Phase 2 Trial of Siltuximab for the Treatment of Cytokine Release Syndrome and Immune Effector Cell Associated Neurotoxicity Related to CAR-T Cell Therapy

Background: CAR T-cell therapy is a promising treatment option for hematological malignancies. However, toxicities such as cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS) associated with CAR T-cell therapies are challenging to manage. Tocilizumab, an anti-interleukin - 6 receptor (IL-6R) monoclonal antibody, can lead to a paradoxical increase in circulating IL-6 levels (Nishimoto et al. Blood 2008), which may result in worsening of CRS/ICANS. Therefore, in this phase 2 study, we utilized siltuximab, an IL-6 binding monoclonal antibody, to assess its efficacy for the treatment of CRS and/or ICANS in patients receiving standard CAR T-cell therapy and herein report results of the clinical trial (NCT04975555). Methods We enrolled pts ≥ 18yrs with R/R large B-cell lymphoma (LBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL) or multiple myeloma (MM) planned to receive CAR T-cell therapy. Pts with persistent Grade 1 CRS/ICANS ≥ 12 hours or grade ≥2 CRS/ICANS received a dose of siltuximab 11mg/kg over one hour. Repeat dose of siltuximab and corticosteroids were permitted if CRS/ICANS persisted ≥12 hours. Pts requiring rescue tocilizumab for non-responsive or worsening CRS after 2 doses of siltuximab were considered as non-responders. CRS/ICANS were assessed per the ASTCT consensus grading. The primary endpoint was CRS resolution rate within 14 days of first siltuximab infusion. CRS resolution defined as absence of symptoms leading to onset of CRS for a duration of 24 hours measured from the first normal temperature recorded. The secondary endpoints included were rates of resolution of ICANS within 28 days from onset, adverse event profile, overall response rate for CAR T-cell therapy. Results: Amongst 20 pts (15 LBCL, 2 FL, 1 MCL, 2 MM) enrolled on the study, the median age was 59 yrs (range, 38-79). Fourteen pts received Axi-cel, 2 pts received Liso-cel, 2 pts received Ide-cel, 1 pt each received Tisa-cel and Brexu-cel, respectively. CRS occurred in 19 pts of which 10 pts developed CRS with ICANS while 1 pt developed ICANS only. Amongst 19 pts with CRS, 15 pts had a CRS resolution with a median time to CRS resolution of 1 hr (range, 1-104) from the most recent siltuximab dose. Second dose of siltuximab for persistent CRS was required in 8 pts at 12 hrs and in 4 pts for relapses occurring beyond 24 hrs of CRS resolution. Tocilizumab rescue was required for 4 pts (3pts for worsening CRS) with a median time to CRS resolution of 55 hrs (range, 52-120) from the most recent tocilizumab dose. Amongst 11 pts who experienced ICANS at any point, 5 pts had a resolution of ICANS after siltuximab infusion with a median time to ICANS resolution of 62 hrs (Range, 9 - 216) with remaining 6 pts considered non-responders to siltuximab with either development of new episode of ICANS or increase in grade of ICANS after 2 doses of siltuximab. Corticosteroids were used in all 11 pts and anakinra in 3 pts. The CR rate for CRS was 79% (95% CI: 55-95), and for ICANS with siltuximab was 45% (95%CI 18 - 82). No pt experienced infusion-related reactions to siltuximab. Other adverse events reported were consistent with CAR T-cell therapy-related adverse event profiles. The anti-tumor efficacy of CAR T-cell therapy observed was also consistent with disease and product specific responses [ORR rates in LBCL: 58% with Axi-cel (n=12), 100% with Liso-cel (n=2), 0% in Tisa-cel (n=1)]. Exploratory analysis revealed elevated procalcitonin levels before second dose, and a higher baseline CRP and IL-6 predicted failure of siltuximab for CRS resolution. Conclusion: In this prospective phase 2 trial, siltuximab demonstrated a high response rate (79%) and rapid time to resolution (median 1 hour) of CRS following CAR T-cell therapy. However, the efficacy for ICANS was modest (45%). Importantly, no new adverse events were attributable to siltuximab, and it did not negatively impact anti-tumor efficacy of CAR T-cell therapy. These findings support siltuximab as a safe and effective alternative to tocilizumab for the management of CRS.