Skip to main content

Advertisement

SpringerLink
Log in

Methotrexate dose delivery is more important than ciclosporin level in graft-versus-host disease prophylaxis following T-replete reduced-intensity sibling allogeneic stem cell transplant

  • Original Article
  • Published:
International Journal of Hematology Aims and scope Submit manuscript

Abstract

We investigated the contributions of methotrexate (MTX) and ciclosporin (CsA) prophylaxis to acute/chronic graft-versus-host disease (a/cGvHD) prevention following reduced-intensity conditioned allogeneic haematopoietic stem cell transplant (HSCT). Ninety-two fludarabine–melphalan sibling allo-SCT received CsA. Nine, 30 and 47 patients received no MTX, 2–3 doses and 4 doses, respectively. Cumulative CsA blood level to day 21 (CsA21) was calculated. Grades II–IV aGvHD incidence was 37.2%. In multivariate analysis, MTX omission and increasing donor age significantly associated with aGvHD incidence whilst MTX reduction and CsA21 did not. Median duration of first immunosuppressive therapy (IST) for aGvHD was 68 days; duration of first IST was significantly longer in older patients but was not associated with MTX or CsA21. Extensive cGvHD incidence was 60.6% at 1 year. Reduction of MTX to 2–3 doses, but not MTX omission or CsA21, was associated with greater incidence of cGvHD affecting ≥3 organs. Median IST duration was 22 months; neither MTX nor CsA21 influenced this. IST duration was significantly greater in patients receiving a CD34 dose below median. Neither MTX nor CsA21 altered survival or relapse outcomes. MTX influences GvHD following T-replete RIC sibling HSCT.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Gratwohl A, Baldomero H, Schwendener A, Rocha V, Apperley J, Frauendorfer K, et al. The EBMT activity survey 2007 with focus on allogeneic HSCT for AML and novel cellular therapies. Bone Marrow Transplant. 2009;43:275–91.

    Article  CAS  PubMed  Google Scholar 

  2. Kottaridis PD, Milligan DW, Chopra R, Chakraverty RK, Chakrabarti S, Robinson S, et al. In vivo CAMPATH-1H prevents graft-versus-host disease following nonmyeloablative stem cell transplantation. Blood. 2000;96:2419–25.

    CAS  PubMed  Google Scholar 

  3. Chakrabarti S, MacDonald D, Hale G, Holder K, Turner V, Czarnecka H, et al. T-cell depletion with Campath-1h “in the bag” for matched related allogeneic peripheral blood stem cell transplantation is associated with reduced graft-versus-host disease, rapid immune constitution and improved survival. Br J Haematol. 2003;121:109–18.

    Article  PubMed  Google Scholar 

  4. Delgado J, Pillai S, Benjamin R, Caballero D, Martino R, Nathwani A, et al. The effect of in vivo T cell depletion with alemtuzumab on reduced-intensity allogeneic hematopoietic cell transplantation for chronic lymphocytic leukemia. Biol Blood Marrow Transplant. 2008;14:1288–97.

    Article  CAS  PubMed  Google Scholar 

  5. Malladi RK, Peniket AJ, Littlewood TJ, Towlson KE, Pearce R, Yin J, et al. Alemtuzumab markedly reduces chronic GVHD without affecting overall survival in reduced-intensity conditioning sibling allo-SCT for adults with AML. Bone Marrow Transplant. 2009;43:709–15.

    Article  CAS  PubMed  Google Scholar 

  6. Pérez-Simón JA, Kottaridis PD, Martino R, Craddock C, Caballero D, Chopra R, et al. Nonmyeloablative transplantation with or without alemtuzumab: comparison between 2 prospective studies in patients with lymphoproliferative disorders. Blood. 2002;100:3121–7.

    Article  PubMed  Google Scholar 

  7. Couriel DR, Saliba RM, Giralt S, Khouri I, Andersson B, de Lima M, et al. Acute and chronic graft-versus-host disease after ablative and nonmyeloablative conditioning for allogeneic hematopoietic transplantation. Biol Blood Marrow Transplant. 2004;10:178–85.

    Article  PubMed  Google Scholar 

  8. Mielcarek M, Martin PJ, Leisenring W, Flowers ME, Maloney DG, Sandmaier BM, et al. Graft-versus-host disease after nonmyeloablative versus conventional hematopoietic stem cell transplantation. Blood. 2003;102:756–62.

    Article  CAS  PubMed  Google Scholar 

  9. Pérez-Simón JA, Díez-Campelo M, Martino R, Brunet S, Urbano A, Caballero MD, et al. Influence of the intensity of the conditioning regimen on the characteristics of acute and chronic graft-versus-host disease after allogeneic transplantation. Br J Haematol. 2005;130:394–403.

    Article  PubMed  Google Scholar 

  10. Pérez-Simón JA, Encinas C, Silva F, Arcos MJ, Díez-Campelo M, Sánchez-Guijo FM, et al. Prognostic factors of chronic graft-versus-host disease following allogeneic peripheral blood stem cell transplantation: the National Institutes Health Scale plus the type of onset can predict survival rates and the duration of immunosuppressive therapy. Biol Blood Marrow Transplant. 2008;14:1163–71.

    Article  PubMed  Google Scholar 

  11. Fraser CJ, Bhatia S, Ness K, Carter A, Francisco L, Arora M, et al. Impact of chronic graft-versus-host disease on the health status of hematopoietic cell transplantation survivors: a report from the bone marrow transplant survivor study. Blood. 2006;108:2867–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Lee JH, Lee JH, Choi SJ, Kim S, Seol M, Lee YS, et al. Graft-versus-host disease (GVHD)-specific survival and duration of systemic immunosuppressive treatment in patients who developed chronic GVHD following allogeneic haematopoietic cell transplantation. Br J Haematol. 2003;122:637–44.

    Article  PubMed  Google Scholar 

  13. Stewart BL, Storer B, Storek J, Deeg HJ, Storb R, Hansen JA, et al. Duration of immunosuppressive treatment for chronic graft-versus-host disease. Blood. 2004;104:3501–6.

    Article  CAS  PubMed  Google Scholar 

  14. Sullivan KM, Deeg HJ, Sanders J, Klosterman A, Amos D, Shulman H, et al. Hyperacute graft-v-host disease in patients not given immunosuppression after allogeneic marrow transplantation. Blood. 1986;67:1172–5.

    CAS  PubMed  Google Scholar 

  15. Mrsić M, Labar B, Bogdanić V, Nemet D, Pavletić Z, Plavsić F, et al. Combination of cyclosporin and methotrexate for prophylaxis of acute graft-versus-host disease after allogeneic bone marrow transplantation for leukemia. Bone Marrow Transplant. 1990;6:137–41.

    PubMed  Google Scholar 

  16. Storb R, Deeg HJ, Whitehead J, Appelbaum F, Beatty P, Bensinger W, et al. Methotrexate and cyclosporine compared with cyclosporine alone for prophylaxis of acute graft versus host disease after marrow transplantation for leukemia. N Engl J Med. 1986;314:729–35.

    Article  CAS  PubMed  Google Scholar 

  17. Storb R, Deeg HJ, Farewell V, Doney K, Appelbaum F, Beatty P, et al. Marrow transplantation for severe aplastic anemia: methotrexate alone compared with a combination of methotrexate and cyclosporine for prevention of acute graft-versus-host disease. Blood. 1986;68:119–25.

    CAS  PubMed  Google Scholar 

  18. Storb R, Deeg HJ, Pepe M, Appelbaum F, Anasetti C, Beatty P, et al. Methotrexate and cyclosporine versus cyclosporine alone for prophylaxis of graft-versus-host disease in patients given HLA-identical marrow grafts for leukemia: long-term follow-up of a controlled trial. Blood. 1989;73:1729–34.

    CAS  PubMed  Google Scholar 

  19. Kumar S, Wolf RC, Chen MG, Gastineau DA, Gertz MA, Inwards DJ, et al. Omission of day +11 methotrexate after allogeneic bone marrow transplantation is associated with increased risk of severe acute graft-versus-host disease. Bone Marrow Transplant. 2002;30:161–5.

    Article  CAS  PubMed  Google Scholar 

  20. 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 

  21. Hale G, Zhang MJ, Bunjes D, Prentice HG, Spence D, Horowitz MM, et al. Improving the outcome of bone marrow transplantation by using CD52 monoclonal antibodies to prevent graft-versus-host disease and graft rejection. Blood. 1998;92:4581–90.

    CAS  PubMed  Google Scholar 

  22. Hale G, Jacobs P, Wood L, Fibbe WE, Barge R, Novitzky N, et al. CD52 antibodies for prevention of graft-versus-host disease and graft rejection following transplantation of allogeneic peripheral blood stem cells. Bone Marrow Transplant. 2000;26:69–76.

    Article  CAS  PubMed  Google Scholar 

  23. Malard F, Szydlo RM, Brissot E, Chevallier P, Guillaume T, Delaunay J, et al. Impact of cyclosporine-a concentration on the incidence of severe acute graft-versus-host disease after allogeneic stem cell transplantation. Biol Blood Marrow Transplant. 2010;16:28–34.

    Article  CAS  PubMed  Google Scholar 

  24. Craddock C, Nagra S, Peniket A, Brookes C, Buckley L, Nikolousis E, et al. Factors predicting long term survival after T cell depleted reduced intensity allogeneic stem cell transplantation for acute myeloid leukemia. Haematologica. 2009;95(6):989–95.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Thepot S, Zhou J, Perrot A, Robin M, Xhaard A, de Latour RP, et al. The graft-versus-leukemia effect is mainly restricted to NIH-defined chronic graft-versus-host disease after reduced intensity conditioning before allogeneic stem cell transplantation. Leukemia. 2010;24:1852–8.

    Article  CAS  PubMed  Google Scholar 

  26. Giralt S, Estey E, Albitar M, van Besien K, Rondón G, Anderlini P, et al. Engraftment of allogeneic hematopoietic progenitor cells with purine analog-containing chemotherapy: harnessing graft-versus-leukemia without myeloablative therapy. Blood. 1997;89:4531–6.

    CAS  PubMed  Google Scholar 

  27. 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 HLA-matched sibling donors. Transplantation. 1974;18:295–304.

    Article  CAS  PubMed  Google Scholar 

  28. Shulman HM, Sullivan KM, Weiden PL, McDonald GB, Striker GE, Sale GE, et al. Chronic graft-versus-host syndrome in man. A long-term clinicopathologic study of 20 Seattle patients. Am J Med. 1980;69:204–17.

    Article  CAS  PubMed  Google Scholar 

  29. 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 Transplant. 2005;11:945–56.

    Article  PubMed  Google Scholar 

  30. Fine JP, Gray RJ. A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc. 1999;94:496–509.

    Article  Google Scholar 

  31. Martin PJ, Schoch G, Fisher L, Byers V, Anasetti C, Appelbaum FR, et al. A retrospective analysis of therapy for acute graft-versus-host disease: initial treatment. Blood. 1990;76:1464–72.

    CAS  PubMed  Google Scholar 

  32. Murashige N, Kami M, Mori S, Katayama Y, Kobayashi K, Onishi Y, et al. Characterization of acute graft-versus-host disease following reduced-intensity stem-cell transplantation from an HLA-identical related donor. Am J Hematol. 2008;83:630–4.

    Article  CAS  PubMed  Google Scholar 

  33. Storb R, Antin JH, Cutler C. Should methotrexate plus calcineurin inhibitors be considered standard of care for prophylaxis of acute graft-versus-host disease? Biol Blood Marrow Transplant. 2010;16:S18–27.

    Article  CAS  PubMed  Google Scholar 

  34. Vigouroux S, Tabrizi R, Melot C, Coiffard J, Lafarge X, Marit G, et al. Methotrexate reduces the incidence of severe acute graft-versus-host disease without increasing the risk of relapse after reduced-intensity allogeneic stem cell transplantation from unrelated donors. Biol Blood Marrow Transplant. 2011;17:93–100.

    Article  CAS  PubMed  Google Scholar 

  35. Kollman C, Howe CWS, Anasetti C, Antin JH, Davies SM, Filipovich AH, et al. Donor characteristics as risk factors in recipients after transplantation of bone marrow from unrelated donors: the effect of donor age. Blood 2001;98:2043.

    Article  CAS  PubMed  Google Scholar 

  36. Ozawa S, Nakaseko C, Nishimura M, Maruta A, Cho R, Ohwada C, et al. Chronic graft-versus-host disease after allogeneic bone marrow transplantation from an unrelated donor: incidence, risk factors and association with relapse. A report from the Japan Marrow Donor Program. Br J Haematol. 2007;137:142–51.

    Article  PubMed  Google Scholar 

  37. Nash RA, Antin JH, Karanes C, Fay JW, Avalos BR, Yeager AM, et al. Phase 3 study comparing methotrexate and tacrolimus with methotrexate and cyclosporine for prophylaxis of acute graft-versus-host disease after marrow transplantation from unrelated donors. Blood. 2000;96:2062–8.

    CAS  PubMed  Google Scholar 

  38. Ratanatharathorn V, Nash RA, Przepiorka D, Devine SM, Klein JL, Weisdorf D, et al. Phase III study comparing methotrexate and tacrolimus (prograf, FK506) with methotrexate and cyclosporine for graft-versus-host disease prophylaxis after HLA-identical sibling bone marrow transplantation. Blood. 1998;92:2303–14.

    CAS  PubMed  Google Scholar 

  39. Mohty M, Bilger K, Jourdan E, Kuentz M, Michallet M, Bourhis JH, et al. Higher doses of CD34+ peripheral blood stem cells are associated with increased mortality from chronic graft-versus-host disease after allogeneic HLA-identical sibling transplantation. Leukemia. 2003;17:869–75.

    Article  CAS  PubMed  Google Scholar 

  40. Schultz KR, Nevill TJ, Balshaw RF, Toze CL, Corr T, Currie CJ, et al. Effect of gastrointestinal inflammation and age on the pharmacokinetics of oral microemulsion cyclosporin A in the first month after bone marrow transplantation. Bone Marrow Transplant. 2000;26:545–51.

    Article  CAS  PubMed  Google Scholar 

  41. Hendriks MP, Blijlevens NM, Schattenberg AV, Burger DM, Donnelly JP. Cyclosporine short infusion and C2 monitoring in haematopoietic stem cell transplant recipients. Bone Marrow Transplant. 2006;38:521–5.

    Article  CAS  PubMed  Google Scholar 

  42. Furukawa T, Kurasaki-Ida T, Masuko M, Tsukada N, Okazuka K, Sato N, et al. Pharmacokinetic and pharmacodynamic analysis of cyclosporine A (CsA) to find the best single time point for the monitoring and adjusting of CsA dose using twice-daily 3-h intravenous infusions in allogeneic hematopoietic stem cell transplantation. Int J Hematol. 2010;92:144–51.

    Article  CAS  PubMed  Google Scholar 

  43. Duncan N, Arrazi J, Nagra S, Cook M, Thomson AH, Craddock C. Prediction of intravenous cyclosporine area under the concentration-time curve after allogeneic stem cell transplantation. Ther Drug Monit. 2010;32:353–8.

    Article  CAS  PubMed  Google Scholar 

  44. Oran B, Giralt S, Saliba R, Hosing C, Popat U, Khouri I, et al. Allogeneic hematopoietic stem cell transplantation for the treatment of high-risk acute myelogenous leukemia and myelodysplastic syndrome using reduced-intensity conditioning with fludarabine and melphalan. Biol Blood Marrow Transplant. 2007;13:454–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

We would like to thank Mr Simon Littlewood and Dr Brian Shine for assistance with CsA level and engraftment data collection. This work was funded by the NIHR Biomedical Research Centre Programme.

Author information

Authors and Affiliations

  1. Department of Haematology, Oxford Radcliffe Hospitals NHS Trust, Cancer and Haematology Centre, Churchill Hospital, Old Road, Headington, Oxford, OX3 7LJ, UK

    Patrick Medd, Ian Monk, Ram Malladi, Ruth Clifford, Amanda Ellis, Chris Hatton, Paresh Vyas, Tim Littlewood & Andy Peniket

  2. Nuffield Department of Clinical and Laboratory Sciences, University of Oxford, Oxford, UK

    Robert Danby

  3. NHS Blood and Transplant Oxford Centre, Oxford, UK

    David Roberts

  4. Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK

    Paresh Vyas

Authors
  1. Patrick Medd
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ian Monk
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Robert Danby
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ram Malladi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ruth Clifford
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Amanda Ellis
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. David Roberts
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Chris Hatton
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Paresh Vyas
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Tim Littlewood
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Andy Peniket
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Patrick Medd.

About this article

Cite this article

Medd, P., Monk, I., Danby, R. et al. Methotrexate dose delivery is more important than ciclosporin level in graft-versus-host disease prophylaxis following T-replete reduced-intensity sibling allogeneic stem cell transplant. Int J Hematol 94, 266–278 (2011). https://doi.org/10.1007/s12185-011-0920-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12185-011-0920-x

Keywords

Search

Navigation