Tocilizumab for cytokine release syndrome after allogeneic hematopoietic stem cell transplantation with post-transplant cyclophosphamide

Abstract

Abstract Background: Post-transplant cyclophosphamide (PTCy)-based allogeneic hematopoietic stem cell transplantation (alloHCT) is frequently associated with cytokine release syndrome (CRS). While tocilizumab is effective in managing CRS, its downstream impact on transplant outcomes, particularly graft-versus-host disease (GVHD), remains incompletely understood. Tocilizumab is also an established treatment for acute GVHD and modulates T-cell activity, which may interact with PTCy's immunologic effects. We investigated the impact of tocilizumab use for CRS on transplant outcomes in this setting. Methods: We conducted a retrospective study of adult patients undergoing PTCy-based alloHCT at our institution between January 2014 and December 2023. Patients who developed CRS were stratified by the receipt of tocilizumab (toci group vs. non-toci group). To control for confounding, we performed 1:1 propensity score matching based on age, disease, HLA match, stem cell source, conditioning intensity, and CRS onset. Engraftment, non-relapse mortality (NRM), and GVHD were analyzed using competing risk models. A p-value ≤ 0.05 was considered statistically significant. Results: 346 patients underwent alloHCT with PTCy, with AML (n=135), MDS (n=64), NHL (n=52), Hodgkin lymphoma (n=21) being the most common primary diagnoses. Among these 346 patients who received PTCy, 190 (55%) developed CRS, with a median onset of 2 days, median duration of 3 days, and an average maximum temperature (Tmax) of 102.8°F. Patients with HLA-mismatched donors were more likely to develop CRS than those who received HLA-matched allografts (p<0.001). Unexplained encephalopathy, possibly related to CRS, occurred in 36 patients (19%). A total of 46 patients (24.2%) received tocilizumab for CRS, 5 of whom received more than 1 dose. Six patients required escalation to ICU-level care for hypotension or hypoxia. Compared with those who did not receive tocilizumab, these patients were more likely to have HLA-mismatched donors (98% vs. 81%), receive peripheral blood stem cells (93% vs. 71%), experience earlier CRS onset (median 1 vs. 2 days after transplant), have high-grade CRS (Grade ≥2: 37% vs. 22%), and develop encephalopathy (26% vs. 18%) subsequently. After propensity score matching, 40 patients were included in each group. The two cohorts were well balanced by age, gender, disease type, remission status, performance status, HLA matching, stem cell source, conditioning intensity, and CRS onset day. Both groups had similar incidence of high-grade CRS (Grade ≥2: 32% vs. 31%), though the toci group experienced a significantly shorter CRS duration (median 3 vs. 4 days, p=0.005). Neutrophil engraftment was significantly delayed in the toci group (median 19 vs. 17 days, p = 0.01), while platelet engraftment was comparable (median 32 vs. 29 days). Bacterial infections within 100 days post-transplant were significantly more common in the toci group (65% vs. 28%). Tocilizumab use was associated with a significantly lower incidence of Grade II–IV acute GVHD (100-day incidence: 46% vs. 69%; HR 0.56, 95% CI 0.32–1.00, p = 0.05), although rates of Grade III–IV acute GVHD were similar. Notably, patients in the toci group had a significantly lower 2-year incidence of moderate-to-severe chronic GVHD (6.2% vs. 35%; HR 0.13, 95% CI 0.03–0.56, p < 0.01) and of any chronic GVHD (12% vs. 51%; HR 0.17, 95% CI 0.06–0.49, p < 0.01). There were no significant differences in non-relapse mortality, relapse-free survival, GVHD-free/relapse-free survival (GRFS), or overall survival (OS) between the two groups. Conclusion: In patients undergoing PTCy-based alloHCT, early administration of tocilizumab for CRS is associated with a shorter CRS duration and significant reductions in both acute and chronic GVHD. However, it is also linked to delayed neutrophil engraftment and a higher risk of early bacterial infections. Tocilizumab represents a valuable therapeutic strategy for CRS management in this context, but its use warrants close monitoring of infection.