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

Abstract

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.

Conflict of interest statement

Conflict-of-interest disclosure: The authors declare no competing financial interests.

© 2018 by The American Society of Hematology.

Figures

Figure 1.

ORR. The percentage of patients who experienced an overall response (primary end point) as defined by the sum of patients with SR-aGVHD achieving CRs and PRs after initiation of AAT. NR, nonresponder; Prog, progression.

Figure 2.

OS. Survival from time of initiation of AAT for SR-aGVHD in the entire cohort (n = 40) (A) and those who received ≥8 doses (solid) or <8 doses (hatched) (B).

Figure 3.

AAT increases proportion of activated Tregs to effector memory T cells. Tregs, Treg subsets (naïve and activated), conventional T cells (Tconv), and Tconv subsets (naïve, central memory, effector, and effector memory) were analyzed by FACS at enrollment before AAT administration (Tregs, n = 7; Tconv, n = 9) and after 2 (Tregs, n = 6; Tconv, n = 9) and 4 weeks (Tregs, n = 5; Tconv, n = 6) of AAT treatment. (A) Fold change of Tregs (CD4+CD25+Foxp3+ lymphocytes) expressed as a percentage of CD4+ helper T (Th) cells (number of Tregs/number of viable CD4+ lymphocytes) at 2 and 4 weeks after AAT treatment relative to prior treatment. (B) Fold change of activated Th cells (CD4+CD25+Foxp3loCD45− lymphocytes), naïve Tregs (CD4+CD25+Foxp3loCD45+ lymphocytes), or activated Tregs (CD4+CD25+Foxp3hiCD45− lymphocytes) expressed as a percentage of total Tregs at time points after AAT treatment relative to that observed at enrollment. (C) Fold change of cytotoxic T cells (viable CD3+CD8+CD4−), with naïve (CCR7+CD45RA+), central memory (CCR7+CD45RA−), effector (CCR7−CD45RA−), and effector memory (CCR7−CD45RA+) cells expressed as a percentage of total cytotoxic T cells at time points after AAT treatment relative to that observed at enrollment. Data represent mean values, and the error bars represent the standard errors of the mean. *P < .05.

Figure 4.

AAT levels. Serum levels of AAT were measured in patients with SR-aGVHD at enrollment before administration of ATT and in paired samples obtained at 2, 4, and 8 weeks after the start of AAT treatment. AAT administration was completed after 4 weeks. Median values are depicted. Error bars represent standard deviations. *P = .01; **P < .01. N, number of paired samples at a given time point.