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

Folinic acid administration following MTX as prophylaxis for GVHD in allogeneic HSCT centres in Australia and New Zealand

Bone Marrow Transplantation volume 42, pages 547–550 (2008)Cite this article

Abstract

The use of MTX for GVHD prophylaxis may be associated with significant toxicity, including hepatotoxicity, graft failure and mucositis. Folinic acid may be involved in the amelioration of MTX toxicity. There is, however, no consensus regarding its use. A survey was conducted in Australian and New Zealand transplant centres (n=22) regarding the use of folinic acid following MTX in the transplant setting. Of 18 participating transplant centres, 12 (66%) used folinic acid following MTX—8 (44%) routinely and 4 (22%) only in the presence of significant mucositis. Those centres that did not use routine dosing of folinic acid post transplant chose not to do so on the grounds that they believed that it was not efficacious or may increase the risk of GVHD. Grading of mucositis was inconsistently done. There is wide variation in the use of folinic acid following HSCT. Folinic acid is infrequently used in the adult transplant setting or is used after mucositis is already apparent, practices that appear to run counter to available clinical evidence and to pharmacological data. Further research is required to conclusively determine whether folinic acid has any benefit in the post-BMT setting.

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. Wardley AM, Jayson GC, Swindell R, Morgenstern GR, Chang J, Bloor R et al. Prospective evaluation of oral mucositis in patients receiving myeloablative conditioning regimens and haematopoietic progenitor rescue. Br J Haematol 2000; 110: 292–299.

    Article  CAS  PubMed  Google Scholar 

  2. Bellm LA, Epstein JB, Rose-Ped A, Martin P, Fuchs HJ . Patient reports of complications of bone marrow transplantation. Support Care Cancer 2000; 8: 33–39.

    CAS  PubMed  Google Scholar 

  3. O’Brien SN, Blijlevens NM, Mahfouz TH, Anaissie EJ . Infections in patients with haematological cancer: recent developments. ASH Education Book. Hematology 2003, 438–472.

    Article  Google Scholar 

  4. Sonis ST, Oster G, Fuchs H, Bellm L, Bradford WZ, Edelsberg J et al. Oral mucositis and the clinical and economic outcomes of hematopoietic stem cell transplantation. J Clin Oncol 2001; 19: 2201–2205.

    Article  CAS  PubMed  Google Scholar 

  5. Peterson DE, Cariello A . Mucosal damage: a major risk factor for severe complications after cytotoxic therapy. Semin Onco 2004; 31 (3 Suppl 8): 35–44.

    Article  CAS  Google Scholar 

  6. Blijlevens NM, Donnelly JP, De Pauw BE . Mucosal barrier injury: biology, pathology, clinical counterparts and consequences of intensive treatment for hematological malignancy: an overview. Bone Marrow Transplant 2000; 25: 1269–1278.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Niscola P, Romani C, Cupelli L, Scaramucci L, Tendas A, Dentamaro T et al. Mucositis in patients with hematologic malignancies: an overview. Haematologica 2007; 92: 222–231.

    Article  PubMed  Google Scholar 

  8. Crom WR, Evans WE . Methotrexate: applied pharmacokinetics. Principles of Therapeutic Drug Monitoring, 3rd edn. Applied Therapeutics: Vancouver, BC, 1992, pp 1–42.

    Google Scholar 

  9. Bruce WR, Meeker BE, Valeriote FA . Comparison of the sensitivity of normal hematopoietic and transplanted lymphoma colony-forming cells to chemotherapeutic agents administered in vivo. J Natl Cancer Inst 1966; 37: 233–245.

    CAS  PubMed  Google Scholar 

  10. Genestier L, Paillot R, Fournel S, Ferraro C, Miossec P, Revillard JP . Immunosuppressive properties of methotrexate: apoptosis and clonal deletion of activated peripheral T cells. J Clinic Invest 1998; 102: 322–328.

    Article  CAS  Google Scholar 

  11. Devergie A, Esperou H, Traineau R, Varrin F, Lehn P, Gluckman E . Role of immunosuppressive drugs for prevention of graft-v-host disease after bone marrow transplantation. Nouv Rev Fr Hematol 1989; 31: 73–75.

    CAS  PubMed  Google Scholar 

  12. 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 Transplantation 2002; 30: 161–165.

    Article  CAS  PubMed  Google Scholar 

  13. Tollemar J, Ringden O, Heimdahl A, Lonnqvist B, Sundberg B . Decreased incidence and severity of graft-versus-host disease in HLA matched and mismatched marrow recipients of cyclosporine and methotrexate. Transplant Proc 1988; 20 (3 Suppl 3): 470–479.

    CAS  PubMed  Google Scholar 

  14. Strober BE, Menon K . Folate supplementation during methotrexate therapy for patients with psoriasis. J Am Acad Dermatol 2005; 53: 652–659.

    Article  PubMed  Google Scholar 

  15. Whittle SL, Hughes RA . Folate supplementation and methotrexate treatment in rheumatoid arthritis: a review. Rheumatology 2004; 43: 267–271.

    Article  CAS  PubMed  Google Scholar 

  16. Ortiz Z, Shea B, Suarez Almazor M, Moher D, Wells G, Tugwell P . Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis. Cochrane Database Syst Rev 2000; 2: 1–25 (CD000951).

    Google Scholar 

  17. Cohen IJ . Defining the appropriate dosage of folinic acid after high-dose methotrexate for childhood acute lymphatic leukaemia that will prevent neurotoxicity without rescuing malignant cells in the central nervous system. J Pediatr Hematol Oncol 2004; 26: 156–163.

    Article  PubMed  Google Scholar 

  18. Robien K, Schubert MM, Yasui Y, Martin P, Storb R, Potter JD et al. Folic acid supplementation during methotrexate immunosuppression is not associated with early toxicity, risk of acute graft-versus-host disease or relapse following hematopoietic transplantation. Bone Marrow Transplant 2006; 37: 687–692.

    Article  CAS  PubMed  Google Scholar 

  19. Torres A, Martinez F, Gomez P . Cyclosporin A versus methotrexate, followed by rescue with folinic acid as prophylaxis of acute graft-versus-host disease after bone marrow transplantation. Blut 1989; 58: 63–68.

    Article  CAS  PubMed  Google Scholar 

  20. Nevill TJ, Tirgan MH, Deeg HJ, Klingemann HG, Reece DE, Shepherd JD et al. Influence of post-methotrexate folinic acid rescue on regimen-related toxicity and graft-versus-host disease after allogeneic bone marrow transplantation. Bone Marrow Transplant 1992; 9: 349–354.

    CAS  PubMed  Google Scholar 

  21. Russell JA, Woodman RC, Poon MC, Jones AR, Ruether BA . Addition of low-dose folinic acid to a methotrexate/cyclosporin A regimen for prevention of acute graft-versus-host disease. Bone Marrow Transplant 1994; 14: 397–401.

    CAS  PubMed  Google Scholar 

  22. Ruutu T, Niederwieser D, Gratwohl A, Apperley JF . A survey of the prophylaxis and treatment of acute GVHD in Europe: a report of the European Group for Blood and Marrow, Transplantation (EBMT). Chronic Leukaemia Working Party of the EBMT. Bone Marrow Transplant 1997; 19: 759–764.

    Article  CAS  PubMed  Google Scholar 

  23. Peters C, Minkov M, Gadner H, European Group for Blood and Marrow Transplantation (EBMT) Working Party Paediatric Diseases; International BFM Study Group—Subcommittee Bone Marrow Transplantation (IBFM-SG). Statement of current majority practices in graft-versus-host disease prophylaxis and treatment in children. Bone Marrow Transplant 2000; 26: 405–411.

    Article  CAS  PubMed  Google Scholar 

  24. World Health Organization. Handbook for Reporting Results of Cancer Treatment. World Health Organization: Geneva, 1979, pp 15–22.

  25. Bearman SI, Applebaum FR, Buckner CD . Regimen-related toxicity in patients undergoing bone marrow transplantation. J Clin Oncol 1988; 6: 1562–1568.

    Article  CAS  PubMed  Google Scholar 

  26. National Cancer Institute Common Toxicity Criteria Version 2.0. http://www.fda.gov/cder/cancer/toxicityframe.htm.

  27. Schubert MM, Williams BE, Lloid ME, Donaldson G, Chapko MK . Clinical assessment scale for the rating of oral mucosal changes associated with bone marrow transplantation. Development of an oral mucositis index. Cancer 1992; 15: 2469–2477.

    Article  Google Scholar 

  28. Rapoport AP, Miller Watelet LF, Linder T, Eberly S, Raubertas RF, Lipp J et al. Analysis of factors that correlate with mucositis in recipients of autologous and allogeneic stem-cell transplants. J Clin Oncol 1999; 17: 2446–2453.

    Article  CAS  PubMed  Google Scholar 

  29. Storb R, Deeg HI, 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: 729–735.

    Article  CAS  PubMed  Google Scholar 

  30. Worthington HV, Clarkson JE, Eden OB . Interventions for preventing oral mucositis for patients with cancer receiving treatment. Cochrane Database Syst Rev 2006; 2: 1–93 (CD000978).

    Google Scholar 

  31. Beaven AW, Shea TC . Recombinant human keratinocyte growth factor, palifermin reduces oral mucositis and improves patient outcomes after stem cell transplant. Drugs Today 2007; 43: 461–473.

    Article  CAS  Google Scholar 

  32. Spielberger R, Stiff P, Bensinger W, Gentile T, Weisdorf D, Kewalramani T . Palifermin for oral mucositis after intensive therapy for haematological cancers. N Engl J Med 2004; 351: 2590–2598.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We acknowledge the assistance of all those transplant centres that participated in this research.

Author information

Authors and Affiliations

  1. Department of Haemato-Oncology, Rajiv Gandhi Cancer Institute and Research Center, New Delhi, India

    D Bhurani

  2. Department of Haematology, Westmead Hospital, Westmead, New South Wales, Australia

    M Schifter & I Kerridge

  3. Blood and Marrow Transplant Service, Westmead Hospital, Westmead, New South Wales, Australia

    M Schifter & I Kerridge

Authors
  1. D Bhurani
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M Schifter
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. I Kerridge
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to D Bhurani.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bhurani, D., Schifter, M. & Kerridge, I. Folinic acid administration following MTX as prophylaxis for GVHD in allogeneic HSCT centres in Australia and New Zealand. Bone Marrow Transplant 42, 547–550 (2008). https://doi.org/10.1038/bmt.2008.197

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/bmt.2008.197

Keywords

This article is cited by

Search

Advanced search

Quick links