Optimal minimal residual disease threshold in pediatric acute myeloid leukemia: A retrospective cohort study based on the TARGET database.
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BACKGROUND: Minimal residual disease (MRD) monitoring is a cornerstone of risk stratification in pediatric acute myeloid leukemia (AML), with a threshold of 0.1% conventionally defining positivity by flow cytometry. Advances in flow cytometric technologies, enabling detection of leukemic cells with higher sensitivity and specificity, warrant a reevaluation of whether a lower threshold improves prognostic accuracy. METHODS AND FINDINGS: We conducted a retrospective cohort study using data from the Therapeutically Applicable Research to Generate Effective Treatments (TARGET)-AML initiative. The study population comprised 1,205 pediatric patients with de novo AML treated across Children's Oncology Group (COG) clinical trial centers. Patients were enrolled between September 1996 and December 2016, with a median follow-up of 6.2 years (range: 0.5-20.1 years). The primary objective was to compare the prognostic performance of the traditional MRD threshold (≥0.1%) with a lower threshold (≥0.05%) after induction courses 1 and 2. The main outcome measure was 5-year event-free survival (EFS). Analyses included Kaplan-Meier survival estimates, Cox proportional hazards models to calculate hazard ratios (HR) with 95% confidence intervals (CI), receiver operating characteristic (ROC) curves, and net reclassification improvement (NRI). The optimal threshold for predicting 5-year EFS, determined by ROC analysis, was 0.05% after both induction course 1 (AUC: 0.840, 95%CI[0.76,0.88]) and course 2 (AUC: 0.854, 95%CI[0.78,0.89]). The 0.05% threshold demonstrated higher HR for the first event than the 0.1% threshold (after course 1: HR = 2.8, 95%CI[2.3,3.3]; P < 0.001; after course 2: HR = 3.7, 95%CI[3.0,4.6]; P < 0.001). NRI analysis confirmed significant improvement in risk classification with the 0.05% threshold (overall NRI: 0.15 after course 1, 0.18 after course 2). The main limitation of this study is its retrospective design using historical data from trials conducted over 20 years, which may limit generalizability to contemporary treatments. CONCLUSIONS: A lower MRD threshold of 0.05% provides superior prognostic discrimination compared to the conventional 0.1% threshold in pediatric AML treated in previous COG trials. These findings support testing this more sensitive threshold in future clinical trial designs for improved risk-adapted therapy.