Addition of interleukin-6 inhibition with tocilizumab to standard graft-versus-host disease prophylaxis after allogeneic stem-cell transplantation: a phase 1/2 trial.

摘要: Summary Background Interleukin 6 mediates graft-versus-host disease (GVHD) in experimental allogeneic stem-cell transplantation (allogeneic SCT) and represents an attractive therapeutic target. We aimed to assess whether the humanised anti-interleukin-6 receptor monoclonal antibody, tocilizumab, could attenuate incidence of acute GVHD. Methods undertook a single-group, single-institution phase 1/2 study at Royal Brisbane Women's Hospital Bone Marrow Transplantation unit, QLD, Australia. Eligible patients were 18–65 years old underwent T-replete HLA-matched SCT with either total body irradiation-based myeloablative or reduced-intensity conditioning from unrelated sibling donors. One intravenous dose tocilizumab (8 mg/kg, capped 800 mg, over 60 mins' infusion) was given day before along standard GVHD prophylaxis (cyclosporin [5 mg/kg per on days −1 +1, then 3 maintain levels (trough 140–300 ng/mL) for 100 plus methotrexate [15 mg/m 2 1, 10 3, 6, 11]). The primary endpoint grade 2–4 100, assessed graded as Seattle criteria. Immunological profiles compared non-randomised group receiving SCT, but not treated tocilizumab. This trial is registered Australian New Zealand Clinical Trials Registry, number ACTRN12612000726853. Findings Between Jan 19, 2012, Aug 27, 2013, 48 eligible cyclosporin enrolled into study. 12% (95% CI 5–24), 3–4 4% (1–13). Grade involving skin developed five (10%) gastrointestinal tract four (8%) patients; there no reported cases liver. Low incidences noted both (12% [95% 2–34) fludarabine melphalan [4–27]). Immune reconstitution preserved recipients interleukin-6 inhibition, qualitatively modified suppression known pathogenic STAT3-dependent pathways. Interpretation main detectable dysregulated cytokine secreted after its inhibition potential new simple strategy protect despite robust immune reconstitution; randomised, controlled assessing addition these warranted. Funding National Health Medical Research Council Queensland Health.