Higher NOTCH1 Mutation Load Reveals Favorable Prognosis in Pediatric T-Cell Acute Lymphoblastic Leukemia

Background: Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy, approximately 10-15% of which are derived from T cell precursors and/or immature T-cells. Previously, gene mutations were identified to be associated with the risk stratification, treatment response, and prognosis of pediatric T-ALL patients. NOTCH1 was the most common gene mutation in T-ALL patients. Previous studies only fucosed on the influence of NOTCH1 mutation on the prognosis of pediatric T-ALL, few studies explored the role of variant allele frequency (VAF) in NOTCH1 mutation.

Methods: We retrospectively reviewed children diagonsed as T-ALL in our center from April 2012 to November 2022. All included patients performed RNA sequencing (RNA-seq) using samples collected at diagnosis. Overall survival (OS) was calculated and compared by Kaplan-Meier analysis and log-rank tests. The primary objective of this study was to compare the influence of VAF in NOTCH1 mutation on the prognosis of pediatric T-ALL.

Results: A total of 123 children were enrolled. Among these patients, 98 were male and 25 were female, with a ratio of 3.9:1. The median age of all patients at diagnosis were 8.0 years (range 1.2-16.8 years). The median white blood cell (WBC) at diagnosis were 106.33 (range 1.05-750.20). The median hemoglobin and platelet count at diagnosis were 98.50 (range 37.00-159.00) and 63.00 (range 5.00-412.00), respectively. Regarding to the immunophenotype, there were 7 early thymic precursor (ETP) and 116 non-ETP. Sixty-one of 123 (49.5%) patients have NOTCH1 mutation, which did not influence the 5-year OS (77.1% ± 5.67% vs 74.2% ± 6.01%, P=0.81). Based on the maximally selected log-rank statistic, mean VAF was found to be the cutoff point for differentiating patient prognosis. Patients with a higher mutation load (VAF≥20%, n=37) had superior 5-year OS when compared to patients carrying a lower mutation load (VAF＜20%, n=24)(88.9% ± 5.23% vs 61.7% ± 10.1%, P=0.027).Conclusion: Our study indicated that NOTCH1 mutation did not influence the prognosis of children with T-ALL. While higher NOTCH1 mutation load may have a favorable prognosis, which may contribute to the risk stratification of pediatric T-ALL. Larger-scale and prospective randomized studies are warranted to further evaluate this conclusion.

No relevant conflicts of interest to declare.