The UK NCRI AML16 trial randomised older patients to two courses of DA vs DClo with or without gemtuzumab ozogamicin (GO) on day 1 of course 1. Patients who had at least a PR to course 1 and were in CR/CRi after course 2 could be randomised to a third course (DA) or not, after which they were randomised to maintenance, or not, with 9 six weekly courses of Azacitidine.
The benefit of the addition of GO has been reported . Based on a feasibility study  a schedule of Clofarabine 20mg/m2 days 1–5 was combined with Daunorubicin (Dauno) 50mg/m2 days 1–3, to be compared with Dauno 50mg/m2 days 1–3 + ara-C 100mg/m2 bid days 1–10 (course 1) or days 1–8 (course 2). Those randomised to a 3rd course received Dauno 50mg/m2 days 1, 2 + ara-C 100mg/m2 bid days 1–5. The results of the 530 patients in the Azacitidine randomisation have insufficient follow up.
Between August 2006 and December 2009, 806 patients were randomised between DA and DClo, of whom 683 entered the GO randomisation. The median age was 67 (56-84) years: 72% had de novo, 17% had secondary, and 11% has high risk MDS (marrow blasts >10%): 4%, 73% and 23% had favourable, intermediate or poor risk cytogenetics: 14% were FLT3-ITD and 20% were NPM1 mutant: 30%, 34% and 36% had good, standard or poor Wheatley Scores . Between November 2006 and August 2012, 570 patients were randomised to 2 vs 3 courses. Of these 34% were Wheatley good risk, 40% standard risk and 26% poor risk. The 307 patients in the consolidation randomisation not in the DA vs DClo induction randomisation received DA with or without GO. The demographic, cytogenetic, molecular and allocated treatments were balanced between the arms. Follow-up is complete to 1st January 2012.
In the DA vs DClo randomisation, the overall response rate (ORR) was 68% (CR 60%+ CRi 8%) and survival at 3 years was 22%. The ORR was not different between DA: 71% (CR 63%, CRi 8%) and DClo 66% (CR 57%, CRi 9%), OR 1.26 (0.94-1.70) p=0.12, with 60 day all-cause mortality of 15% and 14% respectively. There were no significant differences between DA and DClo at 3 years in RFS (18% vs 21%, HR 1.00 (0.83-1.20) p=1.0) CIR (74% vs 68%, HR 0.93 (0.77-1.14) p=0.5), death in CR (8% vs 12%, HR 1.52 (0.89-2.57) p=0.12): survival from CR (31% vs 32%, HR 1.02 (0.83-1.24) p=0.9): survival from relapse (7% vs 9%, HR 0.96 (0.77-1.19) p=0.7) and overall survival (23% vs 22%, HR 1.08 (0.93-1.26) p=0.3). The schedules were equi-toxic, and although the recovery of neutrophils and platelets was quicker in the DA arm in both courses DClo patients received significantly less transfusion support, days on antibiotics and hospitalisation. There was no evidence of interaction between the two induction randomisations, or between the DA vs DClo randomisation and any demographic feature.
In the consolidation randomisation, 3 year survival from entry was 34%, with an RFS of 20%. Overall there were no significant differences between the two arms (3-year survival 34% vs 34%; HR 0.91 (0.72-1.15) p=0.4; RFS 19% vs 21%; HR 0.88 (0.72-1.09) p=0.2). There was no evidence of interaction between the number of courses given and any demographic variable including number of courses to CR and best response (CR/CRi), and, importantly, no interaction between consolidation and induction randomisations.
DA and DClo in induction give similar outcomes, with equivalent toxicity, and slightly lower resource usage on the DClo arm. In patients who achieve at least partial remission following course 1 and reach CR or CRi by the end of their second course, there is no significant benefit for a third course of chemotherapy, and no evidence of a particular subgroup who would benefit from a third course.
This study received research support from Genzyme and Cancer Research UK.
Asterisk with author names denotes non-ASH members.