Neurofilament light chain levels as an early predictive biomarker of neurotoxicity after CAR T-cell therapy

Abstract

Immune effector cell-associated neurotoxicity syndrome (ICANS) remains a significant cause of morbidity associated with CD19-targeted chimeric antigen receptor (CAR) T-cell therapy. Early prediction of patients who will develop ICANS would be crucial to better guide individualized management of high-risk patients, but specific predictive markers are still missing. Serum neurofilament light chain (NfL) levels are a sensitive indicator of neuroaxonal injury in neurological diseases. Elevated NfL levels at the time of CAR T-cell infusion have been associated with the severity of ICANS, but their utility for earlier identification of patients with subclinical neurological damage has not been evaluated.We studied all consecutive adult patients who received commercial CAR T cells for relapsed/refractory B-cell lymphomas at Saint-Louis Hospital between January 2019 and February 2023. Patients with pre-existing or current neurological disease were excluded. NfL levels were quantified in frozen serum collected at the time of the decision to treat (ie, the day of leukapheresis) and at the time of treatment (ie, the day of infusion).Of the 150 study patients, 28% developed ICANS of any grade, including 15.3% of grade 2-4. Receiving a CAR construct with a CD28 domain (58% of patients) was the strongest predictor of grade 2-4 ICANS. Serum NfL levels were significantly higher in patients with grade 2-4 ICANS than in those with grade 0-1 ICANS, both at the time of leukapheresis and infusion. In multivariate models, NfL above the cut-off value was independently associated with grade 2-4 ICANS at leukapheresis (NfL>75 pg/mL, OR 4.2, 95% CI 1.2 to 14.2, p=0.022) and infusion (NfL>58 pg/mL, OR 4.3, 95% CI 1.3 to 13.7, p=0.015).In conclusion, high NfL levels at the time of the decision to proceed with CAR T-cell manufacturing may represent an early surrogate of underlying loss of neuroaxonal integrity that increases the risk of subsequent neurotoxicity. Incorporating NfL levels into the decision-making process based on each patient's risk profile could help determine the appropriate CAR product when possible, and guide the prophylactic or therapeutic management of ICANS.

Keywords: Chimeric antigen receptor - CAR; Immune effector cell-associated neurotoxicity syndrome - ICANS; Lymphoma.

Figure 1. Association between serum NfL levels and occurrence of moderate-to-severe ICANS. Upper panel: At the time of decision (TD) to proceed to CAR T-cell therapy: (A) Serum NfL levels were significantly higher in patients who developed moderate-to-severe ICANS (grade 2–4) than in patients with no or mild ICANS (grade 0–1). (B) Cumulative incidence of ICANS 2–4 according to NfL levels above or below the cut-off value (75 pg/mL). (C) Factors associated with occurrence of subsequent grade 2–4 ICANS. Lower panel: At the time of treatment (TT): (D) Serum NfL levels were significantly higher in patients who developed moderate-to-severe ICANS (grade 2–4) than in patients with no or mild ICANS (grade 0–1). (E) Cumulative incidence of ICANS 2–4 according to NfL levels above or below the cut-off value (58 pg/mL). (F) Factors associated with occurrence of subsequent grade 2–4 ICANS. CAR, chimeric antigen receptor; ICANS, immune effector cell-associated neurotoxicity syndrome; NfL, neurofilament light chain; PS, performance status.

Figure 2. Correlation between NfL levels at TD and TT. (A) Regression curve and best fit line are shown. (B) Dynamic changes of NfL levels between TD and TT. (C) Correlation between NfL level at TD, at TT and occurrence of ICANS. ICANS, immune effector cell-associated neurotoxicity syndrome; NfL, neurofilament light chain; TD, time of treatment decision; TT, time of treatment.