Phase 1 clinical trial evaluating abatacept in patients with steroid-refractory chronic graft-versus-host disease

Steroid-refractory chronic graft-versus-host disease (SR-cGVHD) remains a major cause of morbidity and mortality following allogeneic transplantation. Innovative immunotherapeutic strategies are urgently needed for the treatment of SR-cGVHD. We conducted a phase I clinical trial to evaluate the safety, efficacy, and immune effects of abatacept, a novel immunomodulatory drug that acts as an inhibitor of T cell activation via co-stimulatory blockade, in the treatment of SR-cGVHD. The study followed a 3+3 design with two escalating abatacept doses: 3 mg/kg and 10 mg/kg, with an expansion cohort treated at 10 mg/kg. Abatacept was well-tolerated with no dose-limiting toxicities. Of the 16 evaluable patients, 44% achieved a clinical partial response per 2005 NIH Consensus Criteria. Importantly, abatacept resulted in a 51.3% reduction in prednisone usage in clinical responders (mean baseline 27mg versus 14mg; p=0.01). Increased PD-1 expression on circulating CD4 (p=0.009) and CD8 (p=0.007) T cells was observed in clinical responders. In summary, abatacept was safe and led to a marked improvement in NIH cGVHD scores and a significant reduction in prednisone use. In this cohort of heavily pre-treated patients, the results suggest that abatacept may be a promising therapeutic agent for SR-cGVHD, and a phase II trial has been initiated. This trial was registered at www.clinicaltrials.gov as #NCT01954979.