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.
TL;DR
TPFS6 remained prognostic for OS and PFS even after accounting for PD/SD, underscoring the impact of severe toxicity on subsequent survival, and may predict long-term outcomes following CAR-T therapy.
Abstract
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.