Factors Associated with Prolonged CRS and Neurotoxicity after Treatment with Axicabtagene Ciloleucel
Authors: Albittar Aya , Voutsinas Jenna M , Portuguese Andrew J , Huang Jennifer J. , Liang Emily C , Wu Qian , Fan Xinyi , Hirayama Alexandre V , Kimble Erik L , Iovino Lorenzo , Poh Christina , Gopal Ajay K , Shadman Mazyar , Till Brian G , Milano Filippo , Chapuis Aude G , Cassaday Ryan D , Maloney David G , Gauthier Jordan 
Published: December 2023

BACKGROUND
While chimeric antigen receptor T-cell (CAR-T) therapy has transformed the treatment of high-risk B-cell malignancies, it causes significant toxicities, specifically, cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Most of the research to date has focused on the identification of factors associated with the peak severity of CRS and ICANS, which does not capture the duration of these toxicities. Yet protracted toxicities are observed in a subset of patients, and risk factors predictive of CRS/ICANS duration have not been reported. To address this limitation, we have previously reported the use of a novel clinical endpoint: time to CRS and ICANS (CRS/ICANS) resolution, which captures the longitudinal impact of these toxicities while allowing for censoring in the event of early deaths (Gazeau et al, TCT, 2023). Here, we applied this framework to provide the first characterization of factors associated with time to CRS/ICANS resolution in patients receiving the FDA-approved CD19 CAR T-cell product axicabtagene ciloleucel (axi-cel).
METHODS
Eighty-four patients (pts) treated at the Fred Hutch Bezos Family Immunotherapy Clinic with axi-cel per the FDA label outside of a clinical trial between 1/2018 and 4/2022 were included. CRS and ICANS were graded (G) using ASTCT criteria. Cause-specific Cox regression models were used to estimate associations between 60+ pre/post-infusion patient, disease-related, laboratory variables (e.g., platelet count, creatinine, PT, PTT, CRP, IL-6, fibrinogen, ferritin), and time to CRS/ICANS resolution. Endothelial Activation and Stress Index (EASIX) score was calculated at pre-/post-infusion timepoints. Time to CRS/ICANS resolution was defined as the time from axi-cel infusion left-truncated at the time of CRS/ICANS onset until CRS/ICANS symptom resolution (first day of grade 0 for at least three consecutive days), whichever toxicity happened last, censoring for death from any cause.
RESULTS
Baseline characteristics and toxicity outcomes are shown in Table1. The median age at infusion was 62 (range, 25-79). Histology was large B cell lymphoma in 79 pts (94%), and follicular lymphoma in 5 pts (6%). We observed any-grade CRS in 72 pts (86%) and G≥3 CRS in 7 pts (8%). Fifty-two pts (62%) developed any-grade ICANS, and 16 pts (19%) G≥3 ICANS (G1: 15 [18%], G2: 21 [25%], G3: 15 [18%], G4: 1 [1.2%]). The median time to CRS/ICANS resolution was 10 days (95%CI: 9,11). Two pts (2%) died prior to CRS/ICANS resolution.
Using univariate cause-specific Cox regression, the following pre-infusion factors were associated with longer time to CRS/ICANS resolution: lower platelet count at day 0 (HR=0.41, 95%CI: 0.17-0.98, p=0.044), higher PTT at day 0 (HR=0.05, 95%CI: 0.00-0.86, p=0.039), higher preLD creatinine (HR=0.06, 95%CI: 0.01-0.50, p=0.009) and higher EASIX score preLD (HR=0.57, 95%CI:0.35-0.94, p=0.028) and at day 0 (HR=0.52, 95%CI: 0.29-0.96, p=0.035). Cumulative incidence curves of time to CRS/ICANS resolution for select predictors are shown in Figure 1B.
At the time of CRS onset, a higher ferritin level (HR=0.51, 95%CI: 0.27-0.94, p=0.031) and peak CRS severity (HR = 0.73, 95%CI: 0.55-0.97, p=0.029) were associated with longer time to CRS/ICANS resolution. Higher ferritin levels over time (time dependent HR [tdHR]=0.38, 95%CI: 0.19-0.72, p=0.004), higher PTT (tdHR=0.028, 95%CI: 0.01-0.76, p=0.028), and peak ICANS severity (HR=0.58, 95%CI: 0.046, 0.72, p&lt;0.001) were associated with longer time to CRS/ICANS resolution.
In a multivariable Cox model after LASSO variable selection including day 0 PTT, ferritin, EASIX score, and peak CRS severity, lower day 0 platelet count remained independently associated with longer time to CRS/ICANS resolution (HR=6.96 per log10 increase, 95%CI:1.09-44.5, p=0.04; model discrimination: C-index=0.65).
CONCLUSION
This is to our knowledge the first study aimed at the identification of factors associated specifically with the duration of CRS and ICANS after CD19 CAR T-cell therapy. We successfully identified pre- and post-infusion factors associated with prolonged CRS/ICANS duration after CD19 CAR T-cell therapy with axi-cel. Our findings suggest that point-of-care assessments can identify patients at risk of prolonged toxicities and could guide the use of prophylactic corticosteroids or early interventions (e.g., anakinra).