Impact of TP53 mutations on survival outcomes in the CAR-t era of large b-cell lymphoma

Abstract Background: TP53 mutations are associated with poor prognosis and treatment resistance in diffuse large B-cell lymphoma (DLBCL). Chimeric antigen receptor T-cell (CAR-T) therapy offers a novel approach for relapsed/refractory large B-cell lymphoma (r/r LBCL). However, whether CAR-T therapy can overcome the adverse impact of TP53 mutations remains unclear due to inconsistent data from prior studies. Objectives To evaluate the prognostic significance of TP53 mutations in the context of CAR-T therapy and assess whether CAR-T therapy mitigates the negative impact of TP53 mutations on treatment outcomes. Methods This retrospective study included 195 adult patients with r/r LBCL who underwent next-generation sequencing (data cutoff: March 25, 2025). Based on TP53 mutation status and treatment received, patients were classified into four groups: TP53-mutant + CAR-T (n=53), TP53-mutant + non-CAR-T (n=22), TP53 wild-type + CAR-T (n=99), and TP53 wild-type + non-CAR-T (n=21). The median age was 54 years; 91% had stage III–IV disease, and 64% were of the non-GCB subtype. Comprehensive mutational profiling was performed using NGS, but only TP53 mutations were included in the present analysis, as they were preselected as the primary genomic variable of interest.Treatment responses, including ORR and CRR, were assessed approximately 3 months after CAR-T infusion using the Lugano 2014 criteria. Progression-free survival (PFS) and overall survival (OS) were also evaluated.Kaplan–Meier and log-rank tests were used for survival analysis, and Cox regression was applied for univariate analysis. Results The median follow-up for the entire cohort was 42.81 months.Among 152 CAR-T–treated patients, the overall objective response rate (ORR) was 49.3% (75/152), and the complete response rate (CRR) was 36.8% (56/152).Cytokine release syndrome (CRS) of any grade occurred in 124 (81.6%), while 13 (8.6%) experienced grade ≥3 CRS. Immune effector cell-associated neurotoxicity syndrome (ICANS) of any grade was reported in 7 (4.6%), including 4 (2.6%) with grade ≥3 events. In the TP53-mutant + CAR-T group (n=53), the ORR was 30/53 (56.6%), and the CRR was 21/53 (39.6%). Median overall survival (OS) was 12.13 months(95%CI:8.33-15.93), and median progression-free survival (PFS) was 6.87 months(95%CI:1.75-12.00).The 1-year OS rate was 52.6%, and the 1-year PFS rate was 31.8% .In the TP53-mutant + non-CAR-T group (n=22), the ORR was 5/22 (23%), and the median OS was 1.87(95%CI:0.21-3.54) months.Among TP53 wild-type patients, the CAR-T group (n=99) had an ORR of 47/99 (47%), CRR of 37/99 (37%), median OS of 25.15 months(95%CI:13.46-36.85), and PFS of 10.16 months (95%CI:4.36-15.95) .The 1-year OS and PFS rates were 62.4% and 46.3%, respectively; the 2-year OS and PFS rates were 50.6% and 39.6%, respectively.The non-CAR-T group (n=22) had an ORR of 3/22 (14.3%), and a median OS of 7.79 months(95%CI:1.78-13.81). For TP53-mutant patients, CAR-T therapy significantly prolonged OS compared to non-CAR-T treatment (12.13 vs. 2.04 months, p0.0001). A similar benefit was observed in TP53 wild-type patients (25.15 vs. 8.28 months, p=0.0030).Within the CAR-T–treated population, patients with TP53 mutations had a median OS of 12.13 months, compared to 25.15 months in the TP53 wild-type group (p = 0.3423). Similarly, the median PFS was 6.87 months in the TP53-mutant group and 10.16 months in the wild-type group (p = 0.297). These differences were not statistically significant. Univariate analysis identified IPI ≥3 (p=0.011, HR=2.814) and double/triple-hit status (p=0.025, HR=2.229) as predictors of poor survival. Among TP53-mutant patients, non-GCB subtype was associated with improved OS (p=0.006, HR=0.301), and CAR-T therapy remained a strong favorable factor (p0.0001, HR=0.102). Conclusion These findings provide clinical evidence supporting CAR-T therapy in genomically high-risk patients. CAR-T cell therapy significantly improved overall survival in patients with TP53-mutated r/r LBCL compared to chemotherapy-based regimens. While TP53 mutations were traditionally associated with inferior prognosis, their negative impact on survival and response rates was not statistically significant in the CAR-T–treated population. These findings suggest that CAR-T therapy may partially overcome TP53-mediated resistance, warranting validation in larger prospective trials.