α1-Antitrypsin infusion for treatment of steroid-resistant acute graft-versus-host disease.

Corticosteroid resistance after acute graft-versus-host disease (SR-aGVHD) results in high morbidity and mortality after allogeneic hematopoietic cell transplantation. Current immunosuppressive therapies for SR-aGVHD provide marginal effectiveness because of poor response or excessive toxicity, primarily from infection. α1-Antitrypsin (AAT), a naturally abundant serine protease inhibitor, is capable of suppressing experimental GVHD by downmodulating inflammation and increasing ratios of regulatory (Treg) to effector T cells (Teffs). In this prospective multicenter clinical study, we sought to determine the safety and response rate of AAT administration in SR-aGVHD. Forty patients with a median age of 59 years received intravenous AAT twice weekly for 4 weeks as first-line treatment of SR-aGVHD. The primary end point was overall response rate (ORR), the proportion of patients with SR-aGVHD in complete (CR) or partial response by day 28 without addition of further immunosuppression. Treatment was well tolerated without drug-related adverse events. A significant increase in serum levels of AAT was observed after treatment. The ORR and CR rates by day 28 were 65% and 35%, respectively, and included responses in all aGVHD target organs. At day 60, responses were sustained in 73% of patients without intervening immunosuppression. Infectious mortality was 10% at 6 months and 2.5% within 30 days of last AAT infusion. Consistent with preclinical data, correlative samples showed an increase in ratio of activated Tregs to Teffs after AAT treatment. These data suggest that AAT is safe and may be potentially efficacious in treating SR-aGVHD. This trial was registered at www.clinicaltrials.gov as #NCT01700036.

Feasibility of a dietary intervention to modify gut microbial metabolism in patients with hematopoietic stem cell transplantation.

Evaluation of the impact of dietary intervention on gastrointestinal microbiota and metabolites after allogeneic hematopoietic stem cell transplantation (HCT) is lacking. We conducted a feasibility study as the first of a two-phase trial. Ten adults received resistant potato starch (RPS) daily from day -7 to day 100. The primary objective was to test the feasibility of RPS and its effect on intestinal microbiome and metabolites, including the short-chain fatty acid butyrate. Feasibility met the preset goal of 60% or more, adhering to 70% or more doses; fecal butyrate levels were significantly higher when participants were on RPS than when they were not (P < 0.0001). An exploratory objective was to evaluate plasma metabolites. We observed longitudinal changes in plasma metabolites compared to baseline, which were independent of RPS (P < 0.0001). However, in recipients of RPS, the dominant plasma metabolites were more stable compared to historical controls with significant difference at engraftment (P < 0.05). These results indicate that RPS in recipients of allogeneic HCT is feasible; in this study, it was associated with significant alterations in intestinal and plasma metabolites. A phase 2 trial examining the effect of RPS on graft-versus-host disease in recipients of allogeneic HCT is underway. ClinicalTrials.gov registration: NCT02763033 .