Background
Phase III RCT enrolling 657 patients aged 17-60 with untreated AML (favorable risk 13.6%, intermediate 41.1%, indeterminate 26.6%, unfavorable 18.7%), randomized to compare standard- versus high-dose daunorubicin in induction.
Interventions and follow up
Arm A: Cytarabine 100mg/m2 x7d infusion + high-dose daunorubicin 90mg/m2 daily x3d
Arm B: Cytarabine 100mg/m2 x7d infusion + standard daunorubicin 45mg/m2 daily x3d; CR patients received alloHSCT or gemtuzumab ozogamicin followed by autoHSCT
Primary endpoint: Overall survival
mFollow up: 25.2mo
Arm B: Cytarabine 100mg/m2 x7d infusion + standard daunorubicin 45mg/m2 daily x3d; CR patients received alloHSCT or gemtuzumab ozogamicin followed by autoHSCT
Primary endpoint: Overall survival
mFollow up: 25.2mo
Results
mOS (all patients): 23.7mo vs 15.7mo, arm A vs B; multivariate HR 0.72, 95%CI 0.58–0.89; P=.002
mOS (favorable risk): not reached in either arm
mOS (intermediate risk): 32.3mo vs 17.8mo, arm A vs B; HR 0.67; P=.02
mOS (unfavorable risk): <11mo both arms, NS; HR 0.85; P=.45
Complete remission: 70.6% vs 57.3%, arm A vs B
Received consolidation: 57.8% vs 53.6%, arm A vs B
mOS (favorable risk): not reached in either arm
mOS (intermediate risk): 32.3mo vs 17.8mo, arm A vs B; HR 0.67; P=.02
mOS (unfavorable risk): <11mo both arms, NS; HR 0.85; P=.45
Complete remission: 70.6% vs 57.3%, arm A vs B
Received consolidation: 57.8% vs 53.6%, arm A vs B
Adverse events
Cardiac: Grade 3-5 cardiac toxicity 7.9% vs 7.2%; reduced LVEF 1.3% vs 0
Treatment-related mortality: Death during induction 5.5% vs 4.5%, P=.60 (no significant excess with the higher anthracycline dose)
Treatment-related mortality: Death during induction 5.5% vs 4.5%, P=.60 (no significant excess with the higher anthracycline dose)
Conclusions
Intensified induction with high-dose daunorubicin (90mg/m2) significantly improved complete remission and overall survival in younger AML patients, particularly those with favorable/intermediate-risk disease and age <50, without excess early mortality.
Key Limitations
No survival benefit in unfavorable-risk disease; restricted to patients ≤60 years; consolidation strategy heterogeneous (transplant vs gemtuzumab); benefit driven by specific molecular/cytogenetic subgroups identified in post hoc analyses.
Clinical Context
Established high-dose (90mg/m2) daunorubicin as a standard induction backbone in younger AML. A post hoc analysis showed patients with DNMT3A, NPM1, or FLT3-ITD mutations and those aged 50-60 also benefited. ELN guidelines support intensified anthracycline dosing in fit younger adults.