To assess the clinical presentation and prognostic factors for immune effector cell-associated neurotoxicity syndrome (ICANS) and overall mortality in patients with hematological malignancies treated with CD19-targeted chimeric antigen receptor T (CAR-T) cells.

Endothelial dysfunction is linked to two major complications of CAR-T therapy: cytokine release syndrome (CRS) and ICANS.

Retrospective analysis of patients treated with commercial and academic (ARI-0001) CD19 CAR-T across 20 hospitals in Spain (October 2018–April 2024). Prognostic factors for ICANS were analyzed using logistic regression, and global mortality with Cox regression. Endotelial activation was assessed using EASIX pre-lymphodepletion [EASIX-preLD: LDH (U/L) × creatinine (mg/dL) / platelets (10^9 cells/L)], with a cutoff set at 3 (75th percentile).

537 patients (311 male, 58%) with a median age of 59 years (IQR 48-67) were included. 482 (90%) patients received commercial CD19 CAR-T and 55 (10%) ARI-0001. CRS occurred in 471 patients (87.7%; 8.5% were severe). Among them, 215 (45.6%) developed ICANS; 40.5% considered severe. Two patients had ICANS without prior CRS. The median onset and duration of ICANS was 6 days (IQR 5-8) and 4 (IQR 2-8), respectively. The main neurological symptoms were tremor/myoclonus in 172 patients (80%) and encephalopathy in 156 (72%). Independent predictors of ICANS included female sex [HR 1.85, 95%CI 1.1-2.9], treatment with Axicabtagene Cyloleucel (vs ARI-0001) [HR 16.47, 95% CI 6.1-44.4], and prior CRS [HR 44.6, 95%CI 5.8-340.7]. Overall, 212 (40%) patients died at last follow-up [median 9 months, (IQR 4-19)]. Mortality risk was higher in patients with progressive disease at LD (vs stable/response: HR 1.7, 95% CI 1.1-2.6) and with an EASIX-preLD ≥ 3 [HR 2.8, 95%CI 2-3.9], while transformed follicular lymphoma was protective [HR 0.4, 95%CI 0.2-0.7].

EASIX-preLD was a more reliable predictor of mortality than CRS or ICANS. Its incorporation into clinical practice may improve risk stratification and patient management.