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Graft-Versus-Host Disease

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 Transplantation volume 52, pages 423–430 (2017)Cite this article

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Abstract

In order to examine GvHD prophylaxis in umbilical cord blood transplantation (UCBT) in more detail, we compared transplant outcomes after UCBT for acute leukemia among GvHD prophylaxes using registry data. We selected patients transplanted with a calcineurin inhibitor and methotrexate (MTX)/mycophenolate mofetil (MMF) combination. A total of 1516 first myeloablative UCBT between 2000 and 2012 (Cyclosporine A (CyA) plus MTX, 824, Tacrolimus (Tac) plus MTX, 554, Tac plus MMF, 138) were included. With adjusted analyses, Tac plus MMF showed a significantly higher risk for grade II–IV and III–IV acute GvHD than CyA or Tac plus MTX. Although NRM was similar, Tac plus MMF showed a significantly lower risk of relapse than CyA or Tac plus MTX. A significant difference was observed in the risk of overall mortality (OM) between the MTX-containing group and MMF-containing group. In patients with standard-risk disease, there was no significant difference in the risk of OM in any GvHD prophylaxis. However, in patients with advanced-risk disease, Tac plus MMF showed a significantly lower risk of OM. Therefore, MTX-containing prophylaxis is preferred in UCBT for standard-risk disease, whereas MMF-containing prophylaxis is preferred for advanced-risk disease. A prospective study to identify optimal GvHD prophylaxis for UCBT is warranted.

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References

  1. 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 

  2. Laughlin MJ, Eapen M, Rubinstein P, Wagner JE, Zhang MJ, 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 

  3. Ooi J . Cord blood transplantation in adults. Bone Marrow Transplant 2009; 44: 661–666.

    Article  CAS  PubMed  Google Scholar 

  4. Ballen KK, Gluckman E, Broxmeyer HE . Umbilical cord blood transplantation: the first 25 years and beyond. Blood 2013; 122: 491–498.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 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 

  6. Eapen M, Rocha V, Sanz G, Scaradavou A, Zhang MJ, 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: 653–660.

    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: 1631–1638.

    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 Transplant 2012; 18: 780–787.

    Article  PubMed  Google Scholar 

  9. Sakai R, Taguri M, Oshima K, Mori T, Ago H, Adachi S et al. A comparison of tacrolimus and cyclosporine combined with methotrexate for Graft-Versus-Host Disease prophylaxis, stratified by stem cell source: a retrospective nationwide survey. Int J Hematol 2016; 103: 322–333.

    Article  CAS  PubMed  Google Scholar 

  10. Terakura S, Atsuta Y, Tsukada N, Kobayashi T, Tanaka M, Kanda J et al. Comparison of outcomes of 8/8 and 7/8 allele-matched unrelated bone marrow transplantation and single-unit cord blood transplantation in adults with acute leukemia. Biol Blood Marrow Transplant 2016; 22: 330–338.

    Article  PubMed  Google Scholar 

  11. Barker JN, Davies SM, DeFor T, Ramsay NK, Weisdorf DJ, Wagner JE . Survival after transplantation of unrelated donor umbilical cord blood is comparable to that of human leukocyte antigen-matched unrelated donor bone marrow: results of a matched-pair analysis. Blood 2001; 97: 2957–2961.

    Article  CAS  PubMed  Google Scholar 

  12. Pascal L, Tucunduva L, Ruggeri A, Blaise D, Ceballos P, Chevallier P et al. Impact of ATG-containing reduced-intensity conditioning after single- or double-unit allogeneic cord blood transplantation. Blood 2015; 126: 1027–1032.

    Article  CAS  PubMed  Google Scholar 

  13. Mohty M, Gaugler B . Advances in umbilical cord transplantation: the role of thymoglobulin/ATG in cord blood transplantation. Best Pract Res Clin Haematol 2010; 23: 275–282.

    Article  CAS  PubMed  Google Scholar 

  14. Pascal L, Mohty M, Ruggeri A, Tucunduva L, Milpied N, Chevallier P et al. Impact of rabbit ATG-containing myeloablative conditioning regimens on the outcome of patients undergoing unrelated single-unit cord blood transplantation for hematological malignancies. Bone Marrow Transplant 2015; 50: 45–50.

    Article  CAS  PubMed  Google Scholar 

  15. Lindemans CA, Chiesa R, Amrolia PJ, Rao K, Nikolajeva O, de Wildt A et al. Impact of thymoglobulin prior to pediatric unrelated umbilical cord blood transplantation on immune reconstitution and clinical outcome. Blood 2014; 123: 126–132.

    Article  CAS  PubMed  Google Scholar 

  16. Admiraal R, van Kesteren C, Jol-van der Zijde CM, Lankester AC, Bierings MB, Egberts TC et al. Association between anti-thymocyte globulin exposure and CD4+ immune reconstitution in paediatric haemopoietic cell transplantation: a multicentre, retrospective pharmacodynamic cohort analysis. Lancet Haematol 2015; 2: e194–e203.

    Article  PubMed  Google Scholar 

  17. Murata M . Prophylactic and therapeutic treatment of Graft-Versus-Host Disease in Japan. Int J Hematol 2015; 101: 467–486.

    Article  CAS  PubMed  Google Scholar 

  18. Kanda J, Atsuta Y, Wake A, Ichinohe T, Takanashi M, Morishima Y et al. Impact of the direction of HLA mismatch on transplantation outcomes in single unrelated cord blood transplantation. Biol Blood Marrow Transplant 2013; 19: 247–254.

    Article  PubMed  Google Scholar 

  19. 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: 516–522.

    Article  PubMed  Google Scholar 

  20. 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: 366–371.

    Article  CAS  PubMed  Google Scholar 

  21. 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 Transplant 2007; 39: 31–39.

    Article  CAS  PubMed  Google Scholar 

  22. Kharfan-Dabaja M, Mhaskar R, Reljic T, Pidala J, Perkins JB, Djulbegovic B et al. Mycophenolate mofetil versus methotrexate for prevention of Graft-Versus-Host Disease in people receiving allogeneic hematopoietic stem cell transplantation. Cochrane Database Syst Rev 2014; 25: CD010280.

    Google Scholar 

  23. Bolwell B, Sobecks R, Pohlman B, Andresen S, Rybicki L, Kuczkowski E et al. A prospective randomized trial comparing cyclosporine and short course methotrexate with cyclosporine and mycophenolate mofetil for GVHD prophylaxis in myeloablative allogeneic bone marrow transplantation. Bone Marrow Transplant 2004; 34: 621–625.

    Article  CAS  PubMed  Google Scholar 

  24. Nash RA, Johnston L, Parker P, McCune JS, Storer B, Slattery JT et al. A phase I/II study of mycophenolate mofetil in combination with cyclosporine for prophylaxis of acute Graft-Versus-Host Disease after myeloablative conditioning and allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant 2005; 11: 495–505.

    Article  CAS  PubMed  Google Scholar 

  25. Perkins J, Field T, Kim J, Kharfan-Dabaja MA, Fernandez H, Ayala E et al. A randomized phase II trial comparing tacrolimus and mycophenolate mofetil to tacrolimus and methotrexate for acute Graft-Versus-Host Disease prophylaxis. Biol Blood Marrow Transplant 2010; 16: 937–947.

    Article  CAS  PubMed  Google Scholar 

  26. Ram R, Yeshurun M, Vidal L, Shpilberg O, Gafter-Gvili A . Mycophenolate mofetil vs methotrexate for the prevention of graft-versus-host-disease—systematic review and meta-analysis. Leuk Res 2014; 38: 352–360.

    Article  CAS  PubMed  Google Scholar 

  27. Atsuta Y, Suzuki R, Yoshimi A, Gondo H, Tanaka J, Hiraoka A et al. Unification of hematopoietic stem cell transplantation registries in Japan and establishment of the TRUMP System. Int J Hematol 2007; 86: 269–274.

    Article  PubMed  Google Scholar 

  28. Atsuta Y . Introduction of Transplant Registry Unified Management Program 2 (TRUMP2): scripts for TRUMP data analyses, part I (variables other than HLA-related data). Int J Hematol 2016; 103: 3–10.

    Article  PubMed  Google Scholar 

  29. Kanda J . Scripts for TRUMP data analyses. Part II (HLA-related data): statistical analyses specific for hematopoietic stem cell transplantation. Int J Hematol 2016; 103: 11–19.

    Article  CAS  PubMed  Google Scholar 

  30. Bacigalupo A, Ballen K, Rizzo D, Giralt S, Lazarus H, Ho V et al. Defining the intensity of conditioning regimens: working definitions. Biol Blood Marrow Transplant 2009; 15: 1628–1633.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Przepiorka D, Weisdorf D, Martin P, Klingemann H, Beatty P, Hows J et al. 1994 Consensus conference on acute GVHD grading. Bone Marrow Transplant 1995; 15: 825–828.

    Google Scholar 

  32. Lee SJ, Vogelsang G, Flowers MED . Chronic Graft-Versus-Host Disease. Biol Blood Marrow Transplant 2003; 9: 215–233.

    Article  CAS  PubMed  Google Scholar 

  33. Kaplan E, Meier. P . Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 457–481.

    Article  Google Scholar 

  34. 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 

  35. Cox DR . Regression models and life-tables. J R Stat Soc Series B Stat Methodol 1972; 34: 187–220.

    Google Scholar 

  36. Yamamoto H, Uchida N, Matsuno N, Kon A, Nishida A, Ota H et al. I.v. BU/fludarabine plus melphalan or TBI in unrelated cord blood transplantation for high-risk hematological diseases. Bone Marrow Transplant 2015; 50: 607–609.

    Article  CAS  PubMed  Google Scholar 

  37. Sorror ML, Storb RF, Sandmaier BM, Maziarz RT, Pulsipher MA, Maris MB et al. Comorbidity-age index: a clinical measure of biologic age before allogeneic hematopoietic cell transplantation. J Clin Oncol 2014; 32: 3249–3256.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Styczynski J, Cheung YK, Garvin J, Savage DG, Billote GB, Harrison L et al. Outcomes of unrelated cord blood transplantation in pediatric recipients. Bone Marrow Transplant 2004; 34: 129–136.

    Article  CAS  PubMed  Google Scholar 

  39. MacMillan ML, Weisdorf DJ, Wagner JE, DeFor TE, Burns LJ, Ramsay NK et al. Response of 443 patients to steroids as primary therapy for acute Graft-Versus-Host Disease: comparison of grading systems. Biol Blood Marrow Transplant 2002; 8: 387–394.

    Article  CAS  PubMed  Google Scholar 

  40. MacMillan ML, Robin M, Harris AC, DeFor TE, Martin PJ, Alousi A et al. A refined risk score for acute Graft-Versus-Host Disease that predicts response to initial therapy, survival, and transplant-related mortality. Biol Blood Marrow Transplant 2015; 21: 761–767.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Murata M, Nakasone H, Kanda J, Nakane T, Furukawa T, Fukuda T et al. Clinical factors predicting the response of acute Graft-Versus-Host Disease to corticosteroid therapy: an analysis from the GVHD working group of the Japan Society for Hematopoietic Cell Transplantation. Biol Blood Marrow Transplant 2013; 19: 1183–1189.

    Article  CAS  PubMed  Google Scholar 

  42. Arber C, Halter J, Stern M, Rovo A, Gratwohl A ., Tichelli A . Graft source determines human hematopoietic progenitor distribution pattern within the CD34(+) compartment. Bone Marrow Transplant 2011; 46: 650–658.

    Article  CAS  PubMed  Google Scholar 

  43. Theilgaard-Monch K, Raaschou-Jensen K, Palm H, Schjodt K, Heilmann C, Vindelov L et al. Flow cytometric assessment of lymphocyte subsets, lymphoid progenitors, and hematopoietic stem cells in allogeneic stem cell grafts. Bone Marrow Transplant 2001; 28: 1073–1082.

    Article  CAS  PubMed  Google Scholar 

  44. Ogata M, Fukuda T, Teshima T . Human herpesvirus-6 encephalitis after allogeneic hematopoietic cell transplantation: what we do and do not know. Bone Marrow Transplant 2015; 50: 1030–1036.

    Article  CAS  PubMed  Google Scholar 

  45. Scheurer ME, Pritchett JC, Amirian ES, Zemke NR, Lusso P, Ljungman P . HHV-6 encephalitis in umbilical cord blood transplantation: a systematic review and meta-analysis. Bone Marrow Transplant 2013; 48: 574–580.

    Article  CAS  PubMed  Google Scholar 

  46. Iida M, Fukuda T, Uchida N, Murata M, Aotsuka N, Minagawa K et al. Mycophenolate mofetil use after unrelated hematopoietic stem cell transplantation for prophylaxis and treatment of graft-vs-host disease in adult patients in Japan. Clin Transplant 2014; 28: 980–989.

    Article  CAS  PubMed  Google Scholar 

  47. Bejanyan N, Rogosheske J, DeFor T, Lazaryan A, Esbaum K, Holtan S et al. Higher dose of mycophenolate mofetil reduces acute Graft-Versus-Host Disease in reduced-intensity conditioning double umbilical cord blood transplantation. Biol Blood Marrow Transplant 2015; 21: 926–933.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. 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 Transplant 2015; 21: 920–925.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank all the physicians and data managers at the institutes who contributed valuable data on transplantation to JSHCT and all members of the data management committees of JSHCT.

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Authors and Affiliations

  1. Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan

    S Terakura & M Murata

  2. Department of Hematology, Toranomon Hospital Kajigaya, Kawasaki, Japan

    A Wake

  3. Okinaka Memorial Institute of Medical Research, Tokyo, Japan

    A Wake & N Uchida

  4. Division of Hematopoietic Stem Cell Transplantation, National Cancer Center Hospital, Tokyo, Japan

    Y Inamoto & T Fukuda

  5. Department of Medical Oncology, Kanagawa Cancer Center, Yokohama, Japan

    R Sakai

  6. Division of Biostatistics, Tohoku University Graduate School of Medicine, Sendai, Japan

    T Yamaguchi

  7. Department of Cell Processing and Transfusion, Research Hospital, Institute of Medical Science, University of Tokyo, Tokyo, Japan

    S Takahashi

  8. Department of Hematology, Toranomon Hospital, Tokyo, Japan

    N Uchida

  9. Department of Hematology and Rheumatology, Tohoku University Hospital, Sendai, Japan

    Y Onishi

  10. Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan

    K Ohashi

  11. Department of Hematology, Japanese Red Cross Nagoya First Hospital, Nagoya, Japan

    Y Ozawa

  12. Department of Hematology, Kanagawa Cancer Center, Yokohama, Japan

    H Kanamori

  13. Department of Hematology, Nippon Medical School, Tokyo, Japan

    H Yamaguchi

  14. Department of Hematology and Oncology, Hiroshima University Hospital, Hiroshima, Japan

    T Ichinohe

  15. Blood Service Headquarters, Japanese Red Cross Society, Tokyo, Japan

    M Takanashi

  16. Japanese Data Center for Hematopoietic Cell Transplantation, Nagoya, Japan

    Y Atsuta

  17. Department of Healthcare Administration, Nagoya University Graduate School of Medicine, Nagoya, Japan

    Y Atsuta

  18. Department of Hematology, Hokkaido University Graduate School of Medicine, Sapporo, Japan

    T Teshima

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  1. S Terakura
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for the Japan Society for Hematopoietic Cell Transplantation GvHD working group

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Correspondence to S Terakura.

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Terakura, S., Wake, A., Inamoto, Y. 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 Transplant 52, 423–430 (2017). https://doi.org/10.1038/bmt.2016.255

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