alpha(1)-Antitrypsin infusion for treatment of steroid-resistant acute graft-versus-host disease

作者：Magenau John M; Goldstein Steven C; Peltier Dan; Soiffer Robert J; Braun Thomas; Pawarode Attaphol; Riwes Mary M; Kennel Maggi; Antin Joseph H; Cutler Corey S; Ho Vincent T; Alyea Edwin P III; Parkin Brian L; Yanik Gregory A; Choi Sung Won; Lewis Eli C; Dinarello Charles A; Koreth John; Reddy Pavan^*

来源：Blood, 2018, 131(12): 1372-1379.

DOI：10.1182/blood-2017-11-815746

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. alpha(1)-Antitrypsin (AAT), a naturally abundant serine protease inhibitor, is capable of suppressing experimental GVHD by downmodulating inflammation and increasing ratios of regulatory (T-reg) to effector T cells (T(eff)s). 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 T(reg)s to T(eff)s after AAT treatment. These data suggest that AAT is safe and may be potentially efficacious in treating SR-aGVHD.

• 出版日期2018-3-22