Background: Chimeric antigen receptor (CAR) T-cell therapy offers durable remissions for relapsed/refractory (R/R) large B-cell lymphoma (LBCL) and follicular lymphoma. However, with only 40-50% of patients achieving long-term cure, robust pre-treatment risk stratification is a critical unmet need to optimize patient selection and guide therapeutic strategy. While prognostic factors have been identified in pivotal trials, comprehensive data from real-world clinical practice is essential. This study aimed to define prognostic determinants and develop a practical prognostic score using a large, single-center real-world dataset.

Methods: We conducted a retrospective analysis of 93 consecutive patients with R/R LBCL who underwent leukapheresis for commercial CAR T-cell therapy (83 lisocabtagene maraleucel; 10 axicabtagene ciloleucel) at Toranomon Hospital between Feb 2022 and Jun 2025. A comprehensive set of pre-treatment clinical and laboratory variables was evaluated for prognostic significance. Efficacy was assessed by Lugano 2014 criteria, and toxicities were graded per ASTCT consensus criteria. Prognostic factors for progression-free survival (PFS) were identified using univariate and multivariate Cox proportional hazards models.

Results: The cohort represented a heavily pre-treated, high-risk population (median age 66(range, 25-90); median 3 prior lines). The ORR was 66.7% (CR 51.6%). After a median follow-up of 6.7 months, median PFS and OS were not reached. The safety profile was highly manageable. Notably, in univariate analysis, no significant association with PFS was found for several established prognostic factors, including patient age, IPI score, GCB vs. non-GCB subtype, complex karyotype, extranodal or CNS involvement, CD20 antigen loss prior to infusion, or absolute counts of peripheral blood CD3+, CD4+, CD8+ lymphocytes or monocytes.

In contrast, resistance to bridging therapy, elevated pre-lymphodepletion LDH (≥240 U/L), and a shorter time from last chemotherapy to relapse (<3.5 months) were all significantly associated with inferior PFS in univariate analysis. In the subsequent multivariate analysis, sensitivity to bridging therapy remained the most powerful independent predictor of a favorable outcome (HR 0.34 for sensitivity, 95% CI 0.15-0.77). Although the statistical significance of LDH and time to relapse was attenuated in the multivariate model, these three clinically critical pre-treatment factors were selected for our prognostic score. Two post-infusion factors, total dexamethasone dose for toxicity management and prolonged cytopenia, were also identified as independently prognostic.

Based on the three pre-treatment variables, we developed the Toranomon Prognostic Score (TPS). The TPS robustly stratified patients into three distinct risk groups: low-risk (0 points, n=15), intermediate-risk (1-2 points, n=56), and high-risk (3 points, n=9). The corresponding median PFS was not reached, 254 days, and a critically short 140 days, respectively (log-rank p < 0.001).

Conclusion: Our real-world data demonstrates that commercial CAR T-cell therapy is a highly effective treatment for R/R LBCL. Importantly, this study confirms its feasibility even in traditionally challenging subgroups. Our analysis identified key prognostic determinants, both pre- and post-infusion. We developed and validated the TPS, a simple pre-treatment tool based on three readily available factors. By robustly identifying patients at the highest risk for early progression, this score can guide clinical decision-making and help select candidates for trials exploring novel consolidative strategies. Prospective, multicenter validation of the TPS is warranted.

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2025
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