JAMA Oncology | September 1, 2022

Butt, O. H., Zhou, A. Y., Caimi, P. F., Luckett, P. H., Wisch, J. K., Derenoncourt, P. R., Lee, K., Wu, G. F., de Lima, M. J. G., Campian, J. L., Frank, M. J., DiPersio, J. F., Ghobadi, A. and Ances, B. M.

JAMA Oncol. Published online September 01, 2022

https://doi.org/10.1001/jamaoncol.2022.3738

Abstract

Importance  Determining whether neurofilament light chain (NfL) elevations in patients who develop immune effector cell–associated neurotoxicity syndrome (ICANS) occur before or after infusion of cellular product is important to identify high-risk patients and inform whether neuroaxonal injury is latent or a consequence of treatment.

Objective  To quantify serial NfL levels in patients undergoing cellular therapy.

Design, Setting, and Participants  This retrospective 2-center study examined plasma NfL levels in 30 patients with detailed medical and treatment history, including all major pretreatment and posttreatment risk factors. Exclusion criteria included dementia and severe, symptomatic central nervous system (CNS) involvement.

Main Outcomes and Measures  Patients’ NfL levels were measured at 7 time points: baseline (prelymphodepletion), during lymphodepletion, postinfusion day (D) 1, D3, D7, D14, and D30. Prediction accuracy for the development of ICANS was next modeled using receiver operating characteristic (ROC) classification. Finally, univariate and multivariate modeling examined the association between NfL levels, ICANS, and potential risk factors including demographic (age, sex), oncologic (tumor burden, history of CNS involvement), neurologic (history of nononcologic CNS disease or neuropathy), and neurotoxic exposure histories (vincristine, cytarabine, methotrexate, or CNS radiotherapy).

Results  A total of 30 patients (median [range] age, 64 [22-80] years; 12 women [40%] and 18 men [60%]) were included. Individuals who developed ICANS had elevations in NfL prior to lymphodepletion and chimeric antigen receptor T-cell infusion compared with those who did not develop ICANS (no ICANS: 29.4 pg/mL, vs any ICANS: 87.6 pg/mL; P < .001). Baseline NfL levels further predicted ICANS development with high accuracy (area under the ROC curve, 0.96), sensitivity (0.91), and specificity (0.95). Levels of NfL remained elevated across all time points, up to 30 days postinfusion. Baseline NfL levels correlated with ICANS severity but not demographic factors, oncologic history, nononcologic neurologic history, or history of exposure to neurotoxic therapies.

Conclusions and Relevance  In a subset of patients in this cross-sectional study, the risk of developing ICANS was associated with preexisting neuroaxonal injury that was quantifiable with plasma NfL level. This latent neuroaxonal injury was present prior to drug administration but was not associated with historic neurotoxic therapies or nononcologic neurologic disease. Preinfusion NfL may further permit early screening and identification of patients most at risk for ICANS. Additional studies are needed to determine NfL’s utility as a predictive biomarker for early (preemptive or prophylactic) intervention and to delineate the origin of this underlying neural injury.