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.

  • Review Article
  • Published:

Role of extracorporeal photopheresis in the management of acute and chronic graft versus disease: current status

Abstract

Extracorporeal photopheresis (ECP) is a therapy that combines the collection of mononuclear cells by apheresis, the addition of a photosensitizer (8-methoxisoralen), the illumination of the product with ultraviolet A light, and the immediate infusion of the product to the patient. Initially developed and approved to treat T-cell cutaneous lymphomas, soon started to be used to treat graft versus host disease (GvHD) developed after allogeneic hematopoietic-cell transplantation. The high response rate of ECP in skin, ocular, oral, pulmonary, and liver forms of chronic GvHD, the steroid-sparing effect, and the improved overall survival of treated patients, made ECP one of the second-line treatments used to treat steroid-resistant acute and chronic GVHD. Recently, the development of new drugs for treating GVHD has changed the position of ECP in the therapy of GVHD and has started to be used in combination with drugs for increasing the response rate to the treatment in severe or resistant forms of acute and chronic GVHD. ECP remains an essential therapeutic resource in the management of patients with refractory acute and chronic GVHD.

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

Access options

Buy this article

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

Similar content being viewed by others

References

  1. Passweg JR, Baldomero H, Chabannon C, Basak GW, Corbacioglu S, Duarte R, et al. The EBMT activity survey on hematopoietic-cell transplantation and cellular therapy 2018: CAR-T’s come into focus. Bone Marrow Transpl. 2020;55:1604–13. https://doi.org/10.1038/s41409-020-0826-4.

    Article  Google Scholar 

  2. Salas MQ, Pedraza A, Charry P, Suarez-Lledo M, Rodriguez-Lobato LG, Brusosa M, et al. Post-transplantation cyclophosphamide and tacrolimus for graft-versus-host disease prevention after allogeneic hematopoietic cell transplantation from HLA-matched donors has more advantages than limitations. Transplant Cell Ther. 2023. https://doi.org/10.1016/j.jtct.2023.11.020.

  3. Edelson R, Berger C, Gasparro F, Jegasothy B, Heald P, Wintroub B, et al. Treatment of cutaneous T-cell lymphoma by extracorporeal photochemotherapy. Preliminary results. N Engl J Med. 1987;316:297–303. https://doi.org/10.1056/NEJM198702053160603.

    Article  CAS  PubMed  Google Scholar 

  4. Knobler R, Berlin G, Calzavara-Pinton P, Greinix H, Jaksch P, Laroche L. et al. Guidelines on the use of extracorporeal photopheresis. J Eur Acad Dermatol Venereol. 2014;28:1–37. https://doi.org/10.1111/jdv.12311.

    Article  CAS  PubMed  Google Scholar 

  5. Parrish JA, Fitzpatrick TB, Tanenbaum L, Pathak MA. Photochemotherapy of psoriasis with oral methoxsalen and longwave ultraviolet light. N Engl J Med. 1974;291:1207–11. https://doi.org/10.1056/NEJM197412052912301.

    Article  CAS  PubMed  Google Scholar 

  6. Knobler RM, Trautinger F, Graninger W, Macheiner W, Gruenwald C, Neumann R, et al. Parenteral administration of 8-methoxypsoralen in photopheresis. J Am Acad Dermatol. 1993;28:580–4. https://doi.org/10.1016/0190-9622(93)70077-7.

    Article  CAS  PubMed  Google Scholar 

  7. Therakos ECP Immunomodulation. 2024. https://therakos.eu/company/. Accessed 27 March 2024.

  8. Knobler R, Arenberger P, Arun A, Assaf C, Bagot M, Berlin G. et al. European Dermatology Forum—updated guidelines on the use of extracorporeal photopheresis 2020—part 1. J Eur Acad Dermatol Venereol. 2020;34:2693–716. https://doi.org/10.1111/jdv.16890.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Andreu G, Leon A, Heshmati F, Tod M, Menkes CJ, Baudelot J, et al. Extracorporeal photochemotherapy: evaluation of two techniques and use in connective tissue disorders. Transfus Sci. 1994;15:443–54. https://doi.org/10.1016/0955-3886(94)90178-3.

    Article  CAS  PubMed  Google Scholar 

  10. Heshmati F, Andreu G. Extracorporeal photochemotherapy: a historical perspective. Transfus Apher Sci. 2003;28:25–34. https://doi.org/10.1016/S1473-0502(02)00097-6.

    Article  PubMed  Google Scholar 

  11. De Silvestro G. The Italian registry of therapeutic apheresis—2015. Transfus Apher Sci. 2017;56:75–81. https://doi.org/10.1016/j.transci.2016.12.024.

    Article  PubMed  Google Scholar 

  12. Extracorporeal Photopheresis. Amicus Blue. 2024. https://www.amicusblue-fresenius-kabi.com/wp-content/themes/amicus-blue/documents/Amicus_ECP_Brochure.pdf. Accessed 20 May 2024.

  13. Cid J, Carbasse G, Suarez-Lledo M, Moreno DF, Martinez C, Gutierrez-Garcia G, et al. Efficacy and safety of one-day offline extracorporeal photopheresis schedule processing one total blood volume for treating patients with graft-versus-host disease. Transfusion. 2019;59:2636–42. https://doi.org/10.1111/trf.15384.

    Article  PubMed  Google Scholar 

  14. Connelly-Smith L, Alquist CR, Aqui NA, Hofmann JC, Klingel R, Onwuemene OA, et al. Guidelines on the use of therapeutic apheresis in clinical practice—evidence-based approach from the writing committee of the American Society for Apheresis: the ninth special issue. J Clin Apher. 2023;38:77–278. https://doi.org/10.1002/jca.22043.

    Article  PubMed  Google Scholar 

  15. Boluda B, Solana-Altabella A, Cano I, Acuna-Cruz E, Rodriguez-Veiga R, Ballesta-Lopez O, et al. Extracorporeal photopheresis vs standard therapies for steroid-refractory chronic graft-vs-host disease: pharmacoeconomic assessment of hospital resource use in Spain. J Clin Apher. 2021;36:612–20. https://doi.org/10.1002/jca.21901.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Yalniz FF, Murad MH, Lee SJ, Pavletic SZ, Khera N, Shah ND, et al. Steroid refractory chronic graft-versus-host disease: cost-effectiveness analysis. Biol Blood Marrow Transpl. 2018;24:1920–7. https://doi.org/10.1016/j.bbmt.2018.03.008.

    Article  Google Scholar 

  17. Crespo C, Perez-Simon JA, Rodriguez JM, Sierra J, Brosa M. Development of a population-based cost-effectiveness model of chronic graft-versus-host disease in Spain. Clin Ther. 2012;34:1774–87. https://doi.org/10.1016/j.clinthera.2012.06.029.

    Article  PubMed  Google Scholar 

  18. 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. https://doi.org/10.1016/j.jval.2015.01.009.

    Article  PubMed  Google Scholar 

  19. Peacock A, Dehle FC, Mesa Zapata OA, Gennari F, Williams MRI, Hamad N, et al. Cost-effectiveness of extracorporeal photopheresis in patients with chronic graft-vs-host disease. J Health Econ Outcomes Res. 2024;11:23–31. https://doi.org/10.36469/001c.92028.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Gerber A, Bohne M, Rasch J, Struy H, Ansorge S, Gollnick H. Investigation of annexin V binding to lymphocytes after extracorporeal photoimmunotherapy as an early marker of apoptosis. Dermatology. 2000;201:111–7. https://doi.org/10.1159/000018472.

    Article  CAS  PubMed  Google Scholar 

  21. Bladon J, Taylor PC. Extracorporeal photopheresis in cutaneous T-cell lymphoma and graft-versus-host disease induces both immediate and progressive apoptotic processes. Br J Dermatol. 2002;146:59–68. https://doi.org/10.1046/j.1365-2133.2002.04560.x.

    Article  CAS  PubMed  Google Scholar 

  22. Budde H, Berntsch U, Riggert J, Legler TJ. In vitro effects of different 8-methoxypsoralen treatment protocols for extracorporeal photopheresis on mononuclear cells. Cent Eur J Immunol. 2017;42:1–9. https://doi.org/10.5114/ceji.2017.67312.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Knobler R, Barr ML, Couriel DR, Ferrara JL, French LE, Jaksch P, et al. Extracorporeal photopheresis: past, present, and future. J Am Acad Dermatol. 2009;61:652–65. https://doi.org/10.1016/j.jaad.2009.02.039.

    Article  PubMed  Google Scholar 

  24. Xipell M, Molina-Andujar A, Cid J, Pineiro GJ, Montagud-Marrahi E, Cofan F, et al. Immunogenic and immunotolerogenic effects of extracorporeal photopheresis in high immunological risk kidney recipients. A single center case series. J Clin Apher. 2022;37:197–205. https://doi.org/10.1002/jca.21958.

    Article  PubMed  Google Scholar 

  25. Perotti C, Sniecinski I. A concise review on extracorporeal photochemotherapy: where we began and where we are now and where are we going! Transfus Apher Sci. 2015;52:360–8. https://doi.org/10.1016/j.transci.2015.04.011.

    Article  PubMed  Google Scholar 

  26. Mustieles MJ, Lozano M. Vascular access for apheresis: state of the art. Transfus Apher Sci. 2023;62:103669. https://doi.org/10.1016/j.transci.2023.103669.

    Article  PubMed  Google Scholar 

  27. 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 

  28. Vieyra-Garcia PA, Wolf P. Extracorporeal photopheresis: a case of immunotherapy ahead of its time. Transfus Med Hemother. 2020;47:226–35. https://doi.org/10.1159/000508479.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Bozzini S, Del Fante C, Morosini M, Berezhinskiy HO, Auner S, Cattaneo E, et al. Mechanisms of action of extracorporeal photopheresis in the control of bronchiolitis obliterans syndrome (BOS): involvement of circulating miRNAs. Cells. 2022;11. https://doi.org/10.3390/cells11071117.

  30. Malard F, Holler E, Sandmaier BM, Huang H, Mohty M. Acute graft-versus-host disease. Nat Rev Dis Prim. 2023;9:27 https://doi.org/10.1038/s41572-023-00438-1.

    Article  PubMed  Google Scholar 

  31. Zeiser R, Blazar BR. Acute graft-versus-host disease - biologic process, prevention, and therapy. N. Engl J Med. 2017;377:2167–79. https://doi.org/10.1056/NEJMra1609337.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Holtan SG, Yu J, Choe HK, Paranagama D, Tang J, Naim A, et al. Disease progression, treatments, hospitalization, and clinical outcomes in acute GVHD: a multicenter chart review. Bone Marrow Transpl. 2022;57:1581–5. https://doi.org/10.1038/s41409-022-01764-w.

    Article  Google Scholar 

  33. Akahoshi Y, Spyrou N, Hogan WJ, Ayuk F, DeFilipp Z, Weber D, et al. Incidence, clinical presentation, risk factors, outcomes, and biomarkers in de novo late acute GVHD. Blood Adv. 2023;7:4479–91. https://doi.org/10.1182/bloodadvances.2023009885.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. 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 Transpl. 2005;11:945–56. https://doi.org/10.1016/j.bbmt.2005.09.004.

    Article  Google Scholar 

  35. 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. https://doi.org/10.1016/j.bbmt.2014.12.001.

    Article  Google Scholar 

  36. Penack O, Marchetti M, Ruutu T, Aljurf M, Bacigalupo A, Bonifazi F, et al. Prophylaxis and management of graft versus host disease after stem-cell transplantation for haematological malignancies: updated consensus recommendations of the European Society for Blood and Marrow Transplantation. Lancet Haematol. 2020;7:e157–e67. https://doi.org/10.1016/S2352-3026(19)30256-X.

    Article  PubMed  Google Scholar 

  37. Zeiser R, von Bubnoff N, 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 

  38. Penack O, Peczynski C, Boreland W, Lemaitre J, Afanasyeva K, Kornblit B, et al. ECP versus ruxolitinib in steroid-refractory acute GVHD - a retrospective study by the EBMT transplant complications working party. Front Immunol. 2023;14:1283034. https://doi.org/10.3389/fimmu.2023.1283034.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Penack O, Peczynski C, Boreland W, Lemaitre J, Reinhardt HC, Afanasyeva K, et al. ECP versus ruxolitinib in steroid-refractory chronic GVHD—a retrospective study by the EBMT transplant complications working party. Bone Marrow Transpl. 2024;59:380–6. https://doi.org/10.1038/s41409-023-02174-2.

    Article  CAS  Google Scholar 

  40. Modemann F, Ayuk F, Wolschke C, Christopeit M, Janson D, von Pein UM, 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 Transpl. 2020;55:2286–93. https://doi.org/10.1038/s41409-020-0952-z.

    Article  CAS  Google Scholar 

  41. Teshima T, Hill GR. The Pathophysiology and Treatment of Graft-Versus-Host Disease: Lessons Learnt From Animal Models. Front Immunol. 2021;12:715424. https://doi.org/10.3389/fimmu.2021.715424.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Cutler C, Lee SJ, Arai S, Rotta M, Zoghi B, Lazaryan A, et al. Belumosudil for chronic graft-versus-host disease after 2 or more prior lines of therapy: the ROCKstar Study. Blood. 2021;138:2278��89. https://doi.org/10.1182/blood.2021012021.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Bolaños-Meade J, Hamadani M, Wu J, Al Malki MM, Martens MJ, Runaas L, et al. Post-transplantation cyclophosphamide-based graft-versus-host disease prophylaxis. N Engl J Med. 2023;388:2338–48. https://doi.org/10.1056/NEJMoa2215943.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Baumrin E, Loren AW, Falk SJ, Mays JW, Cowen EW. Chronic graft-versus-host disease. Part II: disease activity grading and therapeutic management. J Am Acad Dermatol. 2024;90:19–36. https://doi.org/10.1016/j.jaad.2022.12.023.

    Article  CAS  PubMed  Google Scholar 

  45. Zeiser R, Polverelli N, Ram R, Hashmi SK, Chakraverty R, Middeke JM, et al. Ruxolitinib for glucocorticoid-refractory chronic graft-versus-host disease. N Engl J Med. 2021;385:228–38. https://doi.org/10.1056/NEJMoa2033122.

    Article  CAS  PubMed  Google Scholar 

  46. Rossetti F, Zulian F, Dall’Amico R, Messina C, Montini G, Zacchello F. Extracorporeal photochemotherapy as single therapy for extensive, cutaneous, chronic graft-versus-host disease. Transplantation. 1995;59:149–51. https://doi.org/10.1097/00007890-199501150-00029.

    Article  CAS  PubMed  Google Scholar 

  47. 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  PubMed  Google Scholar 

  48. 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;112:2667–74. https://doi.org/10.1182/blood-2008-03-141481.

    Article  CAS  PubMed  Google Scholar 

  49. Jagasia M, Scheid C, Socie 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 

  50. Sakellari I, Gavriilaki E, Batsis I, Mallouri D, Panteliadou AK, Lazaridou A, et al. Favorable impact of extracorporeal photopheresis in acute and chronic graft versus host disease: prospective single-center study. J Clin Apher. 2018;33:654–60. https://doi.org/10.1002/jca.21660.

    Article  PubMed  Google Scholar 

  51. Ussowicz M, Musial J, Mielcarek M, Tomaszewska A, Nasilowska-Adamska B, Kalwak K, et al. Steroid-sparing effect of extracorporeal photopheresis in the therapy of graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Transplant Proc. 2013;45:3375–80. https://doi.org/10.1016/j.transproceed.2013.07.053.

    Article  CAS  PubMed  Google Scholar 

  52. Flowers ME, Martin PJ. How we treat chronic graft-versus-host disease. Blood. 2015;125:606–15. https://doi.org/10.1182/blood-2014-08-551994.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Penack O, Marchetti M, Aljurf M, Arat M, Bonifazi F, Duarte RF, et al. Prophylaxis and management of graft-versus-host disease after stem-cell transplantation for haematological malignancies: updated consensus recommendations of the European Society for Blood and Marrow Transplantation. Lancet Haematol. 2024;11:e147–e59. https://doi.org/10.1016/S2352-3026(23)00342-3.

    Article  CAS  PubMed  Google Scholar 

  54. Maas-Bauer K, Kiote-Schmidt C, Bertz H, Apostolova P, Wasch R, Ihorst G, et al. Ruxolitinib-ECP combination treatment for refractory severe chronic graft-versus-host disease. Bone Marrow Transplant. 2021;56:909-16. https://doi.org/10.1038/s41409-020-01122-8.

Download references

Author information

Authors and Affiliations

Authors

Contributions

ML, PC, MPM and CM wrote the manuscript. MQS, MSL, FAA, MR, and JC revised the manuscript. All authors have read and approved the final version of the manuscript and are accountable for all aspects of the work.

Corresponding author

Correspondence to Miquel Lozano.

Ethics declarations

Competing interests

ML on behalf of his institution, Clinic Research Foundation, has received research support from Terumo BCT, Fresenius-Kabi, Macopharma, and Sanofi-Genzyme as a consultant ML has received fees from Macopharma. The other authors declare no competing financial interests.

Additional information

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

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lozano, M., Charry, P., de Pablo-Miró, M. et al. Role of extracorporeal photopheresis in the management of acute and chronic graft versus disease: current status. Bone Marrow Transplant (2024). https://doi.org/10.1038/s41409-024-02360-w

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41409-024-02360-w

Search

Quick links