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Chronic graft-versus-host disease in the era of reduced-intensity conditioning

Abstract

In the past decade the field of hematopoietic stem cell transplantation has entered a new era with the introduction of reduced intensity conditioning (RIC) regimens. The impact of RIC on the incidence of chronic graft-versus-host disease (GVHD) has not been evaluated systematically. Factors confounding such analyses include short follow-up in studies, absence of prospective comparison trials, use of a variety of RIC regimens, lack of uniform GVHD prophylaxis and lack of rigorous criteria for the diagnosis and staging of chronic GVHD. This review discusses factors that appear to influence the incidence and clinical presentation of chronic GVHD in the RIC transplantation era. Overall, RIC seems to decrease the incidence and severity of acute GVHD through day 100 post-transplant when compared to conventional conditioning; however, there is little evidence to suggest that chronic GVHD is reduced after RIC. For the more definitive assessments of chronic GVHD after RIC it will be important to study this question in prospective comparison trials with long duration of follow-up. The recent National Institutes of Health chronic GVHD consensus project recommendations provide now the critically needed standardized guidelines for the diagnosis, classification and staging of chronic GVHD.

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References

  1. Weiden PL, Sullivan KM, Flournoy N, Storb R, Thomas ED . Antileukemic effect of chronic graft-versus-host disease: contribution to improved survival after allogeneic marrow transplantation. N Engl J Med 1981; 304: 1529–1533.

    Article  CAS  PubMed  Google Scholar 

  2. Baron F, Storb R . Current roles for allogeneic hematopoietic cell transplantation following nonmyeloablative or reduced-intensity conditioning. Clin Adv Hematol Oncol 2005; 10: 799–819.

    Google Scholar 

  3. Fowler DH . Shared biology of GVHD and GVT effects: potential methods of separation. Crit Rev Oncol Hematol 2006; 57: 225–244.

    Article  PubMed  Google Scholar 

  4. Gale RP, Reisner Y . Graft rejection and graft-versus-host disease: mirror images. Lancet 1986; 1: 1468–1470.

    Article  CAS  PubMed  Google Scholar 

  5. Blazar BR, Lees CJ, Martin PJ, Noelle RJ, Kwon B, Murphy W et al. Host T cells resist graft-versus-host disease mediated by donor leukocyte infusions. J Immunol 2000; 165: 4901–4909.

    Article  CAS  PubMed  Google Scholar 

  6. Goulmy E . Minor histocompatibility antigens: from transplantation problems to therapy of cancer. Hum Immunol 2006; 67: 433–438.

    Article  CAS  PubMed  Google Scholar 

  7. Sullivan KM, Agura E, Anasetti C, Appelbaum F, Badger C, Bearman S et al. Chronic graft-versus-host disease and other late complications of bone marrow transplantation. Semin Hematol 1991; 28: 250–259.

    CAS  PubMed  Google Scholar 

  8. Flowers ME, Kansu E, Sullivan KM . Pathophysiology and treatment of graft-versus host disease. Hematol Oncol Clin North Am 1999; 13: 1091–1112.

    Article  CAS  PubMed  Google Scholar 

  9. Shlomchik WD, Couzens MS, Tang CB, McNiff J, Robert ME, Liu J et al. Prevention of graft versus host disease by inactivation of host antigen-presenting cells. Science 1999; 285: 412–415.

    Article  CAS  PubMed  Google Scholar 

  10. Weinberg K, Blazar BR, Wagner JE, Agura E, Hill BJ, Smogorzewska M et al. Factors affecting thymic function after allogeneic stem cell transplantation. Blood 2001; 97: 1458–1466.

    Article  CAS  PubMed  Google Scholar 

  11. Hess A, Thoburn C, Chen W, Horwitz L . Autoreactive T-cell subsets in acute and chronic syngeneic graft-versus-host disease. Transpl Proc 2001; 33: 1754–1756.

    Article  CAS  Google Scholar 

  12. Blazar BR, Murphy WJ . Bone marrow transplantation and approaches to avoid graft- versus-host disease. Phil Soc R Trans B 2005; 360: 1747–1767.

    Article  CAS  Google Scholar 

  13. Lee SJ . New approaches for preventing and treating chronic graft-versus-host disease. Blood 2005; 105: 4200–4206.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Baron F, Baker JE, Storb R, Gooley TA, Sandmaier BM, Maris MB et al. Kinetics of engraftment in patients with hematologic malignancies given allogeneic hematopoietic cell transplantation after nonmyeloablative conditioning. Blood 2004; 104: 2254–2262.

    Article  CAS  PubMed  Google Scholar 

  15. Antin JH, Weisdorf D, Neuberg D, Nicklow R, Cluothier S, Lee SJ et al. Interleukin-1 blockade does not prevent acute graft-versus-host disease: results of a randomized, double-blind, placebo-controlled trial of interleukin-1 receptor antagonist in allogeneic bone marrow transplantation. Blood 2002; 100: 3479–3482.

    Article  CAS  PubMed  Google Scholar 

  16. Wasch R, Reisser S, Hahn J, Bertz H, Engelhardt M, Kunzmann R et al. Rapid achievement of complete donor chimerism and low regimen-related toxicity after reduced conditioning with fludarabine, carmustine, melphalan and allogeneic transplantation. Bone Marrow Transplant 2000; 26: 243–250.

    Article  CAS  PubMed  Google Scholar 

  17. Bishop MR, Hou JW, Wilson WH, Steinberg SM, Odom J, Castro K et al. Establishment of early donor engraftment after reduced-intensity allogeneic hematopoietic stem cell transplantation to potentiate the graft-versus-lymphoma effect against refractory lymphomas. Biol Blood Marrow Transplant 2003; 9: 162–169.

    Article  PubMed  Google Scholar 

  18. Ueno NT, Cheng YC, Rondon G, Tannir NM, Gajewski JL, Couriel DR et al. Rapid induction of complete donor chimerism by the use of a reduced-intensity conditioning regimen composed of fludarabine and melphalan in allogeneic stem cell transplantation for metastatic solid tumors. Blood 2003; 102: 3829–3836.

    Article  CAS  PubMed  Google Scholar 

  19. Fowler DH, Foley J, Whit-Shan Hou J, Odom J, Castro K, Steinberg SM et al. Clinical ‘cytokine storm’ as revealed by monocyte intracellular flow cytometry: correlation of tumor necrosis factor alpha with severe gut graft-versus-host disease. Clin Gastroenterol Hepatol 2004; 2: 237–245.

    Article  CAS  PubMed  Google Scholar 

  20. Kataoka Y, Iwasaki T, Kuroiwa T, Seto Y, Iwata N, Hashimoto N et al. The role of donor T cells for target organ injuries in acute and chronic graft-versus-host disease. Immunology 2001; 103: 310–318.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Fowler DH, Kurasawa K, Smith R, Eckhaus MA, Gress RE . Donor CD4-enriched cells of Th2 cytokine phenotype regulate graft-versus-host disease without impairing allogeneic engraftment in sublethally irradiated mice. Blood 1994; 84: 3540–3549.

    CAS  PubMed  Google Scholar 

  22. Krenger W, Snyder KM, Byon JC, Falzarano G, Ferrara JL . Polarized type 2 alloreactive CD4+ and CD8+ donor T cells fail to induce experimental acute graft- versus-host disease. J Immunol 1995; 155: 585–593.

    CAS  PubMed  Google Scholar 

  23. Fowler DH, Odom J, Steinberg SM, Chow CK, Foley J, Kogan Y et al. Phase I clinical trial of costimulated, IL-4 polarized donor CD4+ T cells as augmentation of allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant 2006; 12: 1150–1160.

    Article  CAS  PubMed  Google Scholar 

  24. Taylor PA, Lees CJ, Blazar BR . The infusion of ex vivo activated and expanded CD4+CD25+ immune regulatory cells inhibits graft-versus-host disease lethality. Blood 2002; 99: 3493–3499.

    Article  CAS  PubMed  Google Scholar 

  25. Edinger M, Hoffmann P, Ermann J, Drago K, Fathman CG, Strober S et al. CD4+CD25+ regulatory T cells preserve graft-versus-tumor activity while inhibiting graft-versus-host disease after bone marrow transplantation. Nat Med 2003; 9: 1144–1150.

    Article  CAS  PubMed  Google Scholar 

  26. Jones SC, Murphy GF, Korngold R . Post-hematopoietic cell transplantation control of graft-versus-host disease by donor CD425 T cells to allow an effective graft-versusleukemia response. Biol Blood Marrow Transplant 2003; 9: 243–256.

    Article  PubMed  Google Scholar 

  27. Zhang C, Todorov I, Zhang Z, Liu Y, Kandeel F, Forman S et al. Donor CD4+ T and B cells in transplants induce chronic graft-versus-host disease with autoimmune manifestations. Blood 2006; 107: 2993–3001.

    Article  CAS  PubMed  Google Scholar 

  28. Gonzalez M, Quezada SA, Blazar BR, Panoskaltsis-Mortari A, Rudensky AY, Noelle RJ . The balance between donor T cell anergy and suppression versus lethal graft-versus-host disease is determined by host conditioning. J Immunol 2002; 169: 5581–5589.

    Article  CAS  PubMed  Google Scholar 

  29. Anderson BE, McNiff JM, Matte C, Athanasiadis I, Shlomchik WD, Shlomchik MJ . Recipient CD4+ T cells that survive irradiation regulate chronic graft-versus-host disease. Blood 2004; 104: 1565–1573.

    Article  CAS  PubMed  Google Scholar 

  30. Miura Y, Thoburn CJ, Bright EC, Phelps ML, Shin T, Matsui EC et al. Association of Foxp3 regulatory gene expression with graft-versus-host disease. Blood 2004; 104: 2187–2193.

    Article  CAS  PubMed  Google Scholar 

  31. Zorn E, Kim HT, Lee SJ, Floyd BH, Litsa D, Arumugarajah S et al. Reduced frequency of FOXP3+ CD4+CD25+ regulatory T cells in patients with chronic graft-versus-host disease. Blood 2005; 106: 2903–2911.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Clark FJ, Gregg R, Piper K, Dunnion D, Freeman L, Griffiths M et al. Chronic graft-versus-host disease is associated with increased numbers of peripheral blood CD4+CD25high regulatory T cells. Blood 2004; 103: 2410–2416.

    Article  CAS  PubMed  Google Scholar 

  33. Lee SJ, Vogelsang G, Flowers ME . Chronic graft-versus-host disease. Biol Blood Marrow Transpl 2003; 9: 215–233.

    Article  CAS  Google Scholar 

  34. Morris E, Thomson K, Craddock C, Mahendra P, Milligan D, Cook G et al. Outcomes after alemtuzumab-containing reduced-intensity allogeneic transplantation regimen for relapsed and refractory non-Hodgkin lymphoma. Blood 2004; 104: 3865–3871.

    Article  CAS  PubMed  Google Scholar 

  35. Mohty M, Bay JO, Faucher C, Choufi B, Bilger K, Tournilhac O et al. Graft-versu shost disease following allogeneic transplantation from HLA-identical sibling with antithymocyte globulin–based reduced-intensity preparative regimen. Blood 2003; 102: 470–476.

    Article  CAS  PubMed  Google Scholar 

  36. Bacigalupo A . Antithymocyte globulin for prevention of graft-versus-host disease. Curr Opin Hematol 2005; 6: 457–462.

    Article  Google Scholar 

  37. Couriel DR, Saliba RM, Giralt S, Khouri I, Andersson B, de Lima M et al. Acute and chronic graft-versus-host disease after ablative and nonmyeloablative conditioning for allogeneic hematopoietic transplantation. Biol Blood Marrow Transplant 2004; 10: 178–185.

    Article  PubMed  Google Scholar 

  38. Perez-Simon JA, Diez-Campelo M, Martino R, Brunet S, Urbano A, Caballero MD et al. Influence of the intensity of the conditioning regimen on the characteristics of acute and chronic graft-versus-host disease after allogeneic transplantation. Br J Haematol 2005; 130: 394–403.

    Article  PubMed  Google Scholar 

  39. Mielcarek M, Martin PJ, Leisenring W, Flowers ME, Maloney DG, Sandmaier BM et al. Graft-versus-host disease after nonmyeloablative versus conventional hematopoietic stem cell transplantation. Blood 2003; 102: 756–762.

    Article  CAS  PubMed  Google Scholar 

  40. Kim DH, Sohn SK, Baek JH, Kim JG, Lee JW, Min WS et al. Retrospective multicenter study of allogeneic peripheral blood stem cell transplantation followed by reduced intensity conditioning or conventional myeloablative regimen. Acta Haematol 2005; 113: 220–227.

    Article  PubMed  Google Scholar 

  41. Ringden O, Horowitz MM, Gale RP, Biggs JC, Gajewski J, Rimm AA et al. Outcome after allogeneic bone marrow transplant for leukemia in older adults. JAMA 1993; 270: 57–60.

    Article  CAS  PubMed  Google Scholar 

  42. Aoudjhane M, Labopin M, Gorin NC, Shimoni A, Ruutu T, Kolb HJ et al. Comparative outcome of reduced intensity and myeloablative conditioning regimen in HLA identical sibling allogeneic haematopoietic stem cell transplantation for patients older than 50 years of age with acute myeloblastic leukaemia: a retrospective survey from the Acute Leukemia Working Party (ALWP) of the European group for Blood and Marrow Transplantation (EBMT). Leukemia 2005; 19: 2304–2312.

    Article  CAS  PubMed  Google Scholar 

  43. Stem Cell Trialists' Collaborative Group. Allogeneic Peripheral Blood Stem-Cell Compared With Bone Marrow Transplantation in the Management of Hematologic Malignancies: An Individual Patient Data Meta-Analysis of Nine Randomized Trials. J Clin Oncol 2005; 23: 5074–5087.

    Article  Google Scholar 

  44. Miller KB, Roberts TF, Chan G, Schenkein DP, Lawrence D, Sprague K et al. A novel reduced intensity regimen for allogeneic hematopoietic stem cell transplantation associated with a reduced incidence of graft-versus-host disease. Bone Marrow Transplant 2004; 33: 881–889.

    Article  CAS  PubMed  Google Scholar 

  45. Laughlin MJ, Eapen M, Rubinstein P, Wagner JE, Zhang MJ, Champlin RE et al. Outcomes after Transplantation of Cord Blood or Bone Marrow from Unrelated Donors in Adults with Leukemia. N Engl J Med 2004; 351: 2276–2285.

    Article  Google Scholar 

  46. Barker JN, Weisdorf DJ, DeFor TE, Blazar BR, Miller JS, Wagner JE . Rapid and complete donor chimerism in adult recipients of unrelated donor umbilical cord blood transplantation after reduced-intensity conditioning. Blood 2003; 102: 1915–1919.

    Article  CAS  PubMed  Google Scholar 

  47. Heimfeld S . HLA-identical stem cell transplantation: is there an optimal CD34 cell dose? Bone Marrow Transplant 2003; 31: 839–845.

    Article  CAS  PubMed  Google Scholar 

  48. Perez-Simon JA, Campelo MD, Martino R, Sureda A, Caballero D, Canizo C et al. Impact of CD34+ cell dose on the outcome of patients undergoing reduced-intensity conditioning allogeneic peripheral blood stem cell transplantation. Blood 2003; 102: 1108–1113.

    Article  CAS  PubMed  Google Scholar 

  49. Panse JP, Heimfeld S, Guthrie KA, Maris MB, Maloney DG, Baril BB et al. Allogeneic peripheral blood stem cell graft composition affects early T-cell chimaerism and later clinical outcomes after non-myeloablative conditioning. Br J Hematol 2005; 128: 659–667.

    Article  CAS  Google Scholar 

  50. Baron F, Maris MB, Storer BE, Sandmaier BM, Panse J, Chauncey TR et al. High doses of transplanted CD34+ cells are associated with rapid T-cell engraftment and lessened risk of graft rejection, but not more graft-versus-host disease after nonmyeloablative conditioning and unrelated hematopoietic cell transplantation. Leukemia 2005; 19: 822–828.

    Article  CAS  PubMed  Google Scholar 

  51. Storb R, Yu C, Barnett T, Wagner JL, Deeg HJ, Nash RA et al. Stable mixed hematopoietic chimerism in DLA-identical littermate dogs given sublethal total body irradiation before and pharmacological immunosuppression after marrow transplantation. Blood 1997; 89: 3048–3054.

    CAS  PubMed  Google Scholar 

  52. Perruche S, Marandin A, Kleinclauss F, Angonin R, Fresnay S, Baron MH et al. Association of mixed hematopoietic chimerism with elevated circulating autoantibodies and chronic graft-versus-host disease occurrence. Transplantation 2006; 81: 573–582.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ et al. National Institutes of Health Consensus Development Project on criteria for clinical trials in chronic graft-versus-host disease: 1. Diagnosis and Staging Working Group Report. Biol Blood Marrow Transplant 2005; 11: 945–955.

    Article  PubMed  Google Scholar 

  54. Busca A, Rendine S, Locatelli F, Sizzano F, Dall'omo AM, Rossi G et al. Chronic graft-versus-host disease after reduced-intensity stem cell transplantation versus conventional hematopoietic stem cell transplantation. Hematology 2005; 10: 1–10.

    Article  PubMed  Google Scholar 

  55. Baron F, Maris MB, Sandmaier BM, Storer BE, Sorror M, Diaconescu R et al. Graft-versus-tumor effects after allogeneic hematopoietic cell transplantation with non-myeloablative conditioning. J Clin Oncol 2005; 23: 1993–2003.

    Article  PubMed  Google Scholar 

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Acknowledgements

Research Support: This work is supported in part by the intramural programs of the National Cancer Institute, Center for Cancer Research.

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Correspondence to S Z Pavletic.

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Subramaniam, D., Fowler, D. & Pavletic, S. Chronic graft-versus-host disease in the era of reduced-intensity conditioning. Leukemia 21, 853–859 (2007). https://doi.org/10.1038/sj.leu.2404642

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