Predictors and Outcomes of Immune Effector Cell Associated Neurotoxicity Syndrome in Patients Receiving Chimeric Antigen Receptor T-Cell Therapy for Aggressive B-Cell Non-Hodgkin Lymphoma

Abstract

BACKGROUND Chimeric antigen receptor (CAR) T-cell therapy has changed the treatment landscape for aggressive large B-cell non-Hodgkin lymphoma (B-NHL). Immune effector cell-associated neurotoxicity syndrome (ICANS) is recognized as an adverse event of special interest associated with CAR T-cell therapy. However, determinants of ICANS presentation and outcome remain poorly understood. In this multicenter retrospective study, we aimed to determine risk factors for ICANS and clinical outcomes in patients who develop ICANS. METHODS Patients aged ≥18 years with aggressive large B-NHL who underwent apheresis from May 2018 to January 2021 for commercial CAR T-cell therapy at eight academic US medical centers were identified from the Cell Therapy Consortium (CTC) registry. All centers were approved to administer axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) per provider discretion. ICANS and CRS were graded using ASTCT criteria and classified as severe if grade 3-5. Cox regression analysis and the Kaplan Meier method were used for survival outcomes. Laboratory values collected at lymphodepletion were used for the previously reported Endothelial Activation and Stress Index (EASIX) and modified EASIX (m-EASIX) score. Log transformation was applied to reduce skew. Predictors of severe ICANS were identified using logistic regression analysis. Best subset selection and receiver operating characteristic (ROC) analyses were applied to determine optimal predictors. RESULTS Baseline characteristics are summarized in Table 1. A total of 352 patients received axi-cel (n=203) and tisa-cel (n=149) with a median follow-up of 21.6 months. A total of 125 (35.5%) developed ICANS while 227 (69.8%) did not. Of those with ICANS, severe ICANS occurred in 75 (60%) and mild ICANS occurred in 50 (40%). The median age at apheresis was similar at 64 (range 22-89) compared to 62 (range 18-86) among patients with and without ICANS. The majority of patients who developed ICANS (87.2%) received axi-cel. CRS was more common in those with ICANS (94.4% vs. 63.3%). IPI grade 3 or higher was more common in patients who developed ICANS (59.9% vs. 47%). There were similar numbers of patients with bulky, primary refractory, and active CNS disease among patients with and without ICANS. Most patients with ICANS (82%) received steroids compared to those without ICANS (9.4%). Results of cox regression analyses are summarized in Table 2. The development of ICANS did not significantly impact PFS or OS nor did steroid administration. Exploratory analysis showed that severity of ICANS did not influence PFS or OS. Bulky disease (≥10 cm), LDH greater than the upper limit of normal, and peak ferritin greater than 5000 in the first 28-days post-infusion were associated with worse OS. There was a significant interaction term between ICANS and product for OS. We conducted an exploratory analysis stratified by product which showed that the development of ICANS with tisa-cel was associated with inferior OS (HR 3.65, CI: 1.35-9.91, p=0.011) but no difference in PFS. The development of ICANS with axi-cel had no impact on OS or PFS. Risk factors for ICANS evaluated as continuous variables at lymphodepletion included included ferritin (p=0.021), LDH (p=0.004), CRP (p<0.001), EASIX (p=0.004), and m-EASIX (p<0.001). Thrombocytopenia, neutropenia, and creatinine were not associated with severe ICANS. Best subset selection showed that higher CRP was the best model to predict severe ICANS. ROC comparison analysis showed no difference between CRP (AUC 0.64), EASIX (0.64), and m-EASIX (0.66). Post infusion, CRS (OR 2.27, CI: 1.46-3.08, p<0.001) and earlier onset of CRS (OR 0.83, CI: 0.71-0.94, p=0.005) were predictive of severe ICANS while time to steroid administration was not. CONCLUSION In this retrospective analysis, we showed that outcomes were similar in patients with aggressive large B-NHL treated with CAR T-cell therapy who did or did not develop ICANS regardless of severity. In stratified analysis, ICANS was associated with inferior OS in those who received tisa-cel but was limited by small sample size. Pre lymphodepletion CRP alone had the highest discriminatory ability to predict severe ICANS. After infusion, developing CRS and earlier onset of CRS were predictive of ICANS. Future studies should identify novel predictive scores for ICANS which may lead to strategies to prevent neurologic toxicity after CAR T-cell therapy. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal