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.

  • Original Article
  • Published:

Graft-Versus-Host Disease

Replacement of calcineurin inhibitors with daclizumab in patients with transplantation-associated microangiopathy or renal insufficiency associated with graft-versus-host disease

Bone Marrow Transplantation volume 38, pages 445–451 (2006)Cite this article

Abstract

Transplantation-associated microangiopathy (TAM) or renal insufficiency (RI) after allogeneic hematopoietic stem cell transplantation is associated with a high mortality. As calcineurin inhibitors (CI) may contribute to TAM or RI, we evaluated the efficacy of replacing CI by daclizumab in patients with graft-versus-host disease (GVHD). Thirteen patients with GVHD-associated TAM and five patients with RI were treated with daclizumab 1 mg/kg intravenous (i.v.)/week, discontinuation of the CI and continuation of the remaining GVHD treatment. All patients had acute GVHD (steroid-sensitive (n=4), steroid-refractory (n=10)) or chronic GVHD (n=4) and were treated with CI before the start of daclizumab. Nine of 13 patients with TAM treated with daclizumab and discontinuation of CI achieved complete remission of TAM, two had stable disease, and one patient did not respond. Patients receiving daclizumab for RI without TAM showed stabilization (2/5) or improvement (3/5) of renal function. Four of 14 patients with acute GVHD achieved CR, two partial remission, eight patients did not respond and 11/14 died at a median of 39 days after start of the daclizumab. Our data demonstrate that replacement of CI by daclizumab can improve TAM and RI. However, mortality remains high in patients with acute GVHD.

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

Similar content being viewed by others

References

  1. Ruutu T, Hermans J, Niederwieser D, Gratwohl A, Kiehl M, Volin L et al. Thrombotic thrombocytopenic purpura after allogeneic stem cell transplantation: a survey of the European Group for Blood and Marrow Transplantation (EBMT). Br J Haematol 2002; 118: 1112–1119.

    Article  Google Scholar 

  2. Arai S, Allan C, Streiff M, Hutchins GM, Vogelsang GB, Tsai HM . Von Willebrand factor-cleaving protease activity and proteolysis of von Willebrand factor in bone marrow transplant-associated thrombotic microangiopathy. Hematol J 2001; 2: 292–299.

    Article  CAS  Google Scholar 

  3. Bombeli T, Muller M, Straub PW, Haeberli A . Cyclosporine-induced detachment of vascular endothelial cells initiates the intrinsic coagulation system in plasma and whole blood. J Lab Clin Med 1996; 127: 621–634.

    Article  CAS  Google Scholar 

  4. Eissner G, Kohlhuber F, Grell M, Ueffing M, Scheurich P, Hieke A et al. Critical involvement of transmembrane tumor necrosis factor-alpha in endothelial programmed cell death mediated by ionizing radiation and bacterial endotoxin. Blood 1995; 86: 4184–4193.

    CAS  PubMed  Google Scholar 

  5. Eissner G, Multhoff G, Holler E . Influence of bacterial endotoxin on the allogenicity of human endothelial cells. Bone Marrow Transplant 1998; 21: 1286–1288.

    Article  CAS  Google Scholar 

  6. Eissner G, Multhoff G, Gerbitz A, Kirchner S, Bauer S, Haffner S et al. Fludarabine induces apoptosis, activation, and allogenicity in human endothelial and epithelial cells: protective effect of defibrotide. Blood 2002; 100: 334–340.

    Article  CAS  Google Scholar 

  7. Hernandez GL, Volpert OV, Iniguez MA, Lorenzo E, Martinez-Martinez S, Grau R et al. Selective inhibition of vascular endothelial growth factor-mediated angiogenesis by cyclosporin A: roles of the nuclear factor of activated T cells and cyclooxygenase 2. J Exp Med 2001; 193: 607–620.

    Article  CAS  Google Scholar 

  8. Holler E, Kolb HJ, Hiller E, Mraz W, Lehmacher W, Gleixner B et al. Microangiopathy in patients on cyclosporine prophylaxis who developed acute graft-versus-host disease after HLA-identical bone marrow transplantation. Blood 1989; 73: 2018–2024.

    CAS  PubMed  Google Scholar 

  9. Lindner H, Holler E, Ertl B, Multhoff G, Schreglmann M, Klauke I et al. Peripheral blood mononuclear cells induce programmed cell death in human endothelial cells and may prevent repair: role of cytokines. Blood 1997; 89: 1931–1938.

    CAS  PubMed  Google Scholar 

  10. Wilasrusmee C, Da Silva M, Siddiqui J, Bruch D, Kittur S, Wilasrusmee S et al. Role of endothelin-1 in microvascular dysfunction caused by cyclosporin A. J Am Coll Surg 2003; 196: 584–591.

    Article  Google Scholar 

  11. Woywodt A, Schroeder M, Mengel M, Schwarz A, Gwinner W, Haller H et al. Circulating endothelial cells are a novel marker of cyclosporine-induced endothelial damage. Hypertension 2003; 41: 720–723.

    Article  CAS  Google Scholar 

  12. Furlan M, Lammle B . Aetiology and pathogenesis of thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome: the role of von Willebrand factor-cleaving protease. Best Pract Res Clin Haematol 2001; 14: 437–454.

    Article  CAS  Google Scholar 

  13. Elliott MA, Nichols Jr WL, Plumhoff EA, Ansell SM, Dispenzieri A, Gastineau DA et al. Posttransplantation thrombotic thrombocytopenic purpura: a single-center experience and a contemporary review. Mayo Clin Proc 2003; 78: 421–430.

    Article  Google Scholar 

  14. Busca A, Uderzo C . BMT: bone marrow transplant associated thrombotic microangiopathy. Hematology 2000; 5: 53–67.

    Article  Google Scholar 

  15. Fuge R, Bird JM, Fraser A, Hart D, Hunt L, Cornish JM et al. The clinical features, risk factors and outcome of thrombotic thrombocytopenic purpura occurring after bone marrow transplantation. Br J Haematol 2001; 113: 58–64.

    Article  CAS  Google Scholar 

  16. Hahn T, Alam AR, Lawrence D, Ford L, Baer MR, Bambach B et al. Thrombotic microangiopathy after allogeneic blood and marrow transplantation is associated with dose-intensive myeloablative conditioning regimens, unrelated donor, and methylprednisolone T-cell depletion. Transplantation 2004; 78: 1515–1522.

    Article  Google Scholar 

  17. 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: 1924–1929.

    Article  CAS  Google Scholar 

  18. Kanamori H, Takaishi Y, Takabayashi M, Tanaka M, Yamaji S, Tomita N et al. Clinical significance of fragmented red cells after allogeneic bone marrow transplantation. Int J Hematol 2003; 77: 180–184.

    Article  Google Scholar 

  19. Ruutu T, Barosi G, Benjamin RJ, Clark RE, George JN, Gratwohl A et al. Diagnostic criteria for hematopoietic stem cell transplantation associated microangiopathy (TAM): results of the consensus process by an International working group. Blood 2005; 106: Abstract 120a.

  20. Daly AS, Hasegawa WS, Lipton JH, Messner HA, Kiss TL . Transplantation-associated thrombotic microangiopathy is associated with transplantation from unrelated donors, acute graft-versus-host disease and venoocclusive disease of the liver. Transfus Apheresis Sci 2002; 27: 3–12.

    Article  Google Scholar 

  21. Uderzo C, Fumagalli M, De Lorenzo P, Busca A, Vassallo E, Bonanomi S et al. Impact of thrombotic thrombocytopenic purpura on leukemic children undergoing bone marrow transplantation. Bone Marrow Transplant 2000; 26: 1005–1009.

    Article  CAS  Google Scholar 

  22. Bayik MM, Akoglu T, Tuglular TF, Akoglu E, Tezal M, Ulutin O et al. Treatment of thrombotic thrombocytopenic purpura with defibrotid. Am J Hematol 1993; 43: 74–75.

    Article  CAS  Google Scholar 

  23. Corti P, Uderzo C, Tagliabue A, Della VA, Annaloro C, Tagliaferri E et al. Defibrotide as a promising treatment for thrombotic thrombocytopenic purpura in patients undergoing bone marrow transplantation. Bone Marrow Transplant 2002; 29: 542–543.

    Article  CAS  Google Scholar 

  24. Pogliani EM, Perseghin P, Parma M, Pioltelli P, Corneo G . Defibrotide in recurrent thrombotic thrombocytopenic purpura. Clin Appl Thromb Hemost 2000; 6: 69–70.

    Article  CAS  Google Scholar 

  25. Vangelista A, Frasca GM, Raimondi C, Liviano-D'Arcangelo G, Bonomini V . Effects of defibrotide in acute renal failure due to thrombotic microangiopathy. Haemostasis 1986; 16 (Suppl 1): 51–54.

    PubMed  Google Scholar 

  26. Ho VT, Cutler C, Carter S, Martin P, Adams R, Horowitz M et al. Blood and marrow transplant clinical trials network toxicity committee consensus summary: thrombotic microangiopathy after hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2005; 11: 571–575.

    Article  Google Scholar 

  27. Allford SL, Bird JM, Marks DI . Thrombotic thrombocytopenic purpura following stem cell transplantation. Leuk Lymphoma 2002; 43: 1921–1926.

    Article  Google Scholar 

  28. Pettitt AR, Clark RE . Thrombotic microangiopathy following bone marrow transplantation. Bone Marrow Transplant 1994; 14: 495–504.

    CAS  PubMed  Google Scholar 

  29. Teruya J, Styler M, Verde S, Topolsky D, Crilley P . Questionable efficacy of plasma exchange for thrombotic thrombocytopenic purpura after bone marrow transplantation. J Clin Apheresis 2001; 16: 169–174.

    Article  CAS  Google Scholar 

  30. Hingorani SR, Guthrie K, Batchelder A, Schoch G, Aboulhosn N, Manchion J et al. Acute renal failure after myeloablative hematopoietic cell transplant: incidence and risk factors. Kidney Int 2005; 67: 272–277.

    Article  Google Scholar 

  31. Noel C, Hazzan M, Noel-Walter MP, Jouet JP . Renal failure and bone marrow transplantation. Nephrol Dial Transplant 1998; 13: 2464–2466.

    Article  CAS  Google Scholar 

  32. Parikh CR, McSweeney PA, Korular D, Ecder T, Merouani A, Taylor J et al. Renal dysfunction in allogeneic hematopoietic cell transplantation. Kidney Int 2002; 62: 566–573.

    Article  Google Scholar 

  33. Zager RA, O'Quigley J, Zager BK, Alpers CE, Shulman HM, Gamelin LM et al. Acute renal failure following bone marrow transplantation: a retrospective study of 272 patients. Am J Kidney Dis 1989; 13: 210–216.

    Article  CAS  Google Scholar 

  34. Pulla B, Barri YM, Anaissie E . Acute renal failure following bone marrow transplantation. Renal Fail 1998; 20: 421–435.

    Article  CAS  Google Scholar 

  35. Tran HT, Acharya MK, McKay DB, Sayegh MH, Carpenter CB, Auchincloss Jr H et al. Avoidance of cyclosporine in renal transplantation: effects of daclizumab, mycophenolate mofetil, and steroids. J Am Soc Nephrol 2000; 11: 1903–1909.

    CAS  PubMed  Google Scholar 

  36. Oberholzer J, Triponez F, Martin PY, Williamson C, Morel P . Daclizumab as escape therapy for late acute kidney rejection in the presence of FK506 nephrotoxicity. Transplant Int 2000; 13: 169–171.

    Article  CAS  Google Scholar 

  37. 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: 83–89.

    CAS  PubMed  Google Scholar 

  38. Willenbacher W, Basara N, Blau IW, Fauser AA, Kiehl MG . Treatment of steroid refractory acute and chronic graft-versus-host disease with daclizumab. Br J Haematol 2001; 112: 820–823.

    Article  CAS  Google Scholar 

  39. Wolff D, Roessler V, Steiner B, Wilhelm S, Weirich V, Brenmoehl J et al. Treatment of steroid-resistant acute graft-versus-host disease with daclizumab and etanercept. Bone Marrow Transplant 2005; 35: 1003–1010.

    Article  CAS  Google Scholar 

  40. Emre S, Gondolesi G, Polat K, Ben Haim M, Artis T, Fishbein TM et al. Use of daclizumab as initial immunosuppression in liver transplant recipients with impaired renal function. Liver Transplant 2001; 7: 220–225.

    Article  CAS  Google Scholar 

  41. Goebel J, Stevens E, Forrest K, Roszman TL . Daclizumab (Zenapax) inhibits early interleukin-2 receptor signal transduction events. Transpl Immunol 2000; 8: 153–159.

    Article  CAS  Google Scholar 

  42. Silva VA, Frei-Lahr D, Brown RA, Herzig GP . Plasma exchange and vincristine in the treatment of hemolytic uremic syndrome/thrombotic thrombocytopenic purpura associated with bone marrow transplantation. J Clin Apheresis 1991; 6: 16–20.

    Article  CAS  Google Scholar 

  43. Zeigler ZR, Shadduck RK, Nemunaitis J, Andrews DF, Rosenfeld CS . Bone marrow transplant-associated thrombotic microangiopathy: a case series. Bone Marrow Transplant 1995; 15: 247–253.

    CAS  PubMed  Google Scholar 

  44. Biedermann BC, Sahner S, Gregor M, Tsakiris DA, Jeanneret C, Pober JS et al. Endothelial injury mediated by cytotoxic T lymphocytes and loss of microvessels in chronic graft versus host disease. Lancet 2002; 359: 2078–2083.

    Article  Google Scholar 

  45. Biedermann BC, Tsakiris DA, Gregor M, Pober JS, Gratwohl A . Combining altered levels of effector transcripts in circulating T cells with a marker of endothelial injury is specific for active graft-versus-host disease. Bone Marrow Transplant 2003; 32: 1077–1084.

    Article  CAS  Google Scholar 

  46. Chopra R, Eaton JD, Grassi A, Potter M, Shaw B, Salat C et al. Defibrotide for the treatment of hepatic veno-occlusive disease: results of the European compassionate-use study. Br J Haematol 2000; 111: 1122–1129.

    Article  CAS  Google Scholar 

  47. Lee SJ, Zahrieh D, Agura E, MacMillan ML, Maziarz RT, McCarthy Jr PL et al. Effect of up-front daclizumab when combined with steroids for the treatment of acute graft-versus-host disease: results of a randomized trial. Blood 2004; 104: 1559–1564.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Haematology and Oncology, University of Rostock, Rostock, Germany

    D Wolff, S Wilhelm, I Hilgendorf, B Steiner, C Kahl, C Junghanss, G Hartung, J Casper & M Freund

  2. Department of Haematology/Oncology, University Hospital of Regensburg, Regensburg, Germany

    J Hahn & E Holler

  3. Department of Internal Medicine III, Campus Benjamin Franklin, Charité – University Hospital Berlin, Berlin, Germany

    C Gentilini & L Uharek

Authors
  1. D Wolff
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S Wilhelm
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J Hahn
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. C Gentilini
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. I Hilgendorf
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. B Steiner
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. C Kahl
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. C Junghanss
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. G Hartung
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. J Casper
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. L Uharek
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. E Holler
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. M Freund
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to D Wolff.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wolff, D., Wilhelm, S., Hahn, J. et al. Replacement of calcineurin inhibitors with daclizumab in patients with transplantation-associated microangiopathy or renal insufficiency associated with graft-versus-host disease. Bone Marrow Transplant 38, 445–451 (2006). https://doi.org/10.1038/sj.bmt.1705454

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.bmt.1705454

Keywords

This article is cited by

Search

Advanced search

Quick links