The 2020 Society for Immunotherapy of Cancer (SITC) clinical practice guidelines for the management of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) recommend consideration of tocilizumab early in the course of CRS for older adult patients or patients with extensive comorbidities, as well as adult patients who develop American Society for Transplantation and Cellular Therapy (ASTCT) grade 2 CRS. Tocilizumab may be administered in pediatric patients who develop prolonged ASTCT grade 2 CRS or an intolerance to fever. Notably, panel recommendations are not specific to patients with CRS on bispecific T cell engager (BiTE) therapy; patients who have previously undergone BiTE therapy may be treated with chimeric antigen receptor (CAR) T-cells, depending on individual expression of target antigens. There is no discussion regarding the efficacy or safety of tocilizumab in this patient subgroup. [1]
The 2022 guidelines from the American Society of Clinical Oncology (ASCO) regarding the management of immune-related adverse events in CAR T-cell therapy, including CRS and ICANS, suggest the use of tocilizumab, with or without corticosteroids, for the treatment of severe or prolonged CRS associated with CAR T-cell therapy. Tocilizumab use for the prevention of CRS is not described. Additionally, the guidelines note there is limited experience regarding other therapies and specific guidance for BiTE therapy is not provided. [2]
According to a 2023 consensus report from the European Myeloma Network on the prevention and management of adverse events during treatment with bispecific antibodies and CAR T-cells in multiple myeloma, tocilizumab may be used to effectively manage CRS; incidence and severity of CRS related to BiTE administration may be diminished with tocilizumab premedication, stepwise dosing, dexamethasone premedication, or temporary drug discontinuation, although data were not provided to corroborate tocilizumab efficacy. If a fever develops within 72 hours and there is no improvement with symptomatic treatments, a 60-minute infusion of tocilizumab (8 mg/kg) is suggested, with corticosteroids administered to patients with persistent (>3 days) or high-grade symptoms and patients with symptoms refractory to tocilizumab. There is no discussion regarding the safety of tocilizumab in this patient subgroup. [3], [4]
Additionally, a 2020 review article discussed the use of tocilizumab in the management of CRS, with consideration towards its place in therapy in the management of CRS. Based on the results of a retrospective analysis of data from prospective clinical trials conducted in patients who developed CRS after treatment with tisagenlecleucel (CTL019) and axicabtagene ciloleucel (KTE-C19, axi-cel), tocilizumab is approved for the treatment of severe or life-threatening CAR T cell-induced CRS in adults and pediatrics (aged ≥ 2 years). To avoid altering the efficacy of CAR-T-cell therapy, the general consensus suggests administering tocilizumab at the time of moderate to severe signs of CRS. In the absence of clinical improvement, tocilizumab administration may be repeated every 8 hours to a maximum of four doses. Concomitant administration of steroids may be considered if no improvement is observed with the first dose of tocilizumab. While rare cases of CRS refractory to tocilizumab are reported, the mechanism of failure is unclear; however, it could be related to inadequate tocilizumab dosing to suppress IL-6 cytokines, alternative cytokines resulting in hypercytokinemia, or compensatory feedback in IL-6 signaling. The efficacy of tocilizumab is well-established in the management of CAR-T-associated CRS without suppressing T-cell function and/or inducing T-cell apoptosis. Future studies are warranted to demonstrate an optimal timing of administration, especially in patient populations with a higher risk of developing CRS. Until the published date of review, no evidence demonstrated the benefits of using tocilizumab for the prevention or treatment of toxicity due to ICANS. Although the potential for BiTE therapy including CRS is described within the review, the use of prophylactic tocilizumab specifically for this purpose is not addressed. [5]
A 2023 prospective study evaluated the use of prophylactic tocilizumab to reduce CRS incidence in patients treated with teclistamab. In the MajesTEC-1 trial, CRS occurred in 72.1% of patients receiving the recommended phase 2 dose of teclistamab (1.5 mg/kg weekly), prompting this investigation. In this study, 14 patients received subcutaneous teclistamab following two step-up doses, with tocilizumab administered as a single IV dose (8 mg/kg) within 4 hours before the first teclistamab dose. CRS occurred in 4 patients (29%), with no events reaching grade 3 or higher; the median time to onset and duration were both 2 days. All cases were managed effectively with tocilizumab, allowing uninterrupted teclistamab treatment. Seven patients had grade 3 or 4 neutropenia, consistent with the overall MajesTEC-1 population, and 2 experienced grade 3 or 4 infections, with 2 reporting neurotoxic adverse events. Among response-evaluable patients, 4 of 7 responded to treatment. The authors concluded that a single dose of tocilizumab before teclistamab treatment reduced CRS incidence compared to the MajesTEC-1 population, with no new safety signals and no impact on treatment response. However, only the abstract was available for scrutiny, limiting a comprehensive assessment. [6], [7]