[The value of minimal residual disease-guided risk stratification in different subtypes of pediatric B-cell acute...

Objective: To evaluate the clinical value of minimal residual disease (MRD)-guided risk stratification in different subtypes of pediatric B-cell acute lymphoblastic leukemia (B-ALL). Methods: In this retrospective cohort study, a total of 666 newly diagnosed B-ALL children admitted to the Children's Hospital, Zhejiang University School of Medicine between October 2018 and June 2023 were enrolled. Risk stratification (low, intermediate, and high risk) and treatment were conducted according to the Zhejiang Children's Hospital acute lymphoblastic leukemia (ZJCH-ALL)-2019 protocol. Based on the cytogenetic and molecular biological characteristics of leukemia cells, patients were categorized into three groups: ETV6::RUNX1 fusion gene-positive group, hyperdiploid group, and non-ETV6::RUNX1 and non-hyperdiploid B-ALL (NENH-B-ALL) group. The adjustments in risk stratification based on MRD levels across these groups were analyzed. The value of MRD-based risk adjustment strategies in different B-ALL subgroups was assessed using Kaplan-Meier survival analysis and the Cox proportional hazards model. Results: Among the 666 patients, there were 379 males and 287 females, with the age of onset 4.7 (3.2, 7.6) years. The ETV6::RUNX1-positive, hyperdiploid, and NENH-B-ALL groups comprised 168 (25.2%), 199 (29.9%) and 293 (44.0%) patients, respectively; additionally, 6 patients exhibited both hyperdiploidy and ETV6::RUNX1 positivity. Risk stratification was adjusted based on MRD levels on day 15 and day 29 in 153 (23.0%) and 5 (0.8%) patients, respectively. The 5-year overall survival (OS) and event-free survival (EFS) rates for all 666 patients were (95.9±0.8)% and (92.1±1.2)%, respectively. Notably, EFS was significantly superior in the ETV6::RUNX1-positive and hyperdiploid groups compared to NENH-B-ALL group ((97.6±1.2)% and (96.5±1.4)% vs. (85.6±2.4)%, P<0.001). In the ETV6::RUNX1-positive group, the 5-year EFS rates for the low, intermediate, and high-risk groups were 100%, (98.5±1.5)%, and (80.0±10.7)%, respectively (P<0.001). In the hyperdiploid group, the 5-year EFS rates were (96.7±1.9)%, 100%, and (87.7±6.7)% (P<0.001). In the NENH-B-ALL group, the 5-year EFS rates were (97.2±1.9)%, (85.8±3.6)%, and (74.4±5.4)% (P<0.001). Multivariate analysis identified age ≥10 years (HR=3.37, 95%CI 1.81-6.27), initial white blood cell count ≥50×10⁹/L (HR=2.31, 95%CI 1.24-4.32), MRD ≥0.1% on day 15 (HR=1.88, 95%CI 1.01-3.49), MRD ≥0.01% on day 29 (HR=2.72, 95%CI 1.19-6.21), and NENH-B-ALL subtypes (HR=1.66, 95%CI 1.16-2.39) as independent adverse prognostic factors (all P<0.05). Conclusions: In patients with ETV6::RUNX1 positivity or hyperdiploidy, after MRD-guided risk stratification and treatment intensification enabled intermediate-risk patients to achieve survival rates comparable to those of low-risk patients. Conversely, in NENH-B-ALL, although MRD effectively stratified patients into low, intermediate and high-risk groups, treatment adjustments failed to eliminate the prognostic disparities.