Systemic Inflammation and CAR-T Specific Toxicities as Major Drivers of Nonrelapse Mortality: Analysis from the Italian Prospective Observational CART-SIE Study

Background: Chimeric antigen receptor (CAR)-T cell therapy has revolutionized outcomes in relapsed/refractory lymphomas; however, nonrelapse mortality (NRM) has emerged as a notable concern, with older age and infections identified as major determinants of NRM in real-life studies. Objective: The aim of the present study was to describe the rate and causes of NRM after CAR-T cells and identify risk factors. Study design: Within the framework of the prospective, multicenter, observational CART-SIE study, we analyzed the causes and determinants of NRM in a large real-world cohort of lymphoma patients receiving CAR-T cells from 2019 to 2025. Associations between NRM and clinical or biological factors were assessed using Fine and Gray subdistribution hazard models. Results: From 2019 to 2025, 1132 patients were enrolled in the CART-SIE study; among those, 932 were evaluable for outcomes, with a median follow-up of 17.8 months (IQR 6.3–25.4). In this cohort, 305 deaths were observed, mainly occurring after disease progression (n = 258); overall, 47 deaths were solely attributable to NRM (5%), either early (<=28 days, 40.4%), late (29–90 days, 23.4%), or very late (>90 days, 36.2%). The 1- and 2-year cumulative incidence of NRM were 5.5% and 8.8%, respectively. Infections were the leading cause (51%), followed by CAR-T acute toxicities (CRS, ICANS, and HLH/MAS; 30%), and secondary malignancies (11%). In univariable analysis, age > 60 years, diabetes, atrial fibrillation, high CAR-HEMATOTOX score, elevated ferritin, baseline cytopenias, CRS grade >= 3, any-grade or grade >= 3 ICANS, and infectious events were identified as risk factors for NRM.