A novel severe toxicity-free, and progression-free survival endpoint predicts outcomes after CD19 chimeric antigen receptor-T cell therapy in large B-cell lymphoma

作者：Aditi Saha, Junmin Whiting, Razan Mohty, Kristen Flores, Jongphil Kim, Taiga Nishihori, Julio C. Chávez, Sameh Gaballa, Farhad Khimani, Hien Liu, Bijal Shah, Marian Dam, Muhammad Jaffer, Sepideh Mokhtari, Nima Ghalehsari, Hany Elmariah, Christina Bachmeier, J. A. Guevara, Heather Jim, Abu‐Sayeef Mirza, Brahm H. Segal, Doris K. Hansen, Nelli Bejanyan, Fabiana Perna, Rawan Faramand, Michael D. Jain, Frederick L. Locke, Aleksandr Lazaryan · 发表于：Bone Marrow Transplantation · 年份：2026 · DOI：10.1038/s41409-026-02936-8 · 研究领域：CAR-T cell therapy research、Lymphoma Diagnosis and Treatment、Cutaneous lymphoproliferative disorders research

CD19-directed chimeric antigen receptor-T cell (CAR-T) therapies have transformed treatment for relapsed/refractory large B-cell lymphoma (LBCL), yet heterogeneity in toxicity and efficacy persists. To address this, we developed a novel composite endpoint: severe toxicity-free and progression-free survival at 6 months (TPFS6), defined as absence of severe CRS, ICANS, progressive/stable disease (PD/SD), and non-relapse mortality (NRM) within 6 months of CAR-T therapy. In our cohort, 37% achieved TPFS6. Events contributing to TPFS6 failure included severe CRS (6.8%), ICANS (30.3%), NRM (1.7%), and PD/SD (61.2%). Multivariable analysis demonstrated female sex (p = 0.01), ECOG < 2 (p = 0.05), and lower LDH and CRP (both p = 0.004) predicted TPFS6. With a median follow-up of 36.2 months, the estimated 2-year OS and PFS were 54.5% and 39.6%, respectively. Landmark analysis showed TPFS6 was associated with improved OS (HR = 0.19; 95% CI: 0.11-0.35; p < 0.001) and PFS (HR = 0.33; 95% CI: 0.16-0.67; p = 0.002). CAR-T product type was not significantly associated with OS but was with PFS (HR = 3.09; 95% CI: 1.27-7.50; p = 0.013). TPFS6 remained prognostic for OS and PFS even after accounting for PD/SD, underscoring the impact of severe toxicity on subsequent survival. TPFS6 is a clinically meaningful endpoint integrating efficacy and safety and may predict long-term outcomes following CAR-T therapy.