In the phase III AML2012 trial, which had early termination of enrollment and results of which were reported in the Journal of Clinical Oncology, Tierens et al found that mitoxantrone-based induction resulted in better outcomes vs liposomal daunorubicin–based induction in pediatric patients with acute myeloid leukemia.
Study Details
The study was planned to randomly assign 300 patients; however, production of liposomal daunorubicin stopped in 2017, preventing full enrollment. A total of 194 patients from sites in 11 countries were randomly assigned to receive induction with mitoxantrone plus etoposide/cytarabine (MEC; n = 97) or liposomal daunorubicin plus etoposide/cytarabine (DxEC; n = 97). Measurable residual disease (MRD) was determined by flow cytometry after induction. The primary endpoint of the study was the proportion of patients with MRD < 0.1% on day 22 after induction 1. Patients with MRD ≥ 15% after induction 1 or ≥ 0.1% after induction 2 or FLT3-ITD with wild-type NPM1 were stratified to high-risk therapy with hematopoietic stem cell transplantation (HSCT).
Key Findings
Overall, 75% of patients were stratified as standard risk and 19% as high risk. No significant difference was observed between the MEC group vs DxEC group in proportions of patients with MRD < 0.1% on day 22 after induction 1 (34% vs 30%, P = .65); however, at the last evaluation before induction 2, the proportions were 61% in the MEC group vs 47% in the DxEC group (P = .061).
Median follow-up was 71 months. Among all patients, 5-year event-free survival was 71.9% in the MEC group vs 56.6% in the DxEC group (hazard ratio [HR] for DxEC vs MEC = 1.63, 95% confidence interval [CI] = 1.01–2.64, P = .042), with a cumulative incidence of relapse of 18.8% vs 35.1%. Overall survival at 5 years was 82.3% vs 73.0% (P = .13)
Outcomes more strongly favored the MEC group among standard-risk patients; 5-year event-free survival was 79.9% vs 55.3% (HR for DxEC vs MEC = 2.56, 95% CI = 1.39–4.70, P = .002), cumulative incidence of relapse was 18.7% vs 39.5% (HR = 2.04, 95% CI = 1.17–3.55, P = .012), and 5-year overall survival was 88.6% vs 76.2% (HR = 2.21, 95% CI = 0.96–5.10, P = .055). Among all high-risk patients, 85% received HSCT; 5-year event-free survival was 77.7%, and 5-year overall survival was 83.0%.
The investigators concluded, “The intensification of induction therapy with risk stratification on the basis of response to induction and HSCT for high-risk patients led to improved outcomes. Mitoxantrone had a superior antileukemic effect than liposomal daunorubicin.”
Jonas Abrahamsson, MD, PhD, of the Institution for Clinical Sciences, Department of Pediatrics, Sahlgrenska Academy, University of Gothenburg, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was financed by grants from the Swedish Children’s Cancer Foundation and others. For full disclosures of the study authors, visit ascopubs.org.
