Tocilizumab for Prophylaxis of Cytokine Release Syndrome after Outpatient-Based Haploidentical T-Cell Replete Peripheral Blood Stem Cell Transplantation

Introduction

Cytokine release syndrome (CRS) is a common and potentially severe toxicity associated with haploidentical peripheral blood hematopoietic stem cell transplantation (Haplo-HSCT). CRS is characterized by immune activation and a high level of circulating inflammatory cytokines, particularly interleukin-6 (IL-6). While tocilizumab, an IL-6 receptor-targeted monoclonal antibody has been effectively used to treat CRS in the context of immunotherapy, it has not been evaluated during the acute Haplo-HSCT period. We hypothesized that prophylactic tocilizumab can prevent CRS after Haplo-HSCT. We report the results of a pilot trial to evaluate its use.

Methods

Patients ≥18 years undergoing Haplo-HSCT of peripheral blood in a single center with any underlying diagnosis were included. The conditioning was myeloablative and was administered as follows: cyclophosphamide 350 mg / m2 and fludarabine 25 mg / m2 (days -5-3) or rabbit antithymocyte globulin (2.5 mg / kg days -4, -3), plus melphalan 200 mg / m2 PO (days -2-1). Prophylaxis of graft versus host disease (GVHD) consisted of cyclophosphamide (50 mg / kg / day, days +3 and +4), cyclosporine and mycophenolate mofetil on day +5. The cells were infused on day 0. Tocilizumab was administered on day -1 in a single dose of 4 mg / kg IV. CRS was rated according to Lee et al. The primary outcome included the incidence and severity of CRS, the adverse effects associated with tocilizumab, hospitalization and graft rates and the incidence of GVHD.

Results

Ten patients have enrolled, with an average age of 26 years (range 19-32). The underlying diagnoses were acute lymphoblastic leukemia (n = 7), acute myeloid leukemia (n = 1) and non-Hodgkin lymphoma (n = 2). There were no infusion reactions associated with tocilizumab. Six patients (60%) developed CRS, all grades 1-2, with a median day of onset on day +2 (range 1-3) and a median fever duration of 2 days (range 2-3), often accompanied by nausea, diarrhea, dehydration and transaminitis. All patients were hospitalized; hospitalization was not related to CRS in three patients. 4 patients are alive without relapse (40%), 2 patients alive with relapse (20%), 3 patients died due to transplant-related mortality (30%), one patient dies from relapse (10%). No graft failure occurred and mixed chimerism was observed in a patient. Acute GVHD with steroid response has been diagnosed in 2 cases (20%, grade I / II). The median follow-up is 8.3 months (range 0-20).

Conclusion

What we observe about the prophylactic use of tocilizumab for Haplo-HSCT of peripheral blood is that its administration is feasible, Grades 1-2 CRS was observed in 60% of patients, grades 3-4 were not observed, however the use of tocilizumab did not prevent hospitalizations. More feasibility data is required before starting a definitive randomized trial to evaluate the use of tocilizumab for Haplo-HSCT peripheral blood.