Severity‐Dependent Neuroaxonal Damage Assessed by Serum Neurofilaments in ICANS Patients Undergoing CD19‐Targeted CAR T‐Cell Therapy

Background and Objectives Immune effector cell‐associated neurotoxicity syndrome (ICANS) is a potential complication following Chimeric Antigen Receptor (CAR) T‐cell infusion. Biomarkers to aid in early diagnosis and severity assessment are lacking. We aim to describe and compare serum neurofilament light chain (sNfL) dynamics in non‐Hodgkin lymphoma (NHL) patients undergoing anti‐CD19 CAR T‐cell therapy, based on ICANS presence and severity. Methods This is a case–control study nested within a cohort of NHL patients treated with anti‐CD19 CAR T‐cells at a tertiary care center. From this cohort, we selected those who developed ICANS and had available blood samples. These patients were compared to matched NHL patients without ICANS from the same cohort. sNfL concentrations were measured immediately pre‐infusion and on days 7 and 14 post‐infusion, with z ‐scores calculated against a normative database. Mixed linear and ROC analysis assessed sNfL dynamics by ICANS presence and severity. Results Of 159 patients treated, 54 (34%) developed ICANS. We included 32 patients with ICANS and 22 matched controls. Baseline sNfL concentrations were similarly elevated in both ICANS and non‐ICANS patients. However, on day 7, patients with moderate–severe ICANS (grade ≥ 2) had higher sNfL levels (median z ‐score 2.33) than those with mild or no ICANS (median z ‐score 1.72; p = 0.022). The optimal cutoff to discriminate moderate–severe ICANS from other patients based on sNfL was a z ‐score of 2.14 on day 7 ( p = 0.004). Discussion Moderate–severe ICANS is associated with elevated sNfL levels by day 7 post‐infusion, indicating early neuroaxonal damage and underscoring sNfL as a valuable biomarker for assessing ICANS severity.