CD33 expression combined with D15-MRD positivity identifies poor prognosis in children with ETV6::RUNX1-positive ALL.

While ETV6::RUNX1-positive acute lymphoblastic leukemia (ALL) is generally associated with favorable outcomes, a subset of patients experience relapse despite receiving standard therapy, underscoring the need for early biomarkers to identify high-risk subgroups. In this retrospective study of 345 consecutive pediatric patients with ETV6::RUNX1-positive ALL treated in accordance with the protocol of the Chinese Children's Leukemia Group (CCLG-ALL 2008), CD33 expression (CD33+) on leukemic blasts was detected in 55.9% of patients and was significantly associated with minimal residual disease (MRD) positivity on day 15 (D15-MRD-positive) (65.2% vs. 42.0%, P < 0.001). Multivariate analysis revealed CD33+ status as an independent risk factor for D15-MRD positivity (odds ratio (OR) = 2.66, 95% confidence interval (CI) 1.66-4.26). Among CD33+ patients, those who were D15-MRD-positive had significantly inferior 5-year and 10-year event-free survival (EFS) relative to those who were D15-MRD-negative (5-year EFS: 91.9% ± 2.4% vs. 100%, P = 0.027; 10-year EFS: 89.2% ± 3.0% vs. 100%, P = 0.014). This prognostic association was not observed in CD33-negative patients. In conclusion, the combination of CD33+ and D15-MRD-positivity may identify a distinct high-risk subgroup within ETV6::RUNX1-positive ALL. Early intervention, potentially including CD33-directed therapy, may represent a promising strategy to improve outcomes in this subgroup, although further validation is warranted.