Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): a randomised, open-label, phase 3 study

S Castaigne, C Pautas, C Terré, E Raffoux… - The Lancet, 2012 - thelancet.com
S Castaigne, C Pautas, C Terré, E Raffoux, D Bordessoule, JN Bastie, O Legrand, X Thomas…
The Lancet, 2012thelancet.com
Background The results of the addition of gemtuzumab ozogamicin, an anti-CD33 antibody
conjugate, to the standard treatment for patients with acute myeloid leukaemia in phase 3
trials were contradictory. We investigated whether the addition of low fractionated-dose
gemtuzumab ozogamicin to standard front-line chemotherapy would improve the outcome of
patients with this leukaemia without causing excessive toxicity. Methods In a phase 3, open-
label study, undertaken in 26 haematology centres in France, patients aged 50–70 years …
Background
The results of the addition of gemtuzumab ozogamicin, an anti-CD33 antibody conjugate, to the standard treatment for patients with acute myeloid leukaemia in phase 3 trials were contradictory. We investigated whether the addition of low fractionated-dose gemtuzumab ozogamicin to standard front-line chemotherapy would improve the outcome of patients with this leukaemia without causing excessive toxicity.
Methods
In a phase 3, open-label study, undertaken in 26 haematology centres in France, patients aged 50–70 years with previously untreated de novo acute myeloid leukaemia were randomly assigned with a computer-generated sequence in a 1:1 ratio with block sizes of four to standard treatment (control group) with or without 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). The primary endpoint was event-free survival (EFS). Secondary endpoints were relapse-free (RFS), overall survival (OS), and safety. Analysis was by intention to treat. This study is registered with EudraCT, number 2007-002933-36.
Findings
280 patients were randomly assigned to the control (n=140) and gemtuzumab ozogamicin groups (n=140), and 139 patients were analysed in each group. 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 (odds ratio 1ˇ46, 95% CI 0ˇ20–2ˇ59; p=0ˇ25). At 2 years, EFS was estimated as 17ˇ1% (10ˇ8–27ˇ1) in the control group versus 40ˇ8% (32ˇ8–50ˇ8) in the gemtuzumab ozogamicin group (hazard ratio 0ˇ58, 0ˇ43–0ˇ78; p=0ˇ0003), OS 41ˇ9% (33ˇ1–53ˇ1) versus 53ˇ2% (44ˇ6–63ˇ5), respectively (0ˇ69, 0ˇ49–0ˇ98; p=0ˇ0368), and RFS 22ˇ7% (14ˇ5–35ˇ7) versus 50ˇ3% (41ˇ0–61ˇ6), respectively (0ˇ52, 0ˇ36–0ˇ75; p=0ˇ0003). Haematological toxicity, particularly persistent thrombocytopenia, was more common in the gemtuzumab ozogamicin group than in the control group (22 [16%] vs 4 [3%]; p<0ˇ0001), without an increase in the risk of death from toxicity.
Interpretation
The use of fractionated lower doses of gemtuzumab ozogamicin allows the safe delivery of higher cumulative doses and substantially improves outcomes in patients with acute myeloid leukaemia. The findings warrant reassessment of gemtuzumab ozogamicin as front-line therapy for acute myeloid leukaemia.
Funding
Wyeth (Pfizer).
thelancet.com