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

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Abstract

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.

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References

  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.

    Article  CAS  PubMed  Google Scholar 

  2. Ballen KK, Gluckman E, Broxmeyer HE. Umbilical cord blood transplantation: the first 25 years and beyond. Blood. 2013;122:491–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Ooi J. Cord blood transplantation in adults. Bone Marrow Transpl. 2009;44:661–6.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  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;351:2276–85.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  Google Scholar 

  16. Murata M. Prophylactic and therapeutic treatment of graft-versus-host disease in Japan. Int J Hematol. 2015;101:467–86.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  33. Lin DY. Non-parametric inference for cumulative incidence functions in competing risks studies. Stat Med. 1997;16:901–10.

    Article  CAS  PubMed  Google Scholar 

  34. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. Source J Am Stat Assoc. 1958;53:457–81.

    Article  Google Scholar 

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

    Article  Google Scholar 

  36. Kanda Y. Investigation of the freely available easy-to-use software “EZR” for medical statistics. Bone Marrow Transpl. 2013;48:452–8.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

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.

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Correspondence to Yoshitaka Adachi.

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Adachi, Y., Ozeki, K., Ukai, S. et al. Optimal dosage of methotrexate for GVHD prophylaxis in umbilical cord blood transplantation. Int J Hematol 109, 440–450 (2019). https://doi.org/10.1007/s12185-019-02598-x

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  • DOI: https://doi.org/10.1007/s12185-019-02598-x

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