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

Risk factors for acute graft-versus-host disease grades II–IV after reduced intensity conditioning allogeneic stem cell transplantation with unrelated donors—a single centre study

Bone Marrow Transplantation volume 41, pages 399–405 (2008)Cite this article

Abstract

We analysed factors associated with moderate to severe acute GVHD in 111 patients treated with fludarabin-based reduced intensity conditioning (RIC) and allogeneic haematopoietic stem cell transplantation (HSCT). Most patients had a haematological malignancy. Donors were 97 HLA-A, -B and -DRβ1 identical unrelated and 14 HLA-A, -B or -DRβ1 allele mismatched unrelated donors. In the univariate analysis, we found ten factors associated with acute GVHD. These were diagnosis (P=0.06), GVHD prophylaxis with combinations other than CsA+MTX (P=0.006), graft nucleated (P<0.001) and CD34 (P<0.001) cell-dose, bidirectional ABO mismatch (P=0.001), conditioning (P=0.002), hospital vs home-care (P=0.06), ATG dose (P<0.001), donor herpes virus serology (P=0.07) and an immunized female donor to male recipient (P=0.05). In the multivariate analysis, three factors remained significant: a high CD34 cell dose (P<0.001), low dose (4 mg/kg) ATG (P<0.001), and an immunized female donor to male recipient (P<0.01). Patients receiving a CD34 cell dose ⩾17.0 × 106 per kg had a higher incidence of GVHD, 53.7%, compared to 22.3% in patients receiving a lower dose (P=0.002). In patients without any of these risk factors (n=70), the incidence of acute GVHD was 14.1%, while it was 38.0 and 85.0% in patients with one (n=29) or two (n=10) risk factors (P<0.001). We concluded that risk factors for acute GVHD using RIC are similar as using myeloablative conditioning.

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

Figure 1
Figure 2

Similar content being viewed by others

References

  1. Canals C, Martino R, Sureda A, Altes A, Briones J, Subira M et al. Strategies to reduce transplant-related mortality after allogeneic stem cell transplantation in elderly patients: comparison of reduced intensity conditioning and unmanipulated peripheral blood stem cells vs myeloablative regimen and CD34+ cell selection. Exp Hematol 2003; 31: 1039–1043.

    Article  CAS  PubMed  Google Scholar 

  2. Platzbecker U, Ehninger G, Schmitz N, Bornhauser M . Reduced-intensity conditioning followed by allogeneic hematopoietic transplantation in myeloid diseases. Ann Hematol 2003; 82: 463–468.

    Article  CAS  PubMed  Google Scholar 

  3. Gale RP, Bortin MM, van Bekkum DW, Biggs JC, Dicke KA, Gluckman E et al. Risk factors for acute graft-versus-host disease. Br J Haematol 1987; 67: 397–406.

    Article  CAS  PubMed  Google Scholar 

  4. Mohty M, Bay JO, Faucher C, Choufi B, Bilger K, Tournilhac O et al. Graft-versus-host disease following allogeneic transplantation from HLA-identical sibling with antithymocyte globulin-based reduced-intensity preparative regimen. Blood 2003; 102: 470–476.

    Article  CAS  PubMed  Google Scholar 

  5. Przepiorka D, Smith TL, Folloder J, Khouri I, Ueno NT, Mehra R et al. Risk factors for acute graft-versus-host disease after allogeneic blood stem cell transplantation. Blood 1999; 94: 1465–1470.

    CAS  PubMed  Google Scholar 

  6. Hägglund H, Boström L, Remberger M, Ljungman P, Nilsson B, Ringdén O . Risk factors for acute graft-versus-host disease in 291 consecutive HLA-identical bone marrow transplant recipients. Bone Marrow Transplant 1995; 16: 747–753.

    PubMed  Google Scholar 

  7. Schaffer M, Aldener-Cannava A, Remberger M, Ringden O, Olerup O . Roles of HLA-B, HLA-C and HLA-DPA1 incompatibilities in the outcome of unrelated stem-cell transplantation. Tissue Antigens 2003; 62: 243–250.

    Article  CAS  PubMed  Google Scholar 

  8. Storb R, Yu C, Barnett T, Wagner JL, Deeg HJ, Nash RA et al. Stable mixed hematopoietic chimerism in dog leukocyte antigen-identical littermate dogs given lymph node irradiation before and pharmacologic immunosuppression after marrow transplantation. Blood 1999; 94: 1131–1136.

    CAS  PubMed  Google Scholar 

  9. Slavin S, Nagler A, Naparstek E, Kapelushnik Y, Aker M, Cividalli G et al. Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and nonmalignant hematologic diseases. Blood 1998; 91: 756–763.

    CAS  PubMed  Google Scholar 

  10. Beelen DW, Trenschel R, Casper J, Freund M, Hilger RA, Scheulen ME et al. Dose-escalated treosulphan in combination with cyclophosphamide as a new preparative regimen for allogeneic haematopoietic stem cell transplantation in patients with an increased risk for regimen-related complications. Bone Marrow Transplant 2005; 35: 233–241.

    Article  CAS  PubMed  Google Scholar 

  11. Remberger M, Sundberg B . Cytokine production during myeloablative and reduced intensity therapy before allogeneic stem cell transplantation. Haematologica 2004; 89: 710–716.

    CAS  PubMed  Google Scholar 

  12. Hale G, Waldmann H . Control of graft-versus-host disease and graft rejection by T cell depletion of donor and recipient with Campath-1 antibodies. Results of matched sibling transplants for malignant diseases. Bone Marrow Transplant 1994; 13: 597–611.

    CAS  PubMed  Google Scholar 

  13. Remberger M, Svahn BM, Mattsson J, Ringden O . Dose study of thymoglobulin during conditioning for unrelated donor allogeneic stem-cell transplantation. Transplantation 2004; 78: 122–127.

    CAS  PubMed  Google Scholar 

  14. Ringdén O, Horowitz M, Sondel P, Gale RP, Biggs JC, Champlin RE et al. Methotrexate, cyclosporine or both to prevent graft-versus-host disease after HLA-identical sibling bone marrow transplants for early leukemia. Blood 1993; 18: 1094–1101.

    Google Scholar 

  15. Storb R, Deeg HJ, Fisher L, Appelbaum F, Buckner CD, Bensinger W et al. Cyclosporine v methotrexate for graft-v-host disease prevention in patients given marrow grafts for leukemia: long-term follow-up of three controlled trials. Blood 1988; 71: 293–298.

    CAS  PubMed  Google Scholar 

  16. Ringdén O, Remberger M, Carlens S, Hägglund H, Mattsson J, Aschan J et al. Low incidence of acute graft-versus-host disease, using unrelated HLA-A, -B and -DR compatible donors and conditioning, including anti-T-cell antibodies. Transplantation 1998; 66: 620–625.

    Article  PubMed  Google Scholar 

  17. Ringdén O, Remberger M, Persson U, Ljungman P, Aldener A, Andström E et al. Similar incidence of graft-versus-host disease using HLA-A, -B and -DR identical unrelated bone marrow donors as with HLA-identical siblings. Bone Marrow Transplant 1995; 15: 619–625.

    PubMed  Google Scholar 

  18. Carlens S, Aschan J, Remberger M, Dilber M, Ringdén O . Low dose cyclosporine of short duration increases the risk of mild and moderate GVHD and reduces the risk of relapse in HLA-identical sibling marrow transplant recipients with leukemia. Bone Marrow Transplant 1999; 24: 629–635.

    Article  CAS  PubMed  Google Scholar 

  19. Hägglund H, Ringdén O, Öhman S, Remberger M, Carlens S, Mattsson J . A prospective randomized trial of Filgrastim (r-metHuG-CSF) given at different times after unrelated bone marrow transplantation. Bone Marrow Transplant 1998; 24: 831–836.

    Article  Google Scholar 

  20. Remberger M, Naseh N, Aschan J, Barkholt L, LeBlanc K, Svennberg P et al. G-CSF given after haematopoietic stem cell transplantation using HLA-identical sibling donors is associated to a higher incidence of acute GVHD II–IV. Bone Marrow Transplant 2003; 32: 217–223.

    Article  CAS  PubMed  Google Scholar 

  21. Svahn BM, Remberger M, Myrbäck KE, Holmberg K, Eriksson B, Hentschke P et al. Home care during the pancytopenic phase after allogeneic hematopoietic stem cell transplantation is advantageous compared with hospital care. Blood 2002; 100: 4317–4324.

    Article  CAS  PubMed  Google Scholar 

  22. Remberger M, Ringdén O, Blau I, Ottinger H, Kremens B, Kiehl MG et al. No difference in graft-versus-host disease, relapse and survival comparing peripheral stem cells with bone marrow using unrelated donors. Blood 2001; 98: 1739–1745.

    Article  CAS  PubMed  Google Scholar 

  23. 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: 825–828.

    CAS  PubMed  Google Scholar 

  24. Ringdén O, Båryd I, Gahrton G . Early treatment and prophylaxis of graft-versus-host disease using prednisolone. Excerpta Med Bone Marrow Transplant Eur 1981; 2: 171–177.

    Google Scholar 

  25. Ringden 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: 1390–1397.

    Article  PubMed  Google Scholar 

  26. Ringdén O . Management of graft-versus-host disease. Eur J Haematol 1993; 51: 1–12.

    Article  PubMed  Google Scholar 

  27. Sparrelid E, Hagglund H, Remberger M, Ringdén O, Lönnqvist B, Ljungman P et al. Bacteraemia during the aplastic phase after allogeneic bone marrow transplantation is associated with early death from invasive fungal infection. Bone Marrow Transplant 1998; 22: 795–800.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Ljungman P, Griffiths P, Paya C . Definitions of cytomegalovirus infection and disease in transplant recipients. Clin Infect Dis 2002; 34: 1094–1097.

    Article  PubMed  Google Scholar 

  29. Ljungman P, Lore K, Aschan J, Klaesson S, Lewensohn-Fuchs I, lönnqvist B et al. Use of a semi-quantitative PCR for cytomegalovirus DNA as a basis for pre-emptive antiviral therapy in allogeneic bone marrow transplant patients. Bone Marrow Transplant 1996; 17: 583–587.

    CAS  PubMed  Google Scholar 

  30. Kaplan E, Meier P . Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 457–481.

    Article  Google Scholar 

  31. Gooley T, Leisenring W, Crowley J, Storer B . Estimation of failure probabilities in the presence of competing risks: new representations of old estimators. Stat Med 1999; 18: 695–706.

    Article  CAS  PubMed  Google Scholar 

  32. Fine J, Gray R . Proportional hazard model for the sub-distribution of competing risks. J Am Stat Assoc 1999; 94: 496–509.

    Article  Google Scholar 

  33. Russell JA, Turner AR, Larratt L, Chaundhry A, Morris D, Brown C et al. Adult recipients of matched related donor blood cell transplants given myeloablative regimens including pretransplant antithymocyte globulin have lower mortality related to graft-versus-host disease: a matched pair analysis. Biol Blood Marrow Transplant 2007; 13: 299–306.

    Article  CAS  PubMed  Google Scholar 

  34. Basara N, Baurmann H, Kolbe K, Yaman A, Labopin M, Burchardt A et al. Antithymocyte globulin for the prevention of graft-versus-host disease after unrelated hematopoietic stem cell transplantation for acute myeloid leukemia: results from the multicenter German cooperative study group. Bone Marrow Transplant 2005; 35: 1011–1018.

    Article  CAS  PubMed  Google Scholar 

  35. Schleuning M, Gunther W, Tischer J, Ledderose G, Kolb H-J . Dose-dependent effects of in vitro antithymocyte globulin during conditioning for allogeneic bone marrow transplantation from unrelated donors in patients with chronic phase CML. Bone Marrow Transplant 2003; 32: 243–250.

    Article  CAS  PubMed  Google Scholar 

  36. Duggan P, Booth K, Chaudhry A, Steward D, Ruether JD, Gluck S et al. Unrelated donor BMT recipients given pretransplant low-dose antithymocyte globulin have outcomes equivalent to matched sibling BMT: a matched pair analysis. Bone Marrow Transplant 2002; 30: 681–686.

    Article  CAS  PubMed  Google Scholar 

  37. Bacigalupo A, Lamparelli T, Bruzzi P, Guidi S, Alessandrino PE, di Bartolomeo P et al. Antithymocyte globulin for graft-versus-host disease prophylaxis in transplants from unrelated donors: 2 randomized studies from Gruppo Italiano Trapianti Midollo Osseo (GITMO). Blood 2001; 98: 2942–2947.

    Article  CAS  PubMed  Google Scholar 

  38. Zander A, Kröger N, Schleuning M, Finke J, Zabelina T, Beelen D et al. ATG as part of the conditioning regimen reduces transplant-related mortality (TRM) and improves overall survival after unrelated stem cell transplantation in patients with chronic myelogenous leukemia (CML). Bone Marrow Transplant 2003; 32: 355–361.

    Article  CAS  PubMed  Google Scholar 

  39. Byrne JL, Stainer C, Cull G, Haynes AP, Bessell EM, Hale G et al. The effect of the serotherapy regimen used and the marrow cell dose received on rejection, graft-versus-host disease and outcome following unrelated donor bone marrow transplantation for leukaemia. Bone Marrow Transplant 2000; 25: 411–417.

    Article  CAS  PubMed  Google Scholar 

  40. Atkinson K, Horowitz MM, Gale RP, van Bekkum DW, Gluckman E, Good RA et al. Risk factors for chronic graft-versus-host disease after HLA-identical sibling bone marrow transplantation. Blood 1990; 75: 2459–2464.

    CAS  PubMed  Google Scholar 

  41. Ringdén O, Barrett J, Zhang MJ, Loberiza FR, Bolwell BJ, Cairo MS et al. Decreased treatment failure in recipients of HLA-identical bone marrow or peripheral blood stem cell transplants with high CD34 cell doses. Br J Haematol 2003; 121: 874–885.

    Article  PubMed  Google Scholar 

  42. Ringdén O, Pihlstedt P, Markling L, Aschan J, Båryd I, Ljungman P et al. Prevention of graft-versus-host disease with T-cell depletion or cyclosporin and methotrexate. A randomized trial in adult leukemic marrow recipients. Bone Marrow Transplantation 1991; 7: 221–226.

    PubMed  Google Scholar 

  43. Goldman J, Gale R, Horowitz M, Biggs JC, Champlin RE, Gluckman E et al. Bone marrow transplantation for chronic myelogenous leukemia in chronic phase: increased risk of relapse associated with T-cell depletion. Ann Int Med 1988; 108: 806–814.

    Article  CAS  PubMed  Google Scholar 

  44. Brenner MK, Grob JP, Prentice HG . The use of monoclonal antibodies in graft versus host disease prevention. Haematologia 1986; 19: 167–176.

    CAS  PubMed  Google Scholar 

  45. Le Blanc K, Remberger M, Uzunel M, Mattsson J, Barkholt L, Ringden O . A comparison of nonmyeloablative and reduced-intensity conditioning for allogeneic stem-cell transplantation. Transplantation 2004; 78: 1014–1020.

    Article  CAS  PubMed  Google Scholar 

  46. Bacigalupo A, Van Lint MT, Occhini D, Margiocco M, Ferrari G, Pittaluga PA et al. ABO compatibility and acute graft-versus-host disease following allogeneic bone marrow transplantation. Transplantation 1988; 45: 1091–1094.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This study was supported by grants from the Swedish Cancer Society (0070-B03-17XBC), the Children's Cancer Foundation (03/039), the Swedish Research Council (K2003-32X-05971-23A), the Tobias Foundation, the Stockholm Cancer Society, the Swedish Medical Society and the Karolinska Institutet.

Author information

Authors and Affiliations

  1. Department of Clinical Immunology and Centre for Allogeneic Stem Cell Transplantation, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden

    M Remberger, J Mattsson, Z Hassan, N Karlsson, K LeBlanc, B Omazic, M Okas, D Sairafi & O Ringdén

Authors
  1. M Remberger
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J Mattsson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Z Hassan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. N Karlsson
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. K LeBlanc
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. B Omazic
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. M Okas
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. D Sairafi
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. O Ringdén
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M Remberger.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Remberger, M., Mattsson, J., Hassan, Z. et al. Risk factors for acute graft-versus-host disease grades II–IV after reduced intensity conditioning allogeneic stem cell transplantation with unrelated donors—a single centre study. Bone Marrow Transplant 41, 399–405 (2008). https://doi.org/10.1038/sj.bmt.1705913

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.bmt.1705913

Keywords

This article is cited by

Search

Advanced search

Quick links