Best Practice & Research Clinical Haematology
Volume 21, Issue 2 , Pages 239-250 , June 2008

Modulating graft-versus-host disease to enhance the graft-versus-leukemia effect

  • Edwin P. Alyea, MD (Associate Professor of Medicine)

      Affiliations

    • Corresponding Author InformationTel.: +1 617 632 3903; Fax: +1 617 632 5175.

References 

  1. Barnes DWH, Corp MJ, Loutit JF, et al. Treatment of murine leukaemia with X rays and homologous bone marrow. Preliminary communication. British Medical Journal. 1956;2:626–627
  2. Barnes DWH, Loutit JF. Immunological and histological response following spleen treatment in irradiated mice. In:  Mitchel JS,  Holmes BE,  Smith CL editor. Progress in radiobiology. Edinburgh: Oliver and Boyd; 1956;p. 291
  3. Truitt RL, Johnson BD. Principles of graft-vs.-leukemia reactivity. Biology of Blood and Marrow Transplantation. 1995;1:61–68
  4. Gale RP, Horowitz MM, Ash RC, et al. Identical-twin bone marrow transplants for leukemia. Annals of Internal Medicine. 1994;120:646–652
  5. Horowitz MM, Gale RP, Sondel PM, et al. Graft-versus-leukemia reactions after bone marrow transplantation. Blood. 1990;75:555–562
  6. Goldman JM, Gale RP, Horowitz MM, et al. Bone marrow transplantation for chronic myelogenous leukemia in chronic phase. Increased risk for relapse associated with T-cell depletion. Annals of Internal Medicine. 1988;108:806–814
  7. Apperley JF, Mauro FR, Goldman JM, et al. Bone marrow transplantation for chronic myeloid leukaemia in first chronic phase, Importance of a graft-versus-leukaemia effect. British Journal of Haematology. 1988;69:239–245
  8. Marmont A, Horowitz MM, Gale RP, et al. T-cell depletion of HLA-identical transplants in leukemia. Blood. 1991;78:2120–2130
  9. Weiden PL, Flournoy N, Thomas ED, et al. Antileukemic effect of graft-versus-host disease in recipients of allogeneic-marrow grafts. The New England Journal of Medicine. 1979;300:1068–1073
  10. Weiden PL, Sullivan K, Flournoy N, et al. Antileukemic effect of chronic graft-versus-host disease. Contribution to improved survival after allogeneic marrow transplantation. The New England Journal of Medicine. 1981;304:1529–1533
  11. Horowitz MM. Evidence for a graft versus leukemia effect in clinical bone marrow transplantation. Experimental Hematology. 1988;16:547
  12. Odom LF, August CS, Githens JH, et al. Remission of relapsed leukaemia during a graft-versus-host reaction. A ‘graft-versus-leukaemia reaction’ in man?. The Lancet. 1978;2:537–540
  13. Higano CS, Brixey M, Bryant EM, et al. Durable complete remission of acute nonlymphocytic leukemia associated with discontinuation of immunosuppression following relapse after allogeneic bone marrow transplantation. A case report of a probable graft-versus-leukemia effect. Transfusion. 1990;50:175–177
  14. Collins RH, Rogers ZR, Bennett M, et al. Hematologic relapse of chronic myelogenous leukemia following allogeneic bone marrow transplantation. Apparent graft-versus-leukemia effect following abrupt discontinuation of immunosuppression. Bone Marrow Transplantation. 1992;10:391–395
  15. Porter D, Antin J. Graft-versus-leukemia effect of allogeneic bone marrow transplantation and donor mononuclear cell infusions. In:  Winter J editors. Blood Stem Cell Transplantation. vol. 77:Boston: Kluwer Academic Publishers; 1997;p. 57–85
  16. Kolb HJ, Schattenberg A, Goldman JM, et al. Graft-versus-leukemia effect of donor lymphocyte transfusions in marrow grafted patients. Blood. 1995;86:2041–2050
  17. Collins RH, Shpilberg O, Drobyski WR, et al. Donor leukocyte infusions in 140 patients with relapsed malignancy after allogeneic bone marrow transplantation. [see comments] Journal of Clinical Oncology. 1997;15:433–444
  18. Sullivan KM, Deeg HJ, Sanders J, et al. Hyperacute graft-v-host disease in patients not given immunosuppression after allogeneic marrow transplantation. Blood. 1986;67:1172–1175
  19. Sullivan KM, Storb R, Buckner CD, et al. Graft-versus-host disease as adoptive immunotherapy in patients with advanced hematologic neoplasms. The New England Journal of Medicine. 1989;320:828–834
  20. Koh LP, Chen CS, Tai BC, et al. Impact of postgrafting immunosuppressive regimens on nonrelapse mortality and survival after nonmyeloablative allogeneic hematopoietic stem cell transplant using the fludarabine and low-dose total-body irradiation 200-cGy. Biology of Blood and Marrow Transplantation. 2007;13:790–805
  21. Sullivan KM, Weiden PL, Storb R, et al. Influence of acute and chronic graft-versus-host disease on relapse and survival after bone marrow transplantation from HLA-identical siblings as treatment of acute and chronic leukemia. Blood. 1989;73:1720–1728
  22. Weiden PL, Flournoy N, Sanders JE, et al. Anti-leukemic effect of graft-versus-host disease contributes to improved survival after allogeneic marrow transplantation. Transplantation proceedings. 1981;13:248–251
  23. Nordlander A, Mattsson J, Ringden O, et al. Graft-versus-host disease is associated with a lower relapse incidence after hematopoietic stem cell transplantation in patients with acute lymphoblastic leukemia. Biology of Blood and Marrow Transplantation. 2004;10:195–203
  24. Mielcarek M, Martin PJ, Leisenring W, et al. Graft-versus-host disease after nonmyeloablative versus conventional hematopoietic stem cell transplantation. Blood. 2003;102:756–762
  25. 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;96:2062–2068
  26. 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;92:2303–2314
  27. 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;109:3108–3114
  28. Sarbassov DD, Ali SM, Kim DH, et al. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Current Biology. 2004;14:1296–1302
  29. Baan CC, van der Mast BJ, Klepper M, et al. Differential effect of calcineurin inhibitors, anti-CD25 antibodies and rapamycin on the induction of FOXP3 in human T cells. Transplantation. 2005;80:110–117
  30. Zeiser R, Nguyen VH, Beilhack A, et al. Inhibition of CD4+ CD25+ regulatory T-cell function by calcineurin-dependent interleukin-2 production. Blood. 2006;108:390–399
  31. Battaglia M, Stabilini A, Roncarolo MG. Rapamycin selectively expands CD4+ CD25+ FoxP3+ regulatory T cells. Blood. 2005;105:4743–4748
  32. Sehgal SN. Rapamune (RAPA, rapamycin, sirolimus): mechanism of action immunosuppressive effect results from blockade of signal transduction and inhibition of cell cycle progression. Clinical Biochemistry. 1998;31:335–340
  33. Antin JH, Kim HT, Cutler C, et al. Sirolimus, tacrolimus, and low-dose methotrexate for graft-versus-host disease prophylaxis in mismatched related donor or unrelated donor transplantation. Blood. 2003;102:1601–1605
  34. Cutler C, Kim HT, Hochberg E, et al. Sirolimus and tacrolimus without methotrexate as graft-versus-host disease prophylaxis after matched related donor peripheral blood stem cell transplantation. Biology of Blood and Marrow Transplantation. 2004;10:328–336
  35. Champlin RE, Schmitz N, Horowitz MM, et al. Blood stem cells compared with bone marrow as a source of hematopoietic cells for allogeneic transplantation. IBMTR Histocompatibility and Stem Cell Sources Working Committee and the European Group for Blood and Marrow Transplantation (EBMT). Blood. 2000;95:3702–3709
  36. Cutler C, Antin JH. Peripheral blood stem cells for allogeneic transplantation: a review. Stem Cells. 2001;19:108–117
  37. 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. The New England Journal of Medicine. 2001;344:175–181
  38. Schmitz N, Eapen M, Horowitz MM, et al. Long-term outcome of patients given transplants of mobilized blood or bone marrow: a report from the International Bone Marrow Transplant Registry and the European Group for Blood and Marrow Transplantation. Blood. 2006;108:4288–4290
  39. 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. Biology of Blood and Marrow Transplantation. 2007;13:1461–1468
  40. Valcarcel D, Martino R, Caballero D, et al. Sustained remissions of high-risk acute myeloid leukemia and myelodysplastic syndrome after reduced-intensity conditioning allogeneic hematopoietic transplantation: chronic graft-versus-host disease is the strongest factor improving survival. Journal of Clinical Oncology. 2008;26:577–584
  41. Blaise D, Kuentz M, Fortanier C, et al. Randomized trial of bone marrow versus lenograstim-primed blood cell allogeneic transplantation in patients with early-stage leukemia: a report from the Societe Francaise de Greffe de Moelle. Journal of Clinical Oncology. 2000;18:537–546
  42. Vigorito AC, Azevedo WM, Marques JF, et al. A randomised, prospective comparison of allogeneic bone marrow and peripheral blood progenitor cell transplantation in the treatment of haematological malignancies. Bone Marrow Transplantation. 1998;22:1145–1151
  43. Solano C, Martinez C, Brunet S, et al. Chronic graft-versus-host disease after allogeneic peripheral blood progenitor cell or bone marrow transplantation from matched related donors. A case-control study. Spanish Group of Allo-PBT. Bone Marrow Transplantation. 1998;22:1129–1135
  44. Flowers MED, Parker PM, Johnston LJ, et al. Comparison of chronic graft-versus-host disease after transplantation of peripheral blood stem cells versus bone marrow in allogeneic recipients: long-term follow-up of a randomized trial. Blood. 2002;100:415–419
  45. Henney CS, Kuribayashi K, Kern DE, et al. Interleukin-2 augments natural killer cell activity. Nature. 1981;291:335–338
  46. Trinchieri G, Matsumoto-Kobayashi M, Clark SC, et al. Response of resting human peripheral blood natural killer cells to interleukin 2. The Journal of Experimental Medicine. 1984;160:1147–1169
  47. Fierro MT, Liao XS, Lusso P, et al. In vitro and in vivo susceptibility of human leukemic cells to lymphokine activated killer activity. Leukemia. 1988;2:50–54
  48. Oshimi K, Oshimi Y, Saito H, et al. Cytotoxicity of interleukin-2-activated lymphocytes for autologous normal blood mononuclear cells. Journal of Immunological Methods. 1988;109:161–168
  49. Lotzova E, Savary CA, Herberman RB. Inhibition of clonogenic growth of fresh leukemia cells by unstimulated and IL-2 stimulated NK cells of normal donors. Leukemia Research. 1987;11:1059–1066
  50. Foa R, Fierro MT, Cesano A, et al. Defective lymphokine-activated killer cell generation and activity in acute leukemia patients with active disease. Blood. 1991;78:1041–1046
  51. Foa R, Meloni G, Tosti S, et al. Treatment of acute myeloid leukaemia patients with recombinant interleukin 2: a pilot study. British Journal of Haematology. 1991;77:491–496
  52. Slavin S, Ackerstein A, Kedar E, et al. IL-2 activated cell-mediated immunotherapy: control of minimal residual disease in malignant disorders by allogeneic lymphocytes and IL-2. Bone Marrow Transplantation. 1990;1(6 Suppl):86–90
  53. Weiss L, Reich S, Slavin S. Use of recombinant human interleukin-2 in conjunction with bone marrow transplantation as a model for control of minimal residual disease in malignant hematological disorders: I. Treatment of murine leukemia in conjunction with allogeneic bone marrow transplantation and IL-2-activated cell-mediated immunotherapy. Cancer Investigation. 1992;10:19–26
  54. Lim SH, Newland AC, Kelsey S, et al. Continuous intravenous infusion of high-dose recombinant interleukin-2 for acute myeloid leukaemia – a phase II study. Cancer Immunology Immunotherapy. 1992;34:337–342
  55. Meloni G, Foa R, Vignetti M, et al. Interleukin-2 may induce prolonged remissions in advanced acute myelogenous leukemia. Blood. 1994;84:2158–2163
  56. Macdonald D, Jiang YZ, Gordon AA, et al. Recombinant interleukin 2 for acute myeloid leukaemia in first complete remission: a pilot study. Leukemia Research. 1990;14:967–973
  57. Soiffer RJ, Murray C, Cochran K, et al. Clinical and immunologic effects of prolonged infusion of low-dose recombinant interleukin-2 after autologous and T-cell-depleted allogeneic bone marrow transplantation. Blood. 1992;79:517–526
  58. Blaise D, Attal M, Pico JL, et al. The use of a sequential high dose recombinant interleukin 2 regimen after autologous bone marrow transplantation does not improve the disease free survival of patients with acute leukemia transplanted in first complete remission. Leukemia & Lymphoma. 1997;25:469–478
  59. Slavin S, Or R, Kapelushnik Y, et al. Immunotherapy of minimal residual disease in conjunction with autologous and allogeneic bone marrow transplantation (BMT). Leukemia. 1992;4(6 Suppl):164–166
  60. Soiffer RJ, Murray C, Gonin R, et al. Effect of low-dose interleukin-2 on disease relapse after T-cell-depleted allogeneic bone marrow transplantation. Blood. 1994;84:964–971
  61. Zorn E, Kim HT, Lee SJ, et al. Reduced frequency of FOXP3+ CD4+ CD25+ regulatory T cells in patients with chronic graft-versus-host disease. Blood. 2005;106:2903–2911
  62. Zorn E, Nelson EA, Mohseni M, et al. IL-2 regulates FOXP3 expression in human CD4+ CD25+ regulatory T cells through a STAT-dependent mechanism and induces the expansion of these cells in vivo. Blood. 2006;108:1571–1579
  63. Alpdogan O, Schmaltz C, Muriglan SJ, et al. Administration of interleukin-7 after allogeneic bone marrow transplantation improves immune reconstitution without aggravating graft-versus-host disease. Blood. 2001;98:2256–2265
  64. Teshima T, Hill GR, Pan L, et al. IL-11 separates graft-versus-leukemia effects from graft-versus-host disease after bone marrow transplantation. The Journal of Clinical Investigation. 1999;104:317–325
  65. Bomberger C, Singh-Jairam M, Rodey G, et al. Lymphoid reconstitution after autologous PBSC transplantation with FACS-sorted CD34+ hematopoietic progenitors. Blood. 1998;91:2588–2600
  66. Yang YG, Sergio JJ, Pearson DA, et al. Interleukin-12 preserves the graft-versus-leukemia effect of allogeneic CD8 T cells while inhibiting CD4-dependent graft-versus-host disease in mice. Blood. 1997;90:4651–4660
  67. Reddy P, Teshima T, Hildebrandt G, et al. Interleukin 18 preserves a perforin-dependent graft-versus-leukemia effect after allogeneic bone marrow transplantation. Blood. 2002;100:3429–3431
  68. Slavin S, Naparstek E, Nagler A, et al. Allogeneic cell therapy with donor peripheral blood cells and recombinant human interleukin-2 to treat leukemia relapse after allogeneic bone marrow transplantation. Blood. 1996;87:2195–2204
  69. Porter DL, Roth MS, McGarigle C, et al. Induction of graft-vs-host disease as immunotherapy for relapsed chronic myelogenous leukemia. The New England Journal of Medicine. 1994;330:100–106
  70. Raiola AM, Van Lint MT, Valbonesi M, et al. Factors predicting response and graft-versus-host disease after donor lymphocyte infusions: a study on 593 infusions. Bone Marrow Transplantation. 2003;31:687–693
  71. Guglielmi C, Arcese W, Dazzi F, et al. Donor lymphocyte infusion for relapsed chronic myelogenous leukemia: prognostic relevance of the initial cell dose. Blood. 2002;100:397–405
  72. Mackinnon S, Papadapoulos EB, Carabasi MH, et al. Adoptive immunotherapy evaluating escalating doses of donor leukocytes for relapse of chronic myeloid leukemia after bone marrow transplantation: Separation of graft-versus-leukemia responses from graft-versus-host disease. Blood. 1995;86:1261–1268
  73. Dazzi F, Szydlo RM, Craddock C, et al. Comparison of single-dose and escalating-dose regimens of donor lymphocyte infusion for relapse after allografting for chronic myeloid leukemia. Blood. 2000;95:67–71
  74. Alyea EP, Soiffer RJ, Canning C, et al. Toxicity and efficacy of defined doses of CD4(+) donor lymphocytes for treatment of relapse after allogeneic bone marrow transplant. Blood. 1998;91:3671–3680
  75. Lokhorst HM, Schattenberg A, Cornelissen JJ, et al. Donor leukocyte infusions are effective in relapsed multiple myeloma after allogeneic bone marrow transplantation. Blood. 1997;90:4206–4211
  76. Lokhorst HM, Schattenberg A, Cornelissen JJ, et al. Donor lymphocyte infusions for relapsed multiple myeloma after allogeneic stem-cell transplantation: predictive factors for response and long-term outcome. Journal of Clinical Oncology. 2000;18:3031–3037
  77. Alyea E, Schossman R, Canning C, et al. CD6 T cell depleted allogeneic bone marrow transplant followed by CD4+ donor lymphocyte infusion for patients with multiple myeloma. Blood. 1999;94:609a
  78. Kahl C, Storer BE, Sandmaier BM, et al. Relapse risk in patients with malignant diseases given allogeneic hematopoietic cell transplantation after nonmyeloablative conditioning. Blood. 2007;110:2744–2748
  79. Baron F, Maris MB, Sandmaier BM, et al. Graft-versus-tumor effects after allogeneic hematopoietic cell transplantation with nonmyeloablative conditioning. Journal of Clinical Oncology. 2005;23:1993–2003
  80. Dey BR, McAfee S, Colby C, et al. Impact of prophylactic donor leukocyte infusions on mixed chimerism, graft-versus-host disease, and antitumor response in patients with advanced hematologic malignancies treated with nonmyeloablative conditioning and allogeneic bone marrow transplantation. Biology of Blood and Marrow Transplantation. 2003;9:320–329
  81. Peggs KS, Thomson K, Hart DP, et al. Dose-escalated donor lymphocyte infusions following reduced intensity transplantation: toxicity, chimerism, and disease responses. Blood. 2004;103:1548–1556
  82. Bethge WA, Hegenbart U, Stuart MJ, et al. Adoptive immunotherapy with donor lymphocyte infusions after allogeneic hematopoietic cell transplantation following nonmyeloablative conditioning. Blood. 2004;103:790–795
  83. Peggs KS, Sureda A, Qian W, et al. Reduced-intensity conditioning for allogeneic haematopoietic stem cell transplantation in relapsed and refractory Hodgkin lymphoma: impact of alemtuzumab and donor lymphocyte infusions on long-term outcomes. British Journal of Haematology. 2007;139:70–80
  84. Bloor AJ, Thomson K, Chowdhry N, et al. High response rate to donor lymphocyte infusion after allogeneic stem cell transplantation for indolent non-Hodgkin lymphoma. Biology of Blood and Marrow Transplantation. 2008;14:50–58
  85. Schmid C, Schleuning M, Ledderose G, et al. Sequential regimen of chemotherapy, reduced-intensity conditioning for allogeneic stem-cell transplantation, and prophylactic donor lymphocyte transfusion in high-risk acute myeloid leukemia and myelodysplastic syndrome. Journal of Clinical Oncology. 2005;23:5675–5687
  86. Giralt S, Hester J, Huh Y, et al. CD8-depleted donor lymphocyte infusion as treatment for relapsed chronic myelogenous leukemia after allogeneic bone marrow transplantation. Blood. 1995;86:4337–4343
  87. Bonini C, Ferrari G, Verzeletti S, et al. HSV-TK gene transfer into donor lymphocytes for control of allogeneic graft-versus-leukemia. Science. 1997;276:1719–1724
  88. Verzeletti S, Bonini C, Traversari C, et al. Transfer of the HSV-tK gene into donor peripheral blood lymphocytes for in vivo immunomodulation of donor antitumor immunity after allo- BMT. [Meeting abstract] Gene Therapy. 1994;1:S24
  89. Verzeletti S, Bonini C, Traversari C, et al. Retroviral vector gene transfer into donor peripheral blood lymphocytes for in vitro selection and in vivo immunomodulation of donor antitumor immunity after allo-BMT. [Meeting abstract] Journal of Cellular Biochemistry. 1995;21A(Suppl):356

PII: S1521-6926(08)00013-3

doi: 10.1016/j.beha.2008.02.012

Best Practice & Research Clinical Haematology
Volume 21, Issue 2 , Pages 239-250 , June 2008

Article Tools