Early Time-to-Tocilizumab after B Cell Maturation Antigen-Directed Chimeric Antigen Receptor T Cell Therapy in Myeloma

Abstract

Preemptive administration of tocilizumab (toci) to manage cytokine release syndrome (CRS) after chimeric antigen receptor T cell (CAR-T) therapy may reduce rates of serious CRS but conversely may worsen neurotoxicity or risk of infections. Optimal toci administration strategies for patients with relapsed/refractory multiple myeloma (RRMM) receiving B cell maturation antigen (BCMA)-directed CAR-T therapies have not been evaluated. The objective of this study was to identify whether shorter time-to-toci intervals (hours between first fever attributed to CRS and first dose of toci) have any impact on therapy-related toxicities or clinical outcomes among patients with RRMM receiving BCMA-directed CAR-T therapies. We retrospectively analyzed our institution's experience with 4 BCMA-directed CAR-T therapies (idecabtagene vicleucel, bb21217, ciltacabtagene autoleucel, and orvacabtagene autoceucel) for RRMM over a 3-year period ending in June 2020. We divided patients based on the administration of toci and median time-to-toci interval into early-toci (time-to-toci ≤50th percentile), late-toci (time-to-toci >50th percentile), and no-toci (no toci received) groups. We compared the early-toci and late-toci groups with regard to patient characteristics, weight-based CAR-T toxicities, selected toxicities (CRS, neurotoxicity, macrophage activation syndrome, or infections), and clinical outcomes. Of 50 analyzed patients with a median follow-up of 15.3 months, 76% (n = 38) received ≥1 dose of toci (range, 1 to 3) and were classified into early-toci (time-to-toci ≤12 hours) or late-toci (time-to-toci >12 hours) groups. The 2 groups (n = 19 each) had similar CRS grade distributions, hours to CRS onset, CRS-related biomarkers, and incidences of neurotoxicity or severe infections; however, weight-adjusted CAR-T cell doses were higher in the early-toci group (median 5.99 versus 3.80 × 10⁶ cells/kg, P < 0.01). Peak CRS grades (range, 0 to 2) using American Society for Transplantation and Cellular Therapy consensus criteria, neurotoxicity rates, and rates of severe infections were similar between groups; however, the median CRS duration was 18.6 hours for the early-toci group versus 84.7 hours for the late-toci group. The median progression-free survival was 35.7 months in the early-toci group and 13.2 months in the late-toci group. While limited by small sample size and known confounders such as CAR-T cell dose, our analysis suggests that preemptive toci strategies for CRS management with BCMA-directed CAR-T therapy-specifically, toci administration within 12 hours of the first fever attributed to CRS-do not appear to increase rates of therapy-related toxicities or compromise efficacy. However, total CRS duration may be shorter with early-toci workflows. Prospective validation of our findings may lead to improved safety and cost-effectiveness profiles for CAR-T therapy in RRMM.

Keywords: Chimeric antigen; Cytokine release syndrome; Multiple myeloma; Receptors; Tocilizumab.