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 NPM1 and FLT3 Mutations

Abstract

Purpose: To determine the optimal induction chemotherapy regimen for younger adults with newly diagnosed AML without known adverse risk cytogenetics.

Patients and methods: 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).

Results: 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% v 91%) or in day 60 mortality (4.3% v 4.6%). There was no difference in OS (66% v 63%; P = .41); however, the risk of relapse was lower with FLAG-Ida + GO (24% v 41%; P < .001) and 3-year event-free survival was higher (57% v 45%; P < .001). In patients with an NPM1 mutation (30%), 3-year OS was significantly higher with FLAG-Ida + GO (82% v 64%; P = .005). NPM1 measurable residual disease (MRD) clearance was also greater, with 88% versus 77% becoming MRD-negative in peripheral blood after cycle 2 (P = .02). Three-year OS was also higher in patients with a FLT3 mutation (64% v 54%; P = .047). Fewer transplants were performed in patients receiving FLAG-Ida + GO (238 v 278; P = .02). There was no difference in outcome according to the number of GO doses, although NPM1 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.

Conclusion: Overall, FLAG-Ida + GO significantly reduced relapse without improving OS. However, exploratory analyses show that patients with NPM1 and FLT3 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.

Trial registration: ClinicalTrials.gov ISRCTN78449203.

FIG 1.

CONSORT diagram. APL, acute pyomyeloctic leukemia; DA, daunorubicin and Ara-C; FLAG-Ida, fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin; GO, gemtuzumab ozogamicin; HDAC, high-dose cytarabine; LFT, liver function tests.

FIG 2.

Trial schema and treatment protocols. APL, acute promyelocytic leukemia; CR, complete remission; DA, daunorubicin and Ara-C; FLAG-Ida, fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin; G-CSF, granulocyte colony-stimulating factor; GO, gemtuzumab ozogamicin; HDAC, high-dose cytarabine; MRD, measurable residual disease; PB, peripheral blood; ULN, upper limit of normal; WCC, white cell count.

FIG 3.

(A) OS, (B) EFS, (C) CIR, and (D) CIDCR by randomization arm (DA + GO v FLAG-Ida + GO). CIDCR, cumulative incidence of death in remission; CIR, cumulative incidence of relapse; CR, complete remission; DA, daunorubicin and Ara-C; EFS, event-free survival; FLAG-Ida, fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin; GO, gemtuzumab ozogamicin; OS, overall survival.

FIG 4.

(A) OS and (B) EFS in NPM1-mutated AML, (C) OS and (D) EFS in FLT3-mutated AML, and (E) forest plot of OS in NPM1-mutated AML stratified by FLT3 status. Unadjusted analysis of patients receiving GO1/GO2. Unadjusted analyses with DA as referent and FLT3 grouping TKD and ITD patients receiving GO1/GO2. DA, daunorubicin and Ara-C; EFS, event-free survival; FLAG-Ida, fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin; GO, gemtuzumab ozogamicin; HR, hazard ratio; ITD, internal tandem duplication; OS, overall survival; TKD, tyrosine kinase domain.