LANDSCAPE OF DRIVER MUTATIONS AND THEIR CLINICAL IMPACTS IN CHINESE PEDIATRIC PATIENTS WITH MATURE B‐CELL NON‐HODGKIN'S LYMPHOMA AND T‐CELL LYMPHOBLASTIC LYMPHOMA

Abstract

Introduction: Mature B-cell non-Hodgkin's lymphoma (MB-NHL) and T-cell lymphoblastic lymphoma (T-LBL) account for ∼50% and ∼20%, respectively, among the different pediatric NHL entities. Our understanding of the genetic lesions and profiling of these patients may help to improve the clinical management of patients with these lymphomas. The aim of this study is to analyze the mutational status and the associations between genetic features and treatment outcomes in the Chinese pediatric lymphoma cohort. Methods: A total of 207 patients treated at multiple clinical centers of the Chinese Children's Lymphoma Collaborative Group (CNCL) from 2017 to 2023 were included in this retrospective study. Targeted next-generation sequencing (t-NGS) with a panel of lymphoma-related genes was performed on tumor samples collected at the time of initial diagnosis and at tumor of refractory or relapse (r/r), and the correlations of somatic mutations with survival rates as well as with relapse and other clinical factors were analyzed. Results: A total of 136 driver genes with somatic mutations were detected in the entire cohort. In 133 pediatric MB-NHL patients, the most frequently mutated genes from 77 initially diagnostic samples were ID3 (52%), TP53 (47%), CCND3 (30%), ARID1A (29%), and DDX3X (27%) (Figure 1a). In 56 r/r samples, the most commonly mutated genes were TP53 (84%), followed by ID3 (59%), ARID1A (41%), CCND3 (32%), and DDX3X (25%) (Figure 1b). TP53 mutation was significantly more frequent in r/r samples than that in initially diagnostic samples (p < 0.001) and patients with TP53 mutations had poor survival (log-rank p = 0.0013, Figure 1c). Among patients treated with chimeric antigen receptor T-cell (CAR-T) therapy, those with ARID1A mutations exhibited poorer response to CAR-T treatment and shorter overall survival compared with the patients without such mutations (mOS = 180 days, log-rank p = 0.00081, Figure 1d). In 74 pediatric T-LBL patients,the most commonly mutated genes were NOTCH1 (50%), followed by FBXW7 (26%), JAK1 (16%), NRAS (16%), and JAK3 (11%) (Figure 1e). Genes in the JAK signaling pathway were more frequently mutated in Chinese patients than the corresponding western patients, such as JAK1 (16% vs. 2%) and JAK3 (11% vs. 5%). Further analysis showed that the incidence of NOTCH1 (68% vs. 27%) and FBXW7 (37% vs. 12%) mutations in patient group with initial remission (n = 41) was significantly higher than that in patient group with r/r T-LBL (n = 33) (p = 0.005, p = 0.036, respectively, Figure 1f), indicating that NOTCH1 and FBXW7mutations were associated with good prognosis. Keywords: diagnostic and prognostic biomarkers, immunotherapy, non-Hodgkin (pediatric, adolescent, and young adult) No conflicts of interests pertinent to the abstract.