Neurotoxicity of Axicabtagene Ciloleucel in an Ethnically Diverse, Real-World Cohort
Authors: Zeldin Elizabeth , Cheng Samantha J , Quinn Ryann , Pradhan Kith , Goldfinger Mendel , Mantzaris Ioannis , Shah Nishi , Shastri Aditi , Kornblum Noah , Cooper Dennis L , Gupta Ridhi , Shapiro Lauren , Gritsman Kira , Abbasi Ahmed , Verma Amit , Braunschweig Ira , McNeill Katharine , Milstein Mark , Sica R. Alejandro 
Published: December 2024

Introduction
Chimeric antigen receptor T-cell (CART) therapy is a revolutionarily effective approach to treating relapsed or refractory B-cell malignancies such as diffuse large B cell lymphoma (DLBCL). One of the most concerning limitations is neurotoxicity, known as immune effector cell-associated neurotoxicity syndrome (ICANS). ICANS occurred in 60-75% patients treated with axicabtagene ciloleucel in initial clinical trials. ICANS can present as a variety of neurologic symptoms including aphasia, motor abnormalities, and encephalopathy, with a 3% mortality rate. Most of the data available was obtained from clinical trials with minimal enrollment of minority subjects; thus, little data is available on the presence of neurotoxicity in these patient populations and the significance of pre-existing and non-modifiable characteristics.
Methods
We conducted a retrospective study of patients with B-cell lymphoma who received axicabtagene ciloleucel CART cell therapy between June 2018 and July 2022 at Montefiore Medical Center in Bronx, New York. The primary endpoint was to identify risk factors for ICANS in a minority-rich cohort. Neurotoxicity was graded per the American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading. Demographics, baseline functional status, CNS involvement, progression-free survival (PFS), overall survival (OS), and ICANS grade were recorded for statistical analyses. Secondary endpoints included neurological findings, diagnostic tests, and outcomes among patients with ICANS &gt; 0.
Results
Our sample consisted of 49 patients. 47 patients (96%) had DLBCL. Median age was 66 years. Ethnic composition was 17 (35%) Hispanic, 14 (29%) Caucasian, 13 (26%) African American, 2 (4%) Asian, and 3 (6%) unspecified/other patients. Median OS was 48 months and median PFS was 22.3 months. 19 (39%) patients had ICANS &gt; 0. Of the patients with ICANS &gt; 0, 1 patient had grade 1, 8 patients had grade 2, 8 patients had grade 3, and 2 patients had grade 4 ICANS. Cox proportional hazards showed no significant association between ICANS grade and OS or PFS. There was also no association found between ICANS grade and any of the following variables: ECOG, KPS, sex, age, ethnicity, CNS involvement. There was a strong correlation between CRS grade and ICANS grade with a Spearman correlation coefficient 0.5284 (p &lt; .0001).
Among the 19 patients with ICANS &gt; 0, impaired attention was the most common neurologic finding (16 patients), followed by deficits in language (15 patients), orientation (13 patients), abnormal movements (6 patients), and motor strength (4 patients). 3 patients did not score ICANS &gt; 0, but had sensory change, dyspraxia, and decreased fine motor skills. Patients with Grades 3 or 4 had CTH and/or MRI during the hospitalization, but head imaging was inconsistent for those with Grades 1 or 2 ICANS. While most patients recovered from ICANS, 8 (16%) had persistent neurotoxicity and/or died during the hospitalization.
Conclusions
This is one of the largest studies focusing on neurotoxicity in a predominantly minority population. Baseline functional status, sex, age, ethnicity, CNS involvement had no association with ICANS; only CRS was associated with ICANS, as previously shown. Importantly, there were neurologic findings such as sensory changes, dyspraxia, and decreased fine motor skills that are not currently included in ICANS scoring systems though they may represent early ICANS. This stresses the importance of obtaining detailed neurological workup prior to administration of CART therapy such as imaging and neurocognitive testing. We observed a significant number of cases (8 patients, 16%) with serious neurotoxicity which is a higher proportion than seen in clinical trials which do not traditionally enroll marginalized populations.
Given that minorities have lower access to health care, it is important to evaluate the impact of their multiple comorbidities, refractory disease, and socioeconomic status impact on specific toxicities, such as ICANS during CART cell therapy. Our work highlights the need for greater inclusion of underrepresented populations in clinical trials, and further investigation into neurotoxicity in minority populations.