Human-derived α1-antitrypsin is still efficacious in heavily pretreated patients with steroid-resistant gastrointestinal graft-versus-host disease

Abstract Almost half of patients developing graft-versus-host disease (GVHD) will not respond to standard first-line steroid treatment. Alpha-1 antitrypsin (AAT) is able to induce tolerance in pre-clinical models of GVHD. AAT alters the cytokine milieu, promotes a tolerogenic shift of dendritic cells and skew effector T-cells towards regulatory T-cell. Gastrointestinal steroid-refractory (SR)-GVHD is a protein losing enteropathy that might represent the optimal setting to use AAT. Here we analyze the outcome of 16 patients treated with human-derived AAT in advanced-stage gut SR-GVHD, with 2/3 of the patients having failed at least one treatment for SR-GVHD. Overall response rate (ORR) was 44%, with a complete response (CR) rate of 27%. Gastrointestinal response was observed in 61% of patients. Median time to best response was 21 days (range 6-26). At day 56 after AAT, all CRs were maintained and ORR was 39%. One-year overall survival was 48% (95% CI: 26% - 74%). Ancillary studies showed that AAT serum levels were in the normal range at the beginning of treatment while fecal loss was elevated. AAT levels consistently rose after exogenous administration but no correlation was found between serum levels and response. REG3α and IL-33 levels were associated with response while, in contrast to previous reports, regulatory T-cells decreased during AAT treatment. This retrospective analysis confirms previous report of AAT as a promising agent in the management of gut SR-GVHD and prompts for its evaluation at an earlier stage.