Fractionated gemtuzumab ozogamicin dosing improves AML survival
MedWire News: The addition of fractionated doses of gemtuzumab ozogamicin to standard chemotherapy improves survival in patients with de novo acute myeloid leukemia (AML), French researchers report.
"The 3-3-3 gemtuzumab ozogamicin regimen [3 mg/m2 on 3 separate days] allows the delivery of a high cumulative dose of gemtuzumab ozogamicin without excess toxicity," write Sylvie Castaigne (Centre Hospitalier de Versailles) and colleagues in The Lancet.
The researchers explain that gemtuzumab ozogamicin is a humanized anti-CD33 monoclonal antibody linked to calicheamicin. After internalization and intracellular release, delivery of this highly toxic drug is targeted to CD33-expressing leukemic cells (>80% in patients with AML).
In a previous phase II study of patients with AML in first relapse, single-agent gemtuzumab ozogamicin at a dose of 9 mg/m2 on days 1 and 14 was associated with 26% complete remission. However, hematologic toxicity and frequent liver toxicity with veno-occlusive disease were reported with this initial dose and schedule.
In the present phase III study, Castaigne and team investigated whether the addition of low fractionated-dose gemtuzumab ozogamicin to standard front-line chemotherapy (3+7 regimen, combining daunorubicin 50-60 mg/m2 per day for 3 days with continuous cytarabine 100-200 mg/m2 per day for 7 days) would improve the outcome of patients with this leukemia without causing excessive toxicity.
The study, undertaken in 26 hematology centers in France, included 278 patients aged 50-70 years with previously untreated de novo AML. Patients were randomly assigned to standard treatment with (n=139) or without (n=139; control group) five doses of intravenous gemtuzumab ozogamicin (3 mg/m2 on days 1, 4, and 7 during induction and day 1 of each of the two consolidation chemotherapy courses).
Complete response (defined as <5% blasts in a normocellular marrow and an absolute neutrophil count >1×109/L) with or without incomplete platelet recovery to induction occurred in 75% of patients in the control group and 81% of those in the gemtuzumab ozogamicin group, a difference that was not statistically significant.
Despite the similar response rates between the groups, patients given gemtuzumab ozogamicin had significantly lower recurrence rates at 2 years than did those given the standard regimen (recurrence-free survival 50.3 vs 22.7%; hazard ratio [HR] =0.58).
As a consequence of the lower relapse rate, patients in the gemtuzumab ozogamicin group also had significantly improved event-free (40.8 vs 17.1%; HR=0.58) and overall survival (53.2 vs 41.9%; HR=0.69).
Subgroup analyses revealed that the benefit of gemtuzumab ozogamicin was more pronounced in patients with favorable or intermediate cytogenetics than in those with unfavorable cytogenetics, and in those positive for the FLT3-ITD mutation than in FLT3-ITD-negative patients.
In terms of safety, hematologic toxicity, particularly persistent thrombocytopenia, was significantly more common in the gemtuzumab ozogamicin group than in the control group (16 vs 3%), but patients who received gemtuzumab ozogamicin had no increased risk for death from toxicity.
"We believe that our results support the re-evaluation of the place of gemtuzumab ozogamicin in available front-line therapy for acute myeloid leukemia," Castaigne and co-authors conclude.
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By Laura Cowen