Introduction: 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 neurodegeneration, may predict subsequent development of ICANS in a small, single-center cohort. This larger, 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 for this retrospective study included available pre-infusion (up to 2 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 that are known to elevate NfL (dementia, multiple sclerosis, recent stroke). Plasma NfL was assayed using a Simoa HD-1/HD-X kit (QuanterixTM). Post-infusion (within 24hrs) 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 developed ICANS had elevations in NfL (p = 0.00004) with excellent classification (AUC 0.96), sensitivity (0.91) and specificity (0.95). Post-transfusion differences in known post-infusion risk factors were only observed for ferritin (p = 0.003) with an inferior classification (AUC 0.88, sensitivity 0.78, specificity 0.86). Similar results were observed for WBC (AUC 0.77), platelet count (AUC 0.80), CRP (AUC 0.79), and fibrinogen (AUC 0.62).
Impact: Basic: ICANS risk after cellular therapy may reflect latent neural injury in addition to known endothelial and vascular factors.
Translational: Pre-infusion plasma NfL levels are a robust marker for ICANS development.
Clinical: Foreknowledge of ICANS development of may permit early (preemptive/prophylaxis) ICANS-directed therapies, improving patient outcomes.
Organization – Washington University in St. Louis
Butt OH, Zhou AY, Lee K, Wu GF, Caimi PF, de Lima MJG, Campian JL, Dipersio JF, Ghobadi A, Ances BM