Tocilizumab prophylaxis in patients receiving CAR-T cell immunotherapy for hematological malignancies: A systematic review and meta-analysis

Abstract Background: Chimeric antigen receptor-T (CAR-T) cell immunotherapy has revolutionized the therapeutic landscape for patients with relapsed/ refractory hematological malignancies, including lymphomas, acute lymphoblastic leukemia (ALL), and multiple myeloma. Nevertheless, toxicities, such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), are major early complications requiring urgent therapeutic interventions, even ICU admission. Tocilizumab, a monoclonal antibody blocking interleukin 6, is currently a safe and effective treatment agent for CRS management. However, tocilizumab is not frequently used as prophylaxis in patients receiving CAR-T cell immunotherapy as its role is not completely clarified. Therefore, we conducted a systematic review and meta-analysis regarding the role of tocilizumab prophylaxis in patients receiving commercially available CAR-T products. Patients and Methods: The study's protocol was registered in the PROSPERO database (CRD420251052154). Eligible articles were retrieved from MEDLINE (via PubMed), EMBASE (via Ovid), and the Cochrane Library using search terms related to “CAR-T”, “Tocilizumab”, and “Prophylaxis”. Conference proceedings, clinicaltrials.gov, and references of included records were also searched. The search time limit was January 2025. Randomized controlled trials, case-control, cohort (prospective/retrospective) studies, or case series (with more than ten patients), examining patients who were treated with CAR-T cell products and received tocilizumab prophylaxis with a follow-up period of at least 1 month, were included. The following outcomes were examined: incidence and severity of CRS and ICANS, overall survival (OS), progression-free survival (PFS), treatment-related mortality (TRM), overall response rate, incidence and type of adverse events, and incidence of infectious complications. Meta-analysis was performed for each outcome whenever possible using Comprehensive meta-analysis software. Results: 1182 records were retrieved from literature search. Four studies examining 91 patients with hematological malignancies (B-cell non-Hodgkin lymphomas: 76, ALL: 6, in 9 not specified) receiving tocilizumab prophylaxis (1 dose, 8 mg/kg) before CAR-T therapy (Axicabtagene ciloleucel: 38, Tisagenlecleucel: 2, other CD19-CAR-T cell products: 43, in 8 not specified) were included in the qualitative analysis. Prophylactic tocilizumab was found to significantly reduce the risk of any grade CRS risk ratio (RR) = 0.56, 95% confidence interval (CI): 0.33–0.94, Ι2=0 in patients receiving CAR-T therapy compared with those who did not receive prophylactic tocilizumab. Moreover, patients receiving prophylactic tocilizumab had a lower risk of clinically significant grade2 CRS (RR = 0.31, 95% CI: 0.12–0.82, Ι2=0). Two studies reported neurotoxicity rates in patients receiving tocilizumab without available comparison with a control group. A considerable heterogeneity was found at the pooled effect estimate, with 45.6% of patients presenting with ICANS of any grade (95% CI: 0.9%–95.5, Ι2=93%). PFS was examined in patients receiving tocilizumab prophylaxis without a comparator in three studies. 58.3% of patients (95% CI: 41%–74.8, Ι2=27%) receiving tocilizumab prophylaxis experienced a PFS (not otherwise specified in the studies). Additionally, it was shown that patients receiving tocilizumab prophylaxis may be more likely to achieve a complete response post CAR-T infusion compared to those not receiving prophylaxis (odds ratio=2.2, 95% CI: 0.6–8.3, Ι2=0%), based on three studies. Conclusions: Based on these data, tocilizumab prophylaxis prior to infusion in patients who receive CAR-T cell immunotherapy can significantly decrease the risk of both any grade and grade 2 CRS. ICANS incidence was similar to ongoing published data and more than half of patients receiving tocilizumab prophylaxis achieved PFS. The need for larger, randomized controlled trials to confirm the observed effects and determine the impact of prophylactic tocilizumab on OS, TRM, adverse events, and infectious complications is warranted.