ICANS is a common form of neurological immunotoxicity from CAR T-cell therapy (CAR-T). While high tumor burden, product type and cell dose are established risk factors, there are many unknowns. Our objective was to characterize novel neurological and non-neurological risk factors for the development of ICANS in subjects who received CAR-T. We retrospectively identified 93 subjects (60% men, mean age 60) who had undergone CD19 or BCMA-targeting CAR-T for hematological malignancy from 2018 to 2023 at a large academic hospital. Incidence of ICANS was 31.2%, high-grade in 9.7%. A low baseline MOCA score (p=0.008) was associated with ICANS when controlled for baseline ferritin, KPS, and age; loss of points on specific cognitive sub-scores was also significant, with poor attention testing of particular concern. Presence of preexisting cerebrovascular disease, active autoimmune disease, and neurological tumor involvement were not associated with increased risk. ICANS was also associated with older age (p=0.024), elevated baseline ferritin (p=0.006), low KPS (p=0.004), and preceding or concurrent CRS of any grade (<0.001). Increasing ferritin between baseline and Day 5+ (p=0.002) was associated with development of high-grade ICANS, along with prior tocilizumab exposure (p=0.015). Subjects who developed any grade of ICANS had higher 90-day mortality than those who did not (p<0.001). Identification of these additional baseline risk factors for ICANS will help identify high-risk patients ahead of treatment and allow for improved preventative planning and early identification of ICANS.

R.R. reports consulting or advisory role with Allogene, Gilead Sciences, Incyte, TScan, Orca Bio, Pierre Fabre Pharmaceuticals, CareDx, Quell Biotherapeutics, Sana Biotechnology, Sail Biomedicines and Autolus, expert witness role with Bayer, and research funding from Atara Biotherapeutics, Incyte, Sanofi, Immatics, Abbvie, Takeda, Gilead Sciences, CareDx, TScan, Cabaletta, Synthekine, BMS, J&J, Allogene, Genentech, Vittoria Therapeutics, and Imugene. S.F.W reports consulting or advisory role with Novartis, Genentech, and T.G. Therapeutics. The remaining authors declare no completing financial interests.

This study was funded by P30CA013696 (R.R.)

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The IRB of Columbia University gave approval for this work.

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All data produced in the present study are available upon reasonable request to the authors