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Sensitivity of hematological malignancies to graft-versus-host effects: an EBMT megafile analysis

Leukemia volume 28, pages 2235–2240 (2014)Cite this article

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Abstract

After allogeneic stem cell transplantation, graft-versus-host disease (GvHD) occurs through recognition of histocompatibility mismatches by donor T lymphocytes. The same mechanism operates in eliminating malignant cells (the graft-versus-tumor or GvT effect). We hypothesized that comparing the correlation between GvHD and relapse might provide a surrogate marker for the susceptibility of diseases to allo-immune effects. We studied 48 111 first allogeneic transplants performed between 1998 and 2007. In chronic myeloid leukemia (CML), the relapse risk declined clearly and proportionally to severity of acute and chronic GvHD. Acute lymphoblastic leukemia and BCR-ABL-negative myeloproliferative neoplasias were comparably sensitive to GvHD as CML, whereas myelodysplastic syndromes and lymphoproliferative disorders showed intermediate sensitivity. GvHD was only associated with modest reductions in relapse risk in acute myeloid leukemia (AML) and plasma cell disorders (PCDs). Except for PCD, hazard rates for relapse decreased to almost 0 at 48 months of follow-up in all diseases. These data confirm observations of potent GvT effects associated with GvHD. The strength of the GvHD/GvT correlation differs significantly between hematological malignancies. The parallel drop of relapse rates in different diseases despite differences in GvHD/GvT ratios suggests that GvT effects might operate in the absence of GvHD, particularly in AML.

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References

  1. Weiden PL, Flournoy N, Thomas ED, Prentice R, Fefer A, Buckner CD et al. Antileukemic effect of graft-versus-host disease in human recipients of allogeneic-marrow grafts. N Engl J Med 1979; 300: 1068–1073.

    Article  CAS  Google Scholar 

  2. Ringden O, Hermans J, Labopin M, Apperley J, Gorin NC, Gratwohl A . The highest leukaemia-free survival after allogeneic bone marrow transplantation is seen in patients with grade I acute graft-versus-host disease. Acute and Chronic Leukaemia Working Parties of the European Group for Blood and Marrow Transplantation (EBMT). Leuk Lymphoma 1996; 24: 71–79.

    Article  CAS  Google Scholar 

  3. Gratwohl A, Brand R, Apperley J, Biezen AvA, Bandini G, Devergie A et al. Graft-versus-host disease and outcome in HLA-identical sibling transplantations for chronic myeloid leukemia. Blood 2002; 100: 3877–3886.

    Article  CAS  Google Scholar 

  4. Horowitz MM, Gale RP, Sondel PM, Goldman JM, Kersey J, Kolb HJ et al. Graft-versus-leukemia reactions after bone marrow transplantation. Blood 1990; 75: 555–562.

    CAS  Google Scholar 

  5. Radich J . Stem cell transplant for chronic myeloid leukemia in the imatinib era. Semin Hematol 2010; 47: 354–361.

    Article  CAS  Google Scholar 

  6. Gratwohl A, Baldomero H, Schwendener A, Gratwohl M, Apperley J, Frauendorfer K et al. The EBMT activity survey 2008 impact of team size, team density and new trends. Bone Marrow Transplant 2011; 46: 174–191.

    Article  CAS  Google Scholar 

  7. Bruno B, Rotta M, Patriarca F, Mordini N, Allione B, Carnevale-Schianca F et al. A comparison of allografting with autografting for newly diagnosed myeloma. N Engl J Med 2007; 356: 1110–1120.

    Article  CAS  Google Scholar 

  8. Bjorkstrand B, Iacobelli S, Hegenbart U, Gruber A, Greinix H, Volin L et al. Tandem autologous/reduced-intensity conditioning allogeneic stem-cell transplantation versus autologous transplantation in myeloma: long-term follow-up. J Clin Oncol 2011; 29: 3016–3022.

    Article  Google Scholar 

  9. Chakraverty R, Mackinnon S . Allogeneic transplantation for lymphoma. J Clin Oncol 2011; 29: 1855–1863.

    Article  Google Scholar 

  10. Platzbecker U . Allogeneic hematopoietic cell transplantation in patients with myelodysplastic syndromes. Semin Hematol 2012; 49: 342–349.

    Article  Google Scholar 

  11. Glucksberg H, Storb R, Fefer A, Buckner CD, Neiman PE, Clift RA et al. Clinical manifestations of graft-versus-host disease in human recipients of marrow from HL-A-matched sibling donors. Transplantation 1974; 18: 295–304.

    Article  CAS  Google Scholar 

  12. Shulman HM, Sullivan KM, Weiden PL, McDonald GB, Striker GE, Sale GE et al. Chronic graft-versus-host syndrome in man. A long-term clinicopathologic study of 20 Seattle patients. Am J Med 1980; 69: 204–217.

    Article  CAS  Google Scholar 

  13. Passweg JR, Tiberghien P, Cahn JY, Vowels MR, Camitta BM, Gale RP et al. Graft-versus-leukemia effects in T lineage and B lineage acute lymphoblastic leukemia. Bone Marrow Transplant 1998; 21: 153–158.

    Article  CAS  Google Scholar 

  14. Roddie C, Peggs KS . Donor lymphocyte infusion following allogeneic hematopoietic stem cell transplantation. Expert Opin Biol Ther 2011; 11: 473–487.

    Article  Google Scholar 

  15. Delgado J, Milligan DW, Dreger P . Allogeneic hematopoietic cell transplantation for chronic lymphocytic leukemia: ready for prime time? Blood 2009; 114: 2581–2588.

    Article  CAS  Google Scholar 

  16. Weisdorf D, Zhang MJ, Arora M, Horowitz MM, Rizzo JD, Eapen M . Graft-versus-host disease induced graft-versus-leukemia effect: greater impact on relapse and disease-free survival after reduced intensity conditioning. Biol Blood Marrow Transplant 2012; 18: 1727–1733.

    Article  Google Scholar 

  17. Baron F, Labopin M, Niederwieser D, Vigouroux S, Cornelissen JJ, Malm C et al. Impact of graft-versus-host disease after reduced-intensity conditioning allogeneic stem cell transplantation for acute myeloid leukemia: a report from the Acute Leukemia Working Party of the European group for blood and marrow transplantation. Leukemia 2012; 26: 2462–2468.

    Article  CAS  Google Scholar 

  18. 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: 2411–2419.

    Article  CAS  Google Scholar 

  19. Hsu KC, Keever-Taylor CA, Wilton A, Pinto C, Heller G, Arkun K et al. Improved outcome in HLA-identical sibling hematopoietic stem-cell transplantation for acute myelogenous leukemia predicted by KIR and HLA genotypes. Blood 2005; 105: 4878–4884.

    Article  CAS  Google Scholar 

  20. 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: 805–816.

    Article  CAS  Google Scholar 

  21. 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.

    Article  CAS  Google Scholar 

  22. Devine SM, Carter S, Soiffer RJ, Pasquini MC, Hari PN, Stein A et al. Low risk of chronic graft-versus-host disease and relapse associated with T cell-depleted peripheral blood stem cell transplantation for acute myelogenous leukemia in first remission: results of the blood and marrow transplant clinical trials network protocol 0303. Biol Blood Marrow Transplant 2011; 17: 1343–1351.

    Article  Google Scholar 

  23. Chakrabarti S, Marks DI . Should we T cell deplete sibling grafts for acute myeloid leukaemia in first remission? Bone Marrow Transplant 2003; 32: 1039–1050.

    Article  CAS  Google Scholar 

  24. Aversa F, Terenzi A, Tabilio A, Falzetti F, Carotti A, Ballanti S et al. Full haplotype-mismatched hematopoietic stem-cell transplantation: a phase II study in patients with acute leukemia at high risk of relapse. J Clin Oncol 2005; 23: 3447–3454.

    Article  Google Scholar 

  25. Ringden O, Labopin M, Gorin NC, Schmitz N, Schaefer UW, Prentice HG et al. Is there a graft-versus-leukaemia effect in the absence of graft-versus-host disease in patients undergoing bone marrow transplantation for acute leukaemia? Br J Haematol 2000; 111: 1130–1137.

    Article  CAS  Google Scholar 

  26. Giaccone L, Storer B, Patriarca F, Rotta M, Sorasio R, Allione B et al. Long-term follow-up of a comparison of nonmyeloablative allografting with autografting for newly diagnosed myeloma. Blood 2011; 117: 6721–6727.

    Article  CAS  Google Scholar 

  27. Ringden O, Labopin M, Gluckman E, Reiffers J, Vernant JP, Jouet JP et al. Graft-versus-leukemia effect in allogeneic marrow transplant recipients with acute leukemia is maintained using cyclosporin A combined with methotrexate as prophylaxis. Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation. Bone Marrow Transplant 1996; 18: 921–929.

    CAS  Google Scholar 

  28. Kahl C, Storer BE, Sandmaier BM, Mielcarek M, Maris MB, Blume KG et al. Relapse risk in patients with malignant diseases given allogeneic hematopoietic cell transplantation after nonmyeloablative conditioning. Blood 2007; 110: 2744–2748.

    Article  CAS  Google Scholar 

  29. Passweg JR, Baldomero H, Gratwohl A, Bregni M, Cesaro S, Dreger P et al. The EBMT activity survey: 1990-2010. Bone Marrow Transplant 2012; 47: 906–923.

    Article  CAS  Google Scholar 

  30. Estey EH . Acute myeloid leukemia: 2013 update on risk-stratification and management. Am J Hematol 2013; 88: 318–327.

    Article  CAS  Google Scholar 

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Acknowledgements

MS was supported by the Swiss National Science Foundation (grant PPOOP3_128461/1).

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Authors and Affiliations

  1. Department of Biomedicine, Immunotherapy Laboratory, University Hospital Basel and University of Basel, Basel, Switzerland

    M Stern

  2. Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, The Netherlands

    L C de Wreede & R Brand

  3. EBMT Data Office, University Medical Centre Leiden, Leiden, The Netherlands

    A van Biezen

  4. Medizinische Klinik V, Universität Heidelberg, Heidelberg, Germany

    P Dreger

  5. Department of Hematology, CHU Nantes, Nantes, France

    M Mohty

  6. Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands

    T M de Witte

  7. Department of Stem Cell Transplantation, University Medical Center Hamburg Eppendorf, Hamburg, Germany

    N Kröger

  8. Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland

    T Ruutu

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  1. M Stern
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  2. L C de Wreede
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  4. A van Biezen
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  7. T M de Witte
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for the Chronic Malignancies Working Party of the European Group for Blood and Marrow Transplantation

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Correspondence to M Stern.

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Stern, M., de Wreede, L., Brand, R. et al. Sensitivity of hematological malignancies to graft-versus-host effects: an EBMT megafile analysis. Leukemia 28, 2235–2240 (2014). https://doi.org/10.1038/leu.2014.145

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