graft vs leukemia effect


Summary: Immunological rejection of leukemia cells following bone marrow transplantation.

Top Publications

  1. Cornelissen J, Carston M, Kollman C, King R, Dekker A, Lowenberg B, et al. Unrelated marrow transplantation for adult patients with poor-risk acute lymphoblastic leukemia: strong graft-versus-leukemia effect and risk factors determining outcome. Blood. 2001;97:1572-7 pubmed
  2. Ruggeri L, Capanni M, Urbani E, Perruccio K, Shlomchik W, Tosti A, et al. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science. 2002;295:2097-100 pubmed
    ..NK cell alloreactivity may thus provide a powerful tool for enhancing the efficacy and safety of allogeneic hematopoietic transplantation. ..
  3. Ishaqi M, Afzal S, Dupuis A, Doyle J, Gassas A. Early lymphocyte recovery post-allogeneic hematopoietic stem cell transplantation is associated with significant graft-versus-leukemia effect without increase in graft-versus-host disease in pediatric acute lymphoblastic leukemia. Bone Marrow Transplant. 2008;41:245-52 pubmed
    ..Early lymphocyte recovery post-HSCT is associated with a significant GVL without increase in GVHD. ..
  4. Remberger M, Mattsson J, Hentschke P, Aschan J, Barkholt L, Svennilson J, et al. The graft-versus-leukaemia effect in haematopoietic stem cell transplantation using unrelated donors. Bone Marrow Transplant. 2002;30:761-8 pubmed
    ..Overall and relapse-free survival were not improved by the occurrence of acute GVHD. ..
  5. Gluckman E, Rocha V, Arcese W, Michel G, Sanz G, Chan K, et al. Factors associated with outcomes of unrelated cord blood transplant: guidelines for donor choice. Exp Hematol. 2004;32:397-407 pubmed
    ..Overall 3-year survival was 34.4%. Prognostic factors for survival were recipient age, gender, and disease status. Our results provide indications for a better choice of cord blood units according to cord blood cell content and HLA. ..
  6. Hambach L, Nijmeijer B, Aghai Z, Schie M, Wauben M, Falkenburg J, et al. Human cytotoxic T lymphocytes specific for a single minor histocompatibility antigen HA-1 are effective against human lymphoblastic leukaemia in NOD/scid mice. Leukemia. 2006;20:371-4 pubmed
  7. Li J, Giver C, Lu Y, Hossain M, Akhtari M, Waller E. Separating graft-versus-leukemia from graft-versus-host disease in allogeneic hematopoietic stem cell transplantation. Immunotherapy. 2009;1:599-621 pubmed
    ..In this review, we will summarize new findings that support a more complex model for the initiation of GvHD and GvL activities in allogeneic HSCT, and discuss the potential of novel strategies to enhance GvL activity of the transplant. ..
  8. Warren E, Fujii N, Akatsuka Y, Chaney C, Mito J, Loeb K, et al. Therapy of relapsed leukemia after allogeneic hematopoietic cell transplantation with T cells specific for minor histocompatibility antigens. Blood. 2010;115:3869-78 pubmed publisher
    ..This study has been registered at as NCT00107354. ..
  9. Ringden O, Karlsson H, Olsson R, Omazic B, Uhlin M. The allogeneic graft-versus-cancer effect. Br J Haematol. 2009;147:614-33 pubmed publisher
    ..This paper reviews the current knowledge in graft-versus-cancer effects. Future directions, such as immunotherapy using leukaemia-specific CTLs, allo-depleted T-cells and suicide gene manipulated T-cells, are presented. ..

More Information


  1. Kolb H. Graft-versus-leukemia effects of transplantation and donor lymphocytes. Blood. 2008;112:4371-83 pubmed publisher
    ..Recently, we have learned from adoptive immunotherapy of viral diseases and HLA-haploidentical stem cell transplantation that T-cell memory may be essential for the effective treatment of leukemia and other malignancies. ..
  2. de Rijke B, van Horssen Zoetbrood A, Beekman J, Otterud B, Maas F, Woestenenk R, et al. A frameshift polymorphism in P2X5 elicits an allogeneic cytotoxic T lymphocyte response associated with remission of chronic myeloid leukemia. J Clin Invest. 2005;115:3506-16 pubmed
    ..These findings illustrate that the P2X5-encoded mHAg LRH-1 could be an attractive target for specific immunotherapy to treat hematological malignancies recurring after allogeneic stem cell transplantation. ..
  3. Scott B, Sandmaier B, Storer B, Maris M, Sorror M, Maloney D, et al. Myeloablative vs nonmyeloablative allogeneic transplantation for patients with myelodysplastic syndrome or acute myelogenous leukemia with multilineage dysplasia: a retrospective analysis. Leukemia. 2006;20:128-35 pubmed
    ..Randomized prospective studies are needed to further address the optimal choice of transplant conditioning intensity in myeloid neoplasms. ..
  4. Reddy P, Maeda Y, Liu C, Krijanovski O, Korngold R, Ferrara J. A crucial role for antigen-presenting cells and alloantigen expression in graft-versus-leukemia responses. Nat Med. 2005;11:1244-9 pubmed
    ..Moreover, APCs of host origin predominated in GVL responses although donor APCs contributed as the acuity of tumor burden decreased. ..
  5. Liang Y, Liu C, Djeu J, Zhong B, Peters T, Scharffetter Kochanek K, et al. Beta2 integrins separate graft-versus-host disease and graft-versus-leukemia effects. Blood. 2008;111:954-62 pubmed
    ..Our data suggest that strategies to target beta2 integrin have clinical potential to alleviate or prevent GVHD while sparing GVL activity. ..
  6. Lee S, Cho B, Kim S, Choi S, Lee D, Eom K, et al. Allogeneic stem cell transplantation in first complete remission enhances graft-versus-leukemia effect in adults with acute lymphoblastic leukemia: antileukemic activity of chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2007;13:1083-94 pubmed
    ..Interestingly, the influence of cGVHD on relapse risk was prominent in patients with chromosomal translocations or normal cytogenetics. ..
  7. Barrett A, Savani B. Stem cell transplantation with reduced-intensity conditioning regimens: a review of ten years experience with new transplant concepts and new therapeutic agents. Leukemia. 2006;20:1661-72 pubmed
    ..This review examines the origins of RIC SCT, explores the degree to which the initial expectations and purpose of the approach have been realized, and outlines some ways forward for the field. ..
  8. Ruggeri L, Mancusi A, Burchielli E, Aversa F, Martelli M, Velardi A. Natural killer cell alloreactivity in allogeneic hematopoietic transplantation. Curr Opin Oncol. 2007;19:142-7 pubmed
    ..Given the benefits of natural killer cell alloreactivity, it is expected that it will encourage greater use of haploidentical transplants for the large numbers of leukemia patients without matched donors. ..
  9. Spierings E, Goulmy E. Expanding the immunotherapeutic potential of minor histocompatibility antigens. J Clin Invest. 2005;115:3397-400 pubmed
    ..This result represents another example of an mHAg-mediated graft-versus-leukemia response, thereby expanding the number of patients eligible for mHAg-based immunotherapy in the setting of HSCT. ..
  10. Yong A, Rezvani K, Savani B, Eniafe R, Mielke S, Goldman J, et al. High PR3 or ELA2 expression by CD34+ cells in advanced-phase chronic myeloid leukemia is associated with improved outcome following allogeneic stem cell transplantation and may improve PR1 peptide-driven graft-versus-leukemia effects. Blood. 2007;110:770-5 pubmed
    ..The presence of a donor immune response against PR1 may be advantageous and could be exploited therapeutically. ..
  11. Akatsuka Y, Morishima Y, Kuzushima K, Kodera Y, Takahashi T. Minor histocompatibility antigens as targets for immunotherapy using allogeneic immune reactions. Cancer Sci. 2007;98:1139-46 pubmed
  12. Savani B, Mielke S, Adams S, Uribe M, Rezvani K, Yong A, 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 pubmed
    ..7, P=0.028) and improved survival (HR 11.4, P=0.03). Results suggest that T cell-depleted SCT might be improved and the GVL effect enhanced by selecting donors with favorable KIR genotype, and by optimizing CD34 and CD3 doses. ..
  13. Ivanov R, Aarts T, Hol S, Doornenbal A, Hagenbeek A, Petersen E, et al. Identification of a 40S ribosomal protein S4-derived H-Y epitope able to elicit a lymphoblast-specific cytotoxic T lymphocyte response. Clin Cancer Res. 2005;11:1694-703 pubmed
    ..Our findings suggest that CTL specific to certain epitopes of ubiquitously expressed H-Y antigens may specifically target lymphoblasts, contributing to the selective GVL effect of female-to-male stem cell transplantation. ..
  14. Rosinski K, Fujii N, Mito J, Koo K, Xuereb S, Sala Torra O, et al. DDX3Y encodes a class I MHC-restricted H-Y antigen that is expressed in leukemic stem cells. Blood. 2008;111:4817-26 pubmed publisher
    ..This study is registered at as NCT00107354. ..
  15. Yong A, Keyvanfar K, Eniafe R, Savani B, Rezvani K, Sloand E, et al. Hematopoietic stem cells and progenitors of chronic myeloid leukemia express leukemia-associated antigens: implications for the graft-versus-leukemia effect and peptide vaccine-based immunotherapy. Leukemia. 2008;22:1721-7 pubmed publisher
  16. Kawase T, Matsuo K, Kashiwase K, Inoko H, Saji H, Ogawa S, et al. HLA mismatch combinations associated with decreased risk of relapse: implications for the molecular mechanism. Blood. 2009;113:2851-8 pubmed publisher
    ..Donor selection made in consideration of these results might allow the separation of GVL from acute GVHD, especially in HLA-DPB1 mismatch combinations. ..
  17. Molldrem J, Komanduri K, Wieder E. Overexpressed differentiation antigens as targets of graft-versus-leukemia reactions. Curr Opin Hematol. 2002;9:503-8 pubmed
    ..By altering T-cell receptor affinity, peptide specificity can be maintained and the potency of immunity can be enhanced in the MHC-mismatched setting. ..
  18. Spitzer T, McAfee S, Sackstein R, Colby C, Toh H, Multani P, et al. Intentional induction of mixed chimerism and achievement of antitumor responses after nonmyeloablative conditioning therapy and HLA-matched donor bone marrow transplantation for refractory hematologic malignancies. Biol Blood Marrow Transplant. 2000;6:309-20 pubmed
    ..After treatment, striking antitumor responses were observed in the majority of patients with chemotherapy-refractory hematologic malignancies. ..
  19. Molldrem J, Lee P, Wang C, Felio K, Kantarjian H, Champlin R, et al. Evidence that specific T lymphocytes may participate in the elimination of chronic myelogenous leukemia. Nat Med. 2000;6:1018-23 pubmed
    ..This provides for the first time direct evidence of a role for T-cell immunity in clearing malignant cells. ..
  20. Ohata J, Sakurai J, Saito K, Tani K, Asano S, Azuma M. Differential graft-versus-leukaemia effect by CD28 and CD40 co-stimulatory blockade after graft-versus-host disease prophylaxis. Clin Exp Immunol. 2002;129:61-8 pubmed
    ..CD28 blockade may be a favourable strategy for tolerance induction in leukaemia patients undergoing BMT. ..
  21. Kroger N, Schwerdtfeger R, Kiehl M, Sayer H, Renges H, Zabelina T, et al. Autologous stem cell transplantation followed by a dose-reduced allograft induces high complete remission rate in multiple myeloma. Blood. 2002;100:755-60 pubmed
    ..The tandem auto-allotransplant protocol is highly active and provides rapid engraftment with complete donor chimerism and tolerable toxicity. ..
  22. Falkenburg J, van de Corput L, Marijt E, Willemze R. Minor histocompatibility antigens in human stem cell transplantation. Exp Hematol. 2003;31:743-51 pubmed
    ..By in vitro generation of T-cell responses against defined mHags, the efficacy and specificity of cellular immunotherapy against hematologic malignancies in the context of allogeneic transplantation may be improved. ..
  23. Matte C, Liu J, Cormier J, Anderson B, Athanasiadis I, Jain D, et al. Donor APCs are required for maximal GVHD but not for GVL. Nat Med. 2004;10:987-92 pubmed
    ..These studies identify donor APCs as a new target for treating GVHD, which may preserve GVL. ..
  24. Morishima Y, Sasazuki T, Inoko H, Juji T, Akaza T, Yamamoto K, et al. The clinical significance of human leukocyte antigen (HLA) allele compatibility in patients receiving a marrow transplant from serologically HLA-A, HLA-B, and HLA-DR matched unrelated donors. Blood. 2002;99:4200-6 pubmed
    ..Thus, the role of the HLA class I allele in unrelated bone marrow transplantation was elucidated. Notably, HLA-C alleles had a different mode from HLA-A or -B alleles for acute GVHD and survival. ..
  25. Trenado A, Charlotte F, Fisson S, Yagello M, Klatzmann D, Salomon B, et al. Recipient-type specific CD4+CD25+ regulatory T cells favor immune reconstitution and control graft-versus-host disease while maintaining graft-versus-leukemia. J Clin Invest. 2003;112:1688-96 pubmed
    ..These data suggest that recipient-type specific Treg's could be preferentially used in the control of GVHD in future clinical trials. ..
  26. Mullen C, Campbell A, Tkachenko O, Jansson J, Hsu Y. Evidence of B cell immune responses to acute lymphoblastic leukemia in murine allogeneic hematopoietic stem cell transplantation recipients treated with donor lymphocyte infusion and/or vaccination. Biol Blood Marrow Transplant. 2011;17:226-38 pubmed publisher
    ..These studies raise the hypothesis that stimulation of B cell responses after transplantation may provide a novel way to enhance allogeneic graft-versus-leukemia effects associated with transplantation. ..
  27. Khouri I, Saliba R, Admirand J, O Brien S, Lee M, Korbling M, et al. Graft-versus-leukaemia effect after non-myeloablative haematopoietic transplantation can overcome the unfavourable expression of ZAP-70 in refractory chronic lymphocytic leukaemia. Br J Haematol. 2007;137:355-63 pubmed
    ..These results demonstrate a potent graft-versus-leukaemia effect that can overcome the adverse prognostic effect of ZAP-70 expression. ..
  28. Chakraverty R, Eom H, Sachs J, Buchli J, Cotter P, Hsu R, et al. Host MHC class II+ antigen-presenting cells and CD4 cells are required for CD8-mediated graft-versus-leukemia responses following delayed donor leukocyte infusions. Blood. 2006;108:2106-13 pubmed
  29. Borchers S, Provasi E, Silvani A, Radrizzani M, Benati C, Dammann E, et al. Genetically modified donor leukocyte transfusion and graft-versus-leukemia effect after allogeneic stem cell transplantation. Hum Gene Ther. 2011;22:829-41 pubmed publisher
    ..In one patient with CML, loss of bcr-abl gene expression was observed after an expansion of transduced cells. Seven of nine patients are alive and in complete remission. ..
  30. Imamura M, Tanaka J. Graft-versus-leukemia effect of nonmyeloablative stem cell transplantation. Korean J Intern Med. 2009;24:287-98 pubmed publisher
    ..However, a more sophisticated improvement in separating graft-versus-hematological malignancy effects from GVHD is required in the future. ..
  31. Nannya Y, Kataoka K, Hangaishi A, Imai Y, Takahashi T, Kurokawa M. The negative impact of female donor/male recipient combination in allogeneic hematopoietic stem cell transplantation depends on disease risk. Transpl Int. 2011;24:469-76 pubmed publisher
    ..019) and most of them were GVHD-related in standard risk cases. In conclusion, FtoM mismatch has a significant impact on transplant outcome, especially in standard risk cases. ..
  32. Marcenaro E, Carlomagno S, Pesce S, Della Chiesa M, Moretta A, Sivori S. Role of alloreactive KIR2DS1(+) NK cells in haploidentical hematopoietic stem cell transplantation. J Leukoc Biol. 2011;90:661-7 pubmed publisher
    ..Finally, KIR2DS1 expression may also significantly amplify the size of the alloreactive NK cell subset by switching a subset of "not alloreactive" NK cells into potent alloreactive cells. ..
  33. Ustun C, Miller J, Munn D, Weisdorf D, Blazar B. Regulatory T cells in acute myelogenous leukemia: is it time for immunomodulation?. Blood. 2011;118:5084-95 pubmed publisher
    ..Manipulation of Tregs or other types of immunomodulation may become a part of AML treatment in the future. ..
  34. Gutman J, Turtle C, Manley T, Heimfeld S, Bernstein I, Riddell S, et al. Single-unit dominance after double-unit umbilical cord blood transplantation coincides with a specific CD8+ T-cell response against the nonengrafted unit. Blood. 2010;115:757-65 pubmed publisher
    ..Future investigations based on these findings may result in strategies to predict a dominant unit and enhance graft-versus-leukemia effect...
  35. Porter D, Antin J. Donor leukocyte infusions in myeloid malignancies: new strategies. Best Pract Res Clin Haematol. 2006;19:737-55 pubmed
    ..Although many issues remain unsettled, the potential to harness the graft-versus-leukemia activity of allogeneic donor cells provides a powerful new paradigm for the immunotherapy of cancer. ..
  36. Katagiri T, Shiobara S, Nakao S, Wakano M, Muranaka E, Kuba N, et al. Mismatch of minor histocompatibility antigen contributes to a graft-versus-leukemia effect rather than to acute GVHD, resulting in long-term survival after HLA-identical stem cell transplantation in Japan. Bone Marrow Transplant. 2006;38:681-6 pubmed
    ..03). Our data suggest that incompatibility of CD62L, CD31 codon 563 and CD31 codon 125 contributes to a graft-versus-leukemia effect rather than to GVHD, resulting in prolonged survival after HLA-identical SCT. ..
  37. Aversa F, Berneman Z, Locatelli F, Martelli M, Reisner Y, Tabilio A, et al. Fourth International Workshop on Haploidentical Transplants, Naples, Italy, July 8-10, 2004. Blood Cells Mol Dis. 2004;33:159-75 pubmed
    ..The Workshop closed with presentations on tolerance induction that was followed by the results of ongoing registration studies being performed by the Italian GIMEMA group and the European Bone Marrow Transplant group. ..
  38. Vago L, Perna S, Zanussi M, Mazzi B, Barlassina C, Stanghellini M, et al. Loss of mismatched HLA in leukemia after stem-cell transplantation. N Engl J Med. 2009;361:478-88 pubmed publisher
    ..This event leads to relapse. ..
  39. Ilan Y, Margalit M, Ohana M, Gotsman I, Rabbani E, Engelhardt D, et al. Alleviation of chronic GVHD in mice by oral immuneregulation toward recipient pretransplant splenocytes does not jeopardize the graft versus leukemia effect. Hum Immunol. 2005;66:231-40 pubmed
    ..1+ cells; and CD4+/CD8+ lymphocyte ratio. Oral tolerization of BMT donors toward recipient antigens ameliorates cGVHD without hampering the GVL effect. ..
  40. Bitan M, Or R, Shapira M, Ackerstein A, Samuel S, Slavin S. Nonmyeloablative stem cell transplantation using lymphoablative rather than myeloablative conditioning in the prefludarabine era by ATG and limiting doses of cyclophosphamide. Bone Marrow Transplant. 2005;35:953-8 pubmed
    ..Hence, induction of tolerance to donor alloantigens by lymphoablative conditioning while avoiding myeloablative chemotherapy or radiation therapy may serve as a platform for subsequent cell therapy with donor lymphocytes. ..
  41. Chung Y, Fry T, Aplan P. Myeloablative hematopoietic stem cell transplantation improves survival but is not curative in a pre-clinical model of myelodysplastic syndrome. PLoS ONE. 2017;12:e0185219 pubmed publisher
    ..We suggest that NHD13 mice represent a feasible pre-clinical model for the study of HSCT for MDS. ..
  42. Yang T, Chen Z, Kolb H, Buhmann R. A novel nonradioactive CFDA assay to monitor the cellular immune response in myeloid leukemia. Immunobiology. 2013;218:548-53 pubmed publisher
    ..Taken together, the novel, nonradioactive, CFDA-based assay was a robust tool to monitor the antileukemic immune response after DLT in myeloid leukemias. ..
  43. Kato K, Kanda Y, Eto T, Muta T, Gondo H, Taniguchi S, et al. Allogeneic bone marrow transplantation from unrelated human T-cell leukemia virus-I-negative donors for adult T-cell leukemia/lymphoma: retrospective analysis of data from the Japan Marrow Donor Program. Biol Blood Marrow Transplant. 2007;13:90-9 pubmed
    ..Our observations suggest that UBMT could represent a feasible treatment option for ATLL patients and warrant further investigation based on these risk factors. ..
  44. Teuffel O, Schrauder A, Sykora K, Zimmermann M, Reiter A, Welte K, et al. The impact of cyclosporin A on acute graft-versus-host disease after allogeneic bone marrow transplantation in children and adolescents with acute lymphoblastic leukemia. Bone Marrow Transplant. 2005;36:145-50 pubmed
    ..In all cases (6/22), leukemic relapse was the cause of death. We therefore suggest that there is a relation between dose of CsA and relapse rate in childhood ALL transplanted from a MSD. ..
  45. Ohata K, Espinoza J, Lu X, Kondo Y, Nakao S. Mycophenolic acid inhibits natural killer cell proliferation and cytotoxic function: a possible disadvantage of including mycophenolate mofetil in the graft-versus-host disease prophylaxis regimen. Biol Blood Marrow Transplant. 2011;17:205-13 pubmed publisher
    ..These results suggest that MPA is a potent inhibitor of NK cells, and that its inclusion in the GVHD prophylaxis regimen might diminish the graft-versus-leukemia effect of NK cells...
  46. Guo H, Qian X. Clinical applications of adoptive natural killer cell immunotherapy for cancer: current status and future prospects. Onkologie. 2010;33:389-95 pubmed publisher
    ..Future manipulation to improve NK cell adoptive immunotherapy by means of increasing target recognition and reducing inhibitory signaling is being explored. ..
  47. Matthews K, Lim Z, Pearce L, Pagliuca A, Alejandro Madrigal J, Mufti G, et al. Rapid recovery of lymphocyte subsets is not associated with protection from relapse of myelodysplastic syndromes and acute myeloid leukaemia after haematopoietic stem cell transplantation using a reduced intensity conditioning regimen and alemtuzumab. Br J Haematol. 2010;149:879-89 pubmed publisher
  48. Castor M, Rezende B, Resende C, Alessandri A, Fagundes C, Sousa L, et al. The CCL3/macrophage inflammatory protein-1alpha-binding protein evasin-1 protects from graft-versus-host disease but does not modify graft-versus-leukemia in mice. J Immunol. 2010;184:2646-54 pubmed publisher
  49. Loren A, Porter D. Donor leukocyte infusions for the treatment of relapsed acute leukemia after allogeneic stem cell transplantation. Bone Marrow Transplant. 2008;41:483-93 pubmed
    ..This review discusses the rationale, biology, complications and future applications of DLI in acute leukemia patients after allogeneic SCT. ..
  50. Verheyden S, Demanet C. NK cell receptors and their ligands in leukemia. Leukemia. 2008;22:249-57 pubmed
    ..Manipulating NK cell inhibition or activation could lead to new forms of immunotherapy, ultimately leading to the elimination of resistant leukemic cells. ..
  51. Curti A, Ruggeri L, D Addio A, Bontadini A, Dan E, Motta M, et al. Successful transfer of alloreactive haploidentical KIR ligand-mismatched natural killer cells after infusion in elderly high risk acute myeloid leukemia patients. Blood. 2011;118:3273-9 pubmed publisher
    ..In conclusion, infusion of purified NK cells is feasible in elderly patients with high-risk acute myeloid leukemia. This trial was registered at as NCT00799799. ..
  52. Robb R, Hill G. The interferon-dependent orchestration of innate and adaptive immunity after transplantation. Blood. 2012;119:5351-8 pubmed publisher
    ..This Perspective discusses the current literature on the IFNs and their potential modulation within clinical transplantation, focusing particularly on enhancing the therapeutic GVL effects...
  53. Tanaka Y, Nakasone H, Yamazaki R, Wada H, Ishihara Y, Kawamura K, et al. Long-term persistence of limited HTLV-I Tax-specific cytotoxic T cell clones in a patient with adult T cell leukemia/lymphoma after allogeneic stem cell transplantation. J Clin Immunol. 2012;32:1340-52 pubmed publisher
    ..These findings about Tax-specific CTLs provide insights into future directions for studies on immunotherapy against ATL. ..