Biomarker-guided preemption of steroid-refractory graft-versus-host disease with α-1-antitrypsin

Abstract

Steroid-refractory (SR) acute graft-versus-host disease (GVHD) remains a major cause of nonrelapse mortality (NRM) after allogeneic hematopoietic cell transplantation (HCT), but its occurrence is not accurately predicted by pre-HCT clinical risk factors. The Mount Sinai Acute GVHD International Consortium (MAGIC) algorithm probability (MAP) identifies patients who are at high risk for developing SR GVHD as early as 7 days after HCT based on the extent of intestinal crypt damage as measured by the concentrations of 2 serum biomarkers, suppressor of tumorigenesis 2 and regenerating islet-derived 3α. We conducted a multicenter proof-of-concept "preemptive" treatment trial of α-1-antitrypsin (AAT), a serine protease inhibitor with demonstrated activity against GVHD, in patients at high risk for developing SR GVHD. Patients were eligible if they possessed a high-risk MAP on day 7 after HCT or, if initially low risk, became high risk on repeat testing at day 14. Thirty high-risk patients were treated with twice-weekly infusions of AAT for a total of 16 doses, and their outcomes were compared with 90 high-risk near-contemporaneous MAGIC control patients. AAT treatment was well tolerated with few toxicities, but it did not lower the incidence of SR GVHD compared with controls (20% vs 14%, P = .56). We conclude that real-time biomarker-based risk assignment is feasible early after allogeneic HCT but that this dose and schedule of AAT did not change the incidence of SR acute GVHD. This trial was registered at www.clinicaltrials.gov as #NCT03459040.

Conflict of interest statement

Conflict-of-interest disclosure: U.Ö., J.L.M.F., and J.E.L. are co-inventors on a GVHD patent and receive royalties. U.Ö. receives consultancy fees from AffyImmune Therapeutics. J.E.L. receives consultancy fees from Incyte, Mesoblast, OncoImmune, and Talaris and research funding from Biogen, Incyte, and Mesoblast. Z.D. receives consultancy fees from Syndax Pharmaceuticals and research funding from Incyte and Regimmune. Y.B.C. receives consultancy fees from Takeda, Magenta, Daiichi, AbbVie, Equilium, Xenikos, and Celularity. P.M. receives consultancy fees from Sobi and Bellicum. R.N. receives consultancy fees from Viracor. The remaining authors declare no competing financial interests.

© 2020 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

Screening and enrollment of trial patients. D, day; HR, high risk; LR, low risk.

Figure 2.

GVHD-related outcomes. (A) Percentage of SR GVHD in AAT-treated patients (blue; 20%) and controls (magenta; 14%) by day 100. (B) Six-month cumulative incidence of grade II to IV GVHD treated with systemic steroids in AAT-treated patients (40%) and controls (30%). (C) Six-month cumulative incidence of grade III or IV GVHD in AAT-treated patients (17%) and controls (12%).

Figure 3.

NRM, relapse, and OS. (A) Six-month cumulative incidence of NRM in AAT-treated patients (blue; 10%) and controls (red; 16%). (B) Six-month cumulative incidence of relapse in AAT-treated patients (7%) and controls (18%). (C) Six-month OS in AAT-treated patients (86%) and controls (78%).

Figure 4.

MAP at study entry and day 28 post-HCT. (A) Median MAP at study entry (day 7 or 14 post-HCT) in AAT-treated patients (0.22, n = 30) and controls (0.23, n = 90). (B) Median MAP at day 28 post-HCT in AAT-treated patients (0.10, n = 30) and controls (0.14, n = 82). Box and whisker plots show median MAP with whiskers extending from the 10th to the 90th percentile. Values outside this range are drawn as individual points.