Prognostic significance of NOTCH1/FBXW7 mutations in pediatric T cell acute lymphoblastic leukemia: a study of minimal residual disease risk-directed CCLG-ALL 2008 treatment protocol

Abstract

NOTCH1/FBXW7 mutation is common in T-cell acute lymphoblastic leukemia (T-ALL), but controversy looms on its prognostic significance. We screened 98 pediatric T-ALL patients treated on minimal residual disease (MRD) risk-directed CCLG-ALL 2008 protocol. NOTCH1/FBXW7 mutations were analyzed by Sanger sequencing, and MRD was evaluated by flow cytometry. In overall, 51.02 and 8.75% of patients harbored NOTCH1 and FBXW7 mutations respectively. More favorable 10-year overall survival (OS), event-free survival (EFS), and disease-free survival (DFS) were seen in NOTCH1^mut patients (NOTCH1^mut vs. NOTCH1^wt, OS, 82.7 ± 5.6% vs. 62.4 ± 7.4%, p = .020; EFS, 80.9 ± 5.8 vs. 48.4 ± 7.8%, p = .001; DFS, 82.9 ± 5.6 vs. 52.9 ± 7.7%, p = .001). NOTCH1 gene status and MRD post-induction were identified as independent prognostic factors. A combination of NOTCH1 gene status and MRD could distinguish patients with NOTCH1 mutations and MRD < 1 × 10⁻⁴ with 100% OS, EFS, and DFS. These results indicated NOTCH1 mutation predicted a favorable outcome in pediatric T-ALL and may be considered a risk stratification factor.

Keywords:

• T-ALL
• pediatric
• NOTCH1
• FBXW7
• outcome

Acknowledgments

The authors thank all of the patients and their families for their kind cooperation. We thank all of the members of the clinical team who provided care for patients. We thank Dr. Yaguang Peng in Center for Clinical Epidemiology and Evidence-based Medicine in Beijing Children’s Hospital to provide some statistical guidance.

Research consent

Informed consents were obtained from parents or guardians of each patient.

Author contribution

YY and LJ conceived and designed the study, performed the experiments, interpreted the data, and contributed to the manuscript writing. XTL and LSG analyzed the NOTCH1 and FBXW7 sequencing data. HHR helped to collect data. ZRD, ZHY, and LW provided study materials or patients. GC and ZHY coordinated the research and take primary responsibility for the article.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported by the National Natural Science Foundation of China (NSFC) [No.82070154], National Science and Technology Key Projects [No. 2017ZX09304029004], The National Science Foundation of China (NSFC) [No.82170150 and No.82070154], Beijing Municipal Science and Technology Commission [No. 7192066], and Children’ s Medicine Research Project of Beijing Children’s Hospital, Capital Medical University [No. YZZD202006].