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.