Endothelial Activation as a Predictor of Mortality in CD19-Directed CAR-T Therapy
Jose Maria Cabrera Maqueda1, Elianet Fonseca1, Carlos Serra Smith2, Mónica Alaña García3, Gabriel Velilla4, Hernández Chamorro Francisco José5, Sara García Gil-Perotin6, Lorena Martín Aguilar7, Tamara Castillo-Trivino8, Roser Velasco Fargas9, Juan Luis Chico García10, Pablo Cabezudo García11, Cristina Izquierdo Garcia12, Purificación Pérez Cacabelos13, Ines Gonzalez Suarez14, Marga Massot Cladera15, Jaime Gállego Pérez de Larraya16, Estefania Garcia Molina17, Gabriel Torres Iglesias18, Marta Domínguez Gallego19, Lucía Alba Alcántara20, Victor Guerra-Fernandez1, Alba Isasi María Teresa1, Nuria Martínez-Cibrian21, Josep Dalmau22, Eugenia Martinez-Hernandez1, Yolanda Blanco Morgado1
1Department of Neurology, Hospital Clínic de Barcelona; University of Barcelona; Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain, 2Department of Neurology, Hospital General Gregorio Marañón, Madrid, Spain, 3Department of Neurology, Hospital Universitario de Salamanca, Salamanca, Spain, 4Department of Neurology, Hospital Universitario 12 de Octubre, Madrid, Spain, 5Department of Neurology, Hopsital Virgen del Rocío, Sevilla, Spain, 6Deparatment of Neurology, Hospital Universitari i Politècnic La Fe, Valencia, Spain, 7Department of Neurology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain, 8Department of Neurology, Hospital Donostia-Donostia Ospitalea, San Sebastián, Spain, 9Department of Neurology, Neuro-Oncology Unit, Catalan Institute of Oncology, Barcelona, Spain, 10Department of Neurology, Hospital Ramón y Cajal, Madrid, Spain, 11Department of Neurology, Hospital Regional Universitario de Málaga, Málaga, Spain, 12Department of Neurology, Hospital Universitari Germans Trias i Pujol, Badalona, Spain, 13Department of Neurology, Complexo Hospitalario Universitario de Santiago, Santiago de Compostela, Spain, 14Department of Neurology, Hospital Álvaro Cunqueiro, Vigo, Spain, 15Department of Neurology, Complejo Asistencial Son Espases, Palma, Spain, 16Department of Neurology, Clínica Universitaria de Navarra, Navarra, Spain, 17Department of Neurology, Hospital Universitario Virgen de la Arrixaca, Murcia, Spain, 18Department of Neurology, Hospital Universitario La Paz, Madrid, Spain, 19Department of Neurology, Hospital Universitario de la Princesa, Madrid, Spain, 20Department of Neurology, Hospital Universitario Puerta de Hierro, Majadahonda, Spain, 21Department of Hematology, Hospital Clínic de Barcelona; University of Barcelona; Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain, 22Neuroimmunology Program, Fundació de Recerca Clínic Barcelona- Institut d'Investigacions Biomèdiques August Pi i Sunyer; Caixa Research Institute, Barcelona, Spain
Objective:
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.
Background:
Endothelial dysfunction is linked to two major complications of CAR-T therapy: cytokine release syndrome (CRS) and ICANS.
Design/Methods:
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).
Results:
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].
Conclusions:
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.
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