Retrospective Comparison of the Roles of Tocilizumab and Siltuximab in the Management of Toxicity in CAR-T Cell Therapy for Relapsed/Refractory B-NHL
Authors: Liu Rui , Yang Fan , Ma Lixia , Guo Yuelu , Fu Zhonghua , Deng Biping , Chen Chen , Ke Xiaoyan , Hu Kai 
Published: December 2024

Background:

CAR-T cell therapy has demonstrated significant efficacy in treating B-cell non-Hodgkin lymphoma（B-NHL）, though common short-term adverse effects include cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Tocilizumab is currently the standard treatment for managing CRS, while siltuximab, another interleukin-6 antagonist, has been increasingly used in clinical settings in recent years. However, research on the effectiveness of siltuximab in managing CAR-T cell toxicity and its impact on treatment outcomes, particularly in comparison to tocilizumab, remains relatively limited.Aims: Comparing siltuximab and tocilizumab in controlling CRS after CAR-T therapy, regarding efficacy, safety, response rates, and long-term effectiveness. Methods:This retrospective study was conducted at Beijing Gaobroad Hospital, from April 2020 to January 2024, including patients with relapsed/refractory B-cell non-Hodgkin lymphoma who underwent CAR-T cell therapy and experienced CRS. Patients treated with siltuximab or tocilizumab for CRS management were analyzed. Comparative assessments were made between the two groups regarding CRS control rates, incidence of ICANS, infection rates, baseline and peak IL-6 levels before and after treatment, 3-month response rates of CAR-T, and long-term survival outcomes.A total of 49 patients were assessed, with 27 receiving tocilizumab and 22 receiving siltuximab.

Results:

baseline characteristics： The pathological subtypes of the enrolled patients were as follows: DLBCL NOS (n=27), BL(n=5), HGBL (n=5),PMBCL (n=4), FL (n=3), Richter (n=3), tFL(n=1)and PCNSL(n=1). Among the patients, 28/49 (57%) were male, with a median age of 42 years (range 20-65). A total of 20/49 (41%) had an IPI score ≥3, and 27/49 (55%) had received ≥3 prior treatments. The median LDH level was 258.3 (range 105.7-4837.2).

Before administration： Before infusing siltuximab , CRS grading was as follows: G1 in 17/22 cases, G2 in 4/22 cases, G3 in 1/22 case, with no ICANS reported ; baseline IL-6 averaged 222.13 pg/mL(range 6.42-3257.91). Before infusing tocilizumab, CRS grading was: G1 in 17/27 cases, G2 in 4/27 cases, G3 in 2/27 cases, G4 in 4/27 cases, with ICANS G4 in 1/27 case; baseline IL-6 averaged 52.96 pg/mL(range 3.26-350.95). Median time from CAR T infusion to siltuximab administration was 4 days (range 1-16 ), and for tocilizumab, it was 9 days (range 2-29) (p=0.0306); median total dosage was 400 mg (range 100-800) for siltuximab and 400 mg (range 240-1040) for tocilizumab (p=0.0036).

After administration： Within 48 hours, CRS was controlled in 59% (13/22) with siltuximab and 48% (13/27) with tocilizumab. Post-siltuximab, without CRS in 13/22 cases, G1 in 4/22 cases, G2 in 4/22 cases, G3 in 1/22 case; peak IL-6 within 21 days averaged 3125.05 (range 433.52-5023.43). Post-tocilizumab, without CRS in 13/27 cases, G1 in 6/27 cases, G3 in 2/27 cases, G4 in 4/27 cases, G5 in 2/27 cases; ICANS G4 in 3/27 cases (occurs within two days of dosing); peak IL-6 within 21 days averaged 826.46 (range 79.99-2716.3).

Co-administration with steroids was 59% (13/22) with siltuximab and 70% (19/27) with tocilizumab (p=0.409); median steroid use was 11 days (range 2-29 days) with siltuximab and 3 days (range 1-30 days) with tocilizumab (p=0.0351); total steroid doses averaged 62.5 mg (range 4-1582.5 mg) with siltuximab and 27 mg (range 2-1061 mg) with tocilizumab (p=0.1500).Infections occurred in 5% (1/22, bacterial) with siltuximab and 70% (19/27, bacterial 10 and fungal 12) with tocilizumab (p &lt; 0.001).

The 3-month objective response rate (ORR) was 55% (12/22) with siltuximab and 52% (14/27) with tocilizumab. Median progression-free survival (PFS) was 12.72 months with siltuximab and 6.15 months with tocilizumab (p=0.5903). Median overall survival (OS) was not reached with siltuximab and was 14.27 months with tocilizumab (p=0.4256).

Summary/Conclusion:

Siltuximab effectively manages cytokine release syndrome (CRS) similar to tocilizumab but notably reduces immune effector cell-associated neurotoxicity syndrome (ICANS) incidence and lowers infection rates. However, the exact mechanisms behind these benefits need further investigation.