Fractionated Versus Single Dose Gemtuzumab Ozogamicin with Determinants of Benefit in Older AML: UK NCRI AML18 Trial.
Freeman SD., Thomas A., Thomas I., Hills RK., Vyas P., Gilkes AF., Metzner M., Jakobsen NA., Kennedy A., Moore AR., Marquez-Almuina N., Burns S., King S., Andrew G., Gallagher KME., Sellar RS., Cahalin PA., Weber D., Dennis M., Mehta P., Knapper S., Russell NH.
Addition of gemtuzumab ozogamicin (GO) to induction chemotherapy improves outcomes in older patients with acute myeloid leukemia (AML) but it is uncertain whether a fractionated schedule provides additional benefit to a single dose. We randomised 852 older adults (median age 68yrs) with AML/high risk myelodysplasia to GO on day 1 (GO1), or on days 1 and 4 (GO2) of course-1 induction. Median follow-up was 50.2 months. While complete remission rates post course 1 did not significantly differ between arms (GO2 63%, GO1 57%, OR 0.78 (0.59-1.03), P=0.08), there were significantly more patients who achieved CR with MRD <0.1% (50% vs 41% OR 0.72 (0.54-0.96) P=0.027). This differential MRD reduction with GO2 varied across molecular subtypes being greatest for IDH mutations. 5yr overall survival (OS) was 29% for GO2 and 24% for GO1 patients (HR 0.89, P=0.14). In a sensitivity analysis excluding patients found to have adverse cytogenetics /TP53 mutations, 5yr OS was 33% for GO2 and 26% for GO1 (HR 0.83, P=0.045). 228 (27%) patients received an allo-transplant in first remission. OS was superior for transplanted patients on the GO2 arm (HR 0.67, 95%CI 0.47-0.97, P=0.033) however this benefit was lost when patients were censored at transplant. In conclusion, GO2 was associated with greater reduction in MRD and improved survival in older adults with non-adverse risk genetics. This benefit from GO2 was dependent on allo-transplant to translate the better leukemia clearance into improved survival. CT# ISRCTN 31682779.