(ChemotherapyAdvisor) – Fractionated lower doses of gemtuzumab ozogamicin allows safe delivery of higher cumulative doses and substantially improves outcomes in adults with de novo acute myeloid leukemia (AML), a Phase 3 study in the Lancet online April 5 has concluded.

These findings warrant reassessment of gemtuzumab ozogamicin as front-line therapy for AML, the investigators noted. Previously, results of Phase 3 trials had found that addition of gemtuzumab ozogamicin, an anti-CD33 antibody conjugate, to standard treatment for patients with AML improved outcomes; however, the dosing schedule led to frequent complications, including liver toxicity and veno-occlusive disease.

In this open-label study in 26 hematology centers in France, 280 patients aged 50–70 years with previously untreated de novo AML were randomly assigned to standard treatment with (n=140) or without (control group, n=140)  doses of intravenous gemtuzumab ozogamicin 3mg/m2 on days 1, 4, and 7 during induction and day 1 of each of two courses of consolidation chemotherapy.

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Complete response with or without incomplete platelet recovery to induction was 104 (75%) in the control group and 113 (81%) in the gemtuzumab ozogamicin group (OR, 1.46; P=0.25). At two years, event-free survival, the primary end point, was estimated as 17.1% in the control group vs. 40.8% in the gemtuzumab ozogamicin group (HR, 0.58; P=0.0003). Overall survival was 41.9% vs. 53.2% (HR, 0.69; P=0.0368), and relapse-free survival was 22.7% vs. 50.3%, respectively (HR, 0·52; P=0.0003).

Hematological toxicity, particularly persistent thrombocytopenia, was more common in the gemtuzumab ozogamicin group than in the control group (16% vs. 3%; P<0.0001); no increased risk of death from toxicity was observed.

The regimen used in this study allows delivery of a high cumulative dose of gemtuzumab ozogamicin without excess toxicity, the investigators wrote. “We believe that our results support the reevaluation of the place of gemtuzumab ozogamicin in available front-line therapy for acute myeloid leukemia.” They added, “The substantial benefit of adding gemtuzumab ozogamicin is noted not only in patients with acute myeloid leukemia who have favorable cytogenetics, but also in the larger subpopulation of those with intermediate cytogenetics.”

A linked comment noted that “experience with gemtuzumab ozogamicin suggests a need to move beyond focusing on an average result. Instead, emphasis needs to be placed on outcome in various subsets of this highly heterogeneous disease.”