Background
Phase 3 randomized trial, Children’s Oncology Group. N=721 eligible patients aged ≤21 yr with newly diagnosed de novo FLT3 wild-type AML (DA 358; CPX-351 363). Tested whether liposomal daunorubicin/cytarabine (CPX-351) improves outcomes over standard anthracycline/cytarabine induction. Prespecified interim analysis crossed the futility boundary and the randomization was stopped early.
Results
Interventions and follow up: Arm A: Standard DA induction × 2 cycles — daunorubicin + cytarabine.
Arm B: CPX-351 (liposomal daunorubicin/cytarabine) × 2 induction cycles.
Both arms: gemtuzumab ozogamicin in induction 1. Post-induction therapy by end-of-induction-1 (EOI1) risk assignment — high-risk to allogeneic HSCT, low-risk to chemotherapy alone.
Primary endpoint: EFS from study entry.
mFollow up: NR.
Results: 2yr EFS: 62.2% (DA) vs 51.2% (CPX-351), P=.011 — favouring standard DA.
2yr DFS from EOI1, low-risk: 73.8% (DA) vs 57.5% (CPX-351), P=.001.
2yr CIR, low-risk: 23.6% (DA) vs 39.9% (CPX-351), P=.001.
DFS, high-risk: comparable between arms.
OS: NR.
Arm B: CPX-351 (liposomal daunorubicin/cytarabine) × 2 induction cycles.
Both arms: gemtuzumab ozogamicin in induction 1. Post-induction therapy by end-of-induction-1 (EOI1) risk assignment — high-risk to allogeneic HSCT, low-risk to chemotherapy alone.
Primary endpoint: EFS from study entry.
mFollow up: NR.
Results: 2yr EFS: 62.2% (DA) vs 51.2% (CPX-351), P=.011 — favouring standard DA.
2yr DFS from EOI1, low-risk: 73.8% (DA) vs 57.5% (CPX-351), P=.001.
2yr CIR, low-risk: 23.6% (DA) vs 39.9% (CPX-351), P=.001.
DFS, high-risk: comparable between arms.
OS: NR.
Adverse events
Myelosuppression: CPX-351 with concurrent gemtuzumab ozogamicin produced additive marrow suppression with delayed count recovery and delays to continuation therapy.
Grade ≥3 rates by category: NR in abstract.
Treatment-related mortality: NR in abstract.
Grade ≥3 rates by category: NR in abstract.
Treatment-related mortality: NR in abstract.
Conclusions
CPX-351 induction was inferior to standard daunorubicin/cytarabine in de novo pediatric AML, and the randomization was closed early for futility. The EFS difference was driven almost entirely by excess relapse among low-risk patients, while high-risk outcomes were comparable. Standard DA induction remains the pediatric standard of care.
Key Limitations
Interim futility stop limits precision of the effect estimate and precludes mature OS. CPX-351 was dosed at 60 mg/m²/dose and combined with gemtuzumab ozogamicin in induction 1, so additive myelosuppression and the resulting delays in marrow recovery and continuation therapy confound the regimen comparison — the result may indict this backbone rather than the drug. Reported baseline imbalance: the CPX-351 arm carried more CNS disease and fewer favourable core-binding-factor patients. Restricted to FLT3 wild-type AML. Risk assignment was made at EOI1, a post-randomization variable, so the low-risk DFS and CIR comparisons are not fully randomized subgroups.
Clinical Context
CPX-351 (Vyxeos) is FDA approved for newly diagnosed therapy-related AML and AML with myelodysplasia-related changes, in adults and in pediatric patients aged ≥1 yr, on the basis of adult phase 3 data. AAML1831 shows that this benefit does not extend to de novo pediatric AML treated on a gemtuzumab-containing backbone. Conventional anthracycline/cytarabine induction remains the COG and NCCN-endorsed pediatric standard, and these data argue against substituting CPX-351 in de novo pediatric AML outside its approved indications.