A Comparison of Single Dose Gemtuzumab Ozogamicin 3mg/m² and 6mg/m² Combined with Induction Chemotherapy in Younger Patients with AML: Data from the UK NCRI AML17 Trial

On behalf of the UK NCRI AML Study Group.

Gemtuzumab Ozogamicin (GO) was the first antibody directed chemotherapy in cancer, but has had a chequered development in AML. We recently completed an individual patient data meta-analysis (Hills et al Lancet Oncology 15 (9): 986-96, 2014) which confirmed, in an analysis of the 5 randomised trials in adults, that simultaneous administration with induction chemotherapy significantly improved survival by reducing relapse risk in favourable and intermediate risk groups, but not in patients with adverse risk. The analysis further suggested that a single dose of 3mg/m² was as effective at preventing relapse as a 6mg/m² dose, while having less toxicity, and therefore may be the optimal dose level.

A question posed in the UK NCRI AML17 Trial was to directly compare 3mg/m² with 6mg/m² to ascertain whether efficacy or toxicity differences overall or within subgroups could be found. Between 06/2009 and 10/2011 788 patients were randomised: the median age was 50yrs (0-81, 29 <16yrs). 86% had de novo, 9% secondary disease and 5% MDS; 53% were male. 13% were favourable/ 69% intermediate, and 18% adverse cytogenetic risk; median presenting WBC was 9.2 (0.4-386); 18% had a FLT3 ITD and 28% had an NPM1c mutation. The associated chemotherapy was DA (3+10) (n=380) or ADE (10+3+5)(n=403); all children received ADE. GO was administered on day one of the induction chemotherapy. WBCs >30 could be cytoreduced with hydroxyurea or the GO delayed till day 4 of chemotherapy. Liver function biochemistry required to be <2XULN. Toxicity was defined as in NCICTC v.3.

Results:Eighty-seven percent of patients entered CR/CRi with no difference between the arms overall or with in any demographic subgroup (3mg 89% vs 6mg 85%; OR 1.34 (0.88-2.04), p=0.17). The 30-day (3% vs 7%; OR 2.04 (1.10-3.80), p=0.02) and 60-day mortality (5% vs 9%; OR 1.99 (1.17-3.39), p=0.01) were both increased in the 6mg arm. There were 18 vs 36 deaths within 60 days: causes were infection (10 vs 11); infection+haemorrhage (0 vs 1); haemorrhage 3 vs 4; resistant disease 2 vs 6; veno-occlusive disease 0 vs 5; cardiac 1 vs 3; pulmonary 2 vs 1; renal 0 vs 3; multiple 0 vs 2.Relapse free survival at 3 years was 44% overall and 45% for 3mg and 42% for 6mg (OR 1.11 (0.91-1.35), p=0.3). Overall survival at 3 years was 52% and 53% for 3mg and 50% for 6mg (OR 1.12 (0.91-1.36), p=0.3). There was no difference in mortality after day 60. Allografts were given to 324 patients, 183 in CR1, but the distribution on numbers and transplant type was not different between the arms. Neither the 3mg or 6mg dose caused excess post- transplant toxicity. No subgroup showed any suggestion of response or survival benefit from the 6mg dose with the exception of a non-significant benefit for both response rate (test for heterogeneity p=0.02) and overall survival (test for heterogeneity p=0.04) in the adverse cytogenetics patients (n=133).

When grade 3 or 4 toxicities are compared, ALT, creatinine and haematuria in course 1 (7% vs 17%; 1% vs 2%; 1% vs 2% respectively), were the only significant differences in courses 1 & 2. The requirement for red cell and platelet transfusions and days on antibiotics was increased in the 6mg patients in course 1, with slower platelet recovery in course 1. There were no significant grade 3 or 4 toxicity differences or supportive care required in course 2. Central assessment of VOD was confirmed as definite (n=17) or possible (n=5) in 22 of 395 (5.6%) patients on 6mg compared with 2 definite and 0 possible in 2 of 393 on the 3 mg arm (0.5%) (p<0.0001).

Conclusion: Although both the 3mg and 6mg dose have provided benefit when combined with induction chemotherapy, in this large randomised trial we found no benefit in giving a single 6mg/m² dose of GO when compared with 3mg/m², with the possible exception of in the adverse risk patients who showed no evidence of benefit in the recent meta-analysis. Although the difference in toxicity was modest and VOD, although increased, uncommon, this experience suggests that future studies should focussing on optimising the schedule for GO at the 3mg/m² dose, such as the fractionated approach developed by the French ALFA Group. Such studies are underway.

(We are grateful to CRUK for research funding for this trials and to Pfizer for the provision of gemtuzumab ozogamicin)