Gemtuzumab ozogamicin for de novo acute myeloid leukemia: final efficacy and safety updates from the open-label, phase III ALFA-0701 trial

Abstract

The randomized, phase 3 ALFA-0701 trial showed that a reduced and fractionated dose of gemtuzumab ozogamicin added to standard front-line chemotherapy significantly improves event-free survival in adults with de novo acute myeloid leukemia. Here we report an independent review of event-free survival, final overall survival, and additional safety results from ALFA-0701. Patients (N=271) aged 50-70 years with de novo acute myeloid leukemia were randomized to receive conventional front-line induction chemotherapy (3+7 daunorubicin+cytarabine) with/without gemtuzumab ozogamicin 3 mg/m2 on days 1, 4, and 7 during induction. Patients in remission following induction therapy received 2 courses of consolidation therapy (daunorubicin+cytarabine) with/without gemtuzumab ozogamicin (3 mg/2;/day on day 1) according to their initial randomization. The primary endpoint was investigator-assessed event-free survival. Secondary endpoints included overall survival and safety. A blinded independent review confirmed the investigator-assessed event-free survival results (August 1, 2011; hazard ratio, 0.66 [95% CI, 0.49-0.89]; 2-sided p=0.006), corresponding to a 34% reduction in risk of events in the gemtuzumab ozogamicin versus control arm. Final overall survival (April 30, 2013) favored gemtuzumab ozogamicin but was not significant. No differences were observed between arms in early death rate. The main toxicity associated with gemtuzumab ozogamicin was prolonged thrombocytopenia. Veno-occlusive disease (including after transplant) was observed in 6 patients in the gemtuzumab ozogamicin arm and 2 in the control arm. In conclusion, gemtuzumab ozogamicin added to standard intensive chemotherapy has a favorable benefit/risk ratio. These results expand front-line treatment options for adult patients with previously untreated acute myeloid leukemia. (ClinicalTrials.gov identifier: NCT00927498).

Pharmacokinetic/Pharmacodynamic Modeling to Support the Re‐approval of Gemtuzumab Ozogamicin

“…[7][8][9] Additionally, given that efficacy was observed at lower doses in the phase I trials (1-4 mg/m 2 ), and that >90% saturation was observed at 3 mg/m 2 , it was proposed that fractionating the 9 mg/m 2 dose would be safer and at least as efficacious. 10 Hence, a lower but more frequent dose schedule (fractionated regimen) was evaluated in several investigator cooperative studies, including MyloFrance-1, Acute Leukemia French Association (ALFA)-0701, and EORTC/GIMEMA AML-19 [11][12][13][14] (see Table 1).…”

Gemtuzumab ozogamicin and novel antibody-drug conjugates in clinical trials for acute myeloid leukemia

“…No significant difference of CR or CR with incomplete platelet recovery (CR/CRi) after induction treatment was found between the GO and control arm (81% vs 75%, p = 0.25). Contrary to SWOG S0106, the number of early mortalities was similar [6 (4.6%) vs 5 (3.6%)] [40,43]. A total of 85 patients in the study underwent AlloSCT, similar post-transplantation outcome and toxicity profile were observed in patients treated with and without GO [44].…”

“…cytogenetics [40,43]. Aside from cytogenetics, CD33 was another independent biomarker predicting the clinical outcome of GO treatment for adult AML patients.…”

The EMA Review of Mylotarg (Gemtuzumab Ozogamicin) for the Treatment of Acute Myeloid Leukemia

“…Final overall survival (April 30, 2013) favored gemtuzumab ozogamicin but was not significant. No differences were observed between arms in early death rate . The final EFS HR and CI were HR 0.562; 95% CI: 0.415–0.762.…”

“…The most conservative sensitivity analysis performed (blinded independent review; data set April 2013) confirmed the primary analysis, with an EFS derived from investigator assessment being significantly longer for patients in the GO arm (median 17.3 months; 95% CI: 13.4–30.0) than in the control arm (median 9.5 months; 95% CI: 8.1–12.0; HR 0.56; 95% CI: 0.42–0.76; two‐sided p = .0002). Regarding the secondary endpoint, RFS confirmed a statistically significant difference in favor of the GO arm (28.0 months; 95% CI: 16.3 to not estimable in the GO arm and 11.4 months; 95% CI: 10.0–14.4 in the control arm, corresponding to a 47% reduction in the risk of an event for patients in the GO arm compared with those in the control arm) .…”