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Graft-Versus-Host Disease

Relationship between CsA trough blood concentration and severity of acute graft-versus-host disease after paediatric stem cell transplantation from matched-sibling or unrelated donors

Bone Marrow Transplantation volume 32, pages 777–784 (2003)Cite this article

Summary:

In order to determine optimal CsA trough blood concentrations (TBC) in the early post transplantation period, we analysed relationships between TBC and acute graft-versus-host disease (aGVHD) in paediatric SCT. A total of 94 children consecutively underwent allogeneic stem cell transplantation (SCT) from: matched-sibling (MSD) (n=36), mismatched-related (MMRD) (n=3) and unrelated donors (UD) (n=55). GVHD prophylaxis usually included CsA alone or with methotrexate. Antithymocyte globulin was added in UD-SCT. TBC during the first weeks of post transplantation were estimated retrospectively by a Bayesian pharmacokinetic method and statistically associated with aGVHD. In MSD-SCT, the mean TBC during the first 2 weeks post transplantation were 42±10 and 90±7 ng/ml, respectively, in patients with grade II–IV and 0–I aGVHD (P=0.001). In SCT from UD and MMRD, TBC were 73±4 vs 95±8 ng/ml (P=0.284). For TBC >85 ng/ml, no patient developed grade II–IV aGVHD, 10 developed mild aGVHD and 30 had no aGVHD. For TBC <65 ng/ml, 7/11 patients receiving an MSD-SCT and 4/18 receiving an UD- or MMRD-SCT developed grade II–IV aGVHD. The mean TBC corresponding to each grade were: no GVHD: 101±10 ng/ml, mild: 77±11 ng/ml, moderate: 61±13 ng/ml, severe: 56±15 ng/ml (P<0.001). These results reveal a strong relationship between TBC during the early post transplantation period and the severity of aGVHD in paediatric SCT.

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References

  1. Gale RP, Bortin MM, van Bekkum DW et al. Risk factors for acute graft-versus-host disease. Br J Haematol 1987; 67: 397–406.

    Article  CAS  PubMed  Google Scholar 

  2. Weisdorf D, Hakke R, Blazar B et al. Risk factors for acute graft-versus-host disease in histocompatible donor bone marrow transplantation. Transplantation 1991; 51: 1197–1203.

    Article  CAS  PubMed  Google Scholar 

  3. Nash RA, Pepe MS, Storb R et al. Acute graft-versus-host disease: analysis of risk factors after allogeneic marrow transplantation and prophylaxis with cyclosporine and methotrexate. Blood 1992; 80: 1838–1845.

    CAS  PubMed  Google Scholar 

  4. Hägglund H, Bostrom L, Remberger M et al. Risk factors for acute graft-versus-host disease in 291 consecutive HLA-identical bone marrow transplantation. Bone Marrow Transplant 1995; 16: 747–753.

    PubMed  Google Scholar 

  5. Locatelli F, Uderzo C, Dini G et al. Graft-versus-host disease in children: the AIEOP-BMT Group experience with cyclo-sporin A. Bone Marrow Transplant 1993; 12: 627–633.

    CAS  PubMed  Google Scholar 

  6. Balduzzi A, Gooley T, Anasetti C et al. Unrelated donor marrow transplantation in children. Blood 1995; 86: 3247–3256.

    CAS  PubMed  Google Scholar 

  7. Souillet G, Rey S, Bertrand Y et al. Outcome of unrelated bone marrow donor searches in 174 children resulting in 45 patients transplanted in the HLA-matched and -mismatched situation. Bone Marrow Transplant 2000; 26: 31–43.

    Article  CAS  PubMed  Google Scholar 

  8. Locatelli F, Zecca M, Rondelli R et al. Graft versus host disease prophylaxis with low-dose cyclosporine-A reduces the risk of relapse in children with acute leukaemia given HLA-identical sibling bone marrow transplantation: results of a randomised trial. Blood 2000; 95: 1572–1579.

    CAS  PubMed  Google Scholar 

  9. Gustafsson A, Remberger M, Winiarski J et al. Unrelated bone marrow transplantation in children: outcome and a comparison with sibling donor grafting. Bone Marrow Transplant 2000; 25: 1059–1065.

    Article  CAS  PubMed  Google Scholar 

  10. Weiden PL, Flournoy N, Thomas ED et al. Antileukemic effect of graft-versus-host disease in human recipients of bone marrow grafts. N Engl J Med 1979; 300: 1068–1073.

    Article  CAS  PubMed  Google Scholar 

  11. Sullivan KM, Weiden PL, Storb R et al. Influence of acute and chronic graft-versus- host-disease on relapse and survival after bone marrow transplantation from HLA-identical siblings as treatment of acute and chronic leukaemia. Blood 1989; 73: 1720–1728.

    CAS  PubMed  Google Scholar 

  12. Horowitz MM, Gale RP, Sondel PM et al. Graft-versus-leukaemia reactions after bone marrow transplantation. Blood 1990; 75: 555–562.

    CAS  PubMed  Google Scholar 

  13. Gratwohl A, Hermans J, Apperley J et al. Acute graft-versus-host disease: grade and outcome in patients with chronic myelogenous leukaemia. Working party chronic leukaemia of the European group for blood and marrow transplantation. Blood 1995; 86: 813–818.

    CAS  PubMed  Google Scholar 

  14. Weiden PL, Sullivan KM, Flournoy N et al. Antileukemic effect of chronic graft-versus-host disease: contribution to improved survival after allogenic marrow transplantation. N Engl J Med 1981; 304: 1529–1533.

    Article  CAS  PubMed  Google Scholar 

  15. Ringden O, Labopin M, Gluckman E et al. Graft-versus-leukemia effect in allogeneic marrow transplant recipients with acute leukemia is maintained using cyclosporin A combined with methotrexate as prophylaxis. Bone Marrow Transplant 1996; 18: 921–929.

    CAS  PubMed  Google Scholar 

  16. Ringden O, Labopin M, Gluckman E et al. Strong antileukemic effect of chronic graft-versus-host-disease in allogeneic marrow transplant recipients having acute leukemia treated with methotrexate and cyclosporine: The Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT). Transplant Proc 1997; 29: 733–734.

    Article  CAS  PubMed  Google Scholar 

  17. Peters C, Minkov M, Gadner H et al. Statement of current majority practices in graft-versus-host disease prophylaxis and treatment in children. Bone Marrow Transplant 2000; 26: 405–411.

    Article  CAS  PubMed  Google Scholar 

  18. Bacigalupo A, Van Lint MT, Occhini D et al. Increased risk of leukaemia relapse with high-dose cyclosporine A after allogeneic marrow transplantation for acute leukaemia. Blood 1991; 77: 1423–1428.

    CAS  PubMed  Google Scholar 

  19. Tsunoda SM, Aweeka F . The use of therapeutic drug monitoring to optimise immunosuppressive therapy. Clin Pharmacokinet 1996; 30: 107–140.

    Article  CAS  PubMed  Google Scholar 

  20. Yee GC, Self SG, Mc Guire TR et al. Serum cyclosporine concentration and risk of acute graft-versus-host disease after allogeneic marrow transplantation. N Engl J Med 1988; 319: 65–70.

    Article  CAS  PubMed  Google Scholar 

  21. Ghalie R, Fitzsimmons WE, Weinstein A et al. Cyclosporine monitoring improves graft-versus-host disease prophylaxis after bone marrow transplantation. Ann Pharmacother 1994; 28: 379–383.

    Article  CAS  PubMed  Google Scholar 

  22. Hunter AE, Bessell EM, Russell N . Effective prevention of acute GVHD following allogeneic BMT with low leukaemic relapse using methotrexate and therapeutically monitored levels of cyclosporin A. Bone Marrow Transplant 1992; 10: 431–434.

    PubMed  Google Scholar 

  23. Byrne JL, Stainer C, Hyde H et al. Low incidence of acute graft-versus-host disease and recurrent leukaemia in patients undergoing allogeneic haematopoietic stem cell transplantation from sibling donors with methotrexate and dose-monitored cyclosporin A prophylaxis. Bone Marrow Transplant 1998; 22: 541–545.

    Article  CAS  PubMed  Google Scholar 

  24. Carlens S, Aschan J, Remberger M et al. Low-dose cyclosporine of short duration increases the risk of mild and moderate GVHD and reduces the risk of relapse in HLA-identical sibling marrow transplant recipients with leukaemia. Bone Marrow Transplant 1999; 24: 629–635.

    Article  CAS  PubMed  Google Scholar 

  25. Laboratory of Applied Pharmacokinetics. USC* Pack P.C. Collection Clinical Research Programs, Los Angeles. University of Southern California, School of Medicine, 1995, version 10.7.

  26. Jelliffe RW, Schumitzky A, Van Guilder M et al. Individualizing drug dosage regimens: roles of population pharmacokinetic and dynamic models, Bayesian fitting, and adaptive control. Ther Drug Monit 1993; 15: 380–393.

    Article  CAS  PubMed  Google Scholar 

  27. Jelliffe RW . Effect of assumptions concerning assay error patterns upon pharmacokinetic parameter values and model behavior. J Vet Pharmacol Ther 1994; 17:105–109.

    Google Scholar 

  28. Glucksberg H, Storb R, Fefer A et al. Clinical manifestations of graft-versus-host disease in human recipients of marrow from HLA-matched sibling donors. Transplantation 1974; 18: 295–304.

    Article  CAS  PubMed  Google Scholar 

  29. Leger F, Debord J, Le Meur Y et al. Maximum a posteriori Bayesian estimation of oral cyclosporin pharmacokinetics in patients with stable renal transplants. Clin Pharmacokinet. 2002; 41: 71–80.

    Article  CAS  PubMed  Google Scholar 

  30. Serre-Debeauvais F, Iliadis A, Tranchand B et al. Bayesian estimation of cyclosporine clearance in bone marrow graft. Ther Drug Monit 1990; 12: 16–22.

    Article  CAS  PubMed  Google Scholar 

  31. Barrett AJ, Kendra JR, Lucas CF et al. Cyclosporin A as prophylaxis against graft-versus-host disease in 36 patients. Br Med J 1982; 285: 162–166.

    Article  CAS  Google Scholar 

  32. Gratwohl A, Speck B, Wenk M et al. Cyclosporine in human bone marrow transplantation. Serum concentration, graft-versus-host disease, and nephrotoxicity. Transplantation 1983; 36: 40–44.

    Article  CAS  PubMed  Google Scholar 

  33. Biggs JC, Atkinson K, Britton K et al. The use of cyclosporine in human marrow transplantation: absence of a therapeutic window. Transplant Proc 1985; 17: 1239–1241.

    Google Scholar 

  34. Gluckman E, Lokiec F, Devergie A . Pharmacokinetic monitoring of cyclosporine in allogeneic bone marrow transplants. Transplant Proc 1985; 17: 500–501.

    Google Scholar 

  35. Schmidt H, Ehninger G, Dopfer R et al. Correlation between low CsA plasma concentration and severity of acute GVHD in bone marrow transplantation. Blut 1988; 57: 139–142.

    Article  CAS  PubMed  Google Scholar 

  36. Bandini G, Strocchi E, Ricci P et al. Cyclosporine A: correlation of blood levels with acute graft-versus-host disease after bone marrow transplantation. Acta Haematol 1987; 78: 6–12.

    Article  CAS  PubMed  Google Scholar 

  37. Bogdanic V, Mrsic M, Plavsic F et al. Blood cyclosporine concentration and risk of acute GVHD after allogeneic marrow transplantation. Bone Marrow Transplant 1988; 3 (Suppl 2): 67 (Abstract).

    Google Scholar 

  38. Przepiorka D, Shapiro S, Schwingammer TL et al. Cyclosporine and methylprednisolone after allogeneic marrow transplantation: association between low cyclosporine concentration and risk of acute graft-versus-host disease. Bone Marrow Transplant 1991; 7: 461–465.

    CAS  PubMed  Google Scholar 

  39. Ringden O, Hermans J, Labopin M et al. The highest leukaemia-free survival after allogeneic bone marrow transplantation is seen in patients with grade I acute graft-versus-host disease. Leuk Lymphoma 1996; 24: 71–79.

    Article  CAS  PubMed  Google Scholar 

  40. Shaw BE, Pay AL, Potter MN et al. The presence of mild acute graft versus host disease in a T cell depleted unrelated donor transplant setting improves overall survival. Bone Marrow Transplant 2002; 29 (Suppl 2): S39 (Abstract).

    Google Scholar 

  41. Santos GW, Tutschka PJ, Brookmeyer R . Cyclosporine plus methylprednisolone versus cyclophosphamide plus methylprednisolone as prophylaxis for graft-versus-host disease in 107 patients with leukemia: a randomized double-blind study in patients undergoing allogeneic bone marrow transplantation. Clin Transplant 1987; 1: 21–28.

    Google Scholar 

  42. Ruutu T, Niederwieser D, Gratwohl A et al. A survey of the prophylaxis and treatment of acute aGVHD in Europe: a report of the European Group for Blood and Marrow Transplantation (EBMT). Bone Marrow Transplant 1997; 19: 759–764.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Pharmacy, Debrousse Hospital, Lyon, France

    P Martin, N Bleyzac & G Aulagner

  2. Department of Paediatric Immuno-haematology and Bone Marrow Transplantation, Debrousse Hospital, Lyon, France

    G Souillet, C Galambrun & Y Bertrand

  3. ADCAPT, A Charial Hospital, Francheville, France

    N Bleyzac & P H Maire

  4. Laboratory of Applied Pharmacokinetics, University of Southern California, School of Medicine, Los Angeles, CA, USA

    R W Jelliffe

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  1. P Martin
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Correspondence to N Bleyzac.

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Martin, P., Bleyzac, N., Souillet, G. et al. Relationship between CsA trough blood concentration and severity of acute graft-versus-host disease after paediatric stem cell transplantation from matched-sibling or unrelated donors. Bone Marrow Transplant 32, 777–784 (2003). https://doi.org/10.1038/sj.bmt.1704213

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