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Immunotherapy for the prevention and treatment of relapse following hematopoietic cell transplantation

Robert S Negrin, MD
Section Editor
Nelson J Chao, MD
Deputy Editor
Alan G Rosmarin, MD


The majority of patients with malignancy who undergo hematopoietic cell transplantation (HCT) will attain a complete remission. However, many of these patients will have residual disease that is too small to detect using conventional techniques (ie, minimal residual disease) that puts them at risk of eventual relapse. Relapse ultimately occurs in 40 to 75 percent of patients who undergo an autologous HCT and 10 to 40 percent of those who undergo an allogeneic HCT. Discontinuation of immunosuppression followed by immunotherapy with donor lymphocyte infusion (DLI) may be used to treat relapse after allogeneic HCT. Other methods of immunotherapy (eg, interleukin-2, interferon alpha, dendritic cell vaccination) are under investigation for the prevention of or treatment of relapse following autologous or allogeneic HCT.

The rationale for using immunotherapy to prevent and/or treat the reemergence of malignancy is based in part upon the following observations:

Rates of leukemia relapse are much higher in patients who have received identical twin (syngeneic) transplants compared with HLA-identical sibling transplants administered with identical cytotoxic treatment [1]. This suggests that a graft-versus-tumor (GVT) effect plays a major role in reducing the risk of relapse following an allogeneic HCT. (See "Donor selection for hematopoietic cell transplantation", section on 'Identical twin donors'.)

Patients who develop acute or chronic graft-versus-host disease (GVHD), particularly chronic GVHD, have a lower risk of relapse [2,3].

The withdrawal of immunosuppression among patients with relapsing chronic myeloid leukemia after HCT may rarely result in cytogenetic remission occurring in association with GVHD [4]. A similar effect has been described in a patient with relapsing chronic lymphocytic leukemia [5].

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Literature review current through: Nov 2017. | This topic last updated: Dec 23, 2015.
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  1. Gale RP, Horowitz MM, Ash RC, et al. Identical-twin bone marrow transplants for leukemia. Ann Intern Med 1994; 120:646.
  2. 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.
  3. Weiden PL, Sullivan KM, Flournoy N, et al. Antileukemic effect of chronic graft-versus-host disease: contribution to improved survival after allogeneic marrow transplantation. N Engl J Med 1981; 304:1529.
  4. Elmaagacli AH, Beelen DW, Trenn G, et al. Induction of a graft-versus-leukemia reaction by cyclosporin A withdrawal as immunotherapy for leukemia relapsing after allogeneic bone marrow transplantation. Bone Marrow Transplant 1999; 23:771.
  5. Mehta J, Powles R, Singhal S, et al. Clinical and hematologic response of chronic lymphocytic and prolymphocytic leukemia persisting after allogeneic bone marrow transplantation with the onset of acute graft-versus-host disease: possible role of graft-versus-leukemia. Bone Marrow Transplant 1996; 17:371.
  6. Kolb HJ, Schmid C, Barrett AJ, Schendel DJ. Graft-versus-leukemia reactions in allogeneic chimeras. Blood 2004; 103:767.
  7. Depil S, Deconinck E, Milpied N, et al. Donor lymphocyte infusion to treat relapse after allogeneic bone marrow transplantation for myelodysplastic syndrome. Bone Marrow Transplant 2004; 33:531.
  8. MacKinnon S. Who may benefit from donor leucocyte infusions after allogeneic stem cell transplantation? Br J Haematol 2000; 110:12.
  9. Scarisbrick JJ, Dignan FL, Tulpule S, et al. A multicentre UK study of GVHD following DLI: rates of GVHD are high but mortality from GVHD is infrequent. Bone Marrow Transplant 2015; 50:62.
  10. Stern M, de Wreede LC, Brand R, et al. Sensitivity of hematological malignancies to graft-versus-host effects: an EBMT megafile analysis. Leukemia 2014; 28:2235.
  11. Baron F, Dresse MF, Beguin Y. Donor lymphocyte infusion to eradicate recurrent host hematopoiesis after allogeneic BMT for sickle cell disease. Transfusion 2000; 40:1071.
  12. Claret EJ, Alyea EP, Orsini E, et al. Characterization of T cell repertoire in patients with graft-versus-leukemia after donor lymphocyte infusion. J Clin Invest 1997; 100:855.
  13. Wu CJ, Yang XF, McLaughlin S, et al. Detection of a potent humoral response associated with immune-induced remission of chronic myelogenous leukemia. J Clin Invest 2000; 106:705.
  14. Bachireddy P, Hainz U, Rooney M, et al. Reversal of in situ T-cell exhaustion during effective human antileukemia responses to donor lymphocyte infusion. Blood 2014; 123:1412.
  15. Baba J, Watanabe S, Saida Y, et al. Depletion of radio-resistant regulatory T cells enhances antitumor immunity during recovery from lymphopenia. Blood 2012; 120:2417.
  16. Deol A, Lum LG. Role of donor lymphocyte infusions in relapsed hematological malignancies after stem cell transplantation revisited. Cancer Treat Rev 2010; 36:528.
  17. Kolb HJ, Schattenberg A, Goldman JM, et al. Graft-versus-leukemia effect of donor lymphocyte transfusions in marrow grafted patients. Blood 1995; 86:2041.
  18. Collins RH Jr, Shpilberg O, Drobyski WR, et al. Donor leukocyte infusions in 140 patients with relapsed malignancy after allogeneic bone marrow transplantation. J Clin Oncol 1997; 15:433.
  19. 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.
  20. 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. J Clin Oncol 2000; 18:3031.
  21. Salama M, Nevill T, Marcellus D, et al. Donor leukocyte infusions for multiple myeloma. Bone Marrow Transplant 2000; 26:1179.
  22. van de Donk NW, Kröger N, Hegenbart U, et al. Prognostic factors for donor lymphocyte infusions following non-myeloablative allogeneic stem cell transplantation in multiple myeloma. Bone Marrow Transplant 2006; 37:1135.
  23. Levine JE, Braun T, Penza SL, et al. Prospective trial of chemotherapy and donor leukocyte infusions for relapse of advanced myeloid malignancies after allogeneic stem-cell transplantation. J Clin Oncol 2002; 20:405.
  24. Yan CH, Liu DH, Liu KY, et al. Risk stratification-directed donor lymphocyte infusion could reduce relapse of standard-risk acute leukemia patients after allogeneic hematopoietic stem cell transplantation. Blood 2012; 119:3256.
  25. Dazzi F, Szydlo RM, Cross NC, et al. Durability of responses following donor lymphocyte infusions for patients who relapse after allogeneic stem cell transplantation for chronic myeloid leukemia. Blood 2000; 96:2712.
  26. Russell NH, Byrne JL, Faulkner RD, et al. Donor lymphocyte infusions can result in sustained remissions in patients with residual or relapsed lymphoid malignancy following allogeneic haemopoietic stem cell transplantation. Bone Marrow Transplant 2005; 36:437.
  27. Porter DL, Collins RH Jr, Hardy C, et al. Treatment of relapsed leukemia after unrelated donor marrow transplantation with unrelated donor leukocyte infusions. Blood 2000; 95:1214.
  28. Shiobara S, Nakao S, Ueda M, et al. Donor leukocyte infusion for Japanese patients with relapsed leukemia after allogeneic bone marrow transplantation: lower incidence of acute graft-versus-host disease and improved outcome. Bone Marrow Transplant 2000; 26:769.
  29. Kolb HJ. Graft-versus-leukemia effects of transplantation and donor lymphocytes. Blood 2008; 112:4371.
  30. Barrett AJ. Understanding and harnessing the graft-versus-leukaemia effect. Br J Haematol 2008; 142:877.
  31. Martino R, Caballero MD, Pérez-Simón JA, et al. Evidence for a graft-versus-leukemia effect after allogeneic peripheral blood stem cell transplantation with reduced-intensity conditioning in acute myelogenous leukemia and myelodysplastic syndromes. Blood 2002; 100:2243.
  32. Mackinnon S, Papadopoulos 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.
  33. 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.
  34. 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.
  35. 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.
  36. Berger C, Flowers ME, Warren EH, Riddell SR. Analysis of transgene-specific immune responses that limit the in vivo persistence of adoptively transferred HSV-TK-modified donor T cells after allogeneic hematopoietic cell transplantation. Blood 2006; 107:2294.
  37. Di Stasi A, Tey SK, Dotti G, et al. Inducible apoptosis as a safety switch for adoptive cell therapy. N Engl J Med 2011; 365:1673.
  38. Miller JS, Weisdorf DJ, Burns LJ, et al. Lymphodepletion followed by donor lymphocyte infusion (DLI) causes significantly more acute graft-versus-host disease than DLI alone. Blood 2007; 110:2761.
  39. Fontaine P, Roy-Proulx G, Knafo L, et al. Adoptive transfer of minor histocompatibility antigen-specific T lymphocytes eradicates leukemia cells without causing graft-versus-host disease. Nat Med 2001; 7:789.
  40. Meunier MC, Delisle JS, Bergeron J, et al. T cells targeted against a single minor histocompatibility antigen can cure solid tumors. Nat Med 2005; 11:1222.
  41. Wang X, Berger C, Wong CW, et al. Engraftment of human central memory-derived effector CD8+ T cells in immunodeficient mice. Blood 2011; 117:1888.
  42. Cooley S, McCullar V, Wangen R, et al. KIR reconstitution is altered by T cells in the graft and correlates with clinical outcomes after unrelated donor transplantation. Blood 2005; 106:4370.
  43. Introna M, Borleri G, Conti E, et al. Repeated infusions of donor-derived cytokine-induced killer cells in patients relapsing after allogeneic stem cell transplantation: a phase I study. Haematologica 2007; 92:952.
  44. Keil F, Haas OA, Fritsch G, et al. Donor leukocyte infusion for leukemic relapse after allogeneic marrow transplantation: lack of residual donor hematopoiesis predicts aplasia. Blood 1997; 89:3113.
  45. Radich JP, Gehly G, Gooley T, et al. Polymerase chain reaction detection of the BCR-ABL fusion transcript after allogeneic marrow transplantation for chronic myeloid leukemia: results and implications in 346 patients. Blood 1995; 85:2632.
  46. Verneris MR, Karimi M, Baker J, et al. Role of NKG2D signaling in the cytotoxicity of activated and expanded CD8+ T cells. Blood 2004; 103:3065.
  47. Alvarnas JC, Linn YC, Hope EG, Negrin RS. Expansion of cytotoxic CD3+ CD56+ cells from peripheral blood progenitor cells of patients undergoing autologous hematopoietic cell transplantation. Biol Blood Marrow Transplant 2001; 7:216.
  48. Linn YC, Lau LC, Hui KM. Generation of cytokine-induced killer cells from leukaemic samples with in vitro cytotoxicity against autologous and allogeneic leukaemic blasts. Br J Haematol 2002; 116:78.
  49. Leemhuis T, Wells S, Scheffold C, et al. A phase I trial of autologous cytokine-induced killer cells for the treatment of relapsed Hodgkin disease and non-Hodgkin lymphoma. Biol Blood Marrow Transplant 2005; 11:181.
  50. Laport GG, Levine BL, Stadtmauer EA, et al. Adoptive transfer of costimulated T cells induces lymphocytosis in patients with relapsed/refractory non-Hodgkin lymphoma following CD34+-selected hematopoietic cell transplantation. Blood 2003; 102:2004.
  51. Rapoport AP, Stadtmauer EA, Aqui N, et al. Rapid immune recovery and graft-versus-host disease-like engraftment syndrome following adoptive transfer of Costimulated autologous T cells. Clin Cancer Res 2009; 15:4499.
  52. Bornhäuser M, Thiede C, Platzbecker U, et al. Prophylactic transfer of BCR-ABL-, PR1-, and WT1-reactive donor T cells after T cell-depleted allogeneic hematopoietic cell transplantation in patients with chronic myeloid leukemia. Blood 2011; 117:7174.
  53. Porter DL, Levine BL, Bunin N, et al. A phase 1 trial of donor lymphocyte infusions expanded and activated ex vivo via CD3/CD28 costimulation. Blood 2006; 107:1325.
  54. Walter EA, Greenberg PD, Gilbert MJ, et al. Reconstitution of cellular immunity against cytomegalovirus in recipients of allogeneic bone marrow by transfer of T-cell clones from the donor. N Engl J Med 1995; 333:1038.
  55. Rooney CM, Smith CA, Ng CY, et al. Use of gene-modified virus-specific T lymphocytes to control Epstein-Barr-virus-related lymphoproliferation. Lancet 1995; 345:9.
  56. Bollard CM, Aguilar L, Straathof KC, et al. Cytotoxic T lymphocyte therapy for Epstein-Barr virus+ Hodgkin's disease. J Exp Med 2004; 200:1623.
  57. Faber LM, van Luxemburg-Heijs SA, Willemze R, Falkenburg JH. Generation of leukemia-reactive cytotoxic T lymphocyte clones from the HLA-identical bone marrow donor of a patient with leukemia. J Exp Med 1992; 176:1283.
  58. Faber LM, van der Hoeven J, Goulmy E, et al. Recognition of clonogenic leukemic cells, remission bone marrow and HLA-identical donor bone marrow by CD8+ or CD4+ minor histocompatibility antigen-specific cytotoxic T lymphocytes. J Clin Invest 1995; 96:877.
  59. Cooper LJ, Al-Kadhimi Z, Serrano LM, et al. Enhanced antilymphoma efficacy of CD19-redirected influenza MP1-specific CTLs by cotransfer of T cells modified to present influenza MP1. Blood 2005; 105:1622.
  60. Till BG, Jensen MC, Wang J, et al. Adoptive immunotherapy for indolent non-Hodgkin lymphoma and mantle cell lymphoma using genetically modified autologous CD20-specific T cells. Blood 2008; 112:2261.
  61. Brentjens RJ, Davila ML, Riviere I, et al. CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci Transl Med 2013; 5:177ra38.
  62. Porter DL, Levine BL, Kalos M, et al. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med 2011; 365:725.
  63. Brentjens RJ, Rivière I, Park JH, et al. Safety and persistence of adoptively transferred autologous CD19-targeted T cells in patients with relapsed or chemotherapy refractory B-cell leukemias. Blood 2011; 118:4817.
  64. Koehler P, Schmidt P, Hombach AA, et al. Engineered T cells for the adoptive therapy of B-cell chronic lymphocytic leukaemia. Adv Hematol 2012; 2012:595060.
  65. Kochenderfer JN, Dudley ME, Feldman SA, et al. B-cell depletion and remissions of malignancy along with cytokine-associated toxicity in a clinical trial of anti-CD19 chimeric-antigen-receptor-transduced T cells. Blood 2012; 119:2709.
  66. Kalos M, Levine BL, Porter DL, et al. T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci Transl Med 2011; 3:95ra73.
  67. Porter DL, Kalos M, Zheng Z, et al. Chimeric Antigen Receptor Therapy for B-cell Malignancies. J Cancer 2011; 2:331.
  68. Giralt S, Escudier S, Kantarjian H, et al. Preliminary results of treatment with filgrastim for relapse of leukemia and myelodysplasia after allogeneic bone marrow transplantation. N Engl J Med 1993; 329:757.
  69. Law L, Tuscano J, Wun T, et al. Filgrastim treatment of acute myelogenous leukemia (M7) relapse after allogeneic peripheral stem cell transplantation resulting in both graft-versus-leukemia effect with cytogenetic remission and chronic graft-versus-host disease manifesting as polyserositis and subsequent bronchiolitis obliterans with organizing pneumonia. Int J Hematol 2002; 76:360.
  70. Worth LL, Mullen CA, Choroszy M, et al. Treatment of leukemia relapse with recombinant granulocyte-macrophage colony stimulating factor (rhGM-CSF) following unrelated umbilical cord blood transplant: Induction of graft-vs.-leukemia. Pediatr Transplant 2002; 6:439.
  71. Welte K, Ciobanu N, Moore MA, et al. Defective interleukin 2 production in patients after bone marrow transplantation and in vitro restoration of defective T lymphocyte proliferation by highly purified interleukin 2. Blood 1984; 64:380.
  72. Benyunes MC, Massumoto C, York A, et al. Interleukin-2 with or without lymphokine-activated killer cells as consolidative immunotherapy after autologous bone marrow transplantation for acute myelogenous leukemia. Bone Marrow Transplant 1993; 12:159.
  73. Hamon MD, Prentice HG, Gottlieb DJ, et al. Immunotherapy with interleukin 2 after ABMT in AML. Bone Marrow Transplant 1993; 11:399.
  74. Nagler A, Ackerstein A, Or R, et al. Immunotherapy with recombinant human interleukin-2 and recombinant interferon-alpha in lymphoma patients postautologous marrow or stem cell transplantation. Blood 1997; 89:3951.
  75. Stein AS, O'Donnell MR, Slovak ML, et al. Interleukin-2 after autologous stem-cell transplantation for adult patients with acute myeloid leukemia in first complete remission. J Clin Oncol 2003; 21:615.
  76. Attal M, Blaise D, Marit G, et al. Consolidation treatment of adult acute lymphoblastic leukemia: a prospective, randomized trial comparing allogeneic versus autologous bone marrow transplantation and testing the impact of recombinant interleukin-2 after autologous bone marrow transplantation. BGMT Group. Blood 1995; 86:1619.
  77. Thompson JA, Fisher RI, Leblanc M, et al. Total body irradiation, etoposide, cyclophosphamide, and autologous peripheral blood stem-cell transplantation followed by randomization to therapy with interleukin-2 versus observation for patients with non-Hodgkin lymphoma: results of a phase 3 randomized trial by the Southwest Oncology Group (SWOG 9438). Blood 2008; 111:4048.
  78. Higano CS, Chielens D, Raskind W, et al. Use of alpha-2a-interferon to treat cytogenetic relapse of chronic myeloid leukemia after marrow transplantation. Blood 1997; 90:2549.
  79. Arcese W, Mauro FR, Alimena G, et al. Interferon therapy for Ph1 positive CML patients relapsing after T cell-depleted allogeneic bone marrow transplantation. Bone Marrow Transplant 1990; 5:309.
  80. Leda M, Ladon D, Pieczonka A, et al. Donor lymphocyte infusion followed by interferon-alpha plus low dose cyclosporine A for modulation of donor CD3 cells activity with monitoring of minimal residual disease and cellular chimerism in a patient with first hematologic relapse of chronic myelogenous leukemia after allogeneic bone marrow transplantation. Leuk Res 2001; 25:353.
  81. 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.
  82. Schultze JL, Michalak S, Seamon MJ, et al. CD40-activated human B cells: an alternative source of highly efficient antigen presenting cells to generate autologous antigen-specific T cells for adoptive immunotherapy. J Clin Invest 1997; 100:2757.
  83. Reichardt VL, Okada CY, Liso A, et al. Idiotype vaccination using dendritic cells after autologous peripheral blood stem cell transplantation for multiple myeloma--a feasibility study. Blood 1999; 93:2411.
  84. Levenga H, Schaap N, Maas F, et al. Partial T cell-depleted allogeneic stem cell transplantation following reduced-intensity conditioning creates a platform for immunotherapy with donor lymphocyte infusion and recipient dendritic cell vaccination in multiple myeloma. Biol Blood Marrow Transplant 2010; 16:320.
  85. Sykes M, Preffer F, McAfee S, et al. Mixed lymphohaemopoietic chimerism and graft-versus-lymphoma effects after non-myeloablative therapy and HLA-mismatched bone-marrow transplantation. Lancet 1999; 353:1755.
  86. 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.
  87. Ruggeri L, Capanni M, Urbani E, et al. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science 2002; 295:2097.
  88. Davies SM, Ruggieri L, DeFor T, et al. Evaluation of KIR ligand incompatibility in mismatched unrelated donor hematopoietic transplants. Killer immunoglobulin-like receptor. Blood 2002; 100:3825.
  89. Miller JS, Soignier Y, Panoskaltsis-Mortari A, et al. Successful adoptive transfer and in vivo expansion of human haploidentical NK cells in patients with cancer. Blood 2005; 105:3051.