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

Author:

Gergoudis Stephanie C.1,DeFilipp Zachariah2ORCID,Özbek Umut3,Sandhu Karamjeet S.4,Etra Aaron M.1,Choe Hannah K.5,Kitko Carrie L.6,Ayuk Francis7,Aziz Mina1,Baez Janna1,Ben-David Kaitlyn1,Bunworasate Udomsak8,Gandhi Isha1ORCID,Hexner Elizabeth O.9ORCID,Hogan William J.10,Holler Ernst11,Kasikis Stelios1,Kowalyk Steven M.1,Lin Jung-Yi3ORCID,Merli Pietro12ORCID,Morales George1,Nakamura Ryotaro4ORCID,Reshef Ran13,Rösler Wolf14,Srinagesh Hrishikesh1,Young Rachel1,Chen Yi-Bin2,Ferrara James L. M.1,Levine John E.1ORCID

Affiliation:

1. Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY;

2. Blood and Marrow Transplant Program, Massachusetts General Hospital, Boston, MA;

3. Biostatistics Shared Resource Facility, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY;

4. Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, CA;

5. Blood and Marrow Transplantation Program, The Ohio State University Comprehensive Cancer Center, Columbus, OH;

6. Pediatric Blood and Marrow Transplantation Program, Vanderbilt University Medical Center, Nashville, TN;

7. Department of Stem Cell Transplantation, University Medical Center, Hamburg-Eppendorf, Germany;

8. Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand;

9. Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA;

10. Blood and Marrow Transplant Program, Division of Hematology, Mayo Clinic, Rochester, MN;

11. Department of Hematology and Oncology, University Hospital Regensburg, Regensburg, Germany;

12. Department of Pediatric Hematology/Oncology, Istituto di Ricovero e Cura a Carattere Scientifico Ospedale Pediatrico Bambino Gesù, Rome, Italy;

13. Blood and Marrow Transplantation Program, Columbia University Irving Medical Center, New York, NY; and

14. Department of Internal Medicine 5, Hematology/Oncology, University Hospital Erlangen, Erlangen, Germany

Abstract

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.

Publisher

American Society of Hematology

Subject

Hematology

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