International Journal of Hematology

, Volume 109, Issue 4, pp 440–450 | Cite as

Optimal dosage of methotrexate for GVHD prophylaxis in umbilical cord blood transplantation

  • Yoshitaka AdachiEmail author
  • Kazutaka Ozeki
  • Shun Ukai
  • Ken Sagou
  • Nobuaki Fukushima
  • Akio Kohno
Original Article


The combination of methotrexate (MTX) and a calcineurin inhibitor is widely used for GVHD prophylaxis in umbilical cord blood transplantation (UCBT). However, the optimal MTX dosage for GVHD prophylaxis in UCBT remains unclear. In the present study, we investigated the impact of MTX dosage on clinical outcomes following UCBT in a single-center retrospective study. Of 70 UCBT recipients included in this study, 37 received MTX at doses of 10 mg/m2 on day 1, and 7 mg/m2 on days 3 and 6 (low-dose MTX: LD-MTX), and 33 received MTX at doses of 15 mg/m2 on day 1, and 10 mg/m2 on days 3 and 6 (standard-dose MTX: SD-MTX), in addition to tacrolimus (TAC). Grade 3–4 acute GVHD and/or transplant-related complications with endothelial cell damage were considered severe transplant-related complications. Univariate analysis findings revealed that the risk of grade 3–4 acute GVHD was significantly lower in the SD-MTX group than in the LD-MTX group (P = 0.013). Multivariate analysis findings revealed that SD-MTX was significantly associated with a lower incidence of severe transplant-related complications (HR = 0.25; 95% CI, 0.07–0.87; P = 0.029). We conclude that SD-MTX in combination with tacrolimus is optimal for GVHD prophylaxis in UCBT.


Methotrexate Graft-versus-host disease Umbilical cord blood transplantation Endothelial cell damage 



The authors acknowledge all the physicians, nurses, and other staff who participated in the care of the patients in the Department of Hematology and Oncology at Konan Kosei Hospital.

Compliance with ethical standards

Conflict of interest

The authors have no conflict of interest.


  1. 1.
    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;104:3813–20.CrossRefPubMedGoogle Scholar
  2. 2.
    Ballen KK, Gluckman E, Broxmeyer HE. Umbilical cord blood transplantation: the first 25 years and beyond. Blood. 2013;122:491–8.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Ooi J. Cord blood transplantation in adults. Bone Marrow Transpl. 2009;44:661–6.CrossRefGoogle Scholar
  4. 4.
    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;351:2265–75.CrossRefPubMedGoogle Scholar
  5. 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;351:2276–85.CrossRefPubMedGoogle Scholar
  6. 6.
    Eapen M, Rocha V, Sanz G, Scaradavou A, Zhang M-J, Arcese W, et al. Effect of graft source on unrelated donor haemopoietic stem-cell transplantation in adults with acute leukaemia: a retrospective analysis. Lancet Oncol. 2010;11:653–60.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Atsuta Y, Suzuki R, Nagamura-Inoue T, Taniguchi S, Takahashi S, Kai S, et al. Disease-specific analyses of unrelated cord blood transplantation compared with unrelated bone marrow transplantation in adult patients with acute leukemia. Blood. 2009;113:1631–8.CrossRefPubMedGoogle Scholar
  8. 8.
    Atsuta Y, Morishima Y, Suzuki R, Nagamura-Inoue T, Taniguchi S, Takahashi S, et al. Comparison of unrelated cord blood transplantation and Hla-mismatched unrelated bone marrow transplantation for adults with leukemia. Biol Blood Marrow Transpl. 2012;18:780–7.CrossRefGoogle Scholar
  9. 9.
    Long GD, Laughlin M, Madan B, Kurtzberg J, Gasparetto C, Morris A, et al. Unrelated umbilical cord blood transplantation in adult patients. Biol Blood Marrow Transpl. 2003;9:772–80.CrossRefGoogle Scholar
  10. 10.
    Cornetta K, Laughlin M, Carter S, Wall D, Weinthal J, Delaney C, et al. Umbilical cord blood transplantation in adults: results of the prospective Cord Blood Transplantation (COBLT). Biol Blood Marrow Transpl. 2005;11:149–60.CrossRefGoogle Scholar
  11. 11.
    Saavedra S, Sanz G, Jarque I, Moscardó F, Jiménez C, Lorenzo I, et al. Early infections in adult patients undergoing unrelated donor cord blood transplantation. Bone Marrow Transpl. 2002;30:937–43.CrossRefGoogle Scholar
  12. 12.
    Montoro J, Piñana JL, Moscardó F, Sanz J. Infectious complications after umbilical cord-blood transplantation from unrelated donors. Mediterr J Hematol Infect Dis. 2016;8:e2016051.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Ruutu T, van Biezen A, Hertenstein B, Henseler A, Garderet L, Passweg J, et al. Prophylaxis and treatment of GVHD after allogeneic haematopoietic SCT: a survey of centre strategies by the European Group for Blood and Marrow Transplantation. Bone Marrow Transpl. 2012;47:1459–64.CrossRefGoogle Scholar
  14. 14.
    Uchida N, Wake A, Nakano N, Ishiwata K, Takagi S, Tsuji M, et al. Mycophenolate and tacrolimus for graft-versus-host disease prophylaxis for elderly after cord blood transplantation: a matched pair comparison with tacrolimus alone. Transplantation. 2011;92:366–71.CrossRefPubMedGoogle Scholar
  15. 15.
    Kanda J, Ichinohe T, Fuji S, Maeda Y, Ohashi K, Fukuda T, et al. Impact of HLA mismatch direction on the outcome of unrelated bone marrow transplantation: a retrospective analysis from the japan society for hematopoietic cell transplantation. Biol Blood Marrow Transpl. 2015;21:305–11.CrossRefGoogle Scholar
  16. 16.
    Murata M. Prophylactic and therapeutic treatment of graft-versus-host disease in Japan. Int J Hematol. 2015;101:467–86.CrossRefPubMedGoogle Scholar
  17. 17.
    Narimatsu H, Terakura S, Matsuo K, Oba T, Uchida T, Iida H, et al. Short-term methotrexate could reduce early immune reactions and improve outcomes in umbilical cord blood transplantation for adults. Bone Marrow Transpl. 2007;39:31–9.CrossRefGoogle Scholar
  18. 18.
    Nishihira H, Kato K, Isoyama K, Takahashi TA, Kai S, Kato S, et al. The Japanese cord blood bank network experience with cord blood transplantation from unrelated donors for haematological malignancies: an evaluation of graft-versus-host disease prophylaxis. Br J Haematol. 2003;120:516–22.CrossRefPubMedGoogle Scholar
  19. 19.
    Terakura S, Wake A, Inamoto Y, Murata M, Sakai R, Yamaguchi T, et al. Exploratory research for optimal GvHD prophylaxis after single unit CBT in adults: short-term methotrexate reduced the incidence of severe GvHD more than mycophenolate mofetil. Bone Marrow Transpl. 2017;52:423–30.CrossRefGoogle Scholar
  20. 20.
    Terakura S, Kuwatsuka Y, Yamasaki S, Wake A, Kanda J, Inamoto Y, et al. GvHD prophylaxis after single-unit reduced intensity conditioning cord blood transplantation in adults with acute leukemia. Bone Marrow Transpl. 2017;52:1261–7.CrossRefGoogle Scholar
  21. 21.
    Iguchi A, Terashita Y, Sugiyama M, Ohshima J, Sato TZ, Cho Y, et al. Graft-versus-host disease (GVHD) prophylaxis by using methotrexate decreases pre-engraftment syndrome and severe acute GVHD, and accelerates engraftment after cord blood transplantation. Pediatr Transpl. 2016;20:114–9.CrossRefGoogle Scholar
  22. 22.
    Harnicar S, Ponce DM, Hilden P, Zheng J, Devlin SM, Lubin M, et al. Intensified mycophenolate mofetil dosing and higher mycophenolic acid trough levels reduce severe acute graft-versus-host disease after double-unit cord blood transplantation. Biol Blood Marrow Transpl. 2015;21:920–5.CrossRefGoogle Scholar
  23. 23.
    Miyamoto T, Takashima S, Kato K, Takase K, Yoshimoto G, Yoshida S, et al. Comparison of cyclosporine and tacrolimus combined with mycophenolate mofetil in prophylaxis for graft-versus-host disease after reduced-intensity umbilical cord blood transplantation. Int J Hematol. 2017;105:92–9.CrossRefPubMedGoogle Scholar
  24. 24.
    Luft T, Dietrich S, Falk C, Conzelmann M, Hess M, Benner A, et al. Steroid-refractory GVHD: T-cell attack within a vulnerable endothelial system. Blood. 2011;118:1685–92.CrossRefPubMedGoogle Scholar
  25. 25.
    Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J, et al. 1994 Consensus conference on acute GVHD grading. Bone Marrow Transpl. 1995;15: 825–8.Google Scholar
  26. 26.
    Ueda N, Chihara D, Kohno A, Tatekawa S, Ozeki K, Watamoto K, et al. Predictive value of circulating angiopoietin-2 for endothelial damage-related complications in allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transpl. 2014;20:1335–40.CrossRefGoogle Scholar
  27. 27.
    McDonald GB, Hinds MS, Fisher LD, Schoch HG, Wolford JL, Banaji M, et al. Veno-occlusive disease of the liver and multiorgan failure after bone marrow transplantation: a cohort study of 355 patients. Ann Intern Med. 1993;118:255.CrossRefPubMedGoogle Scholar
  28. 28.
    Clark JG, Hansen JA, Hertz MI, Parkman R, Jensen L, Peavy HH. Idiopathic pneumonia syndrome after bone marrow transplantation. Am Rev Respir Dis. 1993;147:1601–6.CrossRefPubMedGoogle Scholar
  29. 29.
    Afessa B, Tefferi A, Litzow MR, Krowka MJ, Wylam ME, Peters SG. Diffuse alveolar hemorrhage in hematopoietic stem cell transplant recipients. Am J Respir Crit Care Med. 2002;166:641–5.CrossRefPubMedGoogle Scholar
  30. 30.
    Nürnberger W, Willers R, Burdach S, Göbel U. Risk factors for capillary leakage syndrome after bone marrow transplantation. Ann Hematol. 1997;74:221–4.CrossRefPubMedGoogle Scholar
  31. 31.
    Cho B-S, Yahng S-A, Lee S-E, Eom K-S, Kim Y-J, Kim H-J, et al. Validation of recently proposed consensus criteria for thrombotic microangiopathy after allogeneic hematopoietic stem-cell transplantation. Transplantation. 2010;90:918–26.CrossRefPubMedGoogle Scholar
  32. 32.
    Inamoto Y, Ito M, Suzuki R, Nishida T, Iida H, Kohno A, et al. Clinicopathological manifestations and treatment of intestinal transplant-associated microangiopathy. Bone Marrow Transpl. 2009;44:43–9.CrossRefGoogle Scholar
  33. 33.
    Lin DY. Non-parametric inference for cumulative incidence functions in competing risks studies. Stat Med. 1997;16:901–10.CrossRefPubMedGoogle Scholar
  34. 34.
    Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. Source J Am Stat Assoc. 1958;53:457–81.CrossRefGoogle Scholar
  35. 35.
    Fine JP, Gray RJ. A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc. 1999;94:496.CrossRefGoogle Scholar
  36. 36.
    Kanda Y. Investigation of the freely available easy-to-use software “EZR” for medical statistics. Bone Marrow Transpl. 2013;48:452–8.CrossRefGoogle Scholar
  37. 37.
    Chen GL, Zhang Y, Hahn T, Abrams S, Ross M, Liu H, et al. Acute GVHD prophylaxis with standard-dose, micro-dose or no MTX after fludarabine/melphalan conditioning. Bone Marrow Transpl. 2014;49:248–53.CrossRefGoogle Scholar
  38. 38.
    Bensinger W, Stem Cell Trialists’ Collaborative Group on behalf of the SCTC. Individual patient data meta-analysis of allogeneic peripheral blood stem cell transplant vs bone marrow transplant in the management of hematological malignancies: indirect assessment of the effect of day 11 methotrexate administration. Bone Marrow Transpl. 2006;38:539–46.CrossRefGoogle Scholar
  39. 39.
    Matsukawa T, Hashimoto D, Sugita J, Nakazawa S, Matsushita T, Kashiwazaki H, et al. Reduced-dose methotrexate in combination with tacrolimus was associated with rapid engraftment and recovery from oral mucositis without affecting the incidence of GVHD. Int J Hematol. 2016;104:117–24.CrossRefPubMedGoogle Scholar
  40. 40.
    Kanda J, Brazauskas R, Hu Z-H, Kuwatsuka Y, Nagafuji K, Kanamori H, et al. Graft-versus-host disease after HLA-matched sibling bone marrow or peripheral blood stem cell transplantation: comparison of north american caucasian and japanese populations. Biol Blood Marrow Transpl. 2016;22:744–51.CrossRefGoogle Scholar
  41. 41.
    Oh H, Loberiza FR, Zhang M, Ringdén O, Akiyama H, Asai T, et al. Comparison of graft-versus-host-disease and survival after HLA-identical sibling bone marrow transplantation in ethnic populations. Blood. 2005;105:1408–16.CrossRefPubMedGoogle Scholar
  42. 42.
    Lekakis L, Giralt S, Couriel D, Shpall E, Hosing C, Khouri I, et al. Phase II study of unrelated cord blood transplantation for adults with high-risk hematologic malignancies. Bone Marrow Transpl. 2006;38:421–6.CrossRefGoogle Scholar
  43. 43.
    Gutman JA, Ross K, Smith C, Myint H, Lee C-K, Salit R, et al. Chronic graft versus host disease burden and late transplant complications are lower following adult double cord blood versus matched unrelated donor peripheral blood transplantation. Bone Marrow Transpl. 2016;51:1588–93.CrossRefGoogle Scholar
  44. 44.
    Frangoul H, Wang L, Harrell FE, Ho R, Domm J. Preengraftment syndrome after unrelated cord blood transplant is a strong predictor of acute and chronic graft-versus-host disease. Biol Blood Marrow Transpl. 2009;15:1485–8.CrossRefGoogle Scholar
  45. 45.
    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.CrossRefPubMedGoogle Scholar
  46. 46.
    Cascone T, Heymach JV. Targeting the angiopoietin/Tie2 pathway: cutting tumor vessels with a double-edged sword? J Clin Oncol. 2012;30:441–4.CrossRefPubMedGoogle Scholar
  47. 47.
    Dietrich S, Falk CS, Benner A, Karamustafa S, Hahn E, Andrulis M, et al. Endothelial vulnerability and endothelial damage are associated with risk of graft-versus-host disease and response to steroid treatment. Biol Blood Marrow Transpl. 2013;19:22–7.CrossRefGoogle Scholar
  48. 48.
    Ma Y, Li L, Shao Y, Bai X, Bai T, Huang X. Methotrexate improves perivascular adipose tissue/endothelial dysfunction via activation of AMPK/eNOS pathway. Mol Med Rep. 2017;15:2353–9.CrossRefPubMedGoogle Scholar
  49. 49.
    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;101:2137–43.CrossRefPubMedGoogle Scholar

Copyright information

© Japanese Society of Hematology 2019

Authors and Affiliations

  1. 1.Department of Hematology and OncologyKonan Kosei HospitalKonanJapan

Personalised recommendations