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:

Anti-α4β7 integrin monoclonal antibody (vedolizumab) for the treatment of steroid-resistant severe intestinal acute graft-versus-host disease

Abstract

Steroid-resistant (SR) acute graft-versus-host disease (aGvHD) is a life-threatening complication of allogeneic stem cell transplantation. Vedolizumab is a monoclonal antibody that impairs homing of T cells to the gastrointestinal (GI) endothelium by blocking the α4β7 integrin. We retrospectively analyzed outcomes following vedolizumab administration for treatment of SR GI GvHD. Overall, 29 patients from three transplantation centers were included. Histopathology was available in 24 (83%) patients. The overall response rate (ORR) was 23/29 (79%); 8 (28%) patients had a complete response and 15 (52%) a partial response. Vedolizumab was administered as a 2nd-line or ≥3rd-line treatment in 13 (45%) and 16 (55%) patients, respectively. ORR in the former groups was 13/13 (100%) versus 10/16 (63%) in the latter (p = 0.012); corresponding CR rates were 7/13 (54%) versus 1/16 (6%) (p = 0.005). Early administration of vedolizumab was also associated with a greater likelihood of patients being off immunosuppression ((9/13 (69%) versus 3/16 (19%), p = 0.007) and free from fatal infectious complications (5/13 versus 14/16, p = 0.006). Overall, our data suggest that vedolizumab, especially if administered early in the disease course, may ameliorate severe SR GI aGvHD. The timing, role, and safety of vedolizumab should be further explored in prospective clinical trials.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Fig. 1

Similar content being viewed by others

References

  1. 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;18:1150–63. https://doi.org/10.1016/j.bbmt.2012.04.005.

    Article  Google Scholar 

  2. Deeg HJ. How I treat refractory acute GVHD. Blood. 2007;109:4119–26. https://doi.org/10.1182/blood-2006-12-041889.

    Article  CAS  Google Scholar 

  3. 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;158:30–45. https://doi.org/10.1111/j.1365-2141.2012.09129.x.

    Article  CAS  Google Scholar 

  4. 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. https://doi.org/10.1038/bmt.2013.107.

    Article  CAS  Google Scholar 

  5. Ibrahim RB, Abidi MH, Cronin SM, Lum LG, Al-Kadhimi Z, Ratanatharathorn V, et al. Nonabsorbable corticosteroids use in the treatment of gastrointestinal graft-versus-host disease. Biol Blood Marrow Transplant. 2009;15:395–405. https://doi.org/10.1016/j.bbmt.2008.12.487.

    Article  CAS  Google Scholar 

  6. Rashidi A, DiPersio JF, Sandmaier BM, Colditz GA, Weisdorf DJ. Steroids versus steroids plus additional agent in frontline treatment of acute graft-versus-host disease: a systematic review and meta-analysis of randomized trials. Biol Blood Marrow Transplant. 2016;22:1133–7. https://doi.org/10.1016/j.bbmt.2016.02.021.

    Article  CAS  Google Scholar 

  7. Beilhack A, Schulz S, Baker J, Beilhack GF, Wieland CB, Herman EI, et al. In vivo analyses of early events in acute graft-versus-host disease reveal sequential infiltration of T-cell subsets. Blood. 2005;106:1113–22. https://doi.org/10.1182/blood-2005-02-0509.

    Article  CAS  Google Scholar 

  8. Chen YB, McDonough S, Chen H, Kennedy J, Illiano C, Attar EC, et al. Expression of alpha4beta7 integrin on memory CD8(+) T cells at the presentation of acute intestinal GVHD. Bone Marrow Transplant. 2013;48:598–603. https://doi.org/10.1038/bmt.2012.191.

    Article  Google Scholar 

  9. Berlin C, Berg EL, Briskin MJ, Andrew DP, Kilshaw PJ, Holzmann B, et al. Alpha 4 beta 7 integrin mediates lymphocyte binding to the mucosal vascular addressin MAdCAM-1. Cell. 1993;74:185–95.

    Article  CAS  Google Scholar 

  10. Soler D, Chapman T, Yang LL, Wyant T, Egan R, Fedyk ER. The binding specificity and selective antagonism of vedolizumab, an anti-alpha4beta7 integrin therapeutic antibody in development for inflammatory bowel diseases. J Pharmacol Exp Ther. 2009;330:864–75. https://doi.org/10.1124/jpet.109.153973.

    Article  CAS  Google Scholar 

  11. Clahsen T, Pabst O, Tenbrock K, Schippers A, Wagner N. Localization of dendritic cells in the gut epithelium requires MAdCAM-1. Clin Immunol. 2015;156:74–84. https://doi.org/10.1016/j.clim.2014.11.005.

    Article  CAS  Google Scholar 

  12. Wyant T, Fedyk E, Abhyankar B. An overview of the mechanism of action of the monoclonal antibody vedolizumab. J Crohns Colitis. 2016;10:1437–44. https://doi.org/10.1093/ecco-jcc/jjw092.

    Article  Google Scholar 

  13. Murai M, Yoneyama H, Ezaki T, Suematsu M, Terashima Y, Harada A, et al. Peyer’s patch is the essential site in initiating murine acute and lethal graft-versus-host reaction. Nat Immunol. 2003;4:154–60. https://doi.org/10.1038/ni879.

    Article  CAS  Google Scholar 

  14. Colombel JF, Sands BE, Rutgeerts P, Sandborn W, Danese S, D’Haens G, et al. The safety of vedolizumab for ulcerative colitis and Crohn’s disease. Gut. 2017;66:839–51. https://doi.org/10.1136/gutjnl-2015-311079.

    Article  CAS  Google Scholar 

  15. Sandborn WJ, Feagan BG, Rutgeerts P, Hanauer S, Colombel JF, Sands BE, et al. Vedolizumab as induction and maintenance therapy for Crohn’s disease. N Engl J Med. 2013;369:711–21. https://doi.org/10.1056/NEJMoa1215739.

    Article  CAS  Google Scholar 

  16. Feagan BG, Rutgeerts P, Sands BE, Hanauer S, Colombel JF, Sandborn WJ, et al. Vedolizumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2013;369:699–710.https://doi.org/10.1056/NEJMoa1215734.

    Article  CAS  Google Scholar 

  17. Sands BE, Feagan BG, Rutgeerts P, Colombel JF, Sandborn WJ, Sy R, et al. Effects of vedolizumab induction therapy for patients with Crohn’s disease in whom tumor necrosis factor antagonist treatment failed. Gastroenterology. 2014;147:618–27 e613. https://doi.org/10.1053/j.gastro.2014.05.008.

    Article  CAS  Google Scholar 

  18. Boland BS, Riedl MA, Valasek MA, Crowe SE, Sandborn WJ. Vedolizumab in patients with common variable immune deficiency and gut inflammation. Am J Gastroenterol. 2017;112:1621. https://doi.org/10.1038/ajg.2017.246.

    Article  Google Scholar 

  19. Bergqvist V, Hertervig E, Gedeon P, Kopljar M, Griph H, Kinhult S, et al. Vedolizumab treatment for immune checkpoint inhibitor-induced enterocolitis. Cancer Immunol Immunother. 2017;66:581–92. https://doi.org/10.1007/s00262-017-1962-6.

    Article  CAS  Google Scholar 

  20. Floisand Y, Lundin KEA, Lazarevic V, Kristiansen JD, Osnes LTN, Tjonnfjord GE, et al. Targeting integrin alpha4beta7 in steroid-refractory intestinal graft-versus-host disease. Biol Blood Marrow Transplant. 2017;23:172–5. https://doi.org/10.1016/j.bbmt.2016.10.009.

    Article  Google Scholar 

  21. Bukauskas A, Griskevicius L, Peceliunas V. Lessons learned from early experiences with vedolizumab for steroid-refractory acute graft- versus-host disease with gastrointestinal involvement. Biol Blood Marrow Transplant. 2017;23:1597. https://doi.org/10.1016/j.bbmt.2017.05.028.

    Article  CAS  Google Scholar 

  22. Coltoff A, Lancman G, Kim S, Steinberg A. Vedolizumab for treatment of steroid-refractory lower gastrointestinal acute graft-versus-host disease. Bone Marrow Transplant. 2018. https://doi.org/10.1038/s41409-018-0094-8.

    Article  CAS  Google Scholar 

  23. Glucksberg H, Storb R, Fefer A, Buckner CD, Neiman PE, Clift RA, et al. Clinical manifestations of graft-versus-host disease in human recipients of marrow from HL-A-matched sibling donors. Transplantation. 1974;18:295–304.

    Article  CAS  Google Scholar 

  24. 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;6:367–71.

    CAS  PubMed  Google Scholar 

  25. Jacobsohn DA, Vogelsang GB. Acute graft versus host disease. Orphanet J Rare Dis. 2007;2:35. https://doi.org/10.1186/1750-1172-2-35.

  26. Korngold R, Sprent J. Lethal graft-versus-host disease after bone marrow transplantation across minor histocompatibility barriers in mice. Prevention by removing mature T cells from marrow. J Exp Med. 1978;148:1687–98.

    Article  CAS  Google Scholar 

  27. Pidala J, Anasetti C. Glucocorticoid-refractory acute graft-versus-host disease. Biol Blood Marrow Transplant. 2010;16:1504–18. https://doi.org/10.1016/j.bbmt.2010.01.007.

    Article  Google Scholar 

  28. 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. https://doi.org/10.1038/bmt.2013.59.

    Article  CAS  Google Scholar 

  29. 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. https://doi.org/10.1016/j.bbmt.2011.06.012.

    Article  CAS  Google Scholar 

  30. Martin PJ, Inamoto Y, Flowers ME, Carpenter PA. Secondary treatment of acute graft-versus-host disease: a critical review. Biol Blood Marrow Transplant. 2012;18:982–8. https://doi.org/10.1016/j.bbmt.2012.04.006.

    Article  Google Scholar 

  31. Wyant T, Leach T, Sankoh S, Wang Y, Paolino J, Pasetti MF, et al. Vedolizumab affects antibody responses to immunisation selectively in the gastrointestinal tract: randomised controlled trial results. Gut. 2015;64:77–83. https://doi.org/10.1136/gutjnl-2014-307127.

    Article  CAS  Google Scholar 

  32. Cornes JS. Number, size, and distribution of Peyer’s patches in the human small intestine: Part I. The development of Peyer’s patches. Gut. 1965;6:225–9.

    Article  CAS  Google Scholar 

  33. Van Kruiningen HJ, West AB, Freda BJ, Holmes KA. Distribution of Peyer’s patches in the distal ileum. Inflamm Bowel Dis. 2002;8:180–5.

    Article  Google Scholar 

  34. Ungar B, Kopylov U, Yavzori M, Fudim E, Picard O, Lahat A, et al. Association of vedolizumab level, anti-drug antibodies, and alpha4beta7 occupancy with response in patients with inflammatory bowel diseases. Clin Gastroenterol Hepatol. 2017. https://doi.org/10.1016/j.cgh.2017.11.050.

    Article  Google Scholar 

Download references

Acknowledgements

We thank our patients and families for their trust and patience.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Ivetta Danylesko.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Danylesko, I., Bukauskas, A., Paulson, M. et al. Anti-α4β7 integrin monoclonal antibody (vedolizumab) for the treatment of steroid-resistant severe intestinal acute graft-versus-host disease. Bone Marrow Transplant 54, 987–993 (2019). https://doi.org/10.1038/s41409-018-0364-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41409-018-0364-5

This article is cited by

Search

Quick links