Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Ruxolitinib–ECP combination treatment for refractory severe chronic graft-versus-host disease

Bone Marrow Transplantation volume 56, pages 909–916 (2021)Cite this article

Subjects

Abstract

Glucocorticoid-refractory (SR) chronic (c) graft-versus-host disease (GVHD) is a multisystem immunological disease and the leading cause of non-relapse mortality (NRM) in patients surviving longer than 2 years after allogeneic hematopoietic cell transplantation. Both ruxolitinib (RUX) and extracorporeal photopheresis (ECP) have shown activity for SR-cGVHD which motivated us to treat refractory cGHVD patients with the RUX–ECP combination. In this retrospective survey, 23 patients received RUX–ECP as salvage therapy for SR-cGVHD. The best response (CR or PR) at any time point during treatment was 74% (17/23) including 9% (2/23) CR and 65% (15/23) PR. The 24-months-survival was 75% (CI 56.0–94.1). Newly diagnosed cytopenia occurred in 22% (5/23) and CMV reactivation was observed in 26% (6/23) of the patients. Serum levels of soluble interleukin-2 receptor (sIL-2R) correlated with response. Our retrospective analysis shows that the RUX–ECP combination is safe and has activity in a fraction of patients with SR-cGVHD, which needs validation in a prospective trial.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: The combination of ruxolitinib and ECP improves symptoms in patients with SR-cGVHD.

Similar content being viewed by others

References

  1. Kröger 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. https://doi.org/10.1056/NEJMoa1506002.

    Article  CAS  PubMed  Google Scholar 

  2. Arai S, Jagasia M, Storer B, Chai X, Pidala J, Cutler C, et al. Global and organ-specific chronic graft-versus-host disease severity according to the 2005 NIH Consensus Criteria. Blood. 2011;118:4242–9. https://doi.org/10.1182/blood-2011-03-344390.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Fraser CJ, Bhatia S, Ness K, Carter A, Francisco L, Arora M, et al. Impact of chronic graft-versus-host disease on the health status of hematopoietic cell transplantation survivors: a report from the Bone Marrow Transplant Survivor Study. Blood. 2006;108:2867–73. https://doi.org/10.1182/blood-2006-02-003954.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Pidala J, Kurland B, Chai X, Majhail N, Weisdorf DJ, Pavletic S, et al. Patient-reported quality of life is associated with severity of chronic graft-versus-host disease as measured by NIH criteria: report on baseline data from the Chronic GVHD Consortium. Blood. 2011;117:4651–7. https://doi.org/10.1182/blood-2010-11-319509.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 Transplant 2015;21:389–401. https://doi.org/10.1016/j.bbmt.2014.12.001.

    Article  PubMed  Google Scholar 

  6. Lee SJ, Klein JP, Barrett AJ, Ringden O, Antin JH, Cahn J-Y, et al. Severity of chronic graft-versus-host disease: association with treatment-related mortality and relapse. Blood. 2002;100:406–14. https://doi.org/10.1182/blood.v100.2.406.

    Article  CAS  PubMed  Google Scholar 

  7. 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. https://doi.org/10.1182/blood-2017-07-793786.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. 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. https://doi.org/10.1038/leu.2015.212.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Zeiser R, Bubnoff N, von, Butler J, Mohty M, Niederwieser D, Or R, et al. Ruxolitinib for glucocorticoid-refractory acute graft-versus-host disease. N Engl J Med. 2020;382:1800–10. https://doi.org/10.1056/NEJMoa1917635.

    Article  PubMed  Google Scholar 

  10. Modemann F, Ayuk F, Wolschke C, Christopeit M, Janson D, von Pein U-M, et al. Ruxolitinib plus extracorporeal photopheresis (ECP) for steroid refractory acute graft-versus-host disease of lower GI-tract after allogeneic stem cell transplantation leads to increased regulatory T cell level. Bone Marrow Transplant. 2020. https://doi.org/10.1038/s41409-020-0952-z.

  11. Spoerl S, Mathew NR, Bscheider M, Schmitt-Graeff A, Chen S, Mueller T, et al. Activity of therapeutic JAK 1/2 blockade in graft-versus-host disease. Blood. 2014;123:3832–42. https://doi.org/10.1182/blood-2013-12-543736.

    Article  CAS  PubMed  Google Scholar 

  12. Nicholson SE, Oates AC, Harpur AG, Ziemiecki A, Wilks AF, Layton JE. Tyrosine kinase JAK1 is associated with the granulocyte-colony-stimulating factor receptor and both become tyrosine-phosphorylated after receptor activation. Proc Natl Acad Sci USA. 1994;91:2985–8. https://doi.org/10.1073/pnas.91.8.2985.

    Article  CAS  PubMed  Google Scholar 

  13. Heine A, Held SAE, Daecke SN, Wallner S, Yajnanarayana SP, Kurts C, et al. The JAK-inhibitor ruxolitinib impairs dendritic cell function in vitro and in vivo. Blood. 2013;122:1192–202. https://doi.org/10.1182/blood-2013-03-484642.

    Article  CAS  PubMed  Google Scholar 

  14. Schwab L, Goroncy L, Palaniyandi S, Gautam S, Triantafyllopoulou A, Mocsai A, et al. Neutrophil granulocytes recruited upon translocation of intestinal bacteria enhance graft-versus-host disease via tissue damage. Nat Med. 2014;20:648–54. https://doi.org/10.1038/nm.3517.

    Article  CAS  PubMed  Google Scholar 

  15. Giroux M, Delisle J-S, Gauthier S-D, Heinonen KM, Hinsinger J, Houde B, et al. SMAD3 prevents graft-versus-host disease by restraining Th1 differentiation and granulocyte-mediated tissue damage. Blood. 2011;117:1734–44. https://doi.org/10.1182/blood-2010-05-287649.

    Article  CAS  PubMed  Google Scholar 

  16. Flowers MED, 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;112:2667–74. https://doi.org/10.1182/blood-2008-03-141481.

    Article  CAS  PubMed  Google Scholar 

  17. Jagasia M, Scheid C, Socié G, Ayuk FA, Tischer J, Donato ML, et al. Randomized controlled study of ECP with methoxsalen as first-line treatment of patients with moderate to severe cGVHD. Blood Adv. 2019;3:2218–29. https://doi.org/10.1182/bloodadvances.2019000145.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Gatza E, Rogers CE, Clouthier SG, Lowler KP, Tawara I, Liu C, et al. Extracorporeal photopheresis reverses experimental graft-versus-host disease through regulatory T cells. Blood. 2008;112:1515–21. https://doi.org/10.1182/blood-2007-11-125542.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Biagi E, Di Biaso I, Leoni V, Gaipa G, Rossi V, Bugarin C, et al. Extracorporeal photochemotherapy is accompanied by increasing levels of circulating CD4+CD25+GITR+Foxp3+CD62L+ functional regulatory T-cells in patients with graft-versus-host disease. Transplantation. 2007;84:31–9. https://doi.org/10.1097/01.tp.0000267785.52567.9c.

    Article  CAS  PubMed  Google Scholar 

  20. Di Biaso I, Di Maio L, Bugarin C, Gaipa G, Dander E, Balduzzi A, et al. Regulatory T cells and extracorporeal photochemotherapy: correlation with clinical response and decreased frequency of proinflammatory T cells. Transplantation. 2009;87:1422–5. https://doi.org/10.1097/TP.0b013e3181a27a5d.

    Article  CAS  PubMed  Google Scholar 

  21. Lee SJ. Classification systems for chronic graft-versus-host disease. Blood. 2017;129:30–7. https://doi.org/10.1182/blood-2016-07-686642.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Zeiser R, Blazar BR. Pathophysiology of chronic graft-versus-host disease and therapeutic targets. N Engl J Med. 2017;377:2565–79. https://doi.org/10.1056/NEJMra1703472.

    Article  CAS  PubMed  Google Scholar 

  23. Cutler C, Miklos D, Kim HT, Treister N, Woo S-B, Bienfang D, et al. Rituximab for steroid-refractory chronic graft-versus-host disease. Blood. 2006;108:756–62. https://doi.org/10.1182/blood-2006-01-0233.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. 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. https://doi.org/10.1111/trf.12059.

    Article  PubMed  Google Scholar 

  25. 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;128:130–7. https://doi.org/10.1182/blood-2016-02-702852.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kim SJ, Lee JW, Jung CW, Min CK, Cho B, Shin HJ, et al. Weekly rituximab followed by monthly rituximab treatment for steroid-refractory chronic graft-versus-host disease: results from a prospective, multicenter, phase II study. Haematologica. 2010;95:1935–42. https://doi.org/10.3324/haematol.2010.026104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Clavert A, Chevallier P, Guillaume T, Delaunay J, Le Gouill S, Mahe B, et al. Safety and efficacy of rituximab in steroid-refractory chronic GVHD. Bone Marrow Transplant 2013;48:734–6. https://doi.org/10.1038/bmt.2012.203.

    Article  CAS  PubMed  Google Scholar 

  28. Couriel DR, Saliba R, Escalón 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. https://doi.org/10.1111/j.1365-2141.2005.05616.x.

    Article  CAS  PubMed  Google Scholar 

  29. Boyiadzis M, Arora M, Klein JP, Hassebroek A, Hemmer M, Urbano-Ispizua A, et al. Impact of chronic graft-versus-host disease on late relapse and survival on 7,489 patients after myeloablative allogeneic hematopoietic cell transplantation for leukemia. Clin Cancer Res. 2015;21:2020–8. https://doi.org/10.1158/1078-0432.CCR-14-0586.

    Article  PubMed  Google Scholar 

  30. Akpek G, Zahurak ML, Piantadosi S, Margolis J, Doherty J, Davidson R, et al. Development of a prognostic model for grading chronic graft-versus-host disease. Blood. 2001;97:1219–26. https://doi.org/10.1182/blood.v97.5.1219.

    Article  CAS  PubMed  Google Scholar 

  31. Verstovsek S, Mesa RA, Gotlib J, Levy RS, Gupta V, DiPersio JF, et al. A double-blind placebo-controlled trial of Ruxolitinib for Myelofibrosis. N Engl J Med. 2012;366:799–807. https://doi.org/10.1056/NEJMoa1110557.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Takenaka K, Nishida T, Asano-Mori Y, Oshima K, Ohashi K, Mori T, et al. Cytomegalovirus reactivation after allogeneic hematopoietic stem cell transplantation is associated with a reduced risk of relapse in patients with acute myeloid leukemia who survived to day 100 after transplantation: The Japan Society for Hematopoietic Cell Transplantation Transplantation-related Complication Working Group. Biol Blood Marrow Transplant 2015;21:2008–16. https://doi.org/10.1016/j.bbmt.2015.07.019.

    Article  PubMed  Google Scholar 

  33. Gor D, Sabin C, Prentice HG, Vyas N, Man S, Griffiths PD, et al. Longitudinal fluctuations in cytomegalovirus load in bone marrow transplant patients: relationship between peak virus load, donor/recipient serostatus, acute GVHD and CMV disease. Bone Marrow Transplant 1998;21:597–605. https://doi.org/10.1038/sj.bmt.1701139.

    Article  CAS  PubMed  Google Scholar 

  34. Greinix HT, Volc-Platzer B, Rabitsch W, Gmeinhart B, Guevara-Pineda C, Kalhs P, et al. Successful use of extracorporeal photochemotherapy in the treatment of severe acute and chronic graft-versus-host disease. Blood. 1998;92:3098–104.

    Article  CAS  Google Scholar 

  35. Couriel DR, Hosing C, Saliba R, Shpall EJ, Anderlini P, Rhodes B, et al. Extracorporeal photochemotherapy for the treatment of steroid-resistant chronic GVHD. Blood. 2006;107:3074–80. https://doi.org/10.1182/blood-2005-09-3907.

    Article  CAS  PubMed  Google Scholar 

  36. Alcindor T, Gorgun G, Miller KB, Roberts TF, Sprague K, Schenkein DP, et al. Immunomodulatory effects of extracorporeal photochemotherapy in patients with extensive chronic graft-versus-host disease. Blood. 2001;98:1622–5. https://doi.org/10.1182/blood.v98.5.1622.

    Article  CAS  PubMed  Google Scholar 

  37. Gorgun G, Miller KB, Foss FM. Immunologic mechanisms of extracorporeal photochemotherapy in chronic graft-versus-host disease. Blood. 2002;100:941–7. https://doi.org/10.1182/blood-2002-01-0068.

    Article  CAS  PubMed  Google Scholar 

  38. Paczesny S. Discovery and validation of graft-versus-host disease biomarkers. Blood. 2013;121:585–94. https://doi.org/10.1182/blood-2012-08-355990.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This study was supported by the Deutsche Forschungsgemeinschaft, Germany, SFB1160 (project P14 to RZ and Z02 to KMB), DFG under Germany’s Excellence Strategy—EXC-2189—Project ID: 390939984, GVHDCure (ERC consolidator grant to RZ), the Wilhelm Sander Stiftung (2008.046.5) and the Jose-Carreras Leukemia foundation grant number DJCLS 01R/2019 (RZ).

Author information

Author notes

  1. These authors contributed equally: Kristina Maas-Bauer, Chrissoula Kiote-Schmidt

Authors and Affiliations

  1. Department of Medicine I, Faculty of Medicine, Medical Center—University of Freiburg, Freiburg, Germany

    Kristina Maas-Bauer, Chrissoula Kiote-Schmidt, Hartmut Bertz, Petya Apostolova, Ralph Wäsch, Jürgen Finke & Robert Zeiser

  2. Clinical Trials Unit, Faculty of Medicine, Medical Center - University of Freiburg, Freiburg, Germany

    Gabriele Ihorst

Authors
  1. Kristina Maas-Bauer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chrissoula Kiote-Schmidt
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hartmut Bertz
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Petya Apostolova
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ralph Wäsch
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Gabriele Ihorst
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jürgen Finke
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Robert Zeiser
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Robert Zeiser.

Ethics declarations

Conflict of interest

RZ received speakers fees from Incyte, Novartis, and Mallinckroth. The other authors have no conflict of interest with this manuscript to disclose.

Ethical approval

The analysis of soluble IL2R was approved by the ethics committee of the University Medical Center Freiburg, ethics approval number: 547/14. Ruxolitinib and ECP are used in clinical routine for cGVHD treatment based on multiple reports showing efficacy. Prior to treatment with ruxolitinib and ECP informed consent was obtained from each patient.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Maas-Bauer, K., Kiote-Schmidt, C., Bertz, H. et al. Ruxolitinib–ECP combination treatment for refractory severe chronic graft-versus-host disease. Bone Marrow Transplant 56, 909–916 (2021). https://doi.org/10.1038/s41409-020-01122-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41409-020-01122-8

This article is cited by

Search

Advanced search

Quick links