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

• Published in: Cancer cell international Vol. 23; no. 1; pp. 1 - 281
• Main Authors: Li, Yang, Liu, Yang, Yang, Keyan, Jin, Ling, Yang, Jing, Huang, Shuang, Liu, Ying, Hu, Bo, Liu, Rong, Liu, Wei, Liu, Ansheng, Zheng, Qinlong, Zhang, Yonghong
• Format: Journal Article
• Language: English
• Published: London BioMed Central 19.11.2023; BMC
• Subjects: B-cell lymphoma; CAR-T cell therapies; Cell cycle; Cell survival; Cell therapy; Chemotherapy; Children; Chimeric antigen receptors; Gene mutations; Hodgkin's lymphoma; Lymphocytes; Lymphocytes B; Lymphocytes T; Lymphoma; Medical prognosis; Mutation; Next-generation sequencing; p53 Protein; Patients; Pediatric B-cell non-hodgkin Lymphomas; Pediatrics; Remission (Medicine); Survival analysis; Tumors
• ISSN: 1475-2867; 1475-2867
• DOI: 10.1186/s12935-023-03122-2

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.