Efficacy of tocilizumab prophylaxis in preventing cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome: A systematic review and meta-analysis

Abstract Introduction: Chimeric antigen receptor T cell therapy (CAR-T) and bispecific antibodies have revolutionized the management of hematological malignancies. Still, serious adverse events such as cytokine release syndrome (CRS) and immune effector-associated neurotoxicity syndrome (ICANS) remain an area of significant concern. Tocilizumab is currently approved for the treatment of CRS; however, we aim to investigate its potential role as a preventive agent. Methods: Following PRISMA guidelines, a comprehensive literature search was conducted on PubMed, Cochrane, Embase, Google Scholar, and ClinicalTrials.gov using MeSH terms and keywords for “ Tocilizumab”, “cytokine release syndrome”, and “immune effector-associated neurotoxicity syndrome.” After screening of 552 references and excluding review articles, 11 studies reporting outcomes with prophylactic Tocilizumab in CAR-T and Bispecific antibody treated patients were included. For outcomes reported in two or more studies, a meta-analysis was conducted using a random-effects model in MetaXL to estimate the pooled prevalence, applying a double-arcsine transformation. Results were expressed as prevalence estimates with 95% confidence intervals (CIs). Some characteristics were described systematically. Results: A total of 430 patients from six retrospective and five prospective studies were included for analysis. The median age was 62 (21-87) years, and 50% (n = 189/374) were male. Underlying malignancies included multiple myeloma (MM) (80%, n= 346), diffuse large B-cell lymphoma (DLBCL) (14%, n = 61), mantle cell lymphoma (MCL) (2%, n = 8), follicular lymphoma (1%, n = 5), B-cell acute lymphoblastic leukemia (B-ALL) (0.5%, n = 2), and others (2%, n = 8). Among the total population, the MM were treated with Bispecific antibodies (n = 346, 80%), and the rest were treated with CAR-T cell therapy. The Bispecific antibodies used were Teclistamab. Eltranatamab, Talquetamab, and Linvoseltamab. The pooled rates for patients who developed CRS and ICANS were 28% (95% CI 0.24-0.33, p = 0.00, I2 = 95%) and 14% (95% CI 0.11-0.17, p = 0.00, I2 = 94%), respectively. The pooled rates for the development of grade 1, grade 2, grade 3, and grade 4 CRS were 18% (95% CI 0.15-0.22, p = 0.00, I2 = 87%), 8% (95% CI 0.05-0.11, p = 0.00, I2 = 88%), 2% (95% CI 0.00-0.05, p = 0.63, I2 = 0%), and 3% (95% CI 0.00-0.07, p = 0.48, I2 = 0%), respectively. The pooled rates for grade 1, grade 2, and grade 3 ICANS were 5% (95% CI 0.03-0.08, p = 0.00, I2 = 82%), 5% (95% CI 0.03-0.0.08, p = 0.00, I2 = 77%), and 6% (95% CI 0.03-0.10, p = 0.00, I2 = 93%), respectively. Among patients who developed CRS and ICANS, the pooled rates of resolution for CRS and ICANS with treatment were 100% (95% CI 0.99-1.00, p = 1.0, I2 = 0%), and 100% (95% CI, 0.99-1.00, p = 1.00, I2 = 0%), respectively. The pooled rates for patients who developed grade ≥3 anemia, neutropenia, and thrombocytopenia were 28% (95% CI 0.22-0.35, p = 0.00, I2 = 82%), 60% (95% CI 0054-0.66, p = 0.00, I2 = 89%), and 28 (95% CI 0.0.22-0.35, p = 0.00, I2 = 82%), respectively. The pooled rates of overall infections and grade 3 or higher infections were 47% (95% CI 0.41-0.52, p = 0.00, I2 = 72%) and 20% (95% CI 0.15-0.25, p = 0.52, I2 = 0%), respectively. The pooled rates for overall response (OR) and complete response (CR) to Bispecific antibodies and CAR-T cell therapy were 65% (95% CI 0.60-0.71, p = 0.42, I2 = 0%), and 35% (95% CI 0.0.27-0.43, p = 0.00, I2 = 85%), respectively. Conclusion: Tocilizumab is a viable option for preventing all grades of CRS and ICANS following CAR-T cell therapy and Bispecific antibodies. Randomized trials with larger patient populations are needed to further demonstrate its efficacy, safety, and the impact on treatment responses.