ArticlesAddition of gemtuzumab ozogamicin to induction chemotherapy in adult patients with acute myeloid leukaemia: a meta-analysis of individual patient data from randomised controlled trials
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
References (27)
- et al.
A feasibility study of simultaneous administration of gemtuzumab ozogamicin with intensive chemotherapy in induction and consolidation in younger patients with acute myeloid leukemia
Blood
(2003) - et al.
A phase 3 study of gemtuzumab ozogamicin during induction and postconsolidation therapy in younger patients with acute myeloid leukemia
Blood
(2013) - et al.
Targeting of the CD33-calicheamicin conjugate Mylotarg (CMA-676) in acute myeloid leukemia: in vivo and in vitro saturation and internalisation by leukemic and normal myeloid cells
Blood
(2001) - et al.
Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): a randomised, open-label, phase 3 study
Lancet
(2012) - et al.
Refinement of cytogenetic classification in acute myeloid leukemia: determination of prognostic significance of rare recurring chromosomal abnormalities among 5876 younger adult patients treated in the United Kingdom Medical Research Council trials
Blood
(2010) - et al.
Effect of adding gemtuzumab ozogamicin to induction chemotherapy for newly diagnosed acute myeloid leukemia: a meta-analysis of prospective randomized phase III trials
Ann Oncol
(2014) - et al.
Induction therapy of AML with ara-C plus daunorubicin versus ara-C plus gemtuzumab ozogamicin: a randomized phase II trial in elderly patients
Ann Oncol
(2012) - et al.
Approval summary: gemtuzumab ozogamicin in relapsed acute myeloid leukemia
Clin Cancer Res
(2001) - et al.
Antibody-targeted chemotherapy of older patients with acute myeloid leukemia in first relapse using Mylotarg (gemtuzumab ozogamicin)
Leukemia
(2002) - et al.
Mylotarg (gemtuzumab ozogamicin) therapy is associated with hepatic venoocclusive disease in patients who have not received stem cell transplantation
Cancer
(2001)
Identification of patients with acute myeloblastic leukemia who benefit from the addition of gemtuzumab ozogamicin: results of the MRC AML15 trial
J Clin Oncol
Addition of gemtuzumab ozogamicin to induction chemotherapy improves survival in older patients with acute myeloid leukemia
J Clin Oncol
Addition of gemtuzumab ozogamycin to chemotherapy improves event-free survival but not overall survival of AML patients with intermediate cytogenetics not eligible for allogeneic transplantation: results of the GOELAMS AML 2006 IR study
Blood (ASH annual meeting abstracts)
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