Impact of Icans on Long-Term Neurocognitive Function in Patients with Diffuse Large B-Cell Lymphoma Receiving CAR T-Cell Therapy
Authors: Makos Olivia Leighton , Shostrom Valerie K , Armitage James Olen , Vose Julie M. , Lunning Matthew , Bociek Robert Gregory , D'Angelo Christopher R 
Published: December 2024

Introduction
Chimeric antigen receptor (CAR)-T cell therapy is associated with a well-described neurotoxicity side effect termed immune effector-cell associated neurotoxicity syndrome (ICANS) in the immediate post-infusion period that patients largely recover from. The incidence of ICANS varies depending on lymphoma type, tumor burden and type of CAR-T product infused (axicabtagene ciloleucel (axi-cel), lisocabtagene maraleucel (liso-cel) and tisagenlecleucel (tisa-cel)). It is unclear if there are any chronic neurological problems that result from experiencing ICANS in the immediate post-infusion period. The purpose of our study was to determine the long-term risk for neurocognitive dysfunction after CAR-T cell infusion. We hypothesized that patients who experienced ICANS would have a greater incidence of self-reported cognitive dysfunction one year or longer after CAR-T therapy than patients who did not experience ICANS.
Methods
To test this hypothesis, we performed a single center prospective study of patient-reported neurocognitive performance. All patients with B-cell non-Hodgkin's lymphoma over one year from receipt of CAR T-cell therapy were eligible to participate.
Neurocognitive performance was evaluated using two different patient-reported outcome measures (PROMs) surveys (Neuro-QOL v2.0 cognitive form and the Neuro-QOL positive affect and well-being form) that were administered over the phone. Patient medical records were reviewed for additional risk factors of interest including Eastern Cooperative Oncology Group (ECOG) score, cytokine release syndrome (CRS) grade, ICANS grade, lymphoma subtype, and disease status. CRS and ICANS were graded using the American Society for Transplantation and Cellular Therapy (ASTCT) criteria.
The primary outcomes were Neuro-QOL v2.0 cognitive t-score and Neuro-QOL positive affect and well-being t-score. Higher scores correlate with higher cognitive performance and well-being. T-tests were used to examine differences in ICANS (Grade 0 vs 1-4), gender (male vs female), race (Caucasian vs not Caucasian), and CAR-T therapy (axi-cel vs tisa-cel/liso-cel). A general linear model was used to examine difference in CRS grade (no CRS vs grade 1 vs grade 2).
Results
Twenty patients participated. Three had ICANS grade 1 (15%), 3 ICANS grade 2 (15%) , 2 ICANS grade 3 (10%), and 1 ICANS grade 4 (5%). Eleven did not experience ICANS (55%) .Six (30%) were female. Seventeen (85%) were Caucasian. Fourteen (70%) received Axi-cel ,one (5%) received Tisa-cel and five (25%) received Liso-cel.
Patients who had any grade ICANS scored 43.18 + 8.39 on the Neuro-QOL cognitive survey and 54.57 + 7.03 on the well-being survey vs patients without ICANS scored 50.59 + 10.08 on the Neuro QOL cognitive survey and 57.39 + 5.15 on the well-being survey (P = 0.09 and 0.31 respectively). Axi-cel patients scored 48.53 +10.20 on the Neuro-QOL cognitive survey and 56.06 + 5.88 on the well-being survey vs. tisa-cel/liso-cel patients scored 44.28 + 9.19 on the Neuro QOL cognitive survey and 56.25 + 7.09 on the well-being survey (P = 0.39 and 0.95 respectively). No effect of CRS on neurocognitive outcomes was observed. Interestingly, female patients scored lower on both the neuro-QOL cognitive survey (43.67 + 11.90) and well-being survey (54.68 + 4.50) than male patients (48.79+ 8.91) and 56.74+6.69. P= 0.30 and 0.50 respectively.
Conclusion
Our study identified a non-statistically significant trend that patients experiencing ICANS toxicity may be at increased risk for long-term neurocognitive dysfunction. Given the limited sample size, additional subjects are being recruited to further evaluate for statistically significant differences. This analysis is ongoing at our institution as more subjects become eligible and data will be updated accordingly.