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Retrospective single center analysis of outcome, risk factors and therapy in steroid refractory graft-versus-host disease after allogeneic hematopoietic cell transplantation

Abstract

Acute and chronic graft-vs.-host disease (aGvHD and cGvHD) are major complications after allogeneic hematopoietic cell transplantation (HCT) leading to substantial morbidity and mortality. This retrospective single-center study analyzes incidence, therapy, and outcome of GvHD in n = 721 patients ≥18 years having received allogeneic HCT 2004–2013 with a special focus on steroid refractory GvHD. Acute (n = 355/49.2%) and chronic (n = 269/37.3%) GvHD were mainly treated by steroids in first-line therapy. The proportion of steroid refractory aGvHD and cGvHD was 35.7% and 31.4%, respectively. As there is no standard therapy for steroid refractory GvHD, a range of different agents was used. In aGvHD, the overall response rate (ORR) of steroid refractory GvHD to second-line treatment was 27.4%. Mycophenolate mofetil (MMF) and mTOR inhibitors led to superior response rates (ORR 50.0% and 53.3%, respectively). In steroid refractory cGvHD therapy, ORR was 44.4%. Use of calcineurin inhibitors (CNI; n = 11/45.5%), MMF (n = 18/50.0%), mTOR inhibitors (n = 10/60.0%), and extracorporeal photophoresis (ECP; n = 16/56.3%) showed ORR above average. Targeted therapies lead to responses in 7.7% (n = 13). This data may help to improve the design of future prospective clinical studies in GvHD.

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References

  1. 1.

    Jagasia M, Arora M, Flowers ME, Chao NJ, McCarthy PL, Cutler CS, et al. Risk factors for acute GVHD and survival after hematopoietic cell transplantation. Blood. 2012;119:296–307.

  2. 2.

    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 Transpl. 2015;21:266–74.

  3. 3.

    Reddy P. Pathophysiology of acute graft-versus-host disease. Hematol Oncol. 2003;21:149–61.

  4. 4.

    Przepiorka D, Weisdorf D, Martin P, Klingemann H-G, Beatty P, Hows J, et al. Consensus conference on acute GVHD grading. Bone Marrow Transplant. 1995;15:825–8.

  5. 5.

    Jagasia MH, Greinix HT, Arora M, Williams KM, Wolff D, Cowen EW, 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 Transpl. 2015;21:389–401 e1.

  6. 6.

    Mirza N, Zierhut M, Korn A, Bornemann A, Vogel W, Schmid-Horch B, et al. Graft versus self (GvS) against T-cell autoantigens is a mechanism of graft-host interaction. Proc Natl Acad Sci USA. 2016;113:13827–32.

  7. 7.

    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;48:1359–61.

  8. 8.

    Mohty B, Mohty M. Long-term complications and side effects after allogeneic hematopoietic stem cell transplantation: an update. Blood Cancer J. 2011;1:e16.

  9. 9.

    Ruutu T, Gratwohl A, de Witte T, Afanasyev B, Apperley J, Bacigalupo A, et al. Prophylaxis and treatment of GVHD: EBMT-ELN working group recommendations for a standardized practice. Bone Marrow Transplant. 2014;49:168–73.

  10. 10.

    Calmettes C, Vigouroux S, Labopin M, Tabrizi R, Turlure P, Lafarge X, et al. Risk factors for steroid-refractory acute graft-versus-host disease after allogeneic stem cell transplantation from matched related or unrelated donors. Biol Blood Marrow Transplant. 2015;21:860–5.

  11. 11.

    Martin PJ, Storer BE, Rowley SD, Flowers ME, Lee SJ, Carpenter PA, et al. Evaluation of mycophenolate mofetil for initial treatment of chronic graft-versus-host disease. Blood. 2009;113:5074–82.

  12. 12.

    Stewart BL, Storer B, Storek J, Deeg HJ, Storb R, Hansen JA, et al. Duration of immunosuppressive treatment for chronic graft-versus-host disease. Blood. 2004;104:3501–6.

  13. 13.

    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;157:732–41.

  14. 14.

    Pavletic SZ, Fowler DH. Are we making progress in GVHD prophylaxis and treatment? Hematol Am Soc Hematol Educ Program. 2012;2012:251–64.

  15. 15.

    Wolff D, Schleuning M, von Harsdorf S, Bacher U, Gerbitz A, Stadler M, et al. Consensus Conference on Clinical Practice in Chronic GVHD: second-line treatment of chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2011;17:1–17.

  16. 16.

    Human D. Declaration of Helsinki. Lancet. 1999;353:1888.

  17. 17.

    Bacigalupo A, Ballen K, Rizzo D, Giralt S, Lazarus H, Ho V, et al. Defining the intensity of conditioning regimens: working definitions. Biol Blood Marrow Transpl. 2009;15:1628–33.

  18. 18.

    Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1958;53:457–81.

  19. 19.

    Scrucca L, Santucci A, Aversa F. Competing risk analysis using R: an easy guide for clinicians. Bone Marrow Transpl. 2007;40:381–7.

  20. 20.

    Labopin M, Latouche A, Suciu S, Santucci A, Canals C, Iacobelli S, et al. Definitions and evaluation of endpoints following stem cells transplantation - recommendation from the European group for Blood and Marrow transplantation (EBMT) 2009. https://portal.ebmt.org/sites/clint2/clint/Documents/Statistical%20Endpoints_CLINT%20Project_final%20version.pdf

  21. 21.

    Cox DR. Regression models and life tabels. J R Stat Soc Ser B (Methodol). 1972;34:187–220.

  22. 22.

    Storb R, Gyurkocza B, Storer BE, Sorror ML, Blume K, Niederwieser D, et al. Graft-versus-host disease and graft-versus-tumor effects after allogeneic hematopoietic cell transplantation. J Clin Oncol. 2013;31:1530–8.

  23. 23.

    Finke J, Bethge WA, Schmoor C, Ottinger HD, Stelljes M, Zander AR, et al. Standard graft-versus-host disease prophylaxis with or without anti-T-cell globulin in haematopoietic cell transplantation from matched unrelated donors: a randomised, open-label, multicentre phase 3 trial. Lancet Oncol. 2009;10:855–64.

  24. 24.

    Flowers ME, Inamoto Y, Carpenter PA, Lee SJ, Kiem HP, Petersdorf EW, et al. Comparative analysis of risk factors for acute graft-versus-host disease and for chronic graft-versus-host disease according to National Institutes of Health consensus criteria. Blood. 2011;117:3214–9.

  25. 25.

    Kroger N, Solano C, Wolschke C, Bandini G, Patriarca F, Pini M, et al. Antilymphocyte globulin for prevention of chronic graft-versus-host disease. N Engl J Med. 2016;374:43–53.

  26. 26.

    Federmann B, Faul C, Meisner C, Vogel W, Kanz L, Bethge WA. Influence of age on outcome after allogeneic hematopoietic cell transplantation: a single center study in patients aged 60. Bone Marrow Transplant. 2015;50:427–31.

  27. 27.

    Haen SP, Pham M, Faul C, Dorfel D, Vogel W, Kanz L, et al. Allogeneic hematopoietic cell transplantation in patients 70 years: which patients may benefit? Blood Cancer J. 2016;6:e443.

  28. 28.

    Haen SP, Groh C, Schumm M, Backert L, Loffler MW, Federmann B, et al. Haploidentical hematopoietic cell transplantation using in vitro T cell depleted grafts as salvage therapy in patients with disease relapse after prior allogeneic transplantation. Ann Hematol. 2017;96:817–27.

  29. 29.

    Schneidawind C, Hagmaier V, Faul C, Kanz L, Bethge W, Schneidawind D. Second allogeneic hematopoietic cell transplantation enables long-term disease-free survival in relapsed acute leukemia. Ann Hematol. 2018;97:2491–2500.

  30. 30.

    Couriel DR, Saliba RM, Giralt S, Khouri I, Andersson B, de Lima M, et al. Acute and chronic graft-versus-host disease after ablative and nonmyeloablative conditioning for allogeneic hematopoietic transplantation. Biol Blood Marrow Transplant. 2004;10:178–85.

  31. 31.

    Perez-Simon JA, Diez-Campelo M, Martino R, Brunet S, Urbano A, Caballero MD, et al. Influence of the intensity of the conditioning regimen on the characteristics of acute and chronic graft-versus-host disease after allogeneic transplantation. Br J Haematol. 2005;130:394–403.

  32. 32.

    Lee SJ, Klein J, Haagenson M, Baxter-Lowe LA, Confer DL, Eapen M, et al. High-resolution donor-recipient HLA matching contributes to the success of unrelated donor marrow transplantation. Blood. 2007;110:4576–83.

  33. 33.

    Alousi AM, Weisdorf DJ, Logan BR, Bolanos-Meade J, Carter S, Difronzo N, 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.

  34. 34.

    Bolanos-Meade J, Logan BR, Alousi AM, Antin JH, Barowski K, Carter SL, et al. Phase 3 clinical trial of steroids/mycophenolate mofetil vs steroids/placebo as therapy for acute GVHD: BMT CTN 0802. Blood. 2014;124:3221–7. quiz 3335

  35. 35.

    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 Transpl. 2009;15:1555–62.

  36. 36.

    Wang Y, Xu LP, Liu KY, Liu DH, Wang J, Chen H, et al. Low-dose MTX combined with low-dose methylprednisolone as a first-line therapy for the treatment of acute GVHD: safety and feasibility. Bone Marrow Transpl. 2011;46:892–8.

  37. 37.

    Arora M, Burns LJ, Davies SM, Macmillan ML, Defor TE, Miller WJ, et al. Chronic graft-versus-host disease: a prospective cohort study. Biol Blood Marrow Transpl. 2003;9:38–45.

  38. 38.

    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;88:1131–6.

  39. 39.

    Castilla-Llorente C, Martin PJ, McDonald GB, Storer BE, Appelbaum FR, Deeg HJ, et al. Prognostic factors and outcomes of severe gastrointestinal GVHD after allogeneic hematopoietic cell transplantation. Bone Marrow Transplant. 2014;49:966–71.

  40. 40.

    Kanamaru A, Takemoto Y, Kakishita E, Dohy H, Kodera Y, Moriyama Y, et al. FK506 treatment of graft-versus-host disease developing or exacerbating during prophylaxis and therapy with cyclosporin and/or other immunosuppressants. Japanese FK506 BMT Study Group. Bone Marrow Transplant. 1995;15:885–9.

  41. 41.

    Furlong T, Martin P, Flowers ME, Carnevale-Schianca F, Yatscoff R, Chauncey T, et al. Therapy with mycophenolate mofetil for refractory acute and chronic GVHD. Bone Marrow Transplant. 2009;44:739–48.

  42. 42.

    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;30:287–95.

  43. 43.

    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;18:406–13.

  44. 44.

    Ghez D, Rubio MT, Maillard N, Suarez F, Chandesris MO, Delarue R, et al. Rapamycin for refractory acute graft-versus-host disease. Transplantation. 2009;88:1081–7.

  45. 45.

    Hoda D, Pidala J, Salgado-Vila N, Kim J, Perkins J, Bookout R, et al. Sirolimus for treatment of steroid-refractory acute graft-versus-host disease. Bone Marrow Transplant. 2010;45:1347–51.

  46. 46.

    Benito AI, Furlong T, Martin PJ, Anasetti C, Appelbaum FR, Doney K, et al. Sirolimus (rapamycin) for the treatment of steroid-refractory acute graft-versus-host disease. Transplantation. 2001;72:1924–9.

  47. 47.

    Pierelli L, Perseghin P, Marchetti M, Messina C, Perotti C, Mazzoni A, 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;53:2340–52.

  48. 48.

    Greinix HT, Volc-Platzer B, Kalhs P, Fischer G, Rosenmayr A, Keil F, et al. Extracorporeal photochemotherapy in the treatment of severe steroid-refractory acute graft-versus-host disease: a pilot study. Blood. 2000;96:2426–31.

  49. 49.

    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;91:405–8.

  50. 50.

    Merlin E, Paillard C, Rochette E, David A, Isfan F, Dore E, et al. Extracorporeal photochemotherapy as second- or first-line therapy of acute GVHD? Bone Marrow Transplant. 2010;45:963–5.

  51. 51.

    Pidala J, Kim J, Roman-Diaz J, Shapiro J, Nishihori T, Bookout R, et al. Pentostatin as rescue therapy for glucocorticoid-refractory acute and chronic graft-versus-host disease. Ann Transplant. 2010;15:21–9.

  52. 52.

    Schmitt T, Luft T, Hegenbart U, Tran TH, Ho AD, Dreger P. Pentostatin for treatment of steroid-refractory acute GVHD: a retrospective single-center analysis. Bone Marrow Transplant. 2011;46:580–5.

  53. 53.

    Przepiorka D, Kernan NA, Ippoliti C, Papadopoulos EB, Giralt S, Khouri I, et al. Daclizumab, a humanized anti-interleukin-2 receptor alpha chain antibody, for treatment of acute graft-versus-host disease. Blood. 2000;95:83–9.

  54. 54.

    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;40:481–6.

  55. 55.

    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;135:382–5.

  56. 56.

    Schmidt-Hieber M, Fietz T, Knauf W, Uharek L, Hopfenmuller W, Thiel E, et al. Efficacy of the interleukin-2 receptor antagonist basiliximab in steroid-refractory acute graft-versus-host disease. Br J Haematol. 2005;130:568–74.

  57. 57.

    Chakupurakal G, Garcia-Marquez MA, Shimabukuro-Vornhagen A, Theurich S, Holtick U, Hallek M, et al. Immunological effects in patients with steroid refractory GvHD following treatment with Basiliximab, a CD25 monoclonal antibody. Eur J Haematol. 2016;97:121–7.

  58. 58.

    Massenkeil G, Rackwitz S, Genvresse I, Rosen O, Dorken B, Arnold R. Basiliximab is well tolerated and effective in the treatment of steroid-refractory acute graft-versus-host disease after allogeneic stem cell transplantation. Bone Marrow Transplant. 2002;30:899–903.

  59. 59.

    Chen X, Wang C, Yin J, Xu J, Wei J, Zhang Y. Efficacy of mesenchymal stem cell therapy for steroid-refractory acute graft-versus-host disease following allogeneic hematopoietic stem cell transplantation: a systematic review and meta-analysis. PLoS ONE. 2015;10:e0136991.

  60. 60.

    Tzakis AG, Abu-Elmagd K, Fung JJ, Bloom EJ, Nour B, Greif F, et al. FK 506 rescue in chronic graft-versus-host-disease after bone marrow transplantation. Transplant Proc. 1991;23:3225–7.

  61. 61.

    Krejci M, Doubek M, Buchler T, Brychtova Y, Vorlicek J, Mayer J. Mycophenolate mofetil for the treatment of acute and chronic steroid-refractory graft-versus-host disease. Ann Hematol. 2005;84:681–5.

  62. 62.

    Lopez F, Parker P, Nademanee A, Rodriguez R, Al-Kadhimi Z, Bhatia R, et al. Efficacy of mycophenolate mofetil in the treatment of chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2005;11:307–13.

  63. 63.

    Couriel DR, Saliba R, Escalon MP, Hsu Y, Ghosh S, Ippoliti C, et al. Sirolimus in combination with tacrolimus and corticosteroids for the treatment of resistant chronic graft-versus-host disease. Br J Haematol. 2005;130:409–17.

  64. 64.

    Abouelnasr A, Roy J, Cohen S, Kiss T, Lachance S. Defining the role of sirolimus in the management of graft-versus-host disease: from prophylaxis to treatment. Biol Blood Marrow Transplant. 2013;19:12–21.

  65. 65.

    Malik MI, Litzow M, Hogan W, Patnaik M, Murad MH, Prokop LJ, et al. Extracorporeal photopheresis for chronic graft-versus-host disease: a systematic review and meta-analysis. Blood Res. 2014;49:100–6.

  66. 66.

    de Waure C, Capri S, Veneziano MA, Specchia ML, Cadeddu C, Di Nardo F, et al. Extracorporeal photopheresis for second-line treatment of chronic graft-versus-host diseases: results from a health technology assessment in Italy. Value Health. 2015;18:457–66.

  67. 67.

    Kharfan-Dabaja MA, Mhaskar AR, Djulbegovic B, Cutler C, Mohty M, Kumar A. Efficacy of rituximab in the setting of steroid-refractory chronic graft-versus-host disease: a systematic review and meta-analysis. Biol Blood Marrow Transplant. 2009;15:1005–13.

  68. 68.

    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;29:2062–8.

  69. 69.

    Jagasia M, Zeiser R, Arbushites M, Delaite P, Gadbaw B, Bubnoff NV. Ruxolitinib for the treatment of patients with steroid-refractory GVHD: an introduction to the REACH trials. Immunotherapy. 2018;10:391–402.

  70. 70.

    Miklos D, Cutler CS, Arora M, Waller EK, Jagasia M, Pusic I, et al. Ibrutinib for chronic graft-versus-host disease after failure of prior therapy. Blood. 2017;130:2243–50.

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Acknowledgements

We thank Diana Kilian for maintaining our HCT database and the nurses and staff of the transplantation ward and outpatient clinic.

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Correspondence to W. A. Bethge.

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