Early Steroid and Anakinra Use to Manage Axicabtagene Ciloleucel Toxicity Reduces the Total Duration of CRS and Icans

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Introduction Axicabtagene ciloleucel (axi-cel) is an effective chimeric antigen receptor T-cell therapy (CAR-T) for relapsed/refractory (R/R) large B-cell lymphoma (LBCL). Optimizing cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) management can improve clinical outcomes. In July 2020, our center adopted a modified Cohort 4 strategy from the registrational ZUMA-1 trial, with earlier steroid use for toxicities. Due to the nationwide tocilizumab (toci) shortage during the COVID-19 pandemic, we used anakinra for recurrent grade (gr) 2 CRS and dexamethasone 10mg (dex10) q6h after an initial toci and dex10 dose. Objectives This study aimed to evaluate the impact of the modified Cohort 4 strategy by analyzing toxicity incidence/duration, treatment response, and drug/healthcare utilization. Methods This single-center, retrospective analysis included 195 patients receiving axi-cel CAR-T therapy from January 2018 to April 2023 for R/R LBCL with 2+ prior therapy lines. We labeled patients treated before 7/1/2020 as the comparator cohort (N=92) and those after as the post-change cohort (N=103). Steroid, anakinra , and toci utilization, plus weekly CAR-T flow cytometry, were collected for 1 month post treatment. Regression analyses were adjusted for age, sex, prior stem cell transplant, LDH , bridging therapy, baseline metabolic tumor volume, and CAR-HEMATOTOX toxicity risk score, with the appropriate link function used for the outcome of interest. Results The median patient age was 63 years (IQR: 55-71), with 43% female and 53% diagnosed with DLBCL . Almost all baseline characteristics were similar between cohorts (Table 1). The post-change cohort had higher anakinra (22% vs. 5%, p <0.01) and steroid (88% vs. 71%, p <0.01) usage rates. Consistent with our new strategy, the post-change cohort also had faster anakinra (adj. HR 5.6 [1.9, 17.1], p <0.01) and steroid (adj. HR 1.8 [1.3, 2.6], p <0.01) time-to-first-dose (Figure 1A). There were no differences in cumulative drug dosage or toci usage patterns. Overall response rate, overall survival , and progression free survival were similar between the cohorts (Table 1). Overall CRS and ICANS rates were similar, though the gr 3+ ICANS rate was nominally higher in the comparator cohort (21% vs. 12%, p = 0.36). The post-change cohort had shorter CRS (adj. est: -0.9 days [95% CI: -1.7, -0.2], p = 0.01) and ICANS duration (adj. est: -2.5 days [-5.0, -0.0], p = 0.05) versus the comparator (Figure 1B). There were no significant differences in peak CAR-T expansion, ICU admissions, or hospitalization length. Conclusion A modified Cohort 4 protocol that limits toci use to initial gr 2 CRS and uses anakinra and dex10 q6h for recurrent CRS resulted in shorter CRS/ICANS duration. This study supports earlier intervention for CAR-T toxicities and establishes anakinra as an adjunctive toxicity management drug.

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