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

Summary Background Gemtuzumab Ozogamicin (GO) was the first example of antibody directed chemotherapy in cancer and developed for Acute Myeloid Leukaemia. Its role has been unclear. Five randomised trials where it was combined with standard induction chemotherapy in adults have produced different results. In an effort to clarify the level of benefit, if any, and in which patients outcomes might be improved, an individual patient data meta-analysis of these 5 trials has been undertaken. Methods All randomised trials of GO in adults (age >15), given in conjunction with the first course of intensive induction chemotherapy for AML (excluding APL) were identified. In a collaboration between the groups involved, source data concerning demographics, treatment was requested in May 2013 and collected in 3325 randomised patients (median age 58). All trials were centrally randomised and open-label, with survival as primary endpoint. Analyses are presented by standard techniques, and within standardised risk groups Results Remission rates were not increased, but by significantly reducing the risk of relapse overall survival at 5 years was improved irrespective of patient age (30.7% vs 34.6%; HR 0.90 (95% CI 0.82-0.98), p=0.01). The survival benefit was particularly clear in those with favourable cytogenetics (55.2% vs 76.3%; HR0.47 (0.31-0.73), p=0.0005), but also observed in intermediate risk patients (34.1% vs 39.4%; HR 0.84 (0.75-0.95), p=0.007) Patients with adverse karyotype did not benefit overall or within any trial. Dose levels of 3mg/m2 were associated with less toxicity and equal efficacy. Interpretation GO can be safely added to conventional induction therapy. For patients who do not have adverse cytogenetics there is a significant survival benefit. These data suggest that the use of GO should be re-evaluated and the license status of GO may need to be reviewed. Role of funding source There was no funder for this meta-analysis.

Dose-related efficacy and toxicity of gemtuzumab ozogamicin in pediatric acute myeloid leukemia

“…Since its approval in 2000 by the FDA, many studies on GO have been performed, and despite the withdrawal of GO in 2010 from the US market, studies on GO are still ongoing and very encouraging efficacy data have recently been published reporting both on adult and childhood AML [17][18][19][20]. In 2014, Gamis et al published a study on the addition of GO to standard chemotherapy in children and adolescents and found an improved EFS through reduction of relapse risk in recipients of GO.…”

“…GO was approved by the US FDA in 2000 for its use in patients with relapsed AML being 60 years or older, but withdrawn in 2010 by Pfizer (previously Wyeth) because of adverse events and doubts regarding its effectiveness in a pivotal study in which mortality with gemtuzumab was 5.7% compared to 1.4% without the agent [16]. Since then, studies in newly diagnosed AML in adults have regenerated interest in the compound [17][18][19][20].…”

The role of targeted therapy in the management of patients with AML

“…67,68 Summarizing all the available phase 3 data from 5 phase 3 trials in adults, a UK National Cancer Research Instiute meta-analysis studied 3325 patients treated in these studies. 69 The metaanalysis showed a statistically significant reduction in relapse rates and improved OS for GO-treated patients across these trials, without appreciable increases in toxicity. The benefits appeared to be limited to patients with favorable or intermediate-risk karyotype, and patients treated on studies with 3 mg/m 2 per dose or fraction experienced lower induction mortality.…”

Acute myeloid leukemia—Major progress over four decades and glimpses into the future

“…This led to a meta-analysis of the 5 randomized trials involving 3,325 patients, which showed that the addition of GO did not increase the CR rate, but reduced significantly the risk of relapse (p 5 0.0001) and improved the 5-year survival rate (p 5 0.01), particularly in patients with favorable cytogenetics (p 5 0.0006) and intermediate cytogenetics (p 5 0.005). The GO dose of 3 mg/m 2 was associated with fewer early deaths than 6 mg/ m 2 , while providing equal efficacy [105]. This led AML experts to ask for reinstituting the availability of GO for the treatment of AML [106,107].…”