Advertisement

Inpatient Management of Mucocutaneous GVHD

  • Toral S. Vaidya
  • Christian Menzer
  • Doris M. Ponce
  • Alina MarkovaEmail author
Hospital-Based Dermatology (L Guggina and A Zhou, Section Editors)
  • 17 Downloads
Part of the following topical collections:
  1. Topical Collection on Hospital-based Dermatology

Abstract

Purpose of Review

Graft-versus-host disease (GVHD) is an immune mediated disorder affecting 30–70% of patients after allogeneic hematopoietic stem cell transplantation (alloHSCT), and is a major cause of morbidity and non-relapse mortality (NRM) as reported by Jagasia, et al. (Blood 119:296-307, •2012). Dermatologists play a critical role in acute and chronic GVHD, as skin involvement is common and often the earliest involved site of disease as reported by MacMillan, et al. (Biol Blood Marrow Transplant 21: 761-7, 2015).

Recent Findings

GVHD shares clinical and histopathological features with a variety of other skin diseases, requiring thorough consideration of differential diagnoses in hematopoietic stem cell transplantation (HSCT) recipients with lesions suggestive of cutaneous GVHD. Treatment considerations for GVHD are influenced by factors such as disease classification, overall grading, organ involvement, associated symptoms, and immunological anti-tumor effect. Several treatments are available and may be indicated as monotherapy or adjuvant therapy to allow faster withdrawal or tapering of immunosuppression. While corticosteroids are often first-line therapy, oral ruxolitinib has been recently approved for treatment of steroid-refractory acute GVHD (aGVHD), and oral ibrutinib has been approved for steroid-refractory chronic GVHD (cGVHD).

Summary

This article provides current clinical, diagnostic, and therapeutic considerations relevant to the hospitalist for both acute and chronic mucocutaneous GVHD. Optimal inpatient management of these diseases requires an interdisciplinary team.

Keywords

Graft versus host disease Acute graft versus host disease Chronic graft versus host disease Inpatient management GVHD Dermatology hospitalist Inpatient dermatology 

Notes

Compliance with Ethical Standards

Conflict of Interest

The authors declare no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    D'Souza A, F.C. Current uses and outcomes of hematopoietic cell transplantation (HCT): CIBMTR summary slides. 2018; Available from: https://www.cibmtr.org. Accessed 11 April 2019.
  2. 2.
    • Zeiser R, Blazar BR. Acute graft-versus-host disease—biologic process, prevention, and therapy. N Engl J Med. 2017;377(22):2167–79 This reference provides an overview of the biologic features of acute GVHD, and preventative and therapeutic strategies based on recent developments. PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Elsabbagh EM, et al. Acute GvHD incidence and outcome: single center experience. Biology of Blood and Marrow Transplantation. 2017;23(3):S231.CrossRefGoogle Scholar
  4. 4.
    Wingard JR, Majhail NS, Brazauskas R, Wang Z, Sobocinski KA, Jacobsohn D, et al. Long-term survival and late deaths after allogeneic hematopoietic cell transplantation. J Clin Oncol. 2011;29(16):2230–9.PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Pidala J, Anasetti C. Glucocorticoid-refractory acute graft-versus-host disease. Biol Blood Marrow Transplant. 2010;16(11):1504–18.PubMedCrossRefGoogle Scholar
  6. 6.
    Ghimire S, et al. Pathophysiology of GvHD and other HSCT-related major complications. Front Immunol. 2017;8:79.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Srinivasan R, 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(6):777–86.PubMedCrossRefGoogle Scholar
  8. 8.
    Klein SA, et al. Long term outcome of patients with steroid-refractory acute intestinal graft versus host disease after treatment with pentostatin. Br J Haematol. 2011;154(1):143–6.PubMedCrossRefGoogle Scholar
  9. 9.
    Schub N, et al. Therapy of steroid-refractory acute GVHD with CD52 antibody alemtuzumab is effective. Bone Marrow Transplant. 2010;46:143.PubMedCrossRefGoogle Scholar
  10. 10.
    Jamani K, et al. Prognosis of grade 3–4 acute GVHD continues to be dismal. Bone Marrow Transplant. 2013;48:1359.PubMedCrossRefGoogle Scholar
  11. 11.
    Hymes SR, Alousi AM, Cowen EW. Graft-versus-host disease: part I. Pathogenesis and clinical manifestations of graft-versus-host disease. J Am Acad Dermatol. 2012;66(4):515 e1–18 quiz 533-4.CrossRefGoogle Scholar
  12. 12.
    Horwitz ME, Sullivan KM. Chronic graft-versus-host disease. Blood Rev. 2006;20(1):15–27.PubMedCrossRefGoogle Scholar
  13. 13.
    Bhushan V, Collins RH Jr. Chronic graft-vs-host disease. Jama. 2003;290(19):2599–603.PubMedCrossRefGoogle Scholar
  14. 14.
    Lee SJ, Vogelsang G, Flowers ME. Chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2003;9(4):215–33.PubMedCrossRefGoogle Scholar
  15. 15.
    Arai S, Arora M, Wang T, Spellman SR, He W, Couriel DR, et al. Increasing incidence of chronic graft-versus-host disease in allogeneic transplantation: a report from the Center for International Blood and Marrow Transplant Research. Biol Blood Marrow Transplant. 2015;21(2):266–74.PubMedCrossRefGoogle Scholar
  16. 16.
    Cooke KR, Luznik L, Sarantopoulos S, Hakim FT, Jagasia M, Fowler DH, et al. The Biology of chronic graft-versus-host disease: a task force report from the National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease. Biol Blood Marrow Transplant. 2017;23(2):211–34.PubMedCrossRefGoogle Scholar
  17. 17.
    Bhatia S, et al. Late mortality after allogeneic hematopoietic cell transplantation and functional status of long-term survivors: report from the Bone Marrow Transplant Survivor Study. Blood. 2007;110(10):3784–92.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Jagasia M, Arora M, Flowers ME, Chao NJ, McCarthy P, Cutler CS, et al. Risk factors for acute GVHD and survival after hematopoietic cell transplantation. Blood. 2012;119(1):296–307.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Sun C-L, et al. Prevalence and predictors of chronic health conditions after hematopoietic cell transplantation: a report from the Bone Marrow Transplant Survivor Study. Blood. 2010;116(17):3129–39.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    MacMillan ML, et al. A refined risk score for acute graft-versus-host disease that predicts response to initial therapy, survival, and transplant-related mortality. Biol Blood Marrow Transplant. 2015;21(4):761–7.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Przepiorka D, et al. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant. 1995;15(6):825–8.PubMedGoogle Scholar
  22. 22.
    Ferrara JL, Levine JE, Reddy P, Holler E. Graft-versus-host disease. Lancet. 2009;373(9674):1550–61.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Wallace AB. The exposure treatment of burns. Lancet. 1951;1(6653):501–4.PubMedCrossRefGoogle Scholar
  24. 24.
    Penas PF, Zaman S. Many faces of graft-versus-host disease. Australas J Dermatol. 2010;51(1):1–10 quiz 11.PubMedCrossRefGoogle Scholar
  25. 25.
    Vargas-Diez E, et al. Life-threatening graft-vs-host disease. Clin Dermatol. 2005;23(3):285–300.PubMedCrossRefGoogle Scholar
  26. 26.
    Macedo FI, et al. Extensive toxic epidermal necrolysis versus acute graft versus host disease after allogenic hematopoietic stem-cell transplantation: challenges in diagnosis and management. J Burn Care Res. 2014;35(6):e431–5.PubMedCrossRefGoogle Scholar
  27. 27.
    Kuykendall TD, Smoller BR. Lack of specificity in skin biopsy specimens to assess for acute graft-versus-host disease in initial 3 weeks after bone-marrow transplantation. J Am Acad Dermatol. 2003;49(6):1081–5.PubMedCrossRefGoogle Scholar
  28. 28.
    Kohler S, Hendrickson MR, Chao NJ, Smoller BR. Value of skin biopsies in assessing prognosis and progression of acute graft-versus-host disease. Am J Surg Pathol. 1997;21(9):988–96.PubMedCrossRefGoogle Scholar
  29. 29.
    Zhou Y, Barnett MJ, Rivers JK. Clinical significance of skin biopsies in the diagnosis and management of graft-vs-host disease in early postallogeneic bone marrow transplantation. Arch Dermatol. 2000;136(6):717–21.PubMedCrossRefGoogle Scholar
  30. 30.
    Lerner KG, Kao GF, Storb R, Buckner CD, Clift RA, Thomas ED. Histopathology of graft-vs.-host reaction (GvHR) in human recipients of marrow from HL-A-matched sibling donors. Transplant Proc. 1974;6(4):367–71.PubMedPubMedCentralGoogle Scholar
  31. 31.
    Barksdale SK, Oberlender SA, Barnhill RL. "Rush" skin biopsy specimens in a tertiary medical center: diagnostic yield and clinical utility. J Am Acad Dermatol. 1998;38(4):548–54.PubMedCrossRefPubMedCentralGoogle Scholar
  32. 32.
    Marra DE, McKee PH, Nghiem P. Tissue eosinophils and the perils of using skin biopsy specimens to distinguish between drug hypersensitivity and cutaneous graft-versus-host disease. J Am Acad Dermatol. 2004;51(4):543–6.PubMedCrossRefPubMedCentralGoogle Scholar
  33. 33.
    • Zeiser R, Blazar BR. Pathophysiology of chronic graft-versus-host disease and therapeutic targets. N Engl J Med. 2017;377(26):2565–79 This reference provides an overview of the biologic features of chronic GVHD; essential diagnostic, staging, and assessment tools; and therapeutic targets that are undergoing clinical testing and may impact clinical care. PubMedCrossRefPubMedCentralGoogle Scholar
  34. 34.
    • Jagasia MH, et al. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2014 Diagnosis and Staging Working Group report. Biol Blood Marrow Transplant. 2015;21(3):389–401 e1 This reference provides the 2014 NIH consensus criteria for diagnosing and scoring the severity of chronic GVHD based on new evidence. PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    • Carpenter PA, et al. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: V. The 2014. Ancillary Therapy and Supportive Care Working Group Report. Biol Blood Marrow Transplant. 2015;21(7):1167–87 This reference provides 2014 NIH recommendations regarding interventions directed at organ-specific control of symptoms or compplications resulting from GVHD and its therapy. PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Arai S, et al. Global and organ-specific chronic graft-versus-host disease severity according to the 2005 NIH Consensus Criteria. Blood. 2011;118(15):4242–9.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    • Strong Rodrigues K, et al. Cutaneous graft-versus-host disease: diagnosis and treatment. Am J Clin Dermatol. 2018;19(1):33–50 This reference reviews skin involvement and updated therapeutic options for both acute and chronic GVHD. PubMedCrossRefPubMedCentralGoogle Scholar
  38. 38.
    Penas PF, et al. Sclerodermatous graft-vs-host disease: clinical and pathological study of 17 patients. Arch Dermatol. 2002;138(7):924–34.PubMedCrossRefGoogle Scholar
  39. 39.
    Bruggen MC, et al. Diverse T-cell responses characterize the different manifestations of cutaneous graft-versus-host disease. Blood. 2014;123(2):290–9.PubMedCrossRefPubMedCentralGoogle Scholar
  40. 40.
    Inamoto Y, Storer BE, Petersdorf EW, Nelson JL, Lee SJ, Carpenter PA, et al. Incidence, risk factors, and outcomes of sclerosis in patients with chronic graft-versus-host disease. Blood. 2013;121(25):5098–103.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Jachiet M, de Masson A, Peffault de Latour R, Rybojad M, Robin M, Bourhis JH, et al. Skin ulcers related to chronic graft-versus-host disease: clinical findings and associated morbidity. Br J Dermatol. 2014;171(1):63–8.PubMedCrossRefPubMedCentralGoogle Scholar
  42. 42.
    Imanguli MM, Alevizos I, Brown R, Pavletic SZ, Atkinson JC. Oral graft-versus-host disease. Oral Dis. 2008;14(5):396–412.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Mueller SM, Haeusermann P, Rovó A, Halter JP, Passweg J, Itin P, et al. Genital chronic GVHD in men after hematopoietic stem cell transplantation: a single-center cross-sectional analysis of 155 patients. Biol Blood Marrow Transplant. 2013;19(11):1574–80.PubMedCrossRefPubMedCentralGoogle Scholar
  44. 44.
    Lee SJ, Vogelsang G, Gilman A, Weisdorf DJ, Pavletic S, Antin JH, et al. A survey of diagnosis, management, and grading of chronic GVHD. Biol Blood Marrow Transplant. 2002;8(1):32–9.PubMedCrossRefPubMedCentralGoogle Scholar
  45. 45.
    Spinelli S, Chiodi S, Costantini S, van Lint M, Raiola AM, Ravera GB, et al. Female genital tract graft-versus-host disease following allogeneic bone marrow transplantation. Haematologica. 2003;88(10):1163–8.PubMedPubMedCentralGoogle Scholar
  46. 46.
    Lee YB, Lee JY. Nail changes in patients with graft-versus-host disease. J Am Acad Dermatol. 2011;64(2):AB91.Google Scholar
  47. 47.
    Hillen U, Häusermann P, Massi D, Janin A, Wolff D, Lawitschka A, et al. Consensus on performing skin biopsies, laboratory workup, evaluation of tissue samples and reporting of the results in patients with suspected cutaneous graft-versus-host disease. J Eur Acad Dermatol Venereol. 2015;29(5):948–54.PubMedCrossRefPubMedCentralGoogle Scholar
  48. 48.
    Clark J, Yao L, Pavletic SZ, Krumlauf M, Mitchell S, Turner ML, et al. Magnetic resonance imaging in sclerotic-type chronic graft-vs-host disease. Arch Dermatol. 2009;145(8):918–22.PubMedCrossRefPubMedCentralGoogle Scholar
  49. 49.
    Bauer DJ, Hood AF, Horn TD. Histologic comparison of autologous graft-vs-host reaction and cutaneous eruption of lymphocyte recovery. Arch Dermatol. 1993;129(7):855–8.PubMedCrossRefPubMedCentralGoogle Scholar
  50. 50.
    Spitzer TR. Engraftment syndrome following hematopoietic stem cell transplantation. Bone Marrow Transplant. 2001;27(9):893–8.PubMedCrossRefPubMedCentralGoogle Scholar
  51. 51.
    Spitzer TR. Engraftment syndrome: double-edged sword of hematopoietic cell transplants. Bone Marrow Transplant. 2015;50(4):469–75.PubMedCrossRefPubMedCentralGoogle Scholar
  52. 52.
    Saliba RM, de Lima M, Giralt S, Andersson B, Khouri IF, Hosing C, et al. Hyperacute GVHD: risk factors, outcomes, and clinical implications. Blood. 2007;109(7):2751–8.PubMedCrossRefPubMedCentralGoogle Scholar
  53. 53.
    Chang L, Frame D, Braun T, Gatza E, Hanauer DA, Zhao S, et al. Engraftment syndrome after allogeneic hematopoietic cell transplantation predicts poor outcomes. Biol Blood Marrow Transplant. 2014;20(9):1407–17.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Park M, Lee SH, Lee YH, Yoo KH, Sung KW, Koo HH, et al. Pre-engraftment syndrome after unrelated cord blood transplantation: a predictor of engraftment and acute graft-versus-host disease. Biol Blood Marrow Transplant. 2013;19(4):640–6.PubMedCrossRefPubMedCentralGoogle Scholar
  55. 55.
    Bolognia JL, Cooper DL, Glusac EJ. Toxic erythema of chemotherapy: a useful clinical term. J Am Acad Dermatol. 2008;59(3):524–9.PubMedCrossRefPubMedCentralGoogle Scholar
  56. 56.
    Chen A, Chao K, Rodriguez L, Munday W, Worswick S. Toxic epidermal necrolysis versus cutaneous Graft-Versus-Host Disease in a hematopoietic stem cell transplant recipient: the role of elafin. Leuk Lymphoma. 2018;59(9):2261–3.PubMedCrossRefPubMedCentralGoogle Scholar
  57. 57.
    Jeanmonod P, et al. Graft-versus-host disease or toxic epidermal necrolysis: diagnostic dilemma after liver transplantation. Transpl Infect Dis. 2012;14(4):422–6.PubMedCrossRefPubMedCentralGoogle Scholar
  58. 58.
    Bircher AJ, Scherer Hofmeier K. Drug hypersensitivity reactions during hematopoietic stem cell transplantation. Curr Probl Dermatol. 2012;43:150–64.PubMedCrossRefPubMedCentralGoogle Scholar
  59. 59.
    Mays SR, Kunishige JH, Truong E, Kontoyiannis DP, Hymes SR. Approach to the morbilliform eruption in the hematopoietic transplant patient. Semin Cutan Med Surg. 2007;26(3):155–62.PubMedCrossRefPubMedCentralGoogle Scholar
  60. 60.
    Byun HJ, Yang JI, Kim BK, Cho KH. Clinical differentiation of acute cutaneous graft-versus-host disease from drug hypersensitivity reactions. J Am Acad Dermatol. 2011;65(4):726–32.PubMedCrossRefGoogle Scholar
  61. 61.
    Kitamura K, et al. Relationship among human herpesvirus 6 reactivation, serum interleukin 10 levels, and rash/graft-versus-host disease after allogeneic stem cell transplantation. J Am Acad Dermatol. 2008;58(5):802–9.PubMedCrossRefGoogle Scholar
  62. 62.
    Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ, et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant. 2005;11(12):945–56.PubMedCrossRefGoogle Scholar
  63. 63.
    Creamer D, Martyn-Simmons CL, Osborne G, Kenyon M, Salisbury JR, Devereux S, et al. Eczematoid graft-vs-host disease: a novel form of chronic cutaneous graft-vs-host disease and its response to psoralen UV-A therapy. Arch Dermatol. 2007;143(9):1157–62.PubMedCrossRefGoogle Scholar
  64. 64.
    Kaffenberger BH, Zuo RC, Gru A, Plotner AN, Sweeney SA, Devine SM, et al. Graft-versus-host disease-associated angiomatosis: a clinicopathologically distinct entity. J Am Acad Dermatol. 2014;71(4):745–53.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Ropert S, Coriat R, Verret B, Perret A, Lucibello F, Chamseddine AN, et al. Colchicine is an active treatment for everolimus-induced oral ulcers. Eur J Cancer. 2017;87:209–11.PubMedCrossRefGoogle Scholar
  66. 66.
    Dermatologic principles and practice in oncology: conditions of the skin, hair, and nails in camcer patients. Hoboken. New Jersey: Wiley&Sons; 2014.Google Scholar
  67. 67.
    Ciavattini A, Clemente N. Female genital tract chronic graft-versus-host disease: review of the literature. Anticancer Res. 2015;35(1):13–7.PubMedGoogle Scholar
  68. 68.
    Dignan FL, Clark A, Amrolia P, Cornish J, Jackson G, Mahendra P, et al. Diagnosis and management of acute graft-versus-host disease. Br J Haematol. 2012;158(1):30–45.PubMedCrossRefGoogle Scholar
  69. 69.
    Harper J, Smith C, Rubins A, Green A, Jackson K, Zigure S, et al. A multicenter study of the pharmacokinetics of tacrolimus ointment after first and repeated application to children with atopic dermatitis. J Invest Dermatol. 2005;124(4):695–9.PubMedCrossRefGoogle Scholar
  70. 70.
    Rubins A, Gutmane R, Valdmane N, Stevenson P, Foster C, Undre N. Pharmacokinetics of 0.1% tacrolimus ointment after first and repeated application to adults with moderate to severe atopic dermatitis. J Invest Dermatol. 2005;125(1):68–71.PubMedCrossRefGoogle Scholar
  71. 71.
    Alaiti S, Kang S, Fiedler VC, Ellis CN, Spurlin DV, Fader D, et al. Tacrolimus (FK506) ointment for atopic dermatitis: a phase I study in adults and children. J Am Acad Dermatol. 1998;38(1):69–76.PubMedCrossRefGoogle Scholar
  72. 72.
    Undre NA, Moloney FJ, Ahmadi S, Stevenson P, Murphy GM. Skin and systemic pharmacokinetics of tacrolimus following topical application of tacrolimus ointment in adults with moderate to severe atopic dermatitis. Br J Dermatol. 2009;160(3):665–9.PubMedCrossRefGoogle Scholar
  73. 73.
    Allen A, Siegfried E, Silverman R, Williams ML, Elias PM, Szabo SK, et al. Significant absorption of topical tacrolimus in 3 patients with Netherton syndrome. Arch Dermatol. 2001;137(6):747–50.PubMedGoogle Scholar
  74. 74.
    McLellan C, O'Neil AI, Cameron M, Reed A, Henderin C, Dellavalle RP, et al. Facilitating informed treatment decisions in acne: a pilot study of a patient Decision Aid. J Cutan Med Surg. 2019;23(1):117–8.PubMedCrossRefGoogle Scholar
  75. 75.
    Jagasia M, et al. Ruxolitinib in combination with corticosteroids for the treatment of steroid-refractory acute graft-vs-host disease: results from the phase 2 REACH1 Trial. Biology of Blood and Marrow Transplantation. 2019;25(3):S52.CrossRefGoogle Scholar
  76. 76.
    Alfred A, Taylor PC, Dignan F, el-Ghariani K, Griffin J, Gennery AR, et al. The role of extracorporeal photopheresis in the management of cutaneous T-cell lymphoma, graft-versus-host disease and organ transplant rejection: a consensus statement update from the UK Photopheresis Society. Br J Haematol. 2017;177(2):287–310.PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Salem B. W.J., Jacobsohn DA, An update on the clinical utility of extracorporeal photopheresis in the treatment of graft-versus-host disease. International Journal of Clinical Transfusion Medicine. 2017;2017(5):19–28.CrossRefGoogle Scholar
  78. 78.
    Martin PJ, Rizzo JD, Wingard JR, Ballen K, Curtin PT, Cutler C, 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(8):1150–63.PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Flowers ME, Apperley JF, van Besien K, Elmaagacli A, Grigg A, Reddy V, et al. A multicenter prospective phase 2 randomized study of extracorporeal photopheresis for treatment of chronic graft-versus-host disease. Blood. 2008;112(7):2667–74.PubMedCrossRefGoogle Scholar
  80. 80.
    Dall'Amico R, Messina C. Extracorporeal photochemotherapy for the treatment of graft-versus-host disease. Ther Apher. 2002;6(4):296–304.PubMedCrossRefGoogle Scholar
  81. 81.
    Garban F, Drillat P, Makowski C, Jacob MC, Richard MJ, Favrot M, et al. Extracorporeal chemophototherapy for the treatment of graft-versus-host disease: hematologic consequences of short-term, intensive courses. Haematologica. 2005;90(8):1096–101.PubMedGoogle Scholar
  82. 82.
    Greinix HT, Knobler RM, Worel N, Schneider B, Schneeberger A, Hoecker P, et al. The effect of intensified extracorporeal photochemotherapy on long-term survival in patients with severe acute graft-versus-host disease. Haematologica. 2006;91(3):405–8.PubMedGoogle Scholar
  83. 83.
    Perfetti P, Carlier P, Strada P, Gualandi F, Occhini D, van Lint M, et al. Extracorporeal photopheresis for the treatment of steroid refractory acute GVHD. Bone Marrow Transplant. 2008;42(9):609–17.PubMedCrossRefGoogle Scholar
  84. 84.
    Alousi AM, et al. A Bayesian, phase II randomized trial of extracorporeal photopheresis (ECP) plus steroids versus steroids-alone in patients with newly diagnosed acute graft vs. host disease (GVHD): The Addition of ECP Improves Gvhd Response and the Ability to Taper Steroids. Blood. 2015;126(23):854.CrossRefGoogle Scholar
  85. 85.
    Nogueira MC, et al. Anti-tumor necrosis factor-a for the treatment of steroid-refractory acute graft-versus-host disease. Braz J Med Biol Res. 2007;40(12):1623–9.PubMedCrossRefGoogle Scholar
  86. 86.
    Couriel D, Carpenter PA, Cutler C, Bolaños-Meade J, Treister NS, Gea-Banacloche J, et al. Ancillary therapy and supportive care of chronic graft-versus-host disease: national institutes of health consensus development project on criteria for clinical trials in chronic Graft-versus-host disease: V. Ancillary Therapy and Supportive Care Working Group Report. Biol Blood Marrow Transplant. 2006;12(4):375–96.PubMedCrossRefGoogle Scholar
  87. 87.
    Patriarca F, Sperotto A, Damiani D, Morreale G, Bonifazi F, Olivieri A, et al. Infliximab treatment for steroid-refractory acute graft-versus-host disease. Haematologica. 2004;89(11):1352–9.PubMedGoogle Scholar
  88. 88.
    Kobbe G, Schneider P, Rohr U, Fenk R, Neumann F, Aivado M, et al. Treatment of severe steroid refractory acute graft-versus-host disease with infliximab, a chimeric human/mouse antiTNFalpha antibody. Bone Marrow Transplant. 2001;28(1):47–9.PubMedCrossRefGoogle Scholar
  89. 89.
    Couriel DR, Saliba R, de Lima M, Giralt S, Andersson B, Khouri I, et al. A phase III study of infliximab and corticosteroids for the initial treatment of acute graft-versus-host disease. Biol Blood Marrow Transplant. 2009;15(12):1555–62.PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Levine JE, Paczesny S, Mineishi S, Braun T, Choi SW, Hutchinson RJ, et al. Etanercept plus methylprednisolone as initial therapy for acute graft-versus-host disease. Blood. 2008;111(4):2470–5.PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Inagaki J, Kodama Y, Fukano R, Noguchi M, Okamura J. Mycophenolate mofetil for treatment of steroid-refractory acute graft-versus-host disease after pediatric hematopoietic stem cell transplantation. Pediatr Transplant. 2015;19(6):652–8.PubMedCrossRefGoogle Scholar
  92. 92.
    Hattori K, Doki N, Kurosawa S, Hino Y, Yamamoto K, Sakaguchi M, et al. Mycophenolate mofetil is effective only for involved skin in the treatment for steroid-refractory acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Ann Hematol. 2017;96(2):319–21.PubMedCrossRefGoogle Scholar
  93. 93.
    MacMillan ML, et al. Early antithymocyte globulin therapy improves survival in patients with steroid-resistant acute graft-versus-host disease. Biol Blood Marrow Transplant. 2002;8:40–6.PubMedCrossRefGoogle Scholar
  94. 94.
    McCaul KG, et al. Treatment of steroid-resistant acute graft-versus-host disease with rabbit antithymocyte globulin. J Hematother Stem Cell Res. 2000;9(3):367–74.PubMedCrossRefGoogle Scholar
  95. 95.
    Graziani F, et al. Treatment of acute graft versus host disease with low dose-alternate day anti-thymocyte globulin. Haematologica. 2002;87(9):973–8.PubMedGoogle Scholar
  96. 96.
    Nishimoto M, Nakamae H, Koh H, Nakamae M, Hirose A, Hayashi Y, et al. Response-guided therapy for steroid-refractory acute GVHD starting with very-low-dose antithymocyte globulin. Exp Hematol. 2015;43(3):177–9.PubMedCrossRefGoogle Scholar
  97. 97.
    Van Lint MT, et al. Treatment of acute graft-versus-host disease with prednisolone: significant survival advantage for day + 5 responders and no advantage for nonresponders receiving anti-thymocyte globulin. Blood. 2006;107(10):4177–81.PubMedCrossRefGoogle Scholar
  98. 98.
    Pidala J, et al. ATG prevents severe acute graft-versus-host disease in mismatched unrelated donor hematopoietic cell transplantation. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2011;17(8):1237–44.CrossRefGoogle Scholar
  99. 99.
    Elgaz S, Kuçi Z, Kuçi S, Bönig H, Bader P. Clinical use of mesenchymal stromal cells in the treatment of acute graft-versus-host disease. Transfus Med Hemother. 2019;46(1):27–34.PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Resnick IB, Barkats C, Shapira MY, Stepensky P, Bloom AI, Shimoni A, et al. Treatment of severe steroid resistant acute GVHD with mesenchymal stromal cells (MSC). Am J Blood Res. 2013;3(3):225–38.PubMedPubMedCentralGoogle Scholar
  101. 101.
    Ball LM, et al. Multiple infusions of mesenchymal stromal cells induce sustained remission in children with steroid-refractory, grade III-IV acute graft-versus-host disease. Br J Haematol. 2013;163(4):501–9.PubMedCrossRefGoogle Scholar
  102. 102.
    Kuci Z, et al. Mesenchymal stromal cells from pooled mononuclear cells of multiple bone marrow donors as rescue therapy in pediatric severe steroid-refractory graft-versus-host disease: a multicenter survey. Haematologica. 2016;101(8):985–94.PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Sanchez-Guijo F, et al. Sequential third-party mesenchymal stromal cell therapy for refractory acute graft-versus-host disease. Biol Blood Marrow Transplant. 2014;20(10):1580–5.PubMedCrossRefGoogle Scholar
  104. 104.
    Lucchini G, et al. Platelet-lysate-expanded mesenchymal stromal cells as a salvage therapy for severe resistant graft-versus-host disease in a pediatric population. Biol Blood Marrow Transplant. 2010;16(9):1293–301.PubMedCrossRefGoogle Scholar
  105. 105.
    Bader P, et al. Effective treatment of steroid and therapy-refractory acute graft-versus-host disease with a novel mesenchymal stromal cell product (MSC-FFM). Bone Marrow Transplant. 2018;53(7):852–62.PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Salmenniemi U, Itälä-Remes M, Nystedt J, Putkonen M, Niittyvuopio R, Vettenranta K, et al. Good responses but high TRM in adult patients after MSC therapy for GvHD. Bone Marrow Transplant. 2017;52(4):606–8.PubMedCrossRefGoogle Scholar
  107. 107.
    Dotoli GM, et al. Mesenchymal stromal cell infusion to treat steroid-refractory acute GvHD III/IV after hematopoietic stem cell transplantation. Bone Marrow Transplant. 2017;52(6):859–62.PubMedCrossRefGoogle Scholar
  108. 108.
    von Dalowski F, et al. Mesenchymal stromal cells for treatment of acute steroid-refractory graft versus host disease: clinical responses and long-term outcome. Stem Cells. 2016;34(2):357–66.CrossRefGoogle Scholar
  109. 109.
    Perez-Simon JA, et al. Mesenchymal stem cells expanded in vitro with human serum for the treatment of acute and chronic graft-versus-host disease: results of a phase I/II clinical trial. Haematologica. 2011;96(7):1072–6.PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Holtan SG, Verneris MR, Schultz KR, Newell LF, Meyers G, He F, et al. Circulating angiogenic factors associated with response and survival in patients with acute graft-versus-host disease: results from Blood and Marrow Transplant Clinical Trials Network 0302 and 0802. Biol Blood Marrow Transplant. 2015;21(6):1029–36.PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Holtan SG, et al. Facilitating resolution of life-threatening acute graft-versus-host disease by supplementation of human chorionic gonadotropin and epidermal growth factor (Pregnyl®): A Phase I Study. Biology of Blood and Marrow Transplantation. 2019;25(3, Supplement):S240–1.CrossRefGoogle Scholar
  112. 112.
    Benito AI, et al. Sirolimus (rapamycin) for the treatment of steroid-refractory acute graft-versus-host disease. Transplantation. 2001;72(12):1924–9.PubMedCrossRefGoogle Scholar
  113. 113.
    Tawara I, Sun Y, Lewis EC, Toubai T, Evers R, Nieves E, et al. Alpha-1-antitrypsin monotherapy reduces graft-versus-host disease after experimental allogeneic bone marrow transplantation. Proc Natl Acad Sci U S A. 2012;109(2):564–9.PubMedCrossRefGoogle Scholar
  114. 114.
    Magenau JM, Goldstein SC, Peltier D, Soiffer RJ, Braun T, Pawarode A, et al. alpha1-Antitrypsin infusion for treatment of steroid-resistant acute graft-versus-host disease. Blood. 2018;131(12):1372–9.PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Bolanos-Meade J, et al. Pentostatin in steroid-refractory acute graft-versus-host disease. J Clin Oncol. 2005;23(12):2661–8.PubMedCrossRefGoogle Scholar
  116. 116.
    Poi MJ, Hofmeister CC, Johnston JS, Edwards RB, Jansak BS, Lucas DM, 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(8):705–12.PubMedPubMedCentralCrossRefGoogle Scholar
  117. 117.
    Flowers ME, Martin PJ. How we treat chronic graft-versus-host disease. Blood. 2015;125(4):606–15.PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Miklos D, et al. Ibrutinib for chronic graft-versus-host disease after failure of prior therapy. Blood. 2017;130(21):2243–50.PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    • Waller EK, et al. Ibrutinib for chronic graft-versus-host disease after failure of prior therapy: 1-year update of a phase 1b/2 study. Biol Blood Marrow Transplant. 2019;25(10):2002–7 This reference provides extended follow-up results of patients in the phase 1b/2 open label study examining the activity and safety of ibrutinib in patients with active chronic GVHD who were steroid-dependent or steroid-refractory. PubMedCrossRefGoogle Scholar
  120. 120.
    Dubovsky JA, et al. Ibrutinib treatment ameliorates murine chronic graft-versus-host disease. J Clin Invest. 2014;124(11):4867–76.PubMedPubMedCentralCrossRefGoogle Scholar
  121. 121.
    Shatzel JJ, Olson SR, Tao DL, McCarty O, Danilov AV, DeLoughery T. Ibrutinib-associated bleeding: pathogenesis, management and risk reduction strategies. J Thromb Haemost. 2017;15(5):835–47.PubMedPubMedCentralCrossRefGoogle Scholar
  122. 122.
    Parra CE, et al. Association of Ibrutinib treatment with bleeding complications in cutaneous surgery. JAMA Dermatol. 2017;153(10):1069–70.PubMedCrossRefGoogle Scholar
  123. 123.
    Richet C, Huynh A, Dimeglio C, Borel C, Lepage B, Boulinguez S, et al. Extracorporeal photopheresis: an efficacious and well-tolerated treatment for cutaneous and oral mucosal chronic graft-versus-host disease. Dermatology. 2018;234(1-2):23–30.PubMedCrossRefGoogle Scholar
  124. 124.
    Pierelli L, 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(10):2340–52.PubMedGoogle Scholar
  125. 125.
    Zeiser R, Burchert A, Lengerke C, Verbeek M, Maas-Bauer K, Metzelder SK, et al. Ruxolitinib in corticosteroid-refractory graft-versus-host disease after allogeneic stem cell transplantation: a multicenter survey. Leukemia. 2015;29(10):2062–8.PubMedPubMedCentralCrossRefGoogle Scholar
  126. 126.
    Iida M, et al. Mycophenolate mofetil use after unrelated hematopoietic stem cell transplantation for prophylaxis and treatment of graft-vs.-host disease in adult patients in Japan. Clin Transpl. 2014;28(9):980–9.CrossRefGoogle Scholar
  127. 127.
    Baudard M, Vincent A, Moreau P, Kergueris MF, Harousseau JL, Milpied N. Mycophenolate mofetil for the treatment of acute and chronic GVHD is effective and well tolerated but induces a high risk of infectious complications: a series of 21 BM or PBSC transplant patients. Bone Marrow Transplant. 2002;30(5):287–95.PubMedCrossRefGoogle Scholar
  128. 128.
    Bates JS, Engemann AM, Hammond JM. Clinical utility of rituximab in chronic graft-versus-host disease. Ann Pharmacother. 2009;43(2):316–21.PubMedCrossRefGoogle Scholar
  129. 129.
    Wang Y, et al. First-line therapy for chronic graft-versus-host disease that includes low-dose methotrexate is associated with a high response rate. Biol Blood Marrow Transplant. 2009;15(4):505–11.PubMedCrossRefGoogle Scholar
  130. 130.
    Jacobsohn DA, Chen AR, Zahurak M, Piantadosi S, Anders V, Bolaños-Meade J, et al. Phase II study of pentostatin in patients with corticosteroid-refractory chronic graft-versus-host disease. J Clin Oncol. 2007;25(27):4255–61.PubMedCrossRefGoogle Scholar
  131. 131.
    Couriel DR, et al. Sirolimus in combination with tacrolimus and corticosteroids for the treatment of resistant chronic graft-versus-host disease. Br J Haematol. 2005;130(3):409–17.PubMedCrossRefGoogle Scholar
  132. 132.
    Olivieri A, et al. Long-term outcome and prospective validation of NIH response criteria in 39 patients receiving imatinib for steroid-refractory chronic GVHD. Blood. 2013;122(25):4111–8.PubMedCrossRefGoogle Scholar
  133. 133.
    Baird K, Comis LE, Joe GO, Steinberg SM, Hakim FT, Rose JJ, et al. Imatinib mesylate for the treatment of steroid-refractory sclerotic-type cutaneous chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2015;21(6):1083–90.PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    Koreth J, Kim HT, Jones KT, Lange PB, Reynolds CG, Chammas MJ, et al. Efficacy, durability, and response predictors of low-dose interleukin-2 therapy for chronic graft-versus-host disease. Blood. 2016;128(1):130–7.PubMedPubMedCentralCrossRefGoogle Scholar
  135. 135.
    Gilman AL, et al. Hydroxychloroquine for the treatment of chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2000;6(3A):327–34.PubMedCrossRefPubMedCentralGoogle Scholar
  136. 136.
    Flynn R, Paz K, du J, Reichenbach DK, Taylor PA, Panoskaltsis-Mortari A, et al. Targeted Rho-associated kinase 2 inhibition suppresses murine and human chronic GVHD through a Stat3-dependent mechanism. Blood. 2016;127(17):2144–54.PubMedPubMedCentralCrossRefGoogle Scholar
  137. 137.
    Jagasia, M., KD025-208: A phase 2a study of KD025 for patients with chronic graft versus host disease (cGVHD)—pharmacodynamics and updated results. Abstract #36., in 2019 TCT Transplantation and Cellular Therapy Meetings of ASBMT and CIBMTR. 2019: Houston, Texas, USA. ; Available from: http://investors.kadmon.com/recent-press-releases/2018/10-17-2018-140348118. Accessed 9 Oct 2019.
  138. 138.
    Powers JG, et al. Wound healing and treating wounds: chronic wound care and management. J Am Acad Dermatol. 2016;74(4):607–25 quiz 625-6.PubMedCrossRefPubMedCentralGoogle Scholar
  139. 139.
    Giuggioli D, Manfredi A, Lumetti F, Colaci M, Ferri C. Scleroderma skin ulcers definition, classification and treatment strategies our experience and review of the literature. Autoimmun Rev. 2018;17(2):155–64.PubMedCrossRefGoogle Scholar
  140. 140.
    Jones JE, Nelson EA, Al-Hity A. Skin grafting for venous leg ulcers. Cochrane Database Syst Rev. 2013;1:CD001737.Google Scholar
  141. 141.
    Falabella AF, Carson P, Eaglstein WH, Falanga V. The safety and efficacy of a proteolytic ointment in the treatment of chronic ulcers of the lower extremity. J Am Acad Dermatol. 1998;39(5 Pt 1):737–40.PubMedCrossRefPubMedCentralGoogle Scholar
  142. 142.
    Lamby P, et al. Allogeneic donor split skin grafts for treatment of refractory ulcers in cutaneous chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation-a retrospective analysis on seven patients. Ann Hematol. 2019;98(8):1867–75.PubMedCrossRefGoogle Scholar
  143. 143.
    Crocchiolo R, Nicolini FE, Sobh M, Ducastelle-Lepretre S, Labussiere H, Dubois V, et al. Treatment of a severe extensive cutaneous chronic GVHD after allo-HSCT using glycerolyzed skin allografts and cultured epidermis from the same donor. Bone Marrow Transplant. 2011;46(8):1153–5.PubMedCrossRefGoogle Scholar
  144. 144.
    Elsaadany BA, Ahmed EM, Aghbary SMH. Efficacy and safety of topical corticosteroids for management of oral chronic graft versus host disease. Int J Dent. 2017;2017:1908768.PubMedPubMedCentralGoogle Scholar
  145. 145.
    Zadik Y, Elad S, Shapira A, Shapira MY. Treatment of oral mucosal manifestations of chronic graft-versus-host disease: dexamethasone vs. budesonide. Expert Opin Pharmacother. 2017;18(3):235–42.PubMedCrossRefGoogle Scholar
  146. 146.
    Kuten-Shorrer M, Woo SB, Treister NS. Oral graft-versus-host disease. Dent Clin N Am. 2014;58(2):351–68.PubMedCrossRefGoogle Scholar
  147. 147.
    Spiryda LB, Laufer MR, Soiffer RJ, Antin JA. Graft-versus-host disease of the vulva and/or vagina: diagnosis and treatment. Biol Blood Marrow Transplant. 2003;9(12):760–5.PubMedCrossRefGoogle Scholar
  148. 148.
    Wolff H, Fischer TW, Blume-Peytavi U. The diagnosis and treatment of hair and scalp diseases. Dtsch Arztebl Int. 2016;113(21):377–86.PubMedPubMedCentralGoogle Scholar
  149. 149.
    Marks DH, et al. Graft-versus-host disease with acute hair loss: a distinctive manifestation of chronic graft-versus-host disease. J Am Acad Dermatol. 2016;74(5):AB135.Google Scholar
  150. 150.
    Ekelem C, Pham C, Atanaskova Mesinkovska N. A systematic review of the outcome of hair transplantation in primary scarring alopecia. Skin Appendage Disord. 2019;5(2):65–71.PubMedCrossRefGoogle Scholar
  151. 151.
    McClanahan DR, English JC 3rd. Therapeutics for adult nail psoriasis and nail lichen planus: a guide for clinicians. Am J Clin Dermatol. 2018;19(4):559–84.PubMedCrossRefGoogle Scholar
  152. 152.
    Ballester-Sanchez R, et al. The role of phototherapy in cutaneous chronic graft-vs-host disease: a retrospective study and review of the literature. Actas Dermosifiliogr. 2015;106(8):651–7.PubMedCrossRefGoogle Scholar
  153. 153.
    Herzinger T, et al. S1-Guidelines on UV phototherapy and photochemotherapy. J Dtsch Dermatol Ges. 2016;14(8):853–76.PubMedCrossRefPubMedCentralGoogle Scholar
  154. 154.
    Pereira MP, Stander S. Novel drugs for the treatment of chronic pruritus. Expert Opin Investig Drugs. 2018;27(12):981–8.PubMedCrossRefPubMedCentralGoogle Scholar
  155. 155.
    Omland SH, Gniadecki R, Hædersdal M, Helweg-Larsen J, Omland LH. Skin cancer risk in hematopoietic stem-cell transplant recipients compared with background population and renal transplant recipients: a population-based cohort study. JAMA Dermatol. 2016;152(2):177–83.PubMedCrossRefPubMedCentralGoogle Scholar
  156. 156.
    Rizzo JD, Curtis RE, Socié G, Sobocinski KA, Gilbert E, Landgren O, et al. Solid cancers after allogeneic hematopoietic cell transplantation. Blood. 2009;113(5):1175–83.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Toral S. Vaidya
    • 1
  • Christian Menzer
    • 1
  • Doris M. Ponce
    • 2
    • 3
  • Alina Markova
    • 1
    • 4
    Email author
  1. 1.Dermatology Service, Department of MedicineMemorial Sloan Kettering Cancer CenterNew YorkUSA
  2. 2.Adult Bone Marrow Transplantation Service, Department of MedicineMemorial Sloan Kettering Cancer CenterNew YorkUSA
  3. 3.Department of MedicineWeill Cornell Medical CollegeNew YorkUSA
  4. 4.Department of DermatologyWeill Cornell Medical CollegeNew YorkUSA

Personalised recommendations