Cancer Cell International (Nov 2023)

Impact of ARID1A and TP53 mutations in pediatric refractory or relapsed mature B-Cell lymphoma treated with CAR-T cell therapy

  • Yang Li,
  • Yang Liu,
  • Keyan Yang,
  • Ling Jin,
  • Jing Yang,
  • Shuang Huang,
  • Ying Liu,
  • Bo Hu,
  • Rong Liu,
  • Wei Liu,
  • Ansheng Liu,
  • Qinlong Zheng,
  • Yonghong Zhang

DOI
https://doi.org/10.1186/s12935-023-03122-2
Journal volume & issue
Vol. 23, no. 1
pp. 1 – 12

Abstract

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Abstract Background Chimeric antigen receptor (CAR)-T cell therapy has been used to treat pediatric refractory or relapsed mature B-cell non-Hodgkin lymphoma (r/r MB-NHL) with significantly improved outcomes, but a proportion of patients display no response or experience relapse after treatment. To investigate whether tumor-intrinsic somatic genetic alterations have an impact on CAR-T cell treatment, the genetic features and treatment outcomes of 89 children with MB-NHL were analyzed. Methods 89 pediatric patients treated at multiple clinical centers of the China Net Childhood Lymphoma (CNCL) were included in this study. Targeted next-generation sequencing for a panel of lymphoma-related genes was performed on tumor samples. Survival rates and relapse by genetic features and clinical factors were analyzed. Survival curves were calculated using a log-rank (Mantel-Cox) test. The Wilcox sum-rank test and Fisher’s exact test were applied to test for group differences. Results A total of 89 driver genes with somatic mutations were identified. The most frequently mutated genes were TP53 (66%), ID3 (55%), and ARID1A (31%). The incidence of ARID1A mutation and co-mutation of TP53 and ARID1A was high in patients with r/r MB-NHL (P = 0.006; P = 0.018, respectively). CAR-T cell treatment significantly improved survival in r/r MB-NHL patients (P = 0.00081), but patients with ARID1A or ARID1A and TP53 co-mutation had poor survival compared to those without such mutations. Conclusion These results indicate that children with MB-NHL harboring ARID1A or TP53 and ARID1A co-mutation are insensitive to initial conventional chemotherapy and subsequent CAR-T cell treatment. Examination of ARID1A and TP53 mutation status at baseline might have prognostic value, and risk-adapted or more effective therapies should be considered for patients with these high-risk genetic alterations.

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