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High-dose, post-transplantation cyclophosphamide to promote graft-host tolerance after allogeneic hematopoietic stem cell transplantation

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Abstract

Graft-versus-host disease, or GVHD, is a major complication of allogeneic hematopoietic stem cell transplantation (alloHSCT) for the treatment of hematologic malignancies. Here, we describe a novel method for preventing GVHD after alloHSCT using high-dose, post-transplantation cyclophosphamide (Cy). Post-transplantation Cy promotes tolerance in alloreactive host and donor T cells, leading to suppression of both graft rejection and GVHD after alloHSCT. High-dose, post-transplantation Cy facilitates partially HLA-mismatched HSCT without severe GVHD and is effective as sole prophylaxis of GVHD after HLA-matched alloHSCT. By reducing the morbidity and mortality of alloHSCT, post-transplantation Cy may expand the applications of this therapy to the treatment of autoimmune diseases and non-malignant hematologic disorders such as sickle cell disease.

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References

  1. Little MT. Storb R: history of haematopoietic stem-cell transplantation. Nat Rev Cancer. 2002;2:231–8.

    Article  PubMed  CAS  Google Scholar 

  2. Barnes DWH, Corp MJ, Loutit JF, Neal FE. Treatment of murine leukaemia with X-rays and homologous bone marrow. Preliminary communication. Br Med J. 1956;2:626.

    Article  PubMed  CAS  Google Scholar 

  3. Weiden PL, Flournoy N, Thomas ED, et al. Antileukemic effect of graft-versus-host disease in human recipients of allogeneic-marrow grafts. N Engl J Med. 1979;300:1068–73.

    PubMed  CAS  Google Scholar 

  4. Horowitz MM, Gale RP, Sondel PM, et al. Graft-versus-leukemia reactions after bone marrow transplantation. Blood. 1990;75:555–62.

    PubMed  CAS  Google Scholar 

  5. Anasetti C, Beatty PG, Storb R, et al. Effect of HLA incompatibility on graft-versus-host disease, relapse, and survival after marrow transplantation for patients with leukemia or lymphoma. Hum Immunol. 1990;29:79–91.

    Article  PubMed  CAS  Google Scholar 

  6. Szydlo R, Goldman JM, Klein JP, et al. Results of allogeneic bone marrow transplants for leukemia using donors other than HLA-identical siblings. J Clin Oncol. 1997;15:1767–77.

    PubMed  CAS  Google Scholar 

  7. Reisner Y, Kapoor N, Kirkpatrick D, et al. Transplantation for acute leukaemia with HLA-A and B nonidentical parental marrow cells fractionated with soybean agglutinin and sheep red blood cells. Lancet. 1981;2:327–31.

    Article  PubMed  CAS  Google Scholar 

  8. Prentice HG, Blacklock HA, Janossy G, et al. Depletion of T lymphocytes in donor marrow prevents significant graft-versus-host disease in matched allogeneic leukaemic marrow transplant recipients. Lancet. 1984;1:472–6.

    Article  PubMed  CAS  Google Scholar 

  9. Ho VT, Soiffer RJ. The history and future of T-cell depletion as graft-versus-host disease prophylaxis for allogeneic hematopoietic stem cell transplantation. Blood. 2001;98:3192–204.

    Article  PubMed  CAS  Google Scholar 

  10. Storb R, Thomas ED. Graft-versus-host disease in dog and man: the seattle experience. Immunol Rev. 1985;88:215–38.

    Article  PubMed  CAS  Google Scholar 

  11. Powles RL, Clink HM, Spence D, et al. Cyclosporin A to prevent graft-versus-host disease in man after allogeneic bone-marrow transplantation. Lancet. 1980;1:327–9.

    Article  PubMed  CAS  Google Scholar 

  12. Storb R, Deeg HJ, Farewell V, et al. Marrow transplantation for severe aplastic anemia: methotrexate alone compared with a combination of methotrexate and cyclosporine for prevention of acute graft-versus-host disease. Blood. 1986;68:119–25.

    PubMed  CAS  Google Scholar 

  13. Fay JW, Wingard JR, Antin JH, et al. FK506 (Tacrolimus) monotherapy for prevention of graft-versus- host disease after histocompatible sibling allogenic bone marrow transplantation. Blood. 1996;87:3514–9.

    PubMed  CAS  Google Scholar 

  14. Liu J, Farmer J, Lane WS, et al. Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes. Cell. 1991;66:807–15.

    Article  PubMed  CAS  Google Scholar 

  15. Bolwell B, Sobecks R, Pohlman B, 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;34:621–5.

    Article  PubMed  CAS  Google Scholar 

  16. Cutler C, Li S, Ho VT, et al. Extended follow-up of methotrexate-free immunosuppression using sirolimus and Tacrolimus in related and unrelated donor peripheral blood stem cell transplantation. Blood. 2007;109:3108–14.

    PubMed  CAS  Google Scholar 

  17. Nash RA, Johnston L, Parker P, 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  PubMed  CAS  Google Scholar 

  18. Ratanatharathorn V, Nash RA, Przepiorka 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;92:2303–14.

    PubMed  CAS  Google Scholar 

  19. Jenkins MK, Schwartz RH, Pardoll DM. Effects of cyclosporine A on T cell development and clonal deletion. Science. 1988;241:1655–8.

    Article  PubMed  CAS  Google Scholar 

  20. Jenkins MK, Chen CA, Jung G, Mueller DL, Schwartz RH. Inhibition of antigen-specific proliferation of type 1 murine T cell clones after stimulation with immobilized anti-CD3 monoclonal antibody. J Immunol. 1990;144:16–22.

    PubMed  CAS  Google Scholar 

  21. Li Y, Li XC, Zheng XX, et al. Blocking both signal 1 and signal 2 of T-cell activation prevents apoptosis of alloreactive T cells and induction of peripheral allograft tolerance. Nat Med. 1999;5:1298–302.

    Article  PubMed  CAS  Google Scholar 

  22. Beschorner WE, Hess AD, Shinn CA, Santos GW. Transfer of cyclosporine-associated syngeneic graft-versus-host disease by thymocytes. Resemblance to chronic graft-versus-host disease. Transplantation. 1988;45:209–15.

    Article  PubMed  CAS  Google Scholar 

  23. Santos GW, Hess AD, Vogelsang GB. Graft-versus-host reactions and disease. Immunol Rev. 1985;88:169–92.

    Article  PubMed  CAS  Google Scholar 

  24. Wagner JE, Thompson JS, Carter SL, Kernan NA. Effect of graft-versus-host disease prophylaxis on 3-year disease-free survival in recipients of unrelated donor bone marrow (T-cell depletion trial): a multi-centre, randomised phase II-III trial. Lancet. 2005;366:733–41.

    Article  PubMed  CAS  Google Scholar 

  25. Eapen M, Logan BR, Confer DL, et al. Peripheral blood grafts from unrelated donors are associated with increased acute and chronic graft-versus-host disease without improved survival. Biol Blood Marrow Transplant. 2007;13:1461–8.

    Article  PubMed  Google Scholar 

  26. Bacigalupo A, Lamparelli T, Gualandi F, et al. Increased risk of leukemia relapse with high dose cyclosporine after allogeneic marrow transplantation for acute leukemia: 10 year follow-up of a randomized study. Blood. 2001;98:3174.

    Article  CAS  Google Scholar 

  27. Schwartz R, Dameshek W. Drug-induced immunological tolerance. Nature. 1959;183:1682–3.

    Article  PubMed  CAS  Google Scholar 

  28. Berenbaum MC. Prolongation of homograft survival in mice with single doses of cyclophosphamide. Nature. 1963;200:84.

    Article  PubMed  CAS  Google Scholar 

  29. Santos GW, Owens AH. Production of graft-versus-host disease in the rat and its treatment with cytotoxic agents. Nature. 1966;210:139–40.

    Article  PubMed  CAS  Google Scholar 

  30. Mayumi H, Himeno K, Tokuda N, Nomoto K. Drug-induced tolerance to allografts in mice. VII. Optimal protocol and mechanism of cyclophosphamide-induced tolerance in an H-2 haplotype-identical strain combination. Transplant Proc. 1986;18:363–9.

    PubMed  CAS  Google Scholar 

  31. Eto M, Mayumi H, Tomita Y, et al. Sequential mechanisms of cyclophosphamide-induced skin allograft tolerance including the intrathymic clonal deletion followed by late breakdown of the clonal deletion. J Immunol. 1990;145:1303–10.

    PubMed  CAS  Google Scholar 

  32. Mayumi H, Umesue M, Nomoto K. Cyclophosphamide-induced immunological tolerance: an overview. Immunobiology. 1996;195:129–39.

    PubMed  CAS  Google Scholar 

  33. Luznik L, Jalla S, Engstrom LW, Iannone R, Fuchs EJ. Durable engraftment of major histocompatibility complex-incompatible cells after nonmyeloablative conditioning with fludarabine, low-dose total body irradiation, and posttransplantation cyclophosphamide. Blood. 2001;98:3456–64.

    Article  PubMed  CAS  Google Scholar 

  34. Luznik L, O’Donnell PV, Symons HJ, et al. HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide. Biol Blood Marrow Transplant. 2008;14:641–50.

    Article  PubMed  CAS  Google Scholar 

  35. Nomoto K, Eto M, Yanaga K, Nishimura Y, Maeda T. Interference with cyclophosphamide-induced skin allograft tolerance by cyclosporin A. J Immunol. 1992;149:2668–74.

    PubMed  CAS  Google Scholar 

  36. Mielcarek M, Martin PJ, Leisenring W, et al. Graft-versus-host disease after nonmyeloablative versus conventional hematopoietic stem cell transplantation. Blood. 2003;102:756–62.

    Article  PubMed  CAS  Google Scholar 

  37. Burroughs LM, O’Donnell PV, Sandmaier BM, et al. Comparison of outcomes of HLA-matched related, unrelated, or HLA-haploidentical related hematopoietic cell transplantation following nonmyeloablative conditioning for relapsed or refractory Hodgkin lymphoma. Biol Blood Marrow Transplant. 2008;14:1279–87.

    Article  PubMed  Google Scholar 

  38. Devetten MP, Hari PN, Carreras J, et al. Unrelated donor reduced-intensity allogeneic hematopoietic stem cell transplantation for relapsed and refractory Hodgkin lymphoma. Biol Blood Marrow Transplant. 2009;15:109–17.

    Article  PubMed  Google Scholar 

  39. Kanda Y, Chiba S, Hirai H, et al. Allogeneic hematopoietic stem cell transplantation from family members other than HLA-identical siblings over the last decade (1991–2000). Blood. 2003;102:1541–7.

    Article  PubMed  CAS  Google Scholar 

  40. Kasamon YL, Luznik L, Leffell MS et al.: Nonmyeloablative HLA-haploidentical BMT with high-dose post-transplantation cyclophosphamide: effect of HLA disparity on outcome. Biol Blood Marrow Transplant. 2010 (Epub ahead of print).

  41. Pocock SJ, Assmann SE, Enos LE, Kasten LE. Subgroup analysis, covariate adjustment and baseline comparisons in clinical trial reporting: current practice and problems. Stat Med. 2002;21:2917–30.

    Article  PubMed  Google Scholar 

  42. Ash RC, Horowitz MM, Gale RP, et al. Bone marrow transplantation from related donors other than HLA- identical siblings: effect of T cell depletion. Bone Marrow Transplant. 1991;7:443–52.

    PubMed  CAS  Google Scholar 

  43. Petersdorf EW, Gooley TA, Anasetti C, et al. Optimizing outcome after unrelated marrow transplantation by comprehensive matching of HLA class I and II alleles in the donor and recipient. Blood. 1998;92:3515–20.

    PubMed  CAS  Google Scholar 

  44. Sasazuki T, Juji T, Morishima Y, et al. Effect of matching of class I HLA alleles on clinical outcome after transplantation of hematopoietic stem cells from an unrelated donor. Japan marrow donor program. N Engl J Med. 1998;339:1177–85.

    Article  PubMed  CAS  Google Scholar 

  45. Morishima Y, Yabe T, Matsuo K, et al. Effects of HLA allele and killer immunoglobulin-like receptor ligand matching on clinical outcome in leukemia patients undergoing transplantation with T-cell-replete marrow from an unrelated donor. Biol Blood Marrow Transplant. 2007;13:315–28.

    Article  PubMed  CAS  Google Scholar 

  46. Anderson BE, McNiff J, Yan J, et al. Memory CD4+ T cells do not induce graft-versus-host disease. J Clin Invest. 2003;112:101–8.

    PubMed  CAS  Google Scholar 

  47. Zheng H, Matte-Martone C, Li H, et al. Effector memory CD4+ T cells mediate graft-versus-leukemia without inducing graft-versus-host disease. Blood. 2008;111:2476–84.

    Article  PubMed  CAS  Google Scholar 

  48. Chen BJ, Cui X, Sempowski GD, Liu C, Chao NJ. Transfer of allogeneic CD62L- memory T cells without graft-versus-host disease. Blood. 2004;103:1534–41.

    Article  PubMed  CAS  Google Scholar 

  49. Luznik L, Slansky JE, Jalla S, et al. Successful therapy of metastatic cancer using tumor vaccines in mixed allogeneic bone marrow chimeras. Blood. 2003;101:1645–52.

    Article  PubMed  CAS  Google Scholar 

  50. Dey BR, McAfee S, Colby C, et al. Anti-tumour response despite loss of donor chimaerism in patients treated with non-myeloablative conditioning and allogeneic stem cell transplantation. Br J Haematol. 2005;128:351–9.

    Article  PubMed  CAS  Google Scholar 

  51. Rubio MT, Saito TI, Kattleman K, et al. Mechanisms of the antitumor responses and host-versus-graft reactions induced by recipient leukocyte infusions in mixed chimeras prepared with nonmyeloablative conditioning: a critical role for recipient CD4+ T cells and recipient leukocyte infusion-derived IFN-{gamma}-producing CD8+ T cells. J Immunol. 2005;175:665–76.

    PubMed  CAS  Google Scholar 

  52. Symons HJ, Levy MY, Wang J et al.: The allogeneic effect revisited: exogenous help for endogenous, tumor-specific T cells. Biol Blood Marrow Transplant. 2010;14:499–509.

    Google Scholar 

  53. Bensinger WI, Martin PJ, Storer B, et al. Transplantation of bone marrow as compared with peripheral-blood cells from HLA-identical relatives in patients with hematologic cancers. N Engl J Med. 2001;344:175–81.

    Article  PubMed  CAS  Google Scholar 

  54. Nash RA, Antin JH, Karanes C, 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;96:2062–8.

    PubMed  CAS  Google Scholar 

  55. Kansu E, Gooley T, Flowers MED, et al. Administration of cyclosporine for 24 months compared with 6 months for prevention of chronic graft-versus-host disease: a prospective randomized clinical trial. Blood. 2001;98:3868–70.

    Article  PubMed  CAS  Google Scholar 

  56. Strauss G, Osen W, Debatin KM. Induction of apoptosis and modulation of activation and effector function in T cells by immunosuppressive drugs. Clin Exp Immunol. 2002;128:255–66.

    Article  PubMed  CAS  Google Scholar 

  57. Luznik L, Fuchs EJ, Chen AR, et al. Post-transplantation high-dose cyclophosphamide (Cy) is effective single agent GVHD prophylaxis that permits prompt immune reconstitution after myeloablative HLA matched related and unrelated bone marrow transplantation (BMT). Biol Blood Marrow Transplant. 2007;13(2 Suppl):4.

    Article  Google Scholar 

  58. Brodsky RA, Luznik L, Bolanos-Meade J, et al. Reduced intensity: HLA-haploidentical BMT with post transplantation cyclophosphamide in nonmalignant hematologic diseases. Bone Marrow Transplant. 2008;42:523–7.

    Article  PubMed  CAS  Google Scholar 

  59. Hutter G, Nowak D, Mossner M, et al. Long-term control of HIV by CCR5 Delta32/Delta32 stem-cell transplantation. N Engl J Med. 2009;360:692–8.

    Article  PubMed  Google Scholar 

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Acknowledgments

The research described herein was supported by grant CA15396 from the National Cancer Institute.

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  1. Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, 288 Bunting-Blaustein Cancer Research Building, 1650 Orleans Street, Baltimore, MD, 21231, USA

    Leo Luznik & Ephraim J. Fuchs

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  1. Leo Luznik
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  2. Ephraim J. Fuchs
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Correspondence to Ephraim J. Fuchs.

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Luznik, L., Fuchs, E.J. High-dose, post-transplantation cyclophosphamide to promote graft-host tolerance after allogeneic hematopoietic stem cell transplantation. Immunol Res 47, 65–77 (2010). https://doi.org/10.1007/s12026-009-8139-0

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