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, yet 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 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%. 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 gt; 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 risk factors for NRM. Multivariable models revealed that, among pre-infusion factors, only high ferritin levels (HR 3.23, 95% CI: 1.37-7.62, P = .007) and diabetes (HR 3.93, 95% CI: 1.28-12.1, P = .017) independently predicted NRM, while only severe CRS, ICANS, and infections remained strong post-infusion predictors. CONCLUSIONS: These findings emphasize the role of host-related factors and inflammation in shaping CAR-T outcomes. Optimized patient selection, rigorous management of acute toxicities, tailored infectious prophylaxis and long-term oncologic surveillance are essential components of long-term survivorship care, aiming to mitigate NRM and sustain long-term benefits of CAR-T cells. Clinical trial registration ClinicalTrials.gov ID: NCT06339255.