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.

Clinical Experience of Alpha 1 Antitrypsin (AAT) Treatment in Pediatric Patients with Primary Immunodeficiencies Facing to Steroid Refractory (SR) Acute Intestinal Graft versus Host Disease (aGvHD)

“…As SR-aGvHD is a major cause of mortality after HSCT, there are studies with pre-emptive treatment with AAT, too. 10 Unfortunately, in a recently published study, AAT wasn't found to improve GvHD outcomes. 10 There are recruiting clinical trials both for prevention (NCT03805789) and primary treatment (NCT04167514) of GvHD with AAT.…”

“…10 Unfortunately, in a recently published study, AAT wasn't found to improve GvHD outcomes. 10 There are recruiting clinical trials both for prevention (NCT03805789) and primary treatment (NCT04167514) of GvHD with AAT. We hope that further studies both with children and adults will help to overcome the disease.…”

“…3 In murine models, it's shown that AAT can suppress GvHD development and provide an alternative treatment for existing GvHD. 4,5 In literature, limited number of studies [6][7][8][9][10] are available. There are also recruiting clinical trials both for prevention (NCT03805789) and primary treatment (NCT04167514) of GvHD.…”

Translational Clinical Strategies for the Prevention of Gastrointestinal Tract Graft Versus Host Disease

“…With respect to GVHD prevention, Gergoudis et al performed a biomarker-guided preemptive study examining whether administration of A1AT could reduce the incidence of GVHD in patients deemed to be at high risk for steroid-resistant complications (107). Thirty patients that were identified as high risk for steroid refractory acute GVHD determined by a composite risk score that included measurement of Reg3a and ST2.…”

Steroid-Refractory Gut Graft-Versus-Host Disease: What We Have Learned From Basic Immunology and Experimental Mouse Model

“…Based on these discoveries, a trial of a-1antitrypsin (AAT), a serine protease inhibitor with demonstrated activity against GVHD, was conducted in patients at high risk for developing SR-GVHD. The trial concluded that real-time biomarker-based risk assignment is feasible early after allogeneic HCT, but the dose and schedule of AAT did not change the incidence of SR-aGVHD (39). Overall, in the absence of a clearly defined resistance mechanism, alternative therapeutic options remain an open-ended question (8).…”