Markedly Delayed Onset ICANS in the Setting of CAR T-Cell-Mediated Aseptic Meningoencephalitis: Two Cases

Objective Immune effector cell-associated neurotoxicity syndrome (ICANS) typically manifests within the first week following chimeric antigen receptor (CAR) T-cell therapy and has rarely been described to develop beyond 1 month after treatment. This report describes the occurrence of markedly delayed ICANS in the setting of non-infectious meningoencephalitis. Methods We report two cases of markedly delayed ICANS with cerebrospinal fluid (CSF) pleocytosis comprised primarily of CAR T-cells. Results Two patients, aged 54 and 67 years, developed ICANS at 71 and 46 days, respectively, following administration of ciltacabtagene autoleucel (cilta-cel), a B-cell maturation antigen (BCMA)-directed CAR T-cell therapy. CSF analysis demonstrated elevated total nucleated cell (TNC) counts of 1055 and 605 cells/μL, respectively, with marked lymphocytic predominance (94% and 90%), of which 90.4% and 95.4% were CAR T-cells. Both patients improved with corticosteroids and immunotherapy. Discussion The identification of CAR T-cells in CSF analysis proved critical for clinical management, enabling early discontinuation of empiric meningeal antimicrobial therapy and implementation of targeted immunosuppressive treatment. This report highlights a rare presentation of markedly delayed ICANS associated with robust infiltration of CAR T-cells into the CSF, expanding our understanding of the temporal spectrum and pathophysiology of ICANS.