ICANS risk model in CD19 CAR-T therapy: insights from serum and CSF cytokine profiling

Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) is a common and potentially severe complication of CD19 CAR-T therapy. While some clinical risk factors have been described, the contribution of cytokines, particularly in plasma and cerebrospinal fluid (CSF), remains limited. This study aimed to identify predictors and characterize cytokine patterns associated with ICANS to develop a multivariable risk model. We retrospectively analyzed 101 adult patients treated with axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel) between 2019 and 2023. Cytokines (interleukin (IL)-1β, IL-6, IL-15, GM-CSF) were measured in plasma pre- and post-infusion, and in CSF during neurotoxicity. ICANS occurred in 36% of patients, more frequently with axi-cel (46% vs. 21%, p < 0.05). Autoimmune disease history and elevated IL-6 and IL-15 were associated with increased risk. CSF cytokines were also elevated during ICANS episodes. A multivariate model predicting any-grade ICANS included CAR-T product, time to cytokine release syndrome (CRS) onset, IL-6 at day 3, and pre-infusion D-dimer (AUC = 0.83). The model for grade 2-4 ICANS included number of prior therapies, grade ≥2 CRS, autoimmune disease, IL-15 at day 0, and GM-CSF (AUC = 0.80). Integrating cytokine profiles with clinical parameters may enable early ICANS risk stratification and improve personalized monitoring in CAR-T recipients.