AbstractBackgroundTP53 mutations have a prognostic significance in relapsed and refractory diffuse large B‐cell lymphoma (rrDLBCL) patients, and their treatment still faces a great challenge. This study aimed to evaluate the prognosis of patients with TP53 mutations (TP53mut) in the context of CAR‐T therapy (Chimeric antigen receptor T‐cell therapy) as well as explore the heterogeneity in their cohort and identify the possible risk factors.MethodsA retrospective study was conducted to investigate the clinical characteristics of rrDLBCL patients withTP53mutations and their prognostic factors, receiving CAR‐T therapy. And the expression level of TP53 and DDX3X, which was an important co‐mutation of TP53 revealed in the cohort, were explored in public databases and cell lines.ResultsThe median overall survival time of 40 patients withTP53mutations was 24.5 months, while their median progression‐free survival time after CAR‐T was 6.8 months. There were no significant differences in the ORR (objective remission rate,X2= 3.0498,p> 0.05) and PFS (after CAR‐T therapy) between the patients with wild‐type and mutatedTP53genes after CAR‐T therapy, while the OS of patients withTP53mutations was significantly worse (p< 0.01). In patients withTP53mutations, the performance status (ECOG score) was identified as the most important prognostic factor, while the efficacies of induction and salvage treatments were also correlated with the prognosis. Among molecular indicators, the co‐mutations of Chr‐17 and those located on the exon 5 of theTP53gene showed a tendency for a worse prognosis. Moreover, the patients withTP53‐DDX3Xco‐mutations were identified as a subgroup with an extremely bad prognosis. The expression levels ofDDX3XandTP53were explored in a public database and the cell lines with their co‐mutations, which indicated that inhibiting theDDX3Xgene could affect the proliferation of rrDLBCL cells and the expression of TP53.ConclusionsThis study indicated rrDLBCL patients with TP53 mutations was still the group of poor prognosis in the CAR‐T therapy era. CAR‐T therapy can benefit some TP53mut patients, and the performance status (ECOG) might help predict their prognosis. The study also revealed a subgroup of TP53‐DDX3X co‐mutations in rrDLBCL, which showed a strong clinical significance.