Association between post-CART terminal complement complex (TCC) levels and clinically significant immune effector cell–associated neurotoxicity syndrome (ICANS).
Authors: George III  , Zhao Qiuhong , Voorhees Timothy , Denlinger Nathan , Epperla Narendranath , Sigmund Audrey M , Sanchez-Petitto Gabriela , Sawalha Yazeed , Bond David Alan , Choe Hannah Kyung , Wall Sarah Allison , Brammer Jonathan Edward , Alinari Lapo , Christian Beth , Cataland Spero , Jaglowski Samantha Mary , Maddocks Kami J. , De Lima Marcos J.G. , Vasu Sumithira , Bezerra Evandro 
Published: June 2024

7036 Background: The cornerstone of ICANS pathogenesis is endothelial dysfunction leading to blood-brain barrier disruption driven by inflammatory cytokines. Endothelial dysfunction is often associated with complement activation as in thrombotic microangiopathy, but the association between complement and ICANS has not yet been investigated. Herein, we describe the association between TCC levels (sC5b-9) and ICANS after CART. Methods: We retrospectively included 42 patients (pts) with B-cell non-Hodgkin lymphoma treated with axi-cel or brexu-cel from 03/2022 - 09/2023 at Ohio State University who had had sC5b-9 levels available pre-lymphodepletion (pre-LD), pre-CART and post-CART infusion. sC5b-9 levels were measured once in each of the timepoints: pre-LD (between D-7 and D-4), pre-CART (between D-3 and D0) and post-CART (between D2 and D8). We defined clinically significant ICANS as peak grade ≥2 (G≥2). Median and interquartile range (IQR) were used to describe the biomarkers levels, and Wilcoxon-rank sum test was used to compare values between groups. Results: Median age was 64 years (26-76), 30 (71%) pts had large B-cell lymphoma and 6 (14%) had untransformed follicular lymphoma who received axi-cel (36, 86%), and 6 (14%) had mantle cell lymphoma who received brexu-cel. Following CART, cytokine-release syndrome (CRS) peak grade was 2 and 1 in 16 (38%) and 22 (52%) of the pts, respectively, and 4 pts (10%) had no CRS. The ICANS peak grade was 4, 3, 2 and 1 in 4 (10%), 2 (5%), 6 (14%) and 6 (14%) of the pts, respectively, and 24 (57%) of the pts had no ICANS. The median time from CART to ICANS peak was 6 days (2-12). Tocilizumab and steroids were used in 28 (67%) and 20 (48%) of the pts, respectively. We compared sC5b-9 levels pre-LD, pre-CART and post-CART between pts that had ICANS peak G≥2 (N = 12) vs. grade 1 or did not have ICANS (G0-1, N = 30). We found that the post-CART sC5b-9 levels were significantly higher among pts who had ICANS G≥2 [median (IQR) 254 (129) vs. 183 (82) ng/mL, p = 0.013]. There was no statistical difference in the levels pre-LD and pre-CART between pts who had ICANS G≥2 vs. G0-1, median (IQR) 176 (103) vs. 159 (94) ng/mL, p = 0.37, and 152 (64) vs. 143 (69) ng/mL, p = 0.89, respectively. We also compared levels of other biomarkers associated with tumor burden, inflammation, and endothelial dysfunction at the same time points sC5b-9 was measured between pts with ICANS G≥2 vs. G0-1 and there were no statistically significant differences: median (IQR) pre-LD LDH 171 (73) vs. 180 (115) U/L, p =0.54, post-CART ferritin 262 (546) vs. 297 (333) ng/mL, p = 0.92 and post-CART fibrinogen 302 (221) vs. 405 (146) mg/dL, p = 0.29. Conclusions: Our findings support an association between post-CART sC5b-9 levels and clinically significant ICANS warranting further investigation of the role of complement in the ICANS pathogenesis and as a therapeutic target.