Assessment of systemic and gastrointestinal tissue damage biomarkers for GVHD risk stratification

Author:

Etra Aaron1,Gergoudis Stephanie1,Morales George1,Spyrou Nikolaos1ORCID,Shah Jay1,Kowalyk Steven1,Ayuk Francis2,Baez Janna1,Chanswangphuwana Chantiya3,Chen Yi-Bin4ORCID,Choe Hannah5,DeFilipp Zachariah4ORCID,Gandhi Isha1ORCID,Hexner Elizabeth6ORCID,Hogan William J.7,Holler Ernst8,Kapoor Urvi1,Kitko Carrie L.9,Kraus Sabrina10,Lin Jung-Yi11ORCID,Al Malki Monzr12,Merli Pietro13ORCID,Pawarode Attaphol14,Pulsipher Michael A.15ORCID,Qayed Muna16ORCID,Reshef Ran17,Rösler Wolf18,Schechter Tal19,Van Hyfte Grace11,Weber Daniela8,Wölfl Matthias20,Young Rachel1,Özbek Umut11,Ferrara James L. M.1,Levine John E.1ORCID

Affiliation:

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

2. 2Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;

3. 3Blood and Marrow Transplantation Program, Chulalongkorn University, Bangkok, Thailand;

4. 4Hematopoietic Cell Transplant and Cellular Therapy Program, Massachusetts General Hospital, Boston, MA;

5. 5Division of Hematology, James Cancer Center, The Ohio State University, Columbus, OH;

6. 6Blood and Marrow Transplantation Program, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA;

7. 7Division of Hematology, Mayo Clinic, Rochester, MN;

8. 8Department of Hematology and Oncology, Internal Medicine III, University of Regensburg, Regensburg, Germany;

9. 9Pediatric Stem Cell Transplant Program, Vanderbilt University Medical Center, Nashville, TN;

10. 10Department of Internal Medicine II, University Hospital of Würzburg, Würzburg, Germany;

11. 11Department of Population Health Science and Policy, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY;

12. 12Hematology/Hematopoietic Cell Transplant, City of Hope National Medical Center, Duarte, CA;

13. 13Ospedale Bambino Gesù, Rome, Italy;

14. 14Blood and Marrow Transplantation Program, University of Michigan, Ann Arbor, MI;

15. 15Division of Hematology, Oncology, and Blood and Marrow Transplantation, Children's Hospital Los Angeles, Los Angeles, CA;

16. 16Aflac Cancer and Blood Disorders Center, Emory University, Atlanta, GA;

17. 17Blood and Marrow Transplantation Program, Columbia University Medical Center, New York, NY;

18. 18Medizin Klinik III/Poliklinik, Universitatsklinik Erlangen, Erlangen, Germany;

19. 19Division of Hematology/Oncology/BMT, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada; and

20. 20Pediatric Blood and Marrow Transplantation Program, Children’s Hospital, University of Würzburg, Würzburg, Germany

Abstract

Abstract We used a rigorous PRoBE (prospective-specimen collection, retrospective-blinded-evaluation) study design to compare the ability of biomarkers of systemic inflammation and biomarkers of gastrointestinal (GI) tissue damage to predict response to corticosteroid treatment, the incidence of clinically severe disease, 6-month nonrelapse mortality (NRM), and overall survival in patients with acute graft-versus-host disease (GVHD). We prospectively collected serum samples of newly diagnosed GVHD patients (n = 730) from 19 centers, divided them into training (n = 352) and validation (n = 378) cohorts, and measured TNFR1, TIM3, IL6, ST2, and REG3α via enzyme-linked immunosorbent assay. Performances of the 4 strongest algorithms from the training cohort (TNFR1 + TIM3, TNFR1 + ST2, TNFR1 + REG3α, and ST2 + REG3α) were evaluated in the validation cohort. The algorithm that included only biomarkers of systemic inflammation (TNFR1 + TIM3) had a significantly smaller area under the curve (AUC; 0.57) than the AUCs of algorithms that contained ≥1 GI damage biomarker (TNFR1 + ST2, 0.70; TNFR1 + REG3α, 0.73; ST2 + REG3α, 0.79; all P < .001). All 4 algorithms were able to predict short-term outcomes such as response to systemic corticosteroids and severe GVHD, but the inclusion of a GI damage biomarker was needed to predict long-term outcomes such as 6-month NRM and survival. The algorithm that included 2 GI damage biomarkers was the most accurate of the 4 algorithms for all endpoints.

Publisher

American Society of Hematology

Subject

Hematology

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