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Simple Summary  The genetic landscape of diffuse large B-cell lymphoma (DLBCL) is heterogenous. So far, detailed studies about  TP53  mutations in DLBCL treated with anti-CD19 chimeric antigen receptor T-cell (CAR T cells) therapy are still missing. Chemotherapy resistance is one of the challenges in  TP53  mutated tumors. New immunomodulatory agents, such as different inhibitors or CAR T cells, have shown durable responses in refractory/relapsed DLBCL in recent years. Although our CAR T cell treated cohort was small, we aimed to investigate the influence of  TP53  mutations on overall survival of patients treated with CAR T cells compared to DLBCL patients without CAR T-cell therapy. Identification of risk factors for treatment failure may aid in choosing the most promising treatment in every setting.    Abstract  Refractory/relapsed diffuse large B-cell lymphoma (DLBCL) is associated with poor outcome. The clinical behavior and genetic landscape of DLBCL is heterogeneous and still not fully understood.  TP53  mutations in DLBCL have been identified as markers of poor prognosis and are often associated with therapeutic resistance. Chimeric antigen receptor T-cell therapy is an innovative therapeutic concept and represents a game-changing therapeutic option by supporting the patient’s own immune system to kill the tumor cells. We investigated the impact of  TP53  mutations on the overall survival of refractory/relapsed DLBCL patients treated with comparable numbers of therapy lines. The minimum number of therapy lines was 2 (median 4), including either anti-CD19 CAR T-cell therapy or conventional salvage therapy. A total of 170 patients with DLBCL and high-grade B-cell lymphoma with  MYC, BCL2,  and/or  BCL6  rearrangements (DHL/THL), diagnosed and treated in our hospital between 2000 and 2021, were included. Twenty-nine of them received CAR T-cell therapy.  TP53  mutations were found in 10/29 (35%) and 31/141 (22%) of patients in the CAR T-cell and conventional groups, respectively. Among the 141 patients not treated with CAR T cells,  TP53  mutation was an independent prognostic factor for overall survival (OS) (median 12 months with  TP53  vs. not reached without  TP53  mutation,  p  < 0.005), but in the CAR T cell treated group, this significance could not be shown (median OS 30 vs. 120 months,  p  = 0.263). The findings from this monocentric retrospective study indicate that  TP53  mutation status does not seem to affect outcomes in DLBCL patients treated with CAR T-cell therapy. Detailed evaluation in large cohorts is warranted.

Influence of TP53 Mutation on Survival of Diffuse Large B-Cell Lymphoma in the CAR T-Cell Era