Neuroaxonal Injury, but Not Astrocyte Injury, Is Associated with CAR T Cell Related Icans.

Background Immune effector cell–associated neurotoxicity syndrome (ICANS) remains a significant toxicity of chimeric antigen receptor (CAR) T-cell therapy. While the etiology remains unclear, history of neurologic injury is a known pre-treatment risk factor for development. We previously demonstrated cumulative neurologic injury can be quantified in patients undergoing cellular therapy by measuring plasma neurofilament light chain (NfL). While baseline elevations in NfL were associated with ICANS, it remains unclear if this reflects predominately neuroaxonal injury or concomitant injury to local astrocytes in adults. Glial fibrillary acidic protein (GFAP) is an known marker of astrocyte injury. Thus, our objective was to measure simultaneous neuroaxonal (NfL) & astrocyte injury (GFAP) in adult patients undergoing cellular therapy. Methods Retrospective 3-center study examined plasma NfL & GFAP levels in 80 patients (50% with ICANS, 23% Grade 3+) at baseline, 7, 15, & 30 days after CD19-directed CAR-T infusion. Logrank testing compared univariate groups with multivariate correction using false discovery rate yielding Benjamini-Hochberg adjusted p values. Subsequent multivariate modeling of ICANS severity included stepwise linear regression (threshold for removal of p > 0.1) and non-linear, partial correlation to examine ICANS grade's association with either NfL or GFAP after accounting for the established risk factor of cytokine release syndrome (CRS) and the other biomarker. Results In adults who develop ICANS, both baseline NfL and GFAP were elevated in univariate analyzes, although distinguishing between low (grade 1, 2) and high (grade 3, 4) ICANS remains challenging (Fig. 1A). Plasma NfL remained elevated on day 7 and day 15, but not day 30. No group differences were observed in GFAP on day 7, 15, or 30 (Fig. 1B). Only baseline NfL (p = 0.004) and history of severe CRS (p = 0.002) were associated with ICANS grade following stepwise linear regression (p = 0.0001). Spearman partial correlations likewise demonstrated an association between ICANS grade and baseline NfL after accounting for CRS and GFAP (r = 0.31, p = 0.007), but not with baseline GFAP when accounting for CRS and NfL (p > 0.1). Conclusion In this larger cohort of adult patients, ICANS risk was associated with preexisting neuroaxonal injury as quantified by NfL. While there is a suggestion of baseline astrocyte dysfunction, this relationship was not observed in modeling that further accounted for CRS severity. Given the exquisite microvascular support needed for axonal maintenance and known additional vascular risk factor for ICANS, the intersection of microvascular/axonal integrity warrants further investigation and may better delineate low vs high grade ICANS. Finally, patients with baseline NfL levels ≥ 46 pg/ml may benefit from early prophylactic intervention or trail consideration to mitigate ICANS risk.