Optimizing Tocilizumab Dosing in CAR-T–associated Cytokine Release Syndrome: When Less is Enough
Chimeric antigen receptor (CAR) T-cell therapy has revolutionized treatment for hematologic malignancies. Cytokine release syndrome (CRS) is the most common adverse event and is a systemic inflammatory response primarily driven by interleukin-6 (IL-6). Tocilizumab, an IL-6 receptor antagonist, is approved for management of CAR-T induced CRS. However, as outlined in the FDA approval summary, the optimal dosing regimen has never been established. In the Netherlands, tocilizumab dosing strategies include weight-based dosing (8 mg/kg, maximum 4 doses) and fixed dosing (600 mg, with an optional second and final dose of 400 mg). We aimed to evaluate differences in C-reactive protein (CRP) inhibition, a biomarker of IL-6 inhibition, and clinical outcomes between weight-based and fixed dosing strategies in patients with CAR-T induced CRS.
A population-based cohort study was conducted. All adult patients with relapsed/refractory large B-cell lymphoma (R/R LBCL) treated with axicabtagene ciloleucel (axi-cel) in the Netherlands, receiving approval from the Dutch CAR-T Tumorboard between May 2020 and December 2023, were included. Patients without CRS, or who did not receive tocilizumab according to either weight-based or fixed dosing strategies, were excluded. Data on clinical characteristics, tocilizumab and corticosteroid use, laboratory values, adverse events, and survival were collected. Mixed-effect models were used to analyze the effect of tocilizumab on CRP levels.
173 patients were infused with axi-cel and received tocilizumab for CRS, according to weight-based (n= 114) or fixed dosing (n= 59) strategies. The weight-based cohort had significantly more primary refractory LBCL, while the fixed cohort had more ≥3 extranodal sites (table 1). Patients in the weight-based cohort received a median cumulative tocilizumab dose of 1200 mg (range: 452-3200 mg), compared to 600 mg (range: 400-1200 mg) in the fixed cohort (p <0.001). No significant differences in CRP levels were observed between the cohorts at any timepoint after first tocilizumab administration (figure 1A). Subgroup analyses of patients receiving 3 or 4 doses of tocilizumab for ongoing CRS “the possibly overdosed” and patients with ongoing CRS despite fixed dosing “the possibly underdosed”, also showed no significant CRP differences (figure 1B). Furthermore, no significant difference was found in CRS grading, CRS resolution time, corticosteroid use, ICU admissions, ICANS prevalence, and survival. However, patients in the weight-based cohort had significantly more grade ≥3 late neutropenia (42% vs 17%; p <0.05) and more early grade 3-4 infections (60% vs 26%; p <0.05), compared to the fixed cohort.
Data from our real-world cohort demonstrate no added value of tocilizumab dosing beyond two fixed doses. Fixed dosing of tocilizumab for CAR-T induced CRS results in comparable CRP inhibition and clinical outcomes with less early infections and neutropenia. Nationwide implementation could reduce costs.