UpToDate
Official reprint from UpToDate®
www.uptodate.com ©2016 UpToDate®

Treatment of acute graft-versus-host disease

Author
Nelson J Chao, MD
Section Editor
Robert S Negrin, MD
Deputy Editor
Alan G Rosmarin, MD

INTRODUCTION

Acute graft-versus-host disease (GVHD) is a common complication of allogeneic hematopoietic cell transplant (HCT) that classically presents in the early post-transplantation period. It is thought to be primarily a T cell mediated disease that occurs when immune cells transplanted from a non-identical donor (the graft) recognize the transplant recipient (the host) as foreign, thereby initiating an immune reaction that causes disease in the transplant recipient. The skin, gastrointestinal tract, and liver are the principal target organs in patients with acute GVHD.

Clinically significant acute GVHD occurs in 9 to 50 percent of patients who receive an allogeneic HCT from a genotypically HLA-identical sibling, despite intensive prophylaxis with immunosuppressive agents, such as methotrexate, cyclosporine, corticosteroids, mycophenolate mofetil, or antithymocyte globulin. Acute GVHD is more common following HCT from matched unrelated donors and haploidentical donors. (See "Donor selection for hematopoietic cell transplantation".)

The management of acute GVHD will be reviewed here. Specific recommendations for the prevention and diagnosis of GVHD are discussed separately. (See "Prevention of acute graft-versus-host disease" and "Clinical manifestations, diagnosis, and grading of acute graft-versus-host disease".)

OVERVIEW

Prevention of GVHD — Prophylaxis of acute graft-versus-host disease (GVHD) centers on immunosuppression of the donor cells, either pharmacologically or via T cell depletion. There is no agreed upon standard regimen, and clinical practice varies by institution. However, each institution must have guidelines for the prevention and management of GVHD in order to be acknowledged by international accrediting organizations. This is discussed in more detail separately. (See "Prevention of acute graft-versus-host disease", section on 'Choice of prophylaxis'.)

Diagnosis of GVHD — Acute GVHD can involve the skin, gastrointestinal tract, and liver. The diagnosis can be made readily on clinical grounds in the patient who presents with a classic rash, abdominal cramps with diarrhea, and a rising serum bilirubin concentration within the first 100 days following hematopoietic cell transplantation (HCT), most often within two to three weeks following HCT. (See "Clinical manifestations, diagnosis, and grading of acute graft-versus-host disease".)

                                

Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Nov 2016. | This topic last updated: Wed May 25 00:00:00 GMT 2016.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2016 UpToDate, Inc.
References
Top
  1. Martin PJ, Rizzo JD, Wingard JR, et al. First- and second-line systemic treatment of acute graft-versus-host disease: recommendations of the American Society of Blood and Marrow Transplantation. Biol Blood Marrow Transplant 2012; 18:1150.
  2. Dignan FL, Clark A, Amrolia P, et al. Diagnosis and management of acute graft-versus-host disease. Br J Haematol 2012; 158:30.
  3. Ruutu T, Gratwohl A, de Witte T, et al. Prophylaxis and treatment of GVHD: EBMT-ELN working group recommendations for a standardized practice. Bone Marrow Transplant 2014; 49:168.
  4. Wolff D, Ayuk F, Elmaagacli A, et al. Current practice in diagnosis and treatment of acute graft-versus-host disease: results from a survey among German-Austrian-Swiss hematopoietic stem cell transplant centers. Biol Blood Marrow Transplant 2013; 19:767.
  5. Furlong T, Storb R, Anasetti C, et al. Clinical outcome after conversion to FK 506 (tacrolimus) therapy for acute graft-versus-host disease resistant to cyclosporine or for cyclosporine-associated toxicities. Bone Marrow Transplant 2000; 26:985.
  6. Alousi AM, Weisdorf DJ, Logan BR, et al. Etanercept, mycophenolate, denileukin, or pentostatin plus corticosteroids for acute graft-versus-host disease: a randomized phase 2 trial from the Blood and Marrow Transplant Clinical Trials Network. Blood 2009; 114:511.
  7. Levine JE, Logan BR, Wu J, et al. Acute graft-versus-host disease biomarkers measured during therapy can predict treatment outcomes: a Blood and Marrow Transplant Clinical Trials Network study. Blood 2012; 119:3854.
  8. Deeg HJ. How I treat refractory acute GVHD. Blood 2007; 109:4119.
  9. Hings IM, Severson R, Filipovich AH, et al. Treatment of moderate and severe acute GVHD after allogeneic bone marrow transplantation. Transplantation 1994; 58:437.
  10. Lee SJ, Zahrieh D, Agura E, et al. Effect of up-front daclizumab when combined with steroids for the treatment of acute graft-versus-host disease: results of a randomized trial. Blood 2004; 104:1559.
  11. Levine JE, Paczesny S, Mineishi S, et al. Etanercept plus methylprednisolone as initial therapy for acute graft-versus-host disease. Blood 2008; 111:2470.
  12. MacMillan ML, Weisdorf DJ, Wagner JE, 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.
  13. Bacigalupo A, van Lint MT, Frassoni F, et al. High dose bolus methylprednisolone for the treatment of acute graft versus host disease. Blut 1983; 46:125.
  14. Kanojia MD, Anagnostou AA, Zander AR, et al. High-dose methylprednisolone treatment for acute graft-versus-host disease after bone marrow transplantation in adults. Transplantation 1984; 37:246.
  15. Neudorf S, Filipovich A, Ramsay N, Kersey J. Prevention and treatment of acute graft-versus-host disease. Semin Hematol 1984; 21:91.
  16. Storb R, Deeg HJ, Whitehead J, et al. Methotrexate and cyclosporine compared with cyclosporine alone for prophylaxis of acute graft versus host disease after marrow transplantation for leukemia. N Engl J Med 1986; 314:729.
  17. Van Lint MT, Uderzo C, Locasciulli A, et al. Early treatment of acute graft-versus-host disease with high- or low-dose 6-methylprednisolone: a multicenter randomized trial from the Italian Group for Bone Marrow Transplantation. Blood 1998; 92:2288.
  18. Mielcarek M, Storer BE, Boeckh M, et al. Initial therapy of acute graft-versus-host disease with low-dose prednisone does not compromise patient outcomes. Blood 2009; 113:2888.
  19. Mielcarek M, Furlong T, Storer BE, et al. Efficacy and Safety Of Lower-Dose Glucocorticoids For Initial Treatment Of Acute Graft-Versus-Host Disease: A Randomized Controlled Trial (abstract). Blood 2013; 122:703.
  20. Ibrahim RB, Abidi MH, Cronin SM, et al. Nonabsorbable corticosteroids use in the treatment of gastrointestinal graft-versus-host disease. Biol Blood Marrow Transplant 2009; 15:395.
  21. Ippoliti C, Champlin R, Bugazia N, et al. Use of octreotide in the symptomatic management of diarrhea induced by graft-versus-host disease in patients with hematologic malignancies. J Clin Oncol 1997; 15:3350.
  22. Beckman RA, Siden R, Yanik GA, Levine JE. Continuous octreotide infusion for the treatment of secretory diarrhea caused by acute intestinal graft-versus-host disease in a child. J Pediatr Hematol Oncol 2000; 22:344.
  23. Ippoliti C, Neumann J. Octreotide in the management of diarrhea induced by graft versus host disease. Oncol Nurs Forum 1998; 25:873.
  24. McDonald GB, Bouvier M, Hockenbery DM, et al. Oral beclomethasone dipropionate for treatment of intestinal graft-versus-host disease: a randomized, controlled trial. Gastroenterology 1998; 115:28.
  25. Hockenbery DM, Cruickshank S, Rodell TC, 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.
  26. van der Meij BS, de Graaf P, Wierdsma NJ, et al. Nutritional support in patients with GVHD of the digestive tract: state of the art. Bone Marrow Transplant 2013; 48:474.
  27. Couriel D, Caldera H, Champlin R, Komanduri K. Acute graft-versus-host disease: pathophysiology, clinical manifestations, and management. Cancer 2004; 101:1936.
  28. Bolaños-Meade J, Vogelsang GB. Novel strategies for steroid-refractory acute graft-versus-host disease. Curr Opin Hematol 2005; 12:40.
  29. Basara N, Blau WI, Römer E, et al. Mycophenolate mofetil for the treatment of acute and chronic GVHD in bone marrow transplant patients. Bone Marrow Transplant 1998; 22:61.
  30. Furlong T, Martin P, Flowers ME, et al. Therapy with mycophenolate mofetil for refractory acute and chronic GVHD. Bone Marrow Transplant 2009; 44:739.
  31. Bolaños-Meade J, Logan BR, Alousi AM, et al. Phase 3 clinical trial of steroids/mycophenolate mofetil vs steroids/placebo as therapy for acute GVHD: BMT CTN 0802. Blood 2014; 124:3221.
  32. Chiang KY, Abhyankar S, Bridges K, et al. Recombinant human tumor necrosis factor receptor fusion protein as complementary treatment for chronic graft-versus-host disease. Transplantation 2002; 73:665.
  33. Busca A, Locatelli F, Marmont F, et al. Recombinant human soluble tumor necrosis factor receptor fusion protein as treatment for steroid refractory graft-versus-host disease following allogeneic hematopoietic stem cell transplantation. Am J Hematol 2007; 82:45.
  34. Kennedy GA, Butler J, Western R, et al. Combination antithymocyte globulin and soluble TNFalpha inhibitor (etanercept) +/- mycophenolate mofetil for treatment of steroid refractory acute graft-versus-host disease. Bone Marrow Transplant 2006; 37:1143.
  35. Wolff D, Roessler V, Steiner B, et al. Treatment of steroid-resistant acute graft-versus-host disease with daclizumab and etanercept. Bone Marrow Transplant 2005; 35:1003.
  36. Bolaños-Meade J, Jacobsohn DA, Margolis J, et al. Pentostatin in steroid-refractory acute graft-versus-host disease. J Clin Oncol 2005; 23:2661.
  37. Poi MJ, Hofmeister CC, Johnston JS, et al. Standard pentostatin dose reductions in renal insufficiency are not adequate: selected patients with steroid-refractory acute graft-versus-host disease. Clin Pharmacokinet 2013; 52:705.
  38. Benito AI, Furlong T, Martin PJ, et al. Sirolimus (rapamycin) for the treatment of steroid-refractory acute graft-versus-host disease. Transplantation 2001; 72:1924.
  39. Gorgun G, Miller KB, Foss FM. Immunologic mechanisms of extracorporeal photochemotherapy in chronic graft-versus-host disease. Blood 2002; 100:941.
  40. Setterblad N, Garban F, Weigl R, et al. Extracorporeal photophoresis increases sensitivity of monocytes from patients with graft-versus-host disease to HLA-DR-mediated cell death. Transfusion 2008; 48:169.
  41. Gatza E, Rogers CE, Clouthier SG, et al. Extracorporeal photopheresis reverses experimental graft-versus-host disease through regulatory T cells. Blood 2008; 112:1515.
  42. Marshall SR. Technology insight: ECP for the treatment of GvHD--can we offer selective immune control without generalized immunosuppression? Nat Clin Pract Oncol 2006; 3:302.
  43. Besnier DP, Chabannes D, Mahé B, et al. Treatment of graft-versus-host disease by extracorporeal photochemotherapy: a pilot study. Transplantation 1997; 64:49.
  44. Smith EP, Sniecinski I, Dagis AC, et al. Extracorporeal photochemotherapy for treatment of drug-resistant graft-vs.-host disease. Biol Blood Marrow Transplant 1998; 4:27.
  45. Greinix HT, Volc-Platzer B, Rabitsch W, et al. Successful use of extracorporeal photochemotherapy in the treatment of severe acute and chronic graft-versus-host disease. Blood 1998; 92:3098.
  46. Kanold J, Merlin E, Halle P, et al. Photopheresis in pediatric graft-versus-host disease after allogeneic marrow transplantation: clinical practice guidelines based on field experience and review of the literature. Transfusion 2007; 47:2276.
  47. Rubegni P, Feci L, Poggiali S, et al. Extracorporeal photopheresis: a useful therapy for patients with steroid-refractory acute graft-versus-host disease but not for the prevention of the chronic form. Br J Dermatol 2013; 169:450.
  48. Jagasia M, Greinix H, Robin M, et al. Extracorporeal photopheresis versus anticytokine therapy as a second-line treatment for steroid-refractory acute GVHD: a multicenter comparative analysis. Biol Blood Marrow Transplant 2013; 19:1129.
  49. Hautmann AH, Wolff D, Hahn J, et al. Extracorporeal photopheresis in 62 patients with acute and chronic GVHD: results of treatment with the COBE Spectra System. Bone Marrow Transplant 2013; 48:439.
  50. Greinix HT, Volc-Platzer B, Kalhs P, et al. Extracorporeal photochemotherapy in the treatment of severe steroid-refractory acute graft-versus-host disease: a pilot study. Blood 2000; 96:2426.
  51. Dall'Amico R, Messina C. Extracorporeal photochemotherapy for the treatment of graft-versus-host disease. Ther Apher 2002; 6:296.
  52. Pierelli L, Perseghin P, Marchetti M, et al. Extracorporeal photopheresis for the treatment of acute and chronic graft-versus-host disease in adults and children: best practice recommendations from an Italian Society of Hemapheresis and Cell Manipulation (SIdEM) and Italian Group for Bone Marrow Transplantation (GITMO) consensus process. Transfusion 2013; 53:2340.
  53. Das-Gupta E, Dignan F, Shaw B, et al. Extracorporeal photopheresis for treatment of adults and children with acute GVHD: UK consensus statement and review of published literature. Bone Marrow Transplant 2014; 49:1251.
  54. Storb R, Gluckman E, Thomas ED, et al. Treatment of established human graft-versus-host disease by antithymocyte globulin. Blood 1974; 44:56.
  55. Doney KC, Weiden PL, Storb R, Thomas ED. Treatment of graft-versus-host disease in human allogeneic marrow graft recipients: a randomized trial comparing antithymocyte globulin and corticosteroids. Am J Hematol 1981; 11:1.
  56. Deeg HJ, Loughran TP Jr, Storb R, et al. Treatment of human acute graft-versus-host disease with antithymocyte globulin and cyclosporine with or without methylprednisolone. Transplantation 1985; 40:162.
  57. Tse JC, Moore TB. Monoclonal antibodies in the treatment of steroid-resistant acute graft-versus-host disease. Pharmacotherapy 1998; 18:988.
  58. Gratama JW, Jansen J, Lipovich RA, et al. Treatment of acute graft-versus-host disease with monoclonal antibody OKT3. Clinical results and effect on circulating T lymphocytes. Transplantation 1984; 38:469.
  59. Gluckman E, Devergie A, Varin F, et al. Treatment of steroid resistant severe acute graft-versus-host disease with a monoclonal pan T OKT3 antibody. Exp Hematol 1984; 12:66.
  60. Hebart H, Ehninger G, Schmidt H, et al. Treatment of steroid-resistant graft-versus-host disease after allogeneic bone marrow transplantation with anti-CD3/TCR monoclonal antibodies. Bone Marrow Transplant 1995; 15:891.
  61. Przepiorka D, Kernan NA, Ippoliti C, et al. Daclizumab, a humanized anti-interleukin-2 receptor alpha chain antibody, for treatment of acute graft-versus-host disease. Blood 2000; 95:83.
  62. Bordigoni P, Dimicoli S, Clement L, et al. Daclizumab, an efficient treatment for steroid-refractory acute graft-versus-host disease. Br J Haematol 2006; 135:382.
  63. Srinivasan R, Chakrabarti S, Walsh T, et al. Improved survival in steroid-refractory acute graft versus host disease after non-myeloablative allogeneic transplantation using a daclizumab-based strategy with comprehensive infection prophylaxis. Br J Haematol 2004; 124:777.
  64. Schmidt-Hieber M, Fietz T, Knauf W, et al. Efficacy of the interleukin-2 receptor antagonist basiliximab in steroid-refractory acute graft-versus-host disease. Br J Haematol 2005; 130:568.
  65. Bay JO, Dhédin N, Goerner M, 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.
  66. Schnitzler M, Hasskarl J, Egger M, et al. Successful treatment of severe acute intestinal graft-versus-host resistant to systemic and topical steroids with alemtuzumab. Biol Blood Marrow Transplant 2009; 15:910.
  67. Drobyski WR, Pasquini M, Kovatovic K, et al. Tocilizumab for the treatment of steroid refractory graft-versus-host disease. Biol Blood Marrow Transplant 2011; 17:1862.
  68. Spoerl S, Mathew NR, Bscheider M, et al. Activity of therapeutic JAK 1/2 blockade in graft-versus-host disease. Blood 2014; 123:3832.
  69. Zeiser R, Burchert A, Lengerke C, et al. Ruxolitinib in corticosteroid-refractory graft-versus-host disease after allogeneic stem cell transplantation: a multicenter survey. Leukemia 2015; 29:2062.
  70. Selmani Z, Naji A, Zidi I, et al. Human leukocyte antigen-G5 secretion by human mesenchymal stem cells is required to suppress T lymphocyte and natural killer function and to induce CD4+CD25highFOXP3+ regulatory T cells. Stem Cells 2008; 26:212.
  71. Wolf D, Wolf AM. Mesenchymal stem cells as cellular immunosuppressants. Lancet 2008; 371:1553.
  72. Le Blanc K, Rasmusson I, Sundberg B, et al. Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet 2004; 363:1439.
  73. Ringdén O, Uzunel M, Rasmusson I, et al. Mesenchymal stem cells for treatment of therapy-resistant graft-versus-host disease. Transplantation 2006; 81:1390.
  74. Le Blanc K, Frassoni F, Ball L, et al. Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. Lancet 2008; 371:1579.
  75. Kebriaei P, Isola L, Bahceci E, et al. Adult human mesenchymal stem cells added to corticosteroid therapy for the treatment of acute graft-versus-host disease. Biol Blood Marrow Transplant 2009; 15:804.
  76. Galipeau J. The mesenchymal stromal cells dilemma--does a negative phase III trial of random donor mesenchymal stromal cells in steroid-resistant graft-versus-host disease represent a death knell or a bump in the road? Cytotherapy 2013; 15:2.
  77. Martin PJ, Uberti JP, Soiffer RJ, et al. Prochymal improves response rates in patients with steroid-refractory acute graft versus host disease involving the liver and gut: Results of a randomized, placebo controlled, multicenter phase III trial in GVHD. Biol Blood Marrow Transplant 2010; 16:S169.
  78. Zhou X, Di Stasi A, Tey SK, et al. Long-term outcome after haploidentical stem cell transplant and infusion of T cells expressing the inducible caspase 9 safety transgene. Blood 2014; 123:3895.
  79. Weisdorf D, Haake R, Blazar B, et al. Treatment of moderate/severe acute graft-versus-host disease after allogeneic bone marrow transplantation: an analysis of clinical risk features and outcome. Blood 1990; 75:1024.
  80. Martin PJ, Schoch G, Fisher L, et al. A retrospective analysis of therapy for acute graft-versus-host disease: secondary treatment. Blood 1991; 77:1821.
  81. Roy J, McGlave PB, Filipovich AH, et al. Acute graft-versus-host disease following unrelated donor marrow transplantation: failure of conventional therapy. Bone Marrow Transplant 1992; 10:77.
  82. Speiser DE, Tiercy JM, Rufer N, et al. High resolution HLA matching associated with decreased mortality after unrelated bone marrow transplantation. Blood 1996; 87:4455.
  83. Sasazuki T, Juji T, Morishima Y, et al. Effect of matching of class I HLA alleles on clinical outcome after transplantation of hematopoietic stem cells from an unrelated donor. Japan Marrow Donor Program. N Engl J Med 1998; 339:1177.