Fludarabine, Cytarabine, Granulocyte Colony-Stimulating Factor, and Idarubicin With Gemtuzumab Ozogamicin Improves Event-Free Survival in Younger Patients With Newly Diagnosed AML and Overall Survival in Patients With <i>NPM1</i> and <i>FLT3</i> Mutations.

Abstract

To determine the optimal induction chemotherapy regimen for younger adults with newly diagnosed AML without known adverse risk cytogenetics. One thousand thirty-three patients were randomly assigned to intensified (fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin [FLAG-Ida]) or standard (daunorubicin and Ara-C [DA]) induction chemotherapy, with one or two doses of gemtuzumab ozogamicin (GO). The primary end point was overall survival (OS). There was no difference in remission rate after two courses between FLAG-Ida + GO and DA + GO (complete remission [CR] + CR with incomplete hematologic recovery 93% <i>v</i> 91%) or in day 60 mortality (4.3% <i>v</i> 4.6%). There was no difference in OS (66% <i>v</i> 63%; <i>P</i> = .41); however, the risk of relapse was lower with FLAG-Ida + GO (24% <i>v</i> 41%; <i>P</i> < .001) and 3-year event-free survival was higher (57% <i>v</i> 45%; <i>P</i> < .001). In patients with an <i>NPM1</i> mutation (30%), 3-year OS was significantly higher with FLAG-Ida + GO (82% <i>v</i> 64%; <i>P</i> = .005). <i>NPM1</i> measurable residual disease (MRD) clearance was also greater, with 88% versus 77% becoming MRD-negative in peripheral blood after cycle 2 (<i>P</i> = .02). Three-year OS was also higher in patients with a <i>FLT3</i> mutation (64% <i>v</i> 54%; <i>P</i> = .047). Fewer transplants were performed in patients receiving FLAG-Ida + GO (238 <i>v</i> 278; <i>P</i> = .02). There was no difference in outcome according to the number of GO doses, although <i>NPM1</i> MRD clearance was higher with two doses in the DA arm. Patients with core binding factor AML treated with DA and one dose of GO had a 3-year OS of 96% with no survival benefit from FLAG-Ida + GO. Overall, FLAG-Ida + GO significantly reduced relapse without improving OS. However, exploratory analyses show that patients with <i>NPM1</i> and <i>FLT3</i> mutations had substantial improvements in OS. By contrast, in patients with core binding factor AML, outcomes were excellent with DA + GO with no FLAG-Ida benefit.