The Addition of Gemtuzumab Ozogamicin to Intensive Chemotherapy in Older Patients with AML Produces a Significant Improvement in Overall Survival: Results of the UK NCRI AML16 Randomized Trial
Authors: Burnett Alan K , Hills Robert K , Hunter Ann E. , Milligan Donald , Kell William J. , Wheatley Keith , Yin John L , Ali Sahra , Kjeldsen Lars , Bowen David , Russell Nigel H. 
Published: October 2019

Abstract
Abstract 582
We previously showed in the MRC AML15 Trial (Burnett et al JCO 2011:29(4):369-77 that 70% of younger patients with AML derived a 10% survival benefit by the addition of the immuno-conjugate, Gemtuzumab Ozogamicin (GO) (Mylotarg™), to induction chemotherapy. In a second trial (AML16 non-intensive) its addition to Low dose Ara-C doubled the CR rate but did not improve OS (Burnett et al. Blood 2010:116 (21): Abstract 18). We now report the result of the NCRI AML16 (Intensive) Trial in which older patients were randomised to receive, or not, GO 3mg/m2 on day 1 of course 1 of induction chemotherapy. Patients were randomised to two courses of DA (daunorubicin/ara-C) or DClo (daunorubicin/clofarabine), followed, or not, by a 3rd course (DA) with or without Azacytidine maintenance.
Between December 2006 and July 2010, 1115 patients were randomised to the GO vs no GO comparison from 149 centres in the UK & Denmark. The median age was 67 years (range 51–84). 806 had de novo AML, 194 secondary disease and 115 high risk MDS (>10% marrow blasts). Of the 806 patients with cytogenetic data, 33 were favourable/629 intermediate/204 adverse risk (Grimwade et al, Blood 1998: 92:2322-33). 96% of those allocated GO received it. The overall response rate was 69% (CR 60%; CRi 9%) with 52% of patients achieving response after course 1. Overall survival at 4 years was 17% with a median follow up of 29.5 months (range 0.5–54.6 months).CR%CRi%ORR%Res Dis %Ind Death %30d mortality %60d mortality %GO629711712915No GO5810682111814p-value0.180.30.070.40.80.8

Induction Results:
There was no significant difference in blood count recovery kinetics; other toxicities and resource usage were not significantly increased with the exception that for course 1 nausea and oral toxicity were marginally higher with GO, more platelet transfusions were given (13.7 vs 9.6 mean units; p<0.001), and marginally more days of IV antibiotics (mean 19.2 days v 18.1 days p=0.03). There were no significant differences for course 2 of treatment.

Relapse/RFS/OS:
The rate of relapse was significantly reduced (GO vs no GO: CIR at 2 years 61% vs 70%; p=0.004), leading to significantly better RFS (28% vs 23% at 2 years; p=0.03), and survival from CR and OS were significantly better on the GO arm (2 year survival from CR 47% vs 39%; p=0.02; 2 year OS 35% vs 29%; p=0.04). While the benefit appeared lower in patients with secondary disease or with adverse cytogenetics (GO vs no GO 2 year OS 19% vs 21% and 13% vs 6%) compared to those with de Novo disease or intermediate cytogenetics (2 year OS 38% vs 32% and 41% vs 36%), as was seen in our previous AML15 trial, in this trial there was no significant evidence of interaction between treatment and any demographics or underlying chemotherapy.

Conclusion:
The addition of GO to induction chemotherapy did not lead to unacceptable increases in toxicity. It improved disease control and delivered a significant OS benefit for older patients overall. While there is no significant interaction, the greater benefit in patients with de novo disease or intermediate risk cytogenetics is consistent over the 2228 patients randomised in the AML15 and AML16 trials.

Disclosures:
Burnett: Pfizer: Consultancy. Off Label Use: Gemtuzumab Ozogamicin in AML.