We hypothesized that clinical risk factors could be identified within 2 weeks of onset of severe (stage 3 or 4) acute gut GVHD for identifying a patient population with a very poor outcome. Among 1462 patients who had allogeneic hematopoietic cell transplantation (HCT) between January 2000 and December 2005, 116 (7.9%) developed stage 3–4 gut GVHD. The median time for onset of stage 3–4 gut GVHD was 35 (4–135) days after allogeneic HCT. Eighty-five of the 116 patients (73%) had corticosteroid resistance before or within 2 weeks after the onset of stage 3–4 gut GVHD. Significant risk factors for mortality included corticosteroid resistance (hazards ratio (HR)=2.93; P=0.0005), age >18 years (HR=4.95; P=0.0004), increased serum bilirubin (HR 2.53; P=0.0001) and overt gastrointestinal bleeding (HR 2.88; P=0.0004). Among patients with stage 3–4 gut GVHD, the subgroup with 0, 1 or 2 risk factors had a favorable prognosis, whereas the subgroup with 3 or 4 risk factors had a dismal prognosis. This information should be considered in designing future studies of severe gut GVHD and in counseling patients about prognosis.
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Leisenring WM, Martin PJ, Petersdorf EW, Regan AE, Aboulhosn N, Stern JM et al. An acute graft-versus-host disease activity index to predict survival after hematopoietic cell transplantation with myeloablative conditioning regimens. Blood 2006; 108: 749–755.
Gooley TA, Chien JW, Pergam SA, Hingorani S, Sorror ML, Boeckh M et al. Reduced mortality after allogeneic hematopoietic-cell transplantation. N Engl J Med 2010; 363: 2091–2101.
Hockenbery DM, Cruickshank S, Rodell TC, Gooley T, Schuening F, Rowley S et al. A randomized, placebo-controlled trial of oral beclomethasone dipropionate as a prednisone-sparing therapy for gastrointestinal graft-versus-host disease. Blood 2007; 109: 4557–4563.
Baehr PH, Levine DS, Bouvier ME, Hockenbery DM, Gooley TA, Stern JG et al. Oral beclomethasone dipropionate for treatment of human intestinal graft-versus-host disease. Transplantation 1995; 60: 1231–1238.
Wakui M, Okamoto S, Ishida A, Kobayashi H, Watanabe R, Yajima T et al. Prospective evaluation for upper gastrointestinal tract acute graft-versus-host disease after hematopoietic stem cell transplantation. Bone Marrow Transplant 1999; 23: 573–578.
Wu D, Hockenbery DM, Brentnall TA, Baehr PH, Ponec RJ, Kuver R et al. Persistent nausea and anorexia after marrow transplantation: a prospective study of 78 patients. Transplantation 1998; 66: 1319–1324.
Mielcarek M, Storer BE, Boeckh M, Carpenter PA, McDonald GB, Deeg HJ et al. Initial therapy of acute graft-versus-host disease with low-dose prednisone does not compromise patient outcomes. Blood 2009; 113: 2888–2894.
Castilla C, Perez-Simon JA, Sanchez-Guijo FM, Diez-Campelo M, Ocio E, Perez-Persona E et al. Oral beclomethasone dipropionate for the treatment of gastrointestinal acute graft-versus-host disease (GVHD). Biol Blood Marrow Transplant 2006; 12: 936–941.
Schwartz JM, Wolford JL, Thornquist MD, Hockenbery DM, Murakami CS, Drennan F et al. Severe gastrointestinal bleeding after hematopoietic cell transplantation, 1987-1997: incidence, causes, and outcome. Am J Gastroenterol 2001; 96: 385–393.
Ross WA, Couriel D . Colonic graft-versus-host disease. Curr Opin Gastroenterol 2005; 21: 64–69.
Martin PJ, Schoch G, Fisher L, Byers V, Anasetti C, Appelbaum FR et al. A retrospective analysis of therapy for acute graft-versus-host disease: Initial treatment. Blood 1990; 76: 1464–1472.
Nash RA, Antin JH, Karanes C, Fay JW, Avalos BR, Yeager AM et al. Phase 3 study comparing methotrexate and tacrolimus with methotrexate and cyclosporine for prophylaxis of acute graft-versus-host disease after marrow transplantation from unrelated donors. Blood 2000; 96: 2062–2068.
Nash RA, Johnston L, Parker P, McCune JS, Storer B, Slattery JT et al. A phase I/II study of mycophenolate mofetil in combination with cyclosporine for prophylaxis of acute graft-versus-host disease after myeloablative conditioning and allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant 2005; 11: 495–505.
McSweeney PA, Niederwieser D, Shizuru JA, Sandmaier BM, Molina AJ, Maloney DG et al. Hematopoietic cell transplantation in older patients with hematologic malignancies: replacing high-dose cytotoxic therapy with graft-versus-tumor effects. Blood 2001; 97: 3390–3400.
Maris MB, Niederwieser D, Sandmaier BM, Storer B, Stuart M, Maloney D et al. HLA-matched unrelated donor hematopoietic cell transplantation after nonmyeloablative conditioning for patients with hematologic malignancies. Blood 2003; 102: 2021–2030.
Ponec RJ, Hackman RC, McDonald GB . Endoscopic and histologic diagnosis of intestinal graft-versus-host disease after marrow transplantation. Gastrointest Endosc 1999; 49: 612–621.
Glucksberg H, Storb R, Fefer A, Buckner CD, Neiman PE, Clift RA et al. Clinical manifestations of graft-versus-host disease in human recipients of marrow from HL-A-matched sibling donors. Transplantation 1974; 18: 295–304.
Przepiorka D, Weisdorf D, Martin P, Klingemann H-G, Beatty P, Hows J et al. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant 1995; 15: 825–828.
Gooley TA, Leisenring W, Crowley J, Storer BE . Estimation of failure probabilities in the presence of competing risks: new representations of old estimators. Stat Med 1999; 18: 695–706.
MacMillan ML, Defor TE, Weisdorf DJ . What predicts high risk acute graft-versus-host disease (GVHD) at onset?: identification of those at highest risk by a novel acute GVHD risk score. Br J Haematol 2012; 157: 732–741.
Robin M, Porcher R, de Castro R, Fisher G, de Latour RP, Ribaud P et al. Initial liver involvement in acute GVHD is predictive for nonrelapse mortality. Transplantation 2009; 88: 1131–1136.
McDonald GB Sale GE . The human gastrointestinal tract after allogeneic marrow transplantation in humans. In: Sale GE Shulman HM (eds) The Pathology of Bone Marrow Transplantation. Masson, Inc.: New York, 1984, 77–103.
Kreisel W, Dahlberg M, Bertz H, Harder J, Potthof K, Deibert P et al. Endoscopic diagnosis of acute intestinal GVHD following allogeneic hematopoietic SCT: a retrospective analysis in 175 patients. Bone Marrow Transplant 2012; 47: 430–438.
Ferrara JL, Harris AC, Greenson JK, Braun TM, Holler E, Teshima T et al. Regenerating islet-derived 3-alpha is a biomarker of gastrointestinal graft-versus-host disease. Blood 2011; 118: 6702–6708.
Harris AC, Ferrara JL, Braun TM, Holler E, Teshima T, Levine JE et al. Plasma biomarkers of lower gastrointestinal and liver acute GVHD. Blood 2012; 119: 2960–2963.
Melson J, Jakate S, Fung H, Arai S, Keshavarzian A . Crypt loss is a marker of clinical severity of acute gastrointestinal graft-versus-host disease. Am J Hematol 2007; 82: 881–886.
MacMillan ML, Weisdorf DJ, Wagner JE, Defor TE, Burns LJ, Ramsay NK et al. Response of 443 patients to steroids as primary therapy for acute graft-versus-host disease: comparison of grading systems. Biol Blood Marrow Transplant 2002; 8: 387–394.
Pidala J, Anasetti C . Glucocorticoid-refractory acute graft-versus-host disease. Biol Blood Marrow Transplant 2010; 16: 1504–1518.
Jamani K, Russell JA, Daly A, Stewart D, Savoie L, Duggan P et al. Prognosis of grade 3-4 acute GVHD continues to be dismal. Bone Marrow Transplant 2013; 48: 1359–1361.
Xhaard A, Rocha V, Bueno B, de Latour RP, Lenglet J, Petropoulou A et al. Steroid-refractory acute GVHD: lack of long-term improved survival using new generation anticytokine treatment. Biol Blood Marrow Transplant 2012; 18: 406–413.
Arai S, Margolis J, Zahurak M, Anders V, Vogelsang GB . Poor outcome in steroid-refractory graft-versus-host disease with antithymocyte globulin treatment. Biol Blood Marrow Transplant 2002; 8: 155–160.
Bay JO, Dhedin N, Goerner M, Vannier JP, Marie-Cardine A, Stamatoullas A et al. Inolimomab in steroid-refractory acute graft-versus-host disease following allogeneic hematopoietic stem cell transplantation: retrospective analysis and comparison with other interleukin-2 receptor antibodies. Transplantation 2005; 80: 782–788.
Carpenter PA, Lowder J, Johnston L, Frangoul H, Khoury H, Parker P et al. A phase II multicenter study of visilizumab, humanized anti-CD3 antibody, to treat steroid-refractory acute graft-versus-host disease. Biol Blood Marrow Transplant 2005; 11: 465–471.
Perales MA, Ishill N, Lomazow WA, Weinstock DM, Papadopoulos EB, Dastigir H et al. Long-term follow-up of patients treated with daclizumab for steroid-refractory acute graft-vs-host disease. Bone Marrow Transplant 2007; 40: 481–486.
Bordigoni P, Dimicoli S, Clement L, Baumann C, Salmon A, Witz F et al. Daclizumab, an efficient treatment for steroid-refractory acute graft-versus-host disease. Br J Haematol 2006; 135: 382–385.
Passweg JR, Orchard K, Buergi A, Gratwohl A, Powles R, Goldman J et al. Autologous/syngeneic stem cell transplantation to treat refractory GvHD. Bone Marrow Transplant 2004; 34: 995–998.
Taniguchi Y, Yoshihara S, Hoshida Y, Inoue T, Fujioka T, Ikegame K et al. Recovery from established graft-vs-host disease achieved by bone marrow transplantation from a third-party allogeneic donor. Exp Hematol 2008; 36: 1216–1225.
Ustun C, JillelLa A, Shah R, Sterling K, Deremer D, Savage N et al. Second allo-SCT from a different donor can improve severe steroid-resistant gut GVHD (Letter to the Editor). Bone Marrow Transplant 2010; 45: 1658–1660.
Taniguchi Y, Ikegame K, Yoshihara S, Sugiyama H, Kawase I, Ogawa H . Treatment of severe life-threatening graft-versus-host disease by autologous peripheral blood stem cell transplantation using a nonmyeloablative preconditioning regimen. Haematologica 2003; 88: ELT06.
We thank Helen Crawford and Bonnie Larson for their excellent support in typing the manuscript. We are also very thankful for the excellent care provided to patients and families by the inpatient and outpatient physicians, nursing teams and support staff at the Fred Hutchinson Cancer Research Center and at the University of Washington Medical Center. This work was supported in part by National Institutes of Health Grants CA018029, HL036444, CA078902 and CA015704. The funding body played no part in the design of the study, collection and analysis of data, or the decision to publish. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or its subsidiary Institutes and Centers.
The authors declare no conflict of interest.
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Castilla-Llorente, C., Martin, P., McDonald, G. et al. Prognostic factors and outcomes of severe gastrointestinal GVHD after allogeneic hematopoietic cell transplantation. Bone Marrow Transplant 49, 966–971 (2014). https://doi.org/10.1038/bmt.2014.69
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