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Ferrara (Abstract)

Cellular Therapy and Transplantation (CTT), Vol. 3, No. 12
doi: 10.3205/ctt-2011-No12-abstract91

© The Authors. This abstract is provided under the following license: Creative Commons Attribution 3.0 Unported

Abstract accepted for "5th Raisa Gorbacheva Memorial Meeting Hematopoietic Stem Cell Transplantation in Children and Adults", Saint Petersburg, Russia, September 18–20, 2011

Preliminary Program

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Advances in GI GvHD

James L.M. Ferrara

University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA

Correspondence: James L.M. Ferrara, M.D., D.Sc., Combined Blood & Marrow Transplant Program, University of Michigan Comprehensive Cancer Center 6303 1500 E Medical Center Dr SPC 5942 Ann Arbor, MI  USA 48109-5942, E-mail: ferrara@spam is badmed.umich.edu


Acute graft-versus-host disease (GvHD) is a leading cause of non-relapse mortality (NRM) after allogeneic hematopoietic cell transplantation (HCT) and is measured by dysfunction in three organ systems: the skin, liver, and gastrointestinal (GI) tract. Acute GvHD of the GI tract affects up to 60% of patients receiving allogeneic HCT, causing nausea, vomiting, anorexia, secretory diarrhea and, in more severe cases, abdominal pain and/or hemorrhage. Acute GvHD typically occurs between two and eight weeks after transplant, but may occur later, and is often clinically indistinguishable from other causes of GI dysfunction such as conditioning regimen toxicity, infection, or medication. Endoscopic biopsy is often used to confirm the diagnosis, but histologic severity on biopsy has not consistently correlated with clinical outcome. Clinical stage two or greater (more than one liter of diarrhea per day) is associated with reduced survival, but daily stool volume can vary considerably. Lower GI GvHD responds poorly to treatment compared to other target organs, and treatment with high-dose systemic steroid therapy carries significant risks, especially infectious complications in profoundly immunosuppressed patients. A non-invasive, reliable blood biomarker specific for GvHD of the GI tract would thus significantly aid in the management of patients with this disorder. In this presentation I will discuss the discovery and validation of a plasma biomarker of acute GIGvHD: regenerating islet-derived 3-alpha (REG3α), a C-type lectin secreted by Paneth cells.

We used an unbiased, large-scale, quantitative proteomic discovery approach to identify candidate biomarkers that were increased in plasma from HCT patients with GI GvHD. Five of the 74 proteins that were increased at least two-fold were of GI origin. We used ELISA to validate the lead candidate, REG3α, an antimicrobial protein secreted by Paneth cells, in samples from 1014 HCT patients from three transplant centers and generated logistic and Cox regression models to test the association of REG3α concentrations with response to treatment and survival outcomes, respectively. Plasma REG3α concentrations were three-fold higher in patients at GI GvHD onset than in all other patients. REG3α levels distinguished GvHD from other causes of diarrhea, and correlated with lower GI GvHD. REG3α concentrations at GvHD onset predicted response to therapy at four weeks, one-year NRM, and overall survival (all p<0.001). In multivariate analysis of 140 patients with lower GI GvHD, three risk factors emerged that all independently predicted NRM at the time of GvHD diagnosis: high Reg3a concentrations, advanced clinical stage, and grade 4 histology. One-year NRM was 25%, 34%, 66%, and 86% for patients with lower GI GvHD and zero, one, two, or three risk factors, respectively (p<0.001). The importance of REG3α as a diagnostic biomarker of GI GvHD with independent prognostic value that can be combined with clinical stage and histologic grade to improve risk stratification of patients with lower GI GVHD will be discussed.

Keywords: acute graft-versus-host disease, gastrointestinal tract, biomarkers