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Unrelated allogeneic bone marrow-derived mesenchymal stem cells for steroid-refractory acute graft-versus-host disease: a phase I/II study

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Abstract

We conducted a multicenter phase I/II study using mesenchymal stem cells (MSCs) manufactured from the bone marrow of healthy unrelated volunteers to treat steroid-refractory acute graft-versus-host disease (aGVHD). Fourteen patients with hematological malignancies who suffered from grade II (9 patients) or III aGVHD (5) were treated. Affected organs were gut (10 patients), skin (9 patients), and liver (3 patients). Seven patients had two involved organs. The median age was 52. No other second-line agents were given. MSCs were given at a dose of 2 × 106 cells/kg for each infusion twice a week for 4 weeks. If needed, patients were continuously given MSCs weekly for an additional 4 weeks. By week 4, 13 of 14 patients (92.9 %) had responded to MSC therapy with a complete response (CR; n = 8) or partial response (PR; n = 5). At 24 weeks, 11 patients (10 with CR and 1 with PR) were alive. At 96 weeks, 8 patients were alive in CR. A total of 6 patients died, attributable to the following: underlying disease relapse (2 patients), breast cancer relapse (1), veno-occlusive disease (1), ischemic cholangiopathy (1), and pneumonia (1). No clear adverse effects associated with MSC infusion were observed. Third party-derived bone marrow MSCs may be safe and effective for patients with steroid-refractory aGVHD.

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References

  1. Bacigalupo A. Management of acute graft-versus-host disease. Br J Haematol. 2007;137:87–98.

    Article  PubMed  CAS  Google Scholar 

  2. Levine JE, Logan B, Wu J, Alousi AM, Ho V, Bolaños-Meade J, et al. Graft-versus-host disease treatment: predictors of survival. Biol Blood Marrow Transplant. 2010;16:1693–9.

    Article  PubMed  Google Scholar 

  3. Ferrara JL, Levine JE, Reddy P. Graft-versus-host disease. Lancet. 2009;373:1550–61.

    Article  PubMed  CAS  Google Scholar 

  4. Deeg HJ. How I treat refractory acute GVHD. Blood. 2007;109:4119–26.

    Article  PubMed  CAS  Google Scholar 

  5. Ho VT, Cutler C. Current and novel therapies in acute GVHD. Best Pract Res Clin Haematol. 2008;21:223–37.

    Article  PubMed  CAS  Google Scholar 

  6. 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.

    Article  PubMed  Google Scholar 

  7. Le Blanc K, Rasmusson I, Sundberg B, Götherström C, Hassan M, Uzunel M, et al. Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet. 2004;363:1439–41.

    Article  PubMed  Google Scholar 

  8. Ringdén O, Uzunel M, Rasmusson I, Remberger M, Sundberg B, Lönnies H, et al. Mesenchymal stem cells for treatment of therapy-resistant graft-versus-host disease. Transplantation. 2006;81:1390–7.

    Article  PubMed  Google Scholar 

  9. Fang B, Song Y, Liao L, Zhang Y, Zhao RC. Favorable response to human adipose tissue-derived mesenchymal stem cells in steroid-refractory acute graft-versus-host disease. Transplant Proc. 2007;39:3358–62.

    Article  PubMed  CAS  Google Scholar 

  10. Müller I, Kordowich S, Holzwarth C, Isensee G, Lang P, Neunhoeffer F, et al. Application of multipotent mesenchymal stromal cells in pediatric patients following allogeneic stem cell transplantation. Blood Cells Mol Dis. 2008;40:25–32.

    Article  PubMed  Google Scholar 

  11. Le Blanc K, Frassoni F, Ball L, Locatelli F, Roelofs H, Lewis I, et al. Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. Lancet. 2008;371:1579–86.

    Article  PubMed  Google Scholar 

  12. Kebriaei P, Isola L, Bahceci E, Holland K, Rowley S, McGuirk J, et al. Adult human mesenchymal stem cells added to corticosteroid therapy for the treatment of acute graft-versus-host disease. Biol Blood Marrow Transplant. 2009;15:804–11.

    Article  PubMed  CAS  Google Scholar 

  13. von Bonin M, Stölzel F, Goedecke A, Richter K, Wuschek N, Hölig K, et al. Treatment of refractory acute GVHD with third-party MSC expanded in platelet lysate-containing medium. Bone Marrow Transplant. 2009;43:245–51.

    Article  Google Scholar 

  14. Lim JH, Lee MH, Yi HG, Kim CS, Kim JH, Song SU. Mesenchymal stromal cells for steroid-refractory acute graft-versus-host disease: a report of two cases. Int J Hematol. 2010;92:204–7.

    Article  PubMed  Google Scholar 

  15. Lucchini G, Introna M, Dander E, Rovelli A, Balduzzi A, Bonanomi S, 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;16:1293–301.

    Article  PubMed  Google Scholar 

  16. Arima N, Nakamura F, Fukunaga A, Hirata H, Machida H, Kouno S, et al. Single intra-arterial injection of mesenchymal stromal cells for treatment of steroid-refractory acute graft-versus-host disease: a pilot study. Cytotherapy. 2010;12:265–8.

    Article  PubMed  Google Scholar 

  17. Prasad VK, Lucas KG, Kleiner GI, Talano JA, Jacobsohn D, Broadwater G, et al. Efficacy and safety of ex vivo cultured adult human mesenchymal stem cells (Prochymal) in pediatric patients with severe refractory acute graft-versus-host disease in a compassionate use study. Biol Blood Marrow Transplant. 2011;17:534–41.

    Article  PubMed  CAS  Google Scholar 

  18. Pérez-Simon JA, López-Villar O, Andreu EJ, Rifón J, Muntion S, Campelo MD, 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;96:1072–6.

    Article  PubMed  Google Scholar 

  19. Wernicke CM, Grunewald TG, Juenger H, Kuci S, Kuci Z, Koehl U, et al. Mesenchymal stromal cells for treatment of steroid-refractory GvHD: a review of the literature and two pediatric cases. Int Arch Med. 2011;4:27.

    Article  PubMed  Google Scholar 

  20. Herrmann R, Sturm M, Shaw K, Purtill D, Cooney J, Wright M, et al. Mesenchymal stromal cell therapy for steroid-refractory acute and chronic graft versus host disease: a phase 1 study. Int J Hematol. 2012;95:182–8.

    Article  PubMed  CAS  Google Scholar 

  21. Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J, et al. 1994 consensus conference on acute GVHD grading. Bone Marrow Transplant. 1995;15:825–8.

    PubMed  CAS  Google Scholar 

  22. Sato K, Ozaki K, Mori M, Muroi K, Ozawa K. Mesenchymal stromal cells for graft-versus-host disease: basic aspects and clinical outcomes. J Clin Exp Hematop. 2010;50:79–89.

    Article  PubMed  Google Scholar 

  23. Martin P. Prochymal® improves response rates in patients with steroid-refractory acute graft-versus-host disease involving the liver and gut: results of a randomized, placebo-controlled, multicentre phase III trial in GvHD. Bone Marrow Transplant. 2010;45:S17.

    Google Scholar 

  24. Daly A. Remestemcel-L, the first cellular therapy product for the treatment of graft-versus-host disease. Drugs Today (Barc). 2012;48:773–83.

    CAS  Google Scholar 

  25. Aldahmash A, Haack-Sørensen M, Al-Nbaheen M, Harkness L, Abdallah BM, Kassem M. Human serum is as efficient as fetal bovine serum in supporting proliferation and differentiation of human multipotent stromal (mesenchymal) stem cells in vitro and in vivo. Stem Cell Rev. 2011;7:860–8.

    Article  PubMed  Google Scholar 

  26. Jung S, Panchalingam KM, Rosenberg L, Behie LA. Ex vivo expansion of human mesenchymal stem cells in defined serum-free media. Stem Cells Int. 2012;2012:123030.

    PubMed  Google Scholar 

Download references

Conflict of interest

K. Muroi and K. Ozawa received payment for consultancy from JCR Pharmaceuticals Co., Ltd. Other authors declare no conflicts of interest.

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Authors and Affiliations

  1. Division of Cell Transplantation and Transfusion, Jichi Medical University Hospital, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan

    Kazuo Muroi

  2. Department of Hematology, Japanese Red Cross Nagoya First Hospital, Nagoya, Japan

    Koichi Miyamura

  3. Hematology Division, Tokyo Metropolitan Komagome Hospital, Tokyo, Japan

    Kazuteru Ohashi

  4. Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan

    Makoto Murata

  5. Department of Hematology, Hamanomachi Hospital, Fukuoka, Japan

    Tetsuya Eto

  6. Department of Internal Medicine, Sapporo Hokuyu Hospital, Sapporo, Japan

    Naoki Kobayashi

  7. Department of Hematology, Toranomon Hospital, Tokyo, Japan

    Shuichi Taniguchi

  8. Department of Hematology, Hokkaido University Graduate School of Medicine, Sapporo, Japan

    Masahiro Imamura

  9. Division of Hematology/Oncology, Department of Internal Medicine, Tokai University School of Medicine, Isehara, Japan

    Kiyoshi Ando

  10. Department of Cell Transplantation and Regenerative Medicine, Tokai University School of Medicine, Isehara, Japan

    Shunichi Kato

  11. Division of Hematology, Keio University School of Medicine, Tokyo, Japan

    Takehiko Mori

  12. Center for Cellular and Molecular Medicine, Kyushu University Graduate School of Medicine, Fukuoka, Japan

    Takanori Teshima

  13. Division of Hematology, Jichi Medical University, Shimotsuke, Japan

    Masaki Mori & Keiya Ozawa

Authors
  1. Kazuo Muroi
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  2. Koichi Miyamura
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  3. Kazuteru Ohashi
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  4. Makoto Murata
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  7. Shuichi Taniguchi
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  8. Masahiro Imamura
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  9. Kiyoshi Ando
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  10. Shunichi Kato
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  11. Takehiko Mori
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  12. Takanori Teshima
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  13. Masaki Mori
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  14. Keiya Ozawa
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Corresponding author

Correspondence to Kazuo Muroi.

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Muroi, K., Miyamura, K., Ohashi, K. et al. Unrelated allogeneic bone marrow-derived mesenchymal stem cells for steroid-refractory acute graft-versus-host disease: a phase I/II study. Int J Hematol 98, 206–213 (2013). https://doi.org/10.1007/s12185-013-1399-4

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  • DOI: https://doi.org/10.1007/s12185-013-1399-4

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