LAUSR

Despite high remission rates after CD19 CAR T-cell therapy in patients with refractory or relapsed B acute lymphoblastic leukemia (r/r B-ALL), relapses were commonly observed [1–4]. To improve long-term disease-free survival (DFS), our and other centers have conducted post-CD19 CAR consolidations with allogeneic hematopoietic stem cell transplantation (allo-HCT) or CD22 CAR T-cell infusion [5–9]. However, some patients still relapsed, but it is unknown which factors caused their relapses. TP53 mutation predicts nonresponse and poor outcome in childhood B-ALL during traditional therapies. Genomic instability caused by TP53 mutation induces leukemia cells to undergo genomic evolution to survive stress and treatment [10–12]. In our previous studies, CAR T therapy can overcome genetic adverse features including TP53 mutation to induce remission [5, 6], but it is unknown whether the long-term outcome would be influenced by TP53 mutation and other genetic aberrations. We analyzed the outcome of 68 r/r B-ALL children (characteristics in Supplementary Tables. 1 and 2) treated with CD19 CAR T cells and post-CAR consolidations of allo-HCT or CD22 CAR T-cell infusion between January 2nd, 2018 and April 19th 2019 in three trials. The details of trials, clinical procedure, and analysis methods were in supplemental methods pp1-8. Sixty-six patients (97.1%) achieved complete remission. With a median follow-up of 11.3 (range, 1–21) months, a promising one-year DFS of 79.6% (95% CI, 65.9–87.8) was achieved (Supplementary Fig. 1a), but 12 patients still relapsed within a median time of 6.3 (range, 1–11.4) months (Fig. 1a and Supplementary Fig. 1b). DFS was comparable between allo-HCT (n= 34) and CD22 CAR T (n= 30) consolidation subgroups (P= 0.232, Supplementary Fig. 1c). Next generation sequencing (NGS) of 339 driver gene mutations related to hematological neoplasm was conducted with samples from 56 patients at enrollment, and 6 matched patients at relapse (details in Supplemental methods pp8). Seventeen gene mutations were identified over three times. These authors contributed equally: Jing Pan, Qinlong Zheng, Xiaoming Feng