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
Authors: Wang Jiasheng , Bhaskar Shakthi , Adedokun Babatunde , Oluwole Olalekan O. , Metheny Leland , Moskop Amy , Jacobson Caron A. , Shouse Geoffrey , Ahmed Sairah , Ghobadi Armin , Dahiya Saurabh , Yan Jiali , Hu Zhen-Huan , Best Timothy , Kim Jenny J. , Mirjah Debbie L. , Pasquini Marcelo C. , Locke Frederick L. 
Published: December 2024

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.