Review Article | Published:

Strategies to enhance the graft versus tumour effect after allogeneic haematopoietic stem cell transplantation

Bone Marrow Transplantationvolume 54pages175189 (2019) | Download Citation


Relapse of haematological malignancies after allogeneic haematopoietic stem cell transplant is a major cause of mortality. The immunological mechanisms that may lead to disease relapse may include immunological immaturity prior to reconstitution of the allogeneic immune system, tumour antigen downregulation or promotion of T-cell exhaustion by interactions with the tumour microenvironment. Current therapeutic strategies for post-transplant relapse are limited in their efficacy and alternative approaches are required. In this review, we discuss the mechanisms of T and NK-cell immune evasion that facilitate relapse of haematological malignancies after allogeneic stem cell transplantation, and explore emerging strategies to augment the allogeneic immune system in order to construct a more potent graft versus tumour response.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1.

    Lim ABM, Curley C, Fong CY, Bilmon I, Beligaswatte A, Purtill D, et al. Acute myeloid leukaemia relapsing after allogeneic haematopoietic stem cell transplantation: prognostic factors and impact of initial therapy of relapse. Intern Med J. 2017.

  2. 2.

    Schmid C, Labopin M, Nagler A, Niederwieser D, Castagna L, Tabrizi R, et al. Treatment, risk factors, and outcome of adults with relapsed AML after reduced intensity conditioning for allogeneic stem cell transplantation. Blood. 2012;119:1599–606.

  3. 3.

    Chalandon Y, Passweg JR, Schmid C, Olavarria E, Dazzi F, Simula MP, et al. Outcome of patients developing GVHD after DLI given to treat CML relapse: a study by the Chronic Leukemia Working Party of the EBMT. Bone Marrow Transplant. 2010;45:558–64.

  4. 4.

    Weiden PL, Flournoy N, Sanders JE, Sullivan KM, Thomas ED. Antileukemic effect of graft-versus-host disease contributes to improved survival after allogeneic marrow transplantation. Transplant Proc. 1981;13(1 Pt 1):248–51.

  5. 5.

    Goldman JM, Apperley JF, Jones L, Marcus R, Goolden AW, Batchelor R, et al. Bone marrow transplantation for patients with chronic myeloid leukemia. N Engl J Med. 1986;314:202–7.

  6. 6.

    Barrett AJ. Mechanisms of the graft-versus-leukemia reaction. Stem Cells. 1997;15:248–58.

  7. 7.

    Korngold R, Sprent J. T cell subsets and graft-versus-host disease. Transplantation. 1987;44:335–9.

  8. 8.

    Bleakley M, Riddell SR. Molecules and mechanisms of the graft-versus-leukaemia effect. Nat Rev Cancer. 2004;4:371–80.

  9. 9.

    Akatsuka Y, Warren EH, Gooley TA, Brickner AG, Lin MT, Hansen JA, et al. Disparity for a newly identified minor histocompatibility antigen, HA-8, correlates with acute graft-versus-host disease after haematopoietic stem cell transplantation from an HLA-identical sibling. Br J Haematol. 2003;123:671–5.

  10. 10.

    Kolb HJ. Graft-versus-leukemia effects of transplantation and donor lymphocytes. Blood. 2008;112:4371–83.

  11. 11.

    Savani BN, Mielke S, Adams S, Uribe M, Rezvani K, Yong AS, et al. Rapid natural killer cell recovery determines outcome after T-cell-depleted HLA-identical stem cell transplantation in patients with myeloid leukemias but not with acute lymphoblastic leukemia. Leukemia. 2007;21:2145–52.

  12. 12.

    Ruggeri L, Capanni M, Urbani E, Perruccio K, Shlomchik WD, Tosti A, et al. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science. 2002;295:2097–2100.

  13. 13.

    Ruggeri L, Mancusi A, Capanni M, Urbani E, Carotti A, Aloisi T, et al. Donor natural killer cell allorecognition of missing self in haploidentical hematopoietic transplantation for acute myeloid leukemia: challenging its predictive value. Blood. 2007;110:433–40.

  14. 14.

    Hsu KC, Gooley T, Malkki M, Pinto-Agnello C, Dupont B, Bignon JD, et al. KIR ligands and prediction of relapse after unrelated donor hematopoietic cell transplantation for hematologic malignancy. Biol Blood Marrow Transplant. 2006;12:828–36.

  15. 15.

    Cooley S, Weisdorf DJ, Guethlein LA, Klein JP, Wang T, Le CT, et al. Donor selection for natural killer cell receptor genes leads to superior survival after unrelated transplantation for acute myelogenous leukemia. Blood. 2010;116:2411–9.

  16. 16.

    Venstrom JM, Pittari G, Gooley TA, Chewning JH, Spellman S, Haagenson M, et al. HLA-C-dependent prevention of leukemia relapse by donor activating KIR2DS1. N Engl J Med. 2012;367:805–16.

  17. 17.

    Cichocki F, Cooley S, Davis Z, DeFor TE, Schlums H, Zhang B, et al. CD56dimCD57+NKG2C+NK cell expansion is associated with reduced leukemia relapse after reduced intensity HCT. Leukemia. 2016;30:456–63.

  18. 18.

    Gill S, Olson JA, Negrin RS. Natural killer cells in allogeneic transplantation: effect on engraftment, graft- versus-tumor, and graft-versus-host responses. Biol Blood Marrow Transplant. 2009;15:765–76.

  19. 19.

    Heidenreich S, Kroger N. Reduction of Relapse after Unrelated Donor Stem Cell Transplantation by KIR-Based Graft Selection. Front Immunol. 2017;8:41

  20. 20.

    Ogonek J, Kralj Juric M, Ghimire S, Varanasi PR, Holler E, Greinix H, et al. Immune Reconstitution after Allogeneic Hematopoietic Stem Cell Transplantation. Front Immunol. 2016;7:507

  21. 21.

    Vago L, Perna SK, Zanussi M, Mazzi B, Barlassina C, Stanghellini MT, et al. Loss of mismatched HLA in leukemia after stem-cell transplantation. N Engl J Med. 2009;361:478–88.

  22. 22.

    Vago L, Toffalori C, Ciceri F, Fleischhauer K. Genomic loss of mismatched human leukocyte antigen and leukemia immune escape from haploidentical graft-versus-leukemia. Semin Oncol. 2012;39:707–15.

  23. 23.

    Brooks DG, Trifilo MJ, Edelmann KH, Teyton L, McGavern DB, Oldstone MB. Interleukin-10 determines viral clearance or persistence in vivo. Nat Med. 2006;12:1301–9.

  24. 24.

    Tinoco R, Alcalde V, Yang Y, Sauer K, Zuniga EI. Cell-intrinsic transforming growth factor-beta signaling mediates virus-specific CD8+T cell deletion and viral persistence in vivo. Immunity. 2009;31:145–57.

  25. 25.

    Wherry EJ. T cell exhaustion. Nat Immunol. 2011;12:492–9.

  26. 26.

    Nguyen S, Dhedin N, Vernant JP, Kuentz M, Al Jijakli A, Rouas-Freiss N, et al. NK-cell reconstitution after haploidentical hematopoietic stem-cell transplantations: immaturity of NK cells and inhibitory effect of NKG2A override GvL effect. Blood. 2005;105:4135–42.

  27. 27.

    Seggewiss R, Einsele H. Immune reconstitution after allogeneic transplantation and expanding options for immunomodulation: an update. Blood. 2010;115:3861–8.

  28. 28.

    van Heijst JW, Ceberio I, Lipuma LB, Samilo DW, Wasilewski GD, Gonzales AM, et al. Quantitative assessment of T cell repertoire recovery after hematopoietic stem cell transplantation. Nat Med. 2013;19:372–7.

  29. 29.

    Weinberg K, Blazar BR, Wagner JE, Agura E, Hill BJ, Smogorzewska M, et al. Factors affecting thymic function after allogeneic hematopoietic stem cell transplantation. Blood. 2001;97:1458–66.

  30. 30.

    Wu T, Young JS, Johnston H, Ni X, Deng R, Racine J, et al. Thymic damage, impaired negative selection, and development of chronic graft-versus-host disease caused by donor CD4+and CD8+T cells. J Immunol. 2013;191:488–99.

  31. 31.

    Lowdell MW, Craston R, Ray N, Koh M, Galatowicz G, Prentice HG. The effect of T cell depletion with Campath-1M on immune reconstitution after chemotherapy and allogeneic bone marrow transplant as treatment for leukaemia. Bone Marrow Transplant. 1998;21:679–86.

  32. 32.

    Goldberg JD, Zheng J, Ratan R, Small TN, Lai KC, Boulad F, et al. Early recovery of T-cell function predicts improved survival after T-cell depleted allogeneic transplant. Leuk Lymphoma. 2017;58:1859–71.

  33. 33.

    Tian DM, Wang Y, Zhang XH, Liu KY, Huang XJ, Chang YJ. Rapid Recovery of CD3+CD8+T Cells on Day 90 Predicts Superior Survival after Unmanipulated Haploidentical Blood and Marrow Transplantation. PLoS One. 2016;11:e0156777

  34. 34.

    Brahmi Z,Hommel-Berrey G,Smith F,Thomson B, NK cells recover early and mediate cytotoxicity via perforin/granzyme and Fas/FasL pathways in umbilical cord blood recipients. Hum Immunol. 2001;62:782–90.

  35. 35.

    Shilling HG, McQueen KL, Cheng NW, Shizuru JA, Negrin RS, Parham P. Reconstitution of NK cell receptor repertoire following HLA-matched hematopoietic cell transplantation. Blood. 2003;101:3730–40.

  36. 36.

    Foley B, Cooley S, Verneris MR, Curtsinger J, Luo X, Waller EK, et al. NK cell education after allogeneic transplantation: dissociation between recovery of cytokine-producing and cytotoxic functions. Blood. 2011;118:2784–92.

  37. 37.

    Crucitti L, Crocchiolo R, Toffalori C, Mazzi B, Greco R, Signori A, et al. Incidence, risk factors and clinical outcome of leukemia relapses with loss of the mismatched HLA after partially incompatible hematopoietic stem cell transplantation. Leukemia. 2015;29:1143–52.

  38. 38.

    Waterhouse M, Pfeifer D, Pantic M, Emmerich F, Bertz H, Finke J. Genome-wide profiling in AML patients relapsing after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2011;17:1450–9 e1451.

  39. 39.

    Toffalori C, Cavattoni I, Deola S, Mastaglio S, Giglio F, Mazzi B, et al. Genomic loss of patient-specific HLA in acute myeloid leukemia relapse after well-matched unrelated donor HSCT. Blood. 2012;119:4813–5.

  40. 40.

    Stolzel F, Hackmann K, Kuithan F, Mohr B, Fussel M, Oelschlagel U, et al. Clonal evolution including partial loss of human leukocyte antigen genes favoring extramedullary acute myeloid leukemia relapse after matched related allogeneic hematopoietic stem cell transplantation. Transplantation. 2012;93:744–9.

  41. 41.

    Nowbakht P, Ionescu MC, Rohner A, Kalberer CP, Rossy E, Mori L, et al. Ligands for natural killer cell-activating receptors are expressed upon the maturation of normal myelomonocytic cells but at low levels in acute myeloid leukemias. Blood. 2005;105:3615–22.

  42. 42.

    Groh V, Wu J, Yee C, Spies T. Tumour-derived soluble MIC ligands impair expression of NKG2D and T-cell activation. Nature. 2002;419:734–8.

  43. 43.

    Boukouaci W, Busson M, Peffault de Latour R, Rocha V, Suberbielle C, Bengoufa D, et al. MICA-129 genotype, soluble MICA, and anti-MICA antibodies as biomarkers of chronic graft-versus-host disease. Blood. 2009;114:5216–24.

  44. 44.

    Wherry EJ, Kurachi M. Molecular and cellular insights into T cell exhaustion. Nat Rev Immunol. 2015;15:486–99.

  45. 45.

    Zhou Q, Munger ME, Veenstra RG, Weigel BJ, Hirashima M, Munn DH, et al. Coexpression of Tim-3 and PD-1 identifies a CD8+T-cell exhaustion phenotype in mice with disseminated acute myelogenous leukemia. Blood. 2011;117:4501–10.

  46. 46.

    Asakura S, Hashimoto D, Takashima S, Sugiyama H, Maeda Y, Akashi K, et al. Alloantigen expression on non-hematopoietic cells reduces graft-versus-leukemia effects in mice. J Clin Invest. 2010;120:2370–8.

  47. 47.

    Meunier MC, Roy-Proulx G, Labrecque N, Perreault C. Tissue distribution of target antigen has a decisive influence on the outcome of adoptive cancer immunotherapy. Blood. 2003;101:766–70.

  48. 48.

    Flutter B, Edwards N, Fallah-Arani F, Henderson S, Chai JG, Sivakumaran S, et al. Nonhematopoietic antigen blocks memory programming of alloreactive CD8+T cells and drives their eventual exhaustion in mouse models of bone marrow transplantation. J Clin Invest. 2010;120:3855–68.

  49. 49.

    Norde WJ, Maas F, Hobo W, Korman A, Quigley M, Kester MG, et al. PD-1/PD-L1 interactions contribute to functional T-cell impairment in patients who relapse with cancer after allogeneic stem cell transplantation. Cancer Res. 2011;71:5111–22.

  50. 50.

    Kong Y, Zhang J, Claxton DF, Ehmann WC, Rybka WB, Zhu L, et al. PD-1(hi)TIM-3(+) T cells associate with and predict leukemia relapse in AML patients post allogeneic stem cell transplantation. Blood Cancer J. 2015;5:e330

  51. 51.

    Shimizu H, Saitoh T, Hatsumi N, Takada S, Handa H, Jimbo T, et al. Prevalence of extramedullary relapses is higher after allogeneic stem cell transplantation than after chemotherapy in adult patients with acute myeloid leukemia. Leuk Res. 2013;37:1477–81.

  52. 52.

    Michonneau D, Sagoo P, Breart B, Garcia Z, Celli S, Bousso P. The PD-1 Axis Enforces an Anatomical Segregation of CTL Activity that Creates Tumor Niches after Allogeneic Hematopoietic Stem Cell Transplantation. Immunity. 2016;44:143–54.

  53. 53.

    Pizzi M, Boi M, Bertoni F, Inghirami G. Emerging therapies provide new opportunities to reshape the multifaceted interactions between the immune system and lymphoma cells. Leukemia. 2016;30:1805–15.

  54. 54.

    Juszczynski P, Ouyang J, Monti S, Rodig SJ, Takeyama K, Abramson J, et al. The AP1-dependent secretion of galectin-1 by Reed Sternberg cells fosters immune privilege in classical Hodgkin lymphoma. Proc Natl Acad Sci USA. 2007;104:13134–9.

  55. 55.

    Steidl C, Lee T, Shah SP, Farinha P, Han G, Nayar T, et al. Tumor-associated macrophages and survival in classic Hodgkin’s lymphoma. N Engl J Med. 2010;362:875–85.

  56. 56.

    Mussai F, De Santo C, Abu-Dayyeh I, Booth S, Quek L, McEwen-Smith RM, et al. Acute myeloid leukemia creates an arginase-dependent immunosuppressive microenvironment. Blood. 2013;122:749–58.

  57. 57.

    Horlad H, Ma C, Yano H, Pan C, Ohnishi K, Fujiwara Y, et al. An IL-27/Stat3 axis induces expression of programmed cell death 1 ligands (PD-L1/2) on infiltrating macrophages in lymphoma. Cancer Sci. 2016;107:1696–704.

  58. 58.

    Kitagawa Y, Ohkura N, Sakaguchi S. Molecular determinants of regulatory T cell development: the essential roles of epigenetic changes. Front Immunol. 2013;4:106

  59. 59.

    Durr C, Pfeifer D, Claus R, Schmitt-Graeff A, Gerlach UV, Graeser R, et al. CXCL12 mediates immunosuppression in the lymphoma microenvironment after allogeneic transplantation of hematopoietic cells. Cancer Res. 2010;70:10170–81.

  60. 60.

    Brandenburg U, Gottlieb D, Bradstock K. Antileukemic effects of rapid cyclosporin withdrawal in patients with relapsed chronic myeloid leukemia after allogeneic bone marrow transplantation. Leuk Lymphoma. 1998;31:545–50.

  61. 61.

    Wudhikarn K, Brunstein CG, Bachanova V, Burns LJ, Cao Q, Weisdorf DJ. Relapse of lymphoma after allogeneic hematopoietic cell transplantation: management strategies and outcome. Biol Blood Marrow Transplant. 2011;17:1497–504.

  62. 62.

    Kekre N, Kim HT, Thanarajasingam G, Armand P, Antin JH, Cutler C, et al. Efficacy of immune suppression tapering in treating relapse after reduced intensity allogeneic stem cell transplantation. Haematologica. 2015;100:1222–7.

  63. 63.

    Mielcarek M, Storer BE, Flowers ME, Storb R, Sandmaier BM, Martin PJ. Outcomes among patients with recurrent high-risk hematologic malignancies after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2007;13:1160–8.

  64. 64.

    Schroeder T, Czibere A, Platzbecker U, Bug G, Uharek L, Luft T, et al. Azacitidine and donor lymphocyte infusions as first salvage therapy for relapse of AML or MDS after allogeneic stem cell transplantation. Leukemia. 2013;27:1229–35.

  65. 65.

    Orti G, Barba P, Fox L, Salamero O, Bosch F, Valcarcel D. Donor lymphocyte infusions in AML and MDS: Enhancing the graft-versus-leukemia effect. Exp Hematol. 2017;48:1–11.

  66. 66.

    Choi SJ, Lee JH, Lee JH, Kim S, Seol M, Lee YS, et al. Treatment of relapsed acute myeloid leukemia after allogeneic bone marrow transplantation with chemotherapy followed by G-CSF-primed donor leukocyte infusion: a high incidence of isolated extramedullary relapse. Leukemia. 2004;18:1789–97.

  67. 67.

    Shaw BE, Mufti GJ, Mackinnon S, Cavenagh JD, Pearce RM, Towlson KE, et al. Outcome of second allogeneic transplants using reduced-intensity conditioning following relapse of haematological malignancy after an initial allogeneic transplant. Bone Marrow Transplant. 2008;42:783–9.

  68. 68.

    McIver ZA, Yin F, Hughes T, Battiwalla M, Ito S, Koklanaris E, et al. Second hematopoietic SCT for leukemia relapsing after myeloablative T cell-depleted transplants does not prolong survival. Bone Marrow Transplant. 2013;48:1192–7.

  69. 69.

    Schluns KS, Kieper WC, Jameson SC, Lefrancois L. Interleukin-7 mediates the homeostasis of naive and memory CD8 T cells in vivo. Nat Immunol. 2000;1:426–32.

  70. 70.

    Bolotin E, Smogorzewska M, Smith S, Widmer M, Weinberg K. Enhancement of thymopoiesis after bone marrow transplant by in vivo interleukin-7. Blood. 1996;88:1887–94.

  71. 71.

    Alpdogan O, Schmaltz C, Muriglan SJ, Kappel BJ, Perales MA, Rotolo JA, et al. Administration of interleukin-7 after allogeneic bone marrow transplantation improves immune reconstitution without aggravating graft-versus-host disease. Blood. 2001;98:2256–65.

  72. 72.

    Alpdogan O, Muriglan SJ, Eng JM, Willis LM, Greenberg AS, Kappel BJ, et al. IL-7 enhances peripheral T cell reconstitution after allogeneic hematopoietic stem cell transplantation. J Clin Invest. 2003;112:1095–107.

  73. 73.

    Perales MA, Goldberg JD, Yuan J, Koehne G, Lechner L, Papadopoulos EB, et al. Recombinant human interleukin-7 (CYT107) promotes T-cell recovery after allogeneic stem cell transplantation. Blood. 2012;120:4882–91.

  74. 74.

    Mishra A, Sullivan L, Caligiuri MA. Molecular pathways: interleukin-15 signaling in health and in cancer. Clin Cancer Res. 2014;20:2044–50.

  75. 75.

    Alpdogan O, Eng JM, Muriglan SJ, Willis LM, Hubbard VM, Tjoe KH, et al. Interleukin-15 enhances immune reconstitution after allogeneic bone marrow transplantation. Blood. 2005;105:865–73.

  76. 76.

    Sauter CT, Bailey CP, Panis MM, Biswas CS, Budak-Alpdogan T, Durham A, et al. Interleukin-15 administration increases graft-versus-tumor activity in recipients of haploidentical hematopoietic SCT. Bone Marrow Transplant. 2013;48:1237–42.

  77. 77.

    Blaser BW, Schwind NR, Karol S, Chang D, Shin S, Roychowdhury S, et al. Trans-presentation of donor-derived interleukin 15 is necessary for the rapid onset of acute graft-versus-host disease but not for graft-versus-tumor activity. Blood. 2006;108:2463–9.

  78. 78.

    Russo A, Oliveira G, Berglund S, Greco R, Gambacorta V, Cieri N, et al. NK cell recovery after haploidentical HSCT with post-transplant cyclophosphamide: dynamics and clinical implications. Blood. 2017.

  79. 79.

    Ciurea SO, Schafer JR, Bassett R, Denman CJ, Cao K, Willis D, et al. Phase 1 clinical trial using mbIL21 ex vivo-expanded donor-derived NK cells after haploidentical transplantation. Blood. 2017;130:1857–68.

  80. 80.

    Passweg JR, Tichelli A, Meyer-Monard S, Heim D, Stern M, Kuhne T, et al. Purified donor NK-lymphocyte infusion to consolidate engraftment after haploidentical stem cell transplantation. Leukemia. 2004;18:1835–8.

  81. 81.

    Gandhi AK, Kang J, Havens CG, Conklin T, Ning Y, Wu L, et al. Immunomodulatory agents lenalidomide and pomalidomide co-stimulate T cells by inducing degradation of T cell repressors Ikaros and Aiolos via modulation of the E3 ubiquitin ligase complex CRL4(CRBN.). Br J Haematol. 2014;164:811–21.

  82. 82.

    Fink EC, Ebert BL. The novel mechanism of lenalidomide activity. Blood. 2015;126:2366–9.

  83. 83.

    Sockel K, Bornhaeuser M, Mischak-Weissinger E, Trenschel R, Wermke M, Unzicker C, et al. Lenalidomide maintenance after allogeneic HSCT seems to trigger acute graft-versus-host disease in patients with high-risk myelodysplastic syndromes or acute myeloid leukemia and del(5q): results of the LENAMAINT trial. Haematologica. 2012;97:e34–35.

  84. 84.

    Kneppers E, van der Holt B, Kersten MJ, Zweegman S, Meijer E, Huls G, et al. Lenalidomide maintenance after nonmyeloablative allogeneic stem cell transplantation in multiple myeloma is not feasible: results of the HOVON 76 Trial. Blood. 2011;118:2413–9.

  85. 85.

    Jaiswal SR, Zaman S, Chakrabarti A, Sen S, Mukherjee S, Bhargava S, et al. Improved Outcome of Refractory/Relapsed Acute Myeloid Leukemia after Post-Transplantation Cyclophosphamide-Based Haploidentical Transplantation with Myeloablative Conditioning and Early Prophylactic Granulocyte Colony-Stimulating Factor-Mobilized Donor Lymphocyte Infusions. Biol Blood Marrow Transplant. 2016;22:1867–73.

  86. 86.

    Coman T, Bachy E, Michallet M, Socie G, Uzunov M, Bourhis JH, et al. Lenalidomide as salvage treatment for multiple myeloma relapsing after allogeneic hematopoietic stem cell transplantation: a report from the French Society of Bone Marrow and Cellular Therapy. Haematologica. 2013;98:776–83.

  87. 87.

    Vander Lugt MT, Braun TM, Hanash S, Ritz J, Ho VT, Antin JH, et al. ST2 as a marker for risk of therapy-resistant graft-versus-host disease and death. N Engl J Med. 2013;369:529–39.

  88. 88.

    Hartwell MJ, Ozbek U, Holler E, Renteria AS, Major-Monfried H, Reddy P, et al. An early-biomarker algorithm predicts lethal graft-versus-host disease and survival. JCI Insight. 2017;2:e89798.

  89. 89.

    Saha A, Aoyama K, Taylor PA, Koehn BH, Veenstra RG, Panoskaltsis-Mortari A, et al. Host programmed death ligand 1 is dominant over programmed death ligand 2 expression in regulating graft-versus-host disease lethality. Blood. 2013;122:3062–73.

  90. 90.

    Saha A, O’Connor RS, Thangavelu G, Lovitch SB, Dandamudi DB, Wilson CB, et al. Programmed death ligand-1 expression on donor T cells drives graft-versus-host disease lethality. J Clin Invest. 2016;126:2642–60.

  91. 91.

    Al-Chaqmaqchi H, Sadeghi B, Abedi-Valugerdi M, Al-Hashmi S, Fares M, Kuiper R, et al. The role of programmed cell death ligand-1 (PD-L1/CD274) in the development of graft versus host disease. PLoS One. 2013;8:e60367

  92. 92.

    Davids MS, Kim HT, Bachireddy P, Costello C, Liguori R, Savell A, et al. Ipilimumab for Patients with Relapse after Allogeneic Transplantation. N Engl J Med. 2016;375:143–53.

  93. 93.

    Herbaux C, Gauthier J, Brice P, Drumez E, Ysebaert L, Doyen H, et al. Efficacy and tolerability of nivolumab after allogeneic transplantation for relapsed Hodgkin lymphoma. Blood. 2017;129:2471–8.

  94. 94.

    Godfrey J, Bishop MR, Syed S, Hyjek E, Kline J. PD-1 blockade induces remissions in relapsed classical Hodgkin lymphoma following allogeneic hematopoietic stem cell transplantation. J Immunother Cancer. 2017;5:11

  95. 95.

    Singh AK, Porrata LF, Aljitawi O, Lin T, Shune L, Ganguly S, et al. Fatal GvHD induced by PD-1 inhibitor pembrolizumab in a patient with Hodgkin’s lymphoma. Bone Marrow Transplant. 2016;51:1268–70.

  96. 96.

    Onizuka M, Kojima M, Matsui K, Machida S, Toyosaki M, Aoyama Y, et al. Successful treatment with low-dose nivolumab in refractory Hodgkin lymphoma after allogeneic stem cell transplantation. Int J Hematol. 2017;106:141–5.

  97. 97.

    Hosen N, Maeda T, Hashii Y, Tsuboi A, Nishida S, Nakata J, et al. Wilms tumor 1 peptide vaccination after hematopoietic stem cell transplant in leukemia patients. Stem Cell Investig. 2016;3:90

  98. 98.

    Rousseau RF, Biagi E, Dutour A, Yvon ES, Brown MP, Lin T, et al. Immunotherapy of high-risk acute leukemia with a recipient (autologous) vaccine expressing transgenic human CD40L and IL-2 after chemotherapy and allogeneic stem cell transplantation. Blood. 2006;107:1332–41.

  99. 99.

    Ho VT, Vanneman M, Kim H, Sasada T, Kang YJ, Pasek M, et al. Biologic activity of irradiated, autologous, GM-CSF-secreting leukemia cell vaccines early after allogeneic stem cell transplantation. Proc Natl Acad Sci USA. 2009;106:15825–30.

  100. 100.

    Burkhardt UE, Hainz U, Stevenson K, Goldstein NR, Pasek M, Naito M, et al. Autologous CLL cell vaccination early after transplant induces leukemia-specific T cells. J Clin Invest. 2013;123:3756–65.

  101. 101.

    Maeda T, Hosen N, Fukushima K, Tsuboi A, Morimoto S, Matsui T, et al. Maintenance of complete remission after allogeneic stem cell transplantation in leukemia patients treated with Wilms tumor 1 peptide vaccine. Blood Cancer J. 2013;3:e130

  102. 102.

    Kantarjian H, Stein A, Gokbuget N, Fielding AK, Schuh AC, Ribera JM, et al. Blinatumomab versus Chemotherapy for Advanced Acute Lymphoblastic Leukemia. N Engl J Med. 2017;376:836–47.

  103. 103.

    Ueda M, de Lima M, Caimi P, Tomlinson B, Little J, Creger R, et al. Concurrent blinatumomab and donor lymphocyte infusions for treatment of relapsed pre-B-cell ALL after allogeneic hematopoietic cell transplant. Bone Marrow Transplant. 2016;51:1253–5.

  104. 104.

    Khan MW, Gul Z. Blinatumomab may induce graft versus host leukemia in patients with pre-B ALL relapsing after hematopoietic stem cell transplant. Clin Case Rep. 2016;4:743–6.

  105. 105.

    Maude SL, Frey N, Shaw PA, Aplenc R, Barrett DM, Bunin NJ, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014;371:1507–17.

  106. 106.

    Lee DW, Kochenderfer JN, Stetler-Stevenson M, Cui YK, Delbrook C, Feldman SA, et al. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. Lancet. 2015;385:517–28.

  107. 107.

    Kochenderfer JN, Dudley ME, Carpenter RO, Kassim SH, Rose JJ, Telford WG, et al. Donor-derived CD19-targeted T cells cause regression of malignancy persisting after allogeneic hematopoietic stem cell transplantation. Blood. 2013;122:4129–39.

  108. 108.

    Brudno JN, Somerville RP, Shi V, Rose JJ, Halverson DC, Fowler DH, et al. Allogeneic T Cells That Express an Anti-CD19 Chimeric Antigen Receptor Induce Remissions of B-Cell Malignancies That Progress After Allogeneic Hematopoietic Stem-Cell Transplantation Without Causing Graft-Versus-Host Disease. J Clin Oncol. 2016;34:1112–21.

  109. 109.

    Ghosh A, Smith M, James SE, Davila ML, Velardi E, Argyropoulos KV, et al. Donor CD19 CAR T cells exert potent graft-versus-lymphoma activity with diminished graft-versus-host activity. Nat Med. 2017;23:242–9.

  110. 110.

    Levine JE, Blazar BR, DeFor T, Ferrara JL, Weisdorf DJ. Long-term follow-up of a phase I/II randomized, placebo-controlled trial of palifermin to prevent graft-versus-host disease (GVHD) after related donor allogeneic hematopoietic cell transplantation (HCT). Biol Blood Marrow Transplant. 2008;14:1017–21.

  111. 111.

    Rizwan R, Levine JE, Defor T, Ferarra JL, Weisdorf DJ, Blazar BR, et al. Peritransplant palifermin use and lymphocyte recovery after T-cell replete, matched related allogeneic hematopoietic cell transplantation. Am J Hematol. 2011;86:879–82.

  112. 112.

    Saber W, Zhang MJ, Steinert P, Chen M, Horowitz MM. The Impact of Palifermin Use on Hematopoietic Cell Transplant Outcomes in Children. Biol Blood Marrow Transplant. 2016;22:1460–6.

  113. 113.

    Khouri MR, Jabbour EJ, Gulbis AM, Turturro F, Ledesma C, Korbling M, et al. Feasibility of Lenalidomide Therapy for Persistent Chronic Lymphocytic Leukemia after Allogeneic Transplantation. Biol Blood Marrow Transplant. 2017;23:1405–10.

  114. 114.

    Shaffer BC, Le Luduec JB, Forlenza C, Jakubowski AA, Perales MA, Young JW, et al. Phase II Study of Haploidentical Natural Killer Cell Infusion for Treatment of Relapsed or Persistent Myeloid Malignancies Following Allogeneic Hematopoietic Cell Transplantation. Biol Blood Marrow Transplant. 2016;22:705–9.

  115. 115.

    Haverkos BM, Abbott D, Hamadani M, Armand P, Flowers ME, Merryman R, et al. PD-1 blockade for relapsed lymphoma post-allogeneic hematopoietic cell transplant: high response rate but frequent GVHD. Blood. 2017;130:221–8.

  116. 116.

    Martinelli G, Boissel N, Chevallier P, Ottmann O, Gokbuget N, Topp MS, et al. Complete Hematologic and Molecular Response in Adult Patients With Relapsed/Refractory Philadelphia Chromosome-Positive B-Precursor Acute Lymphoblastic Leukemia Following Treatment With Blinatumomab: Results From a Phase II, Single-Arm, Multicenter Study. J Clin Oncol. 2017;35:1795–802.

  117. 117.

    Cruz CR, Micklethwaite KP, Savoldo B, Ramos CA, Lam S, Ku S, et al. Infusion of donor-derived CD19-redirected virus-specific T cells for B-cell malignancies relapsed after allogeneic stem cell transplant: a phsase 1 study. Blood. 2013;122:2965–73.

  118. 118.

    Kebriaei P, Bassett R, Lyons G, Valdez B, Ledesma C, Rondon G, et al. Clofarabine Plus Busulfan is an Effective Conditioning Regimen for Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Acute Lymphoblastic Leukemia: Long-Term Study Results. Biol Blood Marrow Transplant. 2017;23:285–92.

  119. 119.

    Franssen LE, Roeven MWH, Hobo W, Doorn R, Oostvogels R, Falkenburg JHF, et al. A phase I/II minor histocompatibility antigen-loaded dendritic cell vaccination trial to safely improve the efficacy of donor lymphocyte infusions in myeloma. Bone Marrow Transplant. 2017;52:1378–83.

  120. 120.

    Shah NN, Loeb DM, Khuu H, Stroncek D, Ariyo T, Raffeld M, et al. Induction of Immune Response after Allogeneic Wilms’ Tumor 1 Dendritic Cell Vaccination and Donor Lymphocyte Infusion in Patients with Hematologic Malignancies and Post-Transplantation Relapse. Biol Blood Marrow Transplant. 2016;22:2149–54.

Download references

Author information


  1. Clinical Haematology and Bone Marrow Transplantation, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Victoria, Australia

    • Eric Wong
    • , Jeff Szer
    •  & David Ritchie
  2. Australian Cancer Research Foundation Translational Research Laboratory, Victoria, Australia

    • Eric Wong
    • , Joanne E Davis
    •  & David Ritchie
  3. Department of Medicine, University of Melbourne, Victoria, Australia

    • Eric Wong
    • , Joanne E Davis
    • , Andrew Grigg
    • , Jeff Szer
    •  & David Ritchie
  4. Department of Clinical Haematology and Olivia Newton John Cancer Research Institute, Austin Hospital, Victoria, Australia

    • Andrew Grigg


  1. Search for Eric Wong in:

  2. Search for Joanne E Davis in:

  3. Search for Andrew Grigg in:

  4. Search for Jeff Szer in:

  5. Search for David Ritchie in:

Conflict of interest

The authors declare that they have no conflict of interest.

Corresponding author

Correspondence to Eric Wong.

About this article

Publication history





Issue Date