NCMP-20. PRE-INFUSION NEUROFILAMENT LIGHT CHAIN (NFL) LEVELS PREDICT THE DEVELOPMENT OF IMMUNE EFFECTOR CELL-ASSOCIATED NEUROTOXICITY SYNDROME (ICANS) – A MULTICENTER RETROSPECTIVE STUDY

Abstract

Abstract BACKGROUND Neurological side effects after chimeric antigen receptor-modified (CAR) T cell therapy, termed immune effector cell-associated neurotoxicity syndrome (ICANS), are common and potentially devastating. We previously demonstrated that pre-infusion plasma neurofilament light chain (NfL), a well-established marker of neurodegeneration, may predict subsequent development of ICANS in a small, single-center cohort. This larger, retrospective multicenter study compares pre-infusion NfL to known post-infusion risk factors for developing ICANs including white blood cell (WBC) count, platelet count, C-reactive protein (CRP), fibrinogen, and ferritin levels. METHODS Inclusion criteria included available pre-infusion (up to 4 weeks prior to lymphodepletion) plasma from patients treated with a CAR T cell therapy (n = 30, 36% with ICANS, ASTCT consensus ICANS grade range 1-4). Exclusion criteria included confounding diagnoses known to elevate NfL levels (dementia, multiple sclerosis, recent stroke). Plasma NfL was assayed using a Simoa HD-1/HD-X kit (QuanterixTM). Post-infusion Day 3 or Day 5 WBC, Platelet, CRP, fibrinogen, and ferritin were obtained from the medical record. Group comparisons were done using log-rank tests with a Bonferroni-derived significance threshold, followed by receiver operating characteristic (ROC) curve classification. RESULTS Prior to infusion, individuals who ultimately developed ICANS had elevations in NfL ([87.6 v 29.4 pg/ml], p = 0.00004) with excellent classification (AUC 0.96), sensitivity (0.91) and specificity (0.95). Among known post-infusion risk factors, only post-infusion Day 3 ferritin (p = 0.004) and Day 5 ferritin (p = 0.003) differed between groups. Classification was inferior for both time points (Day 3 AUC = 0.87, specificity 0.71; Day 5 AUC 0.87, specificity 0.86). CONCLUSION Pre-infusion plasma NfL levels are a robust early marker for the development of ICANS that exceeds known post-infusion markers. Our findings suggest the risk of developing ICANS reflects pre-existing host-factors. Foreknowledge of ICANS development of may permit early, aggressive (preemptive or prophylaxis) ICANS-directed therapies, improving patient outcomes.