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:

Cord Blood Stem Cells

Short-term methotrexate could reduce early immune reactions and improve outcomes in umbilical cord blood transplantation for adults

Abstract

Post transplant immune disorders are problematic in cord blood transplantation (CBT) for adult patients, and optimal prophylaxis has not been established. We investigated whether intensive graft-versus-host disease (GVHD) prophylaxis using short-term methotrexate (MTX) has a prognostic impact on CBT. Post-CBT immune reactions were classified according to time course as pre-engraftment immune reaction (PIR), engraftment syndrome (ES) or acute GVHD. Between March 2001 and November 2005, a total of 77 patients underwent CBT at eight transplantation centers. Median age was 48 years (range, 18–69 years). Preparative regimens comprised myeloablative (n=31) or reduced-intensity (n=46). Acute GVHD prophylaxis included cyclosporine alone (n=23), tacrolimus alone (n=12), cyclosporine plus MTX (n=17), tacrolimus plus short-term MTX (n=23) or cyclosporine plus methylprednisolone (n=2). Cumulative incidences of PIR, ES and grade II–IV GVHD were 36, 12 and 23%, respectively. Short-term MTX exerted significant favorable effects on post-CBT immune reactions (hazard ratio, 0.55; 95% confidence interval (95% CI), 0.31–0.98; P=0.04) in multivariate analysis. Overall survival rates for patients with and without short-term MTX at day 180 were 59% (95% CI, 42–73%) and 16% (95% CI, 6.6–30%) (P=0.0001), respectively. Short-term MTX could offer one optimal regimen to reduce immune reactions and improve outcomes in CBT.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  1. Miyakoshi S, Yuji K, Kami M, Kusumi E, Kishi Y, Kobayashi K et al. Successful engraftment after reduced-intensity umbilical cord blood transplantation for adult patients with advanced hematological diseases. Clin Cancer Res 2004; 10: 3586–3592.

    Article  PubMed  Google Scholar 

  2. Barker JN, Weisdorf DJ, DeFor TE, Blazar BR, Miller JS, Wagner JE . Rapid and complete donor chimerism in adult recipients of unrelated donor umbilical cord blood transplantation after reduced-intensity conditioning. Blood 2003; 102: 1915–1919.

    Article  CAS  PubMed  Google Scholar 

  3. Sanz GF, Saavedra S, Planelles D, Senent L, Cervera J, Barragan E et al. Standardized, unrelated donor cord blood transplantation in adults with hematologic malignancies. Blood 2001; 98: 2332–2338.

    Article  CAS  PubMed  Google Scholar 

  4. Goggins TF, Rizzieri DR . Nonmyeloablative allogeneic stem cell transplantation using alternative donors. Cancer Control 2004; 11: 86–96.

    Article  PubMed  Google Scholar 

  5. Rocha V, Labopin M, Sanz G, Arcese W, Schwerdtfeger R, Bosi A et al. Transplants of umbilical-cord blood or bone marrow from unrelated donors in adults with acute leukemia. N Engl J Med 2004; 351: 2276–2285.

    Article  CAS  PubMed  Google Scholar 

  6. Laughlin MJ, Eapen M, Rubinstein P, Wagner JE, Zhang M-J, Champlin RE et al. Outcomes after transplantation of cord blood or bone marrow from unrelated donors in adults with leukemia. N Engl J Med 2004; 351: 2265–2275.

    Article  CAS  PubMed  Google Scholar 

  7. Koh LP, Chao NJ . Umbilical cord blood transplantation in adults using myeloablative and nonmyeloablative preparative regimens. Biol Blood Marrow Transplant 2004; 10: 1–22.

    Article  PubMed  Google Scholar 

  8. Schoemans H, Theunissen K, Maertens J, Boogaerts M, Verfaillie C, Wagner J . Adult umbilical cord blood transplantation: a comprehensive review. Bone Marrow Transplant 2006; 38: 83–93.

    Article  CAS  PubMed  Google Scholar 

  9. Wagner JE, Barker JN, DeFor TE, Baker KS, Blazar BR, Eide C et al. Transplantation of unrelated donor umbilical cord blood in 102 patients with malignant and nonmalignant diseases: influence of CD34 cell dose and HLA disparity on treatment-related mortality and survival. Blood 2002; 100: 1611–1618.

    CAS  PubMed  Google Scholar 

  10. Kishi Y, Kami M, Miyakoshi S, Kanda Y, Murashige N, Teshima T et al. Early immune reaction after reduced-intensity cord-blood transplantation for adult patients. Transplantation 2005; 80: 34–40.

    Article  PubMed  Google Scholar 

  11. Shimada K, Narimatsu H, Morishita Y, Kohno A, Saito S, Kato Y . Severe regimen-related toxicity of second transplantation for graft failure following reduced-intensity cord blood transplantation in an adult patient. Bone Marrow Transplant 2006; 37: 787–788.

    Article  CAS  PubMed  Google Scholar 

  12. Lazarus HM, Vogelsang GB, Rowe JM . Prevention and treatment of acute graft-versus-host disease: the old and the new. A report from the Eastern Cooperative Oncology Group (ECOG). Bone Marrow Transplant 1997; 19: 577–600.

    Article  CAS  PubMed  Google Scholar 

  13. Takahashi S, Iseki T, Ooi J, Tomonari A, Takasugi K, Shimohakamada Y et al. Single-institute comparative analysis of unrelated bone marrow transplantation and cord blood transplantation for adult patients with hematologic malignancies. Blood 2004; 104: 3813–3820.

    Article  CAS  PubMed  Google Scholar 

  14. 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 

  15. Sullivan KM, Agura E, Anasetti C, Appelbaum F, Badger C, Bearman S et al. Chronic graft-versus-host disease and other late complications of bone marrow transplantation. Semin Hematol 1991; 28: 250–259.

    CAS  PubMed  Google Scholar 

  16. Thiede C, Florek M, Bornhauser M, Ritter M, Mohr B, Brendel C et al. Rapid quantification of mixed chimerism using multiplex amplification of short tandem repeat markers and fluorescence detection. Bone Marrow Transplant 1999; 23: 1055–1060.

    Article  CAS  PubMed  Google Scholar 

  17. Narimatsu H, Kami M, Miyakoshi S, Murashige N, Yuji K, Hamaki T et al. Graft failure following reduced-intensity cord blood transplantation for adult patients. Br J Haematol 2006; 132: 36–41.

    Article  PubMed  Google Scholar 

  18. 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: 1464–1472.

    CAS  PubMed  Google Scholar 

  19. Gooley TA, Leisenring W, Crowley J, Storer BE . 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 

  20. Fine JP, Gray RJ . A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc 1999; 94: 496–497.

    Article  Google Scholar 

  21. Cho BK, Rao VP, Ge Q, Eisen HN, Chen J . Homeostasis-stimulated proliferation drives naive T cells to differentiate directly into memory T cells. J Exp Med 2000; 192: 549–556.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Gluckman E, Rocha V, Boyer-Chammard A, Locatelli F, Arcese W, Pasquini R et al. Outcome of cord-blood transplantation from related and unrelated donors. Eurocord Transplant Group and the European Blood and Marrow Transplantation Group. N Engl J Med 1997; 337: 373–381.

    Article  CAS  PubMed  Google Scholar 

  23. Kurtzberg J, Laughlin M, Graham ML, Smith C, Olson JF, Halperin EC et al. Placental blood as a source of hematopoietic stem cells for transplantation into unrelated recipients. N Engl J Med 1996; 335: 157–166.

    Article  CAS  PubMed  Google Scholar 

  24. Locatelli F, Rocha V, Chastang C, Arcese W, Michel G, Abecasis M et al. Factors associated with outcome after cord blood transplantation in children with acute leukemia. Eurocord – Cord Blood Transplant Group. Blood 1999; 93: 3662–3671.

    CAS  PubMed  Google Scholar 

  25. Rubinstein P, Stevens CE . Placental blood for bone marrow replacement: the New York Blood Center's program and clinical results. Baillieres Best Pract Res Clin Haematol 2000; 13: 565–584.

    Article  CAS  PubMed  Google Scholar 

  26. Locatelli F, Rocha V, Reed W, Bernaudin F, Ertem M, Grafakos S et al. Related umbilical cord blood transplantation in patients with thalassemia and sickle cell disease. Blood 2003; 101: 2137–2143.

    Article  CAS  PubMed  Google Scholar 

  27. Lekakis L, Giralt S, Couriel D, Shpall EJ, Hosing C, Khouri IF et al. Phase II study of unrelated cord blood transplantation for adults with high-risk hematologic malignancies. Bone Marrow Transplant 2006; 38: 421–426.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. 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: 2062–2068.

    CAS  PubMed  Google Scholar 

  29. Hiraoka A, Ohashi Y, Okamoto S, Moriyama Y, Nagao T, Kodera Y et al. Phase III study comparing tacrolimus (FK506) with cyclosporine for graft-versus-host disease prophylaxis after allogeneic bone marrow transplantation. Bone Marrow Transplant 2001; 28: 181–185.

    Article  CAS  PubMed  Google Scholar 

  30. 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: 2303–2314.

    CAS  PubMed  Google Scholar 

  31. Przepiorka D, Petropoulos D, Mullen CA, Danielson M, Mattewada V, Chan KW . Tacrolimus for prevention of graft-versus-host disease after mismatched unrelated donor cord blood transplantation. Bone Marrow Transplant 1999; 23: 1291–1295.

    Article  CAS  PubMed  Google Scholar 

  32. Sayer HG, Longton G, Bowden R, Pepe M, Storb R . Increased risk of infection in marrow transplant patients receiving methylprednisolone for graft-versus-host disease prevention. Blood 1994; 84: 1328–1332.

    CAS  PubMed  Google Scholar 

  33. Hori A, Kami M, Kim SW, Chizuka A, Kojima R, Imataki O et al. Development of early neutropenic fever, with or without bacterial infection, is still a significant complication after reduced-intensity stem cell transplantation. Biol Blood Marrow Transplant 2004; 10: 65–72.

    Article  PubMed  Google Scholar 

  34. Junghanss C, Marr KA, Carter RA, Sandmaier BM, Maris MB, Maloney DG et al. Incidence and outcome of bacterial and fungal infections following nonmyeloablative compared with myeloablative allogeneic hematopoietic stem cell transplantation: a matched control study. Biol Blood Marrow Transplant 2002; 8: 512–520.

    Article  PubMed  Google Scholar 

  35. Engelhard D, Elishoov H, Strauss N, Naparstek E, Nagler A, Simhon A et al. Nosocomial coagulase-negative staphylococcal infections in bone marrow transplantation recipients with central vein catheter. A 5-year prospective study. Transplantation 1996; 61: 430–434.

    Article  CAS  PubMed  Google Scholar 

  36. Narimatsu H, Matsumura T, Kami M, Miyakoshi S, Kusumi E, Takagi S et al. Bloodstream infection after umbilical cord blood transplantation using reduced-intensity stem cell transplantation for adult patients. Biol Blood Marrow Transplant 2005; 11: 429–436.

    Article  PubMed  Google Scholar 

  37. Laughlin MJ, Barker J, Bambach B, Koc ON, Rizzieri DA, Wagner JE et al. Hematopoietic engraftment and survival in adult recipients of umbilical-cord blood from unrelated donors. N Engl J Med 2001; 344: 1815–1822.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Professor Tomoki Naoe (Nagoya University Graduate School of Medicine) for his critical reading of the paper. We wish to thank all the staff and resident members of the participating institutions. A complete list of participating institutions appears in the Appendix.

Author information

Authors and Affiliations

Authors

Consortia

Corresponding author

Correspondence to H Narimatsu.

Appendix

Appendix

This study was conducted at the following institutions in NBMTG: Japanese Red Cross Nagoya First Hospital, Nagoya; Nagoya Daini Red Cross Hospital, Nagoya; Meitetsu Hospital, Nagoya; National Hospital Organization Nagoya Medical Center, Clinical and Research Center, Nagoya; Fujita Health University Hospital, Toyoake; JA Aichi Showa Hospital, Konan; Nagoya University Hospital, Nagoya; and Anjo Kosei Hospital, Anjo, Japan.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Narimatsu, H., Terakura, S., Matsuo, K. et al. Short-term methotrexate could reduce early immune reactions and improve outcomes in umbilical cord blood transplantation for adults. Bone Marrow Transplant 39, 31–39 (2007). https://doi.org/10.1038/sj.bmt.1705539

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.bmt.1705539

Keywords

This article is cited by

Search

Quick links