treatments for acute myeloid leukaemia have gained regulatory approval. One of the few successes was the immunoconjugate drug gemtuzumab ozogamicin (Pfizer, New York, NY, USA), which gained approval in the USA in 2000 (with a dosing schedule of 9 mg/m2 on days 1 and 15 of induction chemotherapy) on the basis of data from a non-randomised, phase 2 study done in 142 patients with relapsed disease.1, 2 The label restricted approval to “older patients with relapse who were not suitable for intensive treatment”.1 A confirmatory randomised trial was required for full approval.

Gemtuzumab ozogamicin was approved in Japan for the same patient population and with the same dosing schedule; however, when combined with frequently used chemotherapy regimens, this schedule resulted in prohibitive toxic effects.3 Results from a dose-finding study4 in which gemtuzumab ozogamicin was combined with frequently used induction and consolidation chemotherapy regimens provided evidence that a single, lower dose of 3 mg/m2 was safe and apparently effective. That study was the prelude to a randomised trial5 in which gemtuzumab ozogamicin was added to different courses of chemotherapy. Feasibility was established in combination with the first and third courses of chemotherapy. On the basis of these data, two large trials were done in which a gemtuzumab ozogamicin dose of 3 mg/m2 was added to induction chemotherapy in younger patients (generally younger than 60 years, although some older patients were included; UK MRC AML15)5 and older patients (generally older than 60 years; UK NCRI AML16).6

The randomised controlled trial required for post-approval support in the USA was done by the South West Oncology Group (SWOG S0106).7 Gemtuzumab ozogamicin (6 mg/m2) was given on day 4 of a traditional 3+7 (daunorubicin plus cytarabine) induction chemotherapy regimen, with patients in the gemtuzumab ozogamicin group given a 45 mg/m2 dose of daunorubicin, whereas those in the control group were given a 60 mg/m2 dose. The French GOELAMS Group adopted a similar design,8 except that both groups received a 60 mg/m2 dose of daunorubicin. Subsequently, in a study by the French ALFA Group,9 gemtuzumab ozogamicin administration was fractionated (3 mg/m2 on days 1, 4, and 7 of a daunorubicin plus cytarabine combination), with each dose of gemtuzumab ozogamicin limited to a maximum of 5 mg, irrespective of body surface area. This strategy was intended to take advantage of CD33 re-expression that occurs after initial exposure to the drug.10 The approach proved to be feasible and had encouraging results in relapsed disease, leading to the ALFA-0701 trial,11 in which patients received fractionated gemtuzumab ozogamicin during both induction and consolidation chemotherapy.

The consensus from the overall results of these trials was that gemtuzumab ozogamicin did not improve disease remission, despite risk of relapse being reduced in four5, 6, 8, 11 of the five5, 6, 8, 11, 12 randomised trials reported, with a significant survival benefit seen in two (NCRI AML166 and ALFA-070111). Furthermore, results from all five randomised trials5, 6, 8, 11, 12 suggested a survival benefit for favourable and intermediate cytogenetic risk groups, but not for patients with adverse cytogenetic characteristics. Unfortunately, the SWOG S0106 trial7 was terminated early by the data monitoring committee because of a significant excess of early mortality in the group given gemtuzumab ozogamicin (17 [6%] of 295 patients died vs four [1%] of 300), which was not counterbalanced by a later benefit. However, notably, early mortality was exceptionally low in the control group, and mortality in the gemtuzumab ozogamicin group was similar to what would be expected with conventional treatments. The findings from this trial were very influential because of its registration status, resulting in gemtuzumab ozogamicin being withdrawn from the US market in June, 2010.

Ultimately the question of whether gemtuzumab ozogamicin provides overall benefit with acceptable early mortality remains unanswered, and the optimum dose and dosing schedule are unknown. To try to answer this question, we did a meta-analysis of individual patient data from the five trials in adults in which gemtuzumab ozogamicin was given in combination with standard induction chemotherapy.

Section snippets

Study design and selection of datasets

We did a meta-analysis of individual patient data from randomised controlled trials of gemtuzumab ozogamicin given at the same time as induction chemotherapy to adult patients with acute myeloid leukaemia. To identify relevant studies, we searched PubMed for reports of randomised controlled trials published in any language up to May 1, 2013, using search terms “randomi*” and “gemtuzumab”. This search was supplemented by data obtained by contacting individual trialists and Pfizer to identify all

Results

We identified five randomised trials5, 6, 7, 8, 11 that met our inclusion criteria, and obtained individual patient data for all 3325 patients who were enrolled in the trials (table). All trials were centrally randomised, open label, and had overall survival as the primary endpoint. For three of the studies5, 6, 7 published data were supplemented by unpublished data provided by the investigators; in addition to the four trials for which final results had been reported,5, 6, 7, 11 source data

Discussion

The results of this meta-analysis of individual patient data show that the addition of gemtuzumab ozogamicin to induction chemotherapy improves overall survival for adult patients with acute myeloid leukaemia. Importantly this analysis differs from others16, 17 that have addressed this issue, primarily because it has the advantages and rigour of individual patient data, enabling, for example, standardisation of risk groups. A further advantage is we have been able to update data from the

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