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Optimizing the use of cyclosporin in allogeneic stem cell transplantation

Abstract

Cyclosporin remains the most widely used immunosuppressive agent in patients undergoing allogeneic stem cell transplantation (SCT). The increased awareness of the impact of the intensity of post-transplant immunosuppression on determining outcome after allogeneic SCT has resulted in a re-examination of whether cyclosporin is currently being optimally used in this population of patients. Recent studies in solid organ transplantation have questioned whether the use of trough levels provides the most accurate reflection of the immunosuppressive actions of cyclosporin and alternative strategies to monitor cyclosporin dosage after liver and kidney transplantation are increasingly being used. As a result there is now interest in examining whether there is scope for translating these advances into the arena of haematopoietic transplantation. In this paper, we will review the rationale underlying the current schedules for dosing and monitoring cyclosporin after allogeneic SCT and identify specific areas in which the use of cyclosporin requires re-evaluation. These include evaluation of whether patient outcome would be improved by using peak cyclosporin levels to determine dosing schedules, analysis of optimal cyclosporin dosing schedules in patients undergoing reduced intensity allografts and investigation of surrogate markers of cyclosporin's immunosuppressive activity.

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References

  1. Powles RL, Clink HM, Spence D, Morgenstern G, Watson JG, Selby PJ et al. Cyclosporin A to prevent graft-versus-host disease in man after allogeneic bone-marrow transplantation. Lancet 1980; 16: 327–329.

    Article  Google Scholar 

  2. Storb R, Deeg HJ, Pepe M, Appelbaum F, Anasetti C, Beatty P et al. Methotrexate and cyclosporine versus cyclosporine alone for prophylaxis of graft-versus-host disease in patients given HLA-identical marrow grafts for leukaemia: long-term follow up of a controlled trial. Blood 1989; 73: 1729–1734.

    CAS  PubMed  Google Scholar 

  3. Ratanatharathorn V, Nash RA, Przepiorka D, Devine SM, Klein JL, Weisdorf D et al. Phase III study comparing methotrexate and tacrolimus (prograf, FK506) with methotrexate and cyclosporine for graft-versus-host disease prophylaxis after HLA-identical sibling bone marrow transplantation. Blood 1998; 92: 2303–2314.

    CAS  PubMed  Google Scholar 

  4. Nash RA, Antin JA, Karanes C, Fay JW, Avalos BR, Yeager AM et al. Phase 3 study comparing methotrexate and tacrolimus with methotrexate and cyclosporine for prophylaxis of acute graft-versus-host disease after marrow transplantation. Blood 2000; 96: 2062–2068.

    CAS  PubMed  Google Scholar 

  5. Hiraoka A, Ohashi Y, Okamoto S, Moriyama Y, Nagao T, Kodera Y et al. Phase III study comparing tacrolimus (FK506) with cyclosporine for graft-versus-host disease prophylaxis after allogeneic bone marrow transplantation. Bone Marrow Transplant 2001; 28: 181–185.

    Article  CAS  PubMed  Google Scholar 

  6. Bolwell B, Sobecks R, Pohlman B, Andresen S, Rybicki L, Kuczkowski E et al. A prospective randomized trial comparing cyclosporine and short course methotrexate with cyclosporine and mycophenolate mofetil for GVHD prophylaxis in myeloablative allogeneic bone marrow transplantation. Bone Marrow Transplant 2004; 34: 621–625.

    Article  CAS  PubMed  Google Scholar 

  7. Antin JH, Kim HT, Cutler C, Ho VT, Lee SJ, Miklos DB et al. Sirolimus, tacrolimus and low-dose methotrexate for graft-versus-host disease prophylaxis in mismatched related donor or unrelated donor malignancies. Blood 2003; 102: 1601–1605.

    Article  CAS  PubMed  Google Scholar 

  8. Cutler C, Kim HT, Hochberg E, Ho V, Alyea E, Lee SJ et al. Sirolimus and tacrolimus without methotrexate as graft-versus-host disease prophylaxis after matched related donor peripheral blood stem cell transplantation. Biol Blood Marrow Transplantation 2004; 10: 328–336.

    Article  CAS  Google Scholar 

  9. Ruutu T, Niederwieser D, Gratwohl A, Apperley JF . A survey of the prophylaxis and treatment of acute GVHD 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 

  10. Duncan N . A survey of practice relating to the dosing, administration and monitoring of i.v. ciclosporin in UK haematology centers. British Oncology Pharmacy Association Annual Symposium; Birmingham, 2004.

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

    CAS  PubMed  Google Scholar 

  12. Bacigalupo A, Lamparelli T, Gualandi F, Bregante S, Raiola A, di Grazia C et al. Increased risk of leukaemia relapse with high dose cyclosporine after allogeneic marrow transplantation for acute leukaemia: 10-year follow-up of a randomized study. Blood 2001; 98: 3174–3175.

    Article  CAS  Google Scholar 

  13. Byrne JL, Stainer C, Hyde H, Miflin G, Haynes AP, Bessell EM et al. Low incidence of acute graft-versus-host disease and recurrent leukaemia in patients undergoing allogeneic haemopoietic 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 

  14. Mengarelli A, Iori AP, Romano A, Cerretti R, Cerilli L, De Propris MS et al. One-year cyclosporine prophylaxis reduces the risk of developing extensive chronic graft-versus-host disease after allongeneic peripheral blood stem cell transplantation. Haematologica 2003; 88: 315–323.

    CAS  PubMed  Google Scholar 

  15. Yu C, Storb R, Mathey B, Deeg HJ, Schuening FG, Graham TC et al. DLA-identical bone marrow grafts after low-dose total body irradiation: effects of high-dose corticosteroids and cyclosporine on engraftment. Blood 1995; 86: 4376–4381.

    CAS  PubMed  Google Scholar 

  16. Tauro S, Craddock C, Peggs K, Begum G, Mahendra P, Cook G et al. Allogeneic stem-cell transplantation using a reduced-intensity conditioning regimen has the capacity to produce durable remissions and long-term disease-free survival in patients with high-risk acute myeloid leukemia and myelodysplasia. J Clin Oncol 2005; 23: 9387–9393.

    Article  CAS  PubMed  Google Scholar 

  17. Calne RY, White DJ, Thiru S, Evans DB, McMaster P, Dunn DC et al. Cyclosporin A in patients receiving renal allografts from cadaver donors. Lancet 1978; ii: 1323.

    Article  Google Scholar 

  18. Kahan BD . Cyclosporine. N Engl J Med 1989; 321: 1725–1738.

    Article  CAS  PubMed  Google Scholar 

  19. Halloran PF, Helms LM, Kung L, Noujaim J . The temporal profile of calcineurin inhibition by cyclosporine in vivo. Transplantation 1999; 68: 1356–1361.

    Article  CAS  PubMed  Google Scholar 

  20. Ptachcinski RJ, Venkataramanan R, Burckart GJ . Clinical pharmacokinetics of ciclosporin. Clin Pharmacokinetics 1986; 11: 107–132.

    Article  CAS  Google Scholar 

  21. Kahan BD . Therapeutic drug monitoring of cyclosporine: 20 years of progress. Transplant Proc 2004; 36 (S1): S378–S391.

    Article  Google Scholar 

  22. Wood AJ, Maurer G, Neiderberger W, Beveridge T . Cyclosporine: pharmacokinetics, metabolism and drug interactions. Transplant Proc 1983; 15: 2409–2412.

    CAS  Google Scholar 

  23. Atkinson K, Biggs JC, Britton K, Short R, Mrongovius R, Concannon A et al. Oral administration of cyclosporin A for recipients of allogeneic marrow transplantation: implications of clinical gut dysfunction. Br J Haematol 1984; 56: 223–231.

    Article  CAS  PubMed  Google Scholar 

  24. Yee GC, Lennon TP, Gmur DG, Carlin J, Schaffer RL, Kennedy MS et al. Clinical pharmacology of cyclosporine in patients undergoing bone marrow transplantation. Transplant Proc 1986; 18: 153–159.

    CAS  PubMed  Google Scholar 

  25. Freeman DJ, Laupacis A, Keown PA, Stiller CR, Carruthers SG . Evaluation of cyclosporin–phenytoin interaction with observations on cyclosporin metabolites. Br J Clin Pharmacol 1984; 18: 887–893.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kramer MR, Marshall SE, Denning DW, Keogh AM, Tucker RM, Galgiani JN et al. Cyclosporine and itraconazole interaction in heart and lung transplant recipients. Ann Intern Med 1990; 113: 327–329.

    Article  CAS  PubMed  Google Scholar 

  27. Canafax DM, Graves NM, Hilligoss DM, Carleton BC, Gardner MJ, Matas AJ . Interaction between cyclosporine and fluconazole in renal allograft recipients. Transplantation 1991; 51: 1014–1018.

    Article  CAS  PubMed  Google Scholar 

  28. Ptachcinski RJ, Carpenter BJ, Burckhart GJ, Venkataramanan R, Rosenthal JT . Effect of erythromycin on cyclosporine levels. N Engl J Med 1985; 313: 1416–1417.

    CAS  PubMed  Google Scholar 

  29. Spicer ST, Liddle C, Chapman JR, Barclay P, Nankivell BJ, Thomas P et al. The mechanism of cyclosporine toxicity induced by clarithromycin. Br J Clin Pharmacol 1997; 43: 194–196.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Citterio F . Evolution of the therapeutic drug monitoring of cyclosporine. Transplant Proc 2004; 36: 420S–425S.

    Article  CAS  PubMed  Google Scholar 

  31. Schmidt H, Ehninger G, Dopfer R, Blaurock M, Naumann R, Einsele H 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 

  32. Yee GC, Self SG, McGuire TR, Carlin J, Sanders JE, Deeg HJ . 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 

  33. Przepiorka D, Shapiro S, Schwinghammer TL, Bloom EJ, Rosenfeld CS, Shadduck RK 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 

  34. Ghalie R, Fitzsimmons WE, Weinstein A, Manson S, Kaizer H . Cyclosporine monitoring improves graft-versus-host-disease prophylaxis after bone marrow transplantation. Ann Pharmacother 1994; 28: 379–383.

    Article  CAS  PubMed  Google Scholar 

  35. Barrett AJ, Kendra JR, Lucas CF, Joss DV, Joshi R, Pendharkar P et al. Cyclosporin A as prophylaxis against graft-versus-host disease in 36 patients. BMJ (Clin Res Ed) 1982; 285: 162–166.

    Article  CAS  Google Scholar 

  36. Gratwohl A, Speck B, Wenk M, Forster I, Muller M, Osterwalder B 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 

  37. Bacigalupo A, Di Georgio F, Frassoni F, VanLint MT, Raffo MR, Gogioso L et al. Cyclosporin A serum and blood levels in marrow graft recipients: correlation with administered dose, serum creatinine and graft-versus host disease. Acta Haematol 1984; 72: 155–162.

    Article  CAS  PubMed  Google Scholar 

  38. Kennedy Ms, Yee GC, McGuire TR, Leonard TM, Crowley JJ, Deeg HJ . Correlation of serum cyclosporine concentrations with renal dysfunction in marrow transplant recipients. Transplantation 1985; 40: 249–253.

    Article  CAS  PubMed  Google Scholar 

  39. Yee GC, Kennedy MS, Gmur DJ, Self SG, Deeg HJ . Monitoring cyclosporin concentrations in marrow transplant recipients: comparison of two assay methods. Bone Marrow Transplant 1987; 1: 289–295.

    CAS  PubMed  Google Scholar 

  40. Kahan BD, Wideman CA, Reid M, Gibbons S, Jarowenko M, Flechner S et al. The value of serial serum trough cyclosporine levels in human renal transplantation. Transplant Proc 1984; 16: 1195–1199.

    CAS  PubMed  Google Scholar 

  41. Holt DW, Marsden JT, Johnston A, Bewick M, Taube DH . Blood cyclosporin concentrations and renal allograft dysfunction. BMJ (Clin Res Ed) 1986; 293: 1057–1059.

    Article  CAS  Google Scholar 

  42. Nankivell BJ, Hibbins M, Chapman JR . Diagnostic utility of whole blood cyclosporine measurements in renal transplantation using triple therapy. Transplantation 1994; 58: 989–996.

    Article  CAS  PubMed  Google Scholar 

  43. Kahan BD, Grevel J . Optimization of cyclosporine therapy in renal transplantation by a pharmacokinetic strategy. Transplantation 1988; 46: 631–644.

    Article  CAS  PubMed  Google Scholar 

  44. White D, Rose M, Wright L, Wallwork J, English TA, Hakim M et al. Failure of whole blood cyclosporine levels to provide a reliable measure of immunosuppression in clinical heart and heart/lung transplantation. Transplant Proc 1988; 20: 422–425.

    CAS  PubMed  Google Scholar 

  45. Henry ML, Bowers VD, Fanning WJ, Sommer BG, Ferguson RM . Cyclosporine levels are not helpful. Transplant Proc 1988; 20: 419–421.

    CAS  PubMed  Google Scholar 

  46. Mahalati K, Belitsky P, Sketris I, West K, Panek R . Neoral monitoring by simplified sparse sampling area under the concentration–time curve. Transplantation 1999; 68: 55–62.

    Article  CAS  PubMed  Google Scholar 

  47. Grant D, Kneteman N, Tchervenkov J, Roy A, Murphy G, Tan A et al. Peak cyclosporine levels (Cmax) correlate with freedom from liver graft rejection. Transplantation 1999; 67: 1133–1137.

    Article  CAS  PubMed  Google Scholar 

  48. Cantarovich M, Barkun JS, Tchervenkov J, Besner JG, Aspeslet L, Metrakos P . Comparison of neoral dose monitoring with cyclosporine trough levels versus 2-hr post dose levels in stable liver transplant patients. Transplantation 1998; 66: 1621–1627.

    Article  CAS  PubMed  Google Scholar 

  49. International Neoral Renal Transplantation Study Group. Randomized, international study of cyclosporine microemulsion absorption profiling in renal transplantation with basiliximab immunoprophylaxis. Am J Transplant 2002; 2: 157–166.

  50. Morris RG, Russ GR, Cervelli MJ, Juneja R, McDonald SP, Mathew TH . Comparison of trough, 2-hour and limited AUC blood sampling for monitoring cyclosporin (Neoral) at day 7 post-renal transplantation and incidence of rejection in the first month. Ther Drug Monit 2002; 24: 479–486.

    Article  CAS  PubMed  Google Scholar 

  51. Grevel J, Walsh MS, Kahan BD . Cyclosporine monitoring in renal transplantation: area under the curve monitoring is superior to trough-level monitoring. Ther Drug Monit 1989; 11: 246–248.

    Article  CAS  PubMed  Google Scholar 

  52. Lindholm A, Kahan BD . Influence of cyclosporine pharmacokinetics, trough concentration and AUC monitoring on outcome after kidney transplantation. Clin Pharmacol Ther 1993; 54: 205–218.

    Article  CAS  PubMed  Google Scholar 

  53. Meyer MM, Munar M, Udeaja J, Bennett W . Efficacy of area under the curve cyclosporine monitoring in renal transplantation. J Am Soc Nephrol 1993; 4: 1306–1315.

    CAS  PubMed  Google Scholar 

  54. Johnston A . Sparse-sampling – a practical method for measurement of AUCs. Focus on Med 1998; 13: 7–10.

    Google Scholar 

  55. Johnston A, Sketris I, Marsden JT, Galustian CG, Fashola T, Taube D et al. A limited sampling strategy for the measurement of cyclosporine AUC. Transplant Proc 1990; 22: 1345–1346.

    CAS  PubMed  Google Scholar 

  56. Cantarovich M, Besner JG, Barkun JS, Elstein E, Loertscher R . Two-hour cyclosporine level determination is the appropriate tool to monitor Neoral therapy. Clin Transplantation 1998; 12: 243–249.

    CAS  Google Scholar 

  57. Levy G . Two-hour cyclosporin concentration (C2) as a monitoring tool for Neoral. Focus on Med 1998; 13: 19–22.

    Google Scholar 

  58. Cantarovich M, Elstein E, De Varennes D, Barkun JS . Clinical benefit of neoral dose monitoring with cyclosporine 2-hr post dose levels compared with trough levels in stable heart transplant patients. Transplantation 1999; 68: 1839–1842.

    Article  CAS  PubMed  Google Scholar 

  59. Canadian Neoral Renal Transplantation Study Group. Absorption profiling of cyclosporine microemulsion (neoral) during the first 2 weeks after renal transplantation. Transplantation 2001; 72: 1024–1032.

  60. Levy G, Burra P, Cavallari A, Duvoux C, Lake J, Mayer AD et al. Improved clinical outcomes for liver transplant recipients using cyclosporine monitoring based on 2-hr post-dose levels (C2). Transplantation 2002; 73: 953–959.

    Article  CAS  PubMed  Google Scholar 

  61. Levy G, Thervet E, Lake J, Uchida K . Patient management by neoral C2 monitoring: an international consensus statement. Transplantation 2002; 73: S12–S18.

    Article  PubMed  Google Scholar 

  62. Holt DW, Armstrong VW, Griesmacher A, Morris RG, Napoli KL, Shaw LM . International Federation of Clinical Chemistry/International Association of Therapeutic Drug Monitoring and Clinical Toxicology Working Group on Immunosuppressive Drug Monitoring. Therap Drug Monitor 2002; 24: 59–67.

    Article  CAS  Google Scholar 

  63. Pai SY, Fruman DA, Leong T, Neuberg D, Rosano TG, McGarigle C et al. Inhibition of calcineurin phosphatase activity in adult bone marrow transplant patients treated with cyclosporin A. Blood 1994; 84: 3974–3979.

    CAS  PubMed  Google Scholar 

  64. Sanquer S, Schwarzinger M, Maury S, Yakouben K, Rafi H, Pautas C et al. Calcineurin activity as a therapeutic index of immunosuppression: a functional, pharmacodynamic approach for GVHD prophylaxis. Transplantation 2004; 77: 854–858.

    Article  CAS  PubMed  Google Scholar 

  65. Delaney MP, Smythe E, Higgins RM, Morris AG . Constitutive and acquired resistance to calcineurin inhibitors in renal transplantation: role of P-glycoprotein-170. Transpl Int 2000; 13: 276–284.

    Article  CAS  PubMed  Google Scholar 

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Duncan, N., Craddock, C. Optimizing the use of cyclosporin in allogeneic stem cell transplantation. Bone Marrow Transplant 38, 169–174 (2006). https://doi.org/10.1038/sj.bmt.1705404

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