Impact of ASTCT Toxicity Grading System on Outcomes After CAR-T for Mature B-Cell Malignancies

The American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading system standardized the classification of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) after chimeric antigen receptor (CAR) T-cell therapy. However, the prognostic relevance of CRS and ICANS, as well as immune effector cell-associated hematological toxicity (ICAHT), remains incompletely defined. In this multicenter retrospective study, adult patients with mature B-cell malignancies treated with CD19-directed CAR-T therapy between 2016 and 2024 at three academic centers were included. CRS and ICANS were graded according to ASTCT criteria, and early ICAHT according to EHA/EBMT consensus definitions. The primary endpoint was non-relapse mortality (NRM); secondary endpoints included overall survival (OS) and progression-free survival (PFS). Outcomes were evaluated using day 30 landmark analyses with multivariable models stratified by center and adjusted for clinically relevant covariates; a complementary sensitivity analysis modeled CRS as a time-dependent covariate for NRM in the full cohort from day 0. Among 560 patients, axi-cel was the most frequently used product (48%), followed by tisa-cel (25%), liso-cel (23%) and brexu-cel (4%). With a median follow-up of 23.9 months, the 2-year cumulative incidence of NRM for the full cohort was 7.2%, with 2-year OS and PFS of 57% and 41%, respectively. Overall, 140 patients (25%) and 61 (11%) developed grade 2 and grade 3 to 4 CRS, respectively; 40 (7%) and 74 (13%) developed grade 2 and grade 3 to 4 ICANS, respectively; and 151 (30%) and 144 (29%) developed grade 2 and grade 3 to 4 early ICAHT, respectively. In a day +30 landmark analysis adjusted for baseline covariates, CRS and early ICAHT severity was not independently associated with NRM, OS, or PFS. In contrast, grade ≥3 ICANS was independently associated with increased NRM (HR: 2.46, 95% CI, 1.00 to 6.04) and inferior OS (HR: 1.79, 95% CI, 1.14 to 2.81), but not with PFS. In the sensitivity analysis, grade 3 to 4 CRS was associated with NRM in univariable but not in multivariable analysis. In this real-world cohort of patients treated with CD19 CAR-T cells, we found that high grade ICANS retained independent prognostic significance for outcomes beyond day 30, whereas CRS and early ICAHT did not; however, severe CRS may still contribute to early treatment-related mortality. These findings support the clinical utility of modern grading systems for outcome interpretation and emphasize neurotoxicity as a priority for preventive interventions after CD19 CAR-T therapy.