Real-World Trends of Cytokine Release Syndrome and Neurologic Events, and Pattern of Their Management Among Patients Receiving Axicabtagene Ciloleucel for Relapsed or Refractory (r/r) Large B-Cell Lymphoma (LBCL) in the US: A CIBMTR Report

Background

Axicabtagene ciloleucel (axi-cel) is an autologous CD19-targeting CAR T-cell product that has demonstrated curative potential for r/r LBCL (Neelapu et al 2023). Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are early adverse events (AEs) that could occur after axi-cel infusion. The management of these toxicities has improved over the years with early use of corticosteroids and tocilizumab, and use of prophylactic corticosteroids (Topp et al 2021; Oluwole et al 2021). As a result, the toxicity profile may change over time. Here, we investigated real-world trends in CRS and ICANS associated with axi-cel use for r/r LBCL and patterns of their management in the US from 2017 to 2023.

Methods

Patients who received commercial axi-cel for third line or later r/r LBCL from October 2017− July 2023 were selected from the Center for International Blood and Marrow Transplant Research (CIBMTR) database. Patients with prior non-transplant cellular therapy or primary central nervous system lymphoma were excluded. Incidences of CRS and ICANS, their maximum grades (ASTCT criteria), treatments, and durations were compared across three periods: 2017–2019, 2020–2021, and 2022–2023 (prophylactic therapy data was unavailable in 2017-2019). Multivariable regressions were conducted for dichotomous and time to event outcomes with period as the main effect while adjusting for patient-, disease-, and treatment-related covariates. Other AEs included prolonged neutropenia, prolonged thrombocytopenia, and clinically significant infections.

Results

A total of 1615 patients from 109 centers received axi-cel, with 923 treated during 2017–2019, 486 during 2020–2021, and 206 during 2022–2023. The median (min, max) age at infusion was 61.6 years (19.6, 90.8), 63.1 years (21.4, 84.4), and 63.2 years (19.9, 85.5), respectively. For the three respective time periods, 36%, 35%, and 35% received 4 or more lines of prior therapy, and 30%, 21%, and 19% had prior hematopoietic cell transplantation, respectively. Use of bridging therapy between leukapheresis and infusion was 34%, 42%, and 58%, while the median (interquartile range [IQR]) time from leukapheresis to infusion was 27 (25-31), 28 (26-33), and 31 (27-35) days, respectively. Prophylactic medications for CRS or ICANS were used in 50% and 62% of patients during 2020–2021 and 2022–2023, respectively.

For the three respective time periods, the incidence of CRS of any grade was 83%, 83%, and 76%, while Grade ≥3 CRS was 11%, 9%, and 3%. The median (IQR) duration of CRS was 7 (4, 10), 6 (4, 8), and 5 (4, 8) days, respectively. Based on the multivariable analysis, patients who received axi-cel during 2022–2023 and 2020–2021 had significantly lower incidences of Grade ≥3 CRS compared to those treated during 2017–2019 (odds ratio [OR] 0.17, 95% confidence interval [CI] 0.07−0.41, and OR 0.63, 95% CI 0.43−0.94, respectively). Moreover, the durations of CRS during 2022–2023 and 2020–2021 were significantly shorter compared to 2017–2019 (hazard ratio [HR] 1.36, 95% CI 1.14−1.64, and HR 1.34, 95% CI 1.18−1.52).

For the three respective time periods, the incidence of ICANS of any grade was 57%, 48%, and 41%, while Grade ≥3 ICANS was 25%, 24%, and 19%. The median (IQR) duration of ICANS was 7.5 (4, 13), 7 (4, 12), and 6 (4, 11) days, respectively. Based on the multivariable analysis, patients who received axi-cel during 2022–2023 and 2020–2021 had a significantly lower incidence of any grade ICANS compared to those treated in 2017–2019 (OR 0.47, 95% CI 0.34−0.66, and OR 0.63, 95% CI 0.50−0.80, respectively). Moreover, the duration of ICANS during 2020–2021 was significantly shorter compared to 2017–2019 (HR 1.21, 95% CI 1.02−1.43).

The rates of use of tocilizumab and corticosteroids for the treatment of CRS/ICANS were consistent for the three periods, although there was an increasing trend of anakinra use (1%, 6%, and 13%, respectively). Additionally, concerning other AEs, there were no significant differences regarding prolonged neutropenia, prolonged thrombocytopenia, or clinically significant infections.

Conclusions

In real-world settings in the US, there is a decreasing trend in incidence, severity, and duration of CRS and ICANS after axi-cel treatment for r/r LBCL.