Abstract
A number of studies were published with contradictory results comparing tacrolimus (Tac) and cyclosporine A (CsA) for graft-versus-host disease (GVHD) prophylaxis, but there are only few that accounted for pharmacokinetic (PK) parameters. In this study, we created a model based on median concentrations, variability of concentrations, and failures to maintain target levels that distinguished patients with low, intermediate, and high risks of acute GVHD (hazard ratios (HR) 1.77, 95%CI 1.36–2.32, p < 0.0001). This model was used to compare 95 patients with CsA and 239 with Tac GVHD prophylaxis. In the multivariate analysis, incorporating PK risk, no differences were observed for grade II–IV acute GVHD (HR 0.73, 95%CI 0.48–1.10, p = 0.13), but grade III–IV acute GVHD was lower in the Tac group (HR 0.47, 95%CI 0.28–0.78, p = 0.004). The observed difference was due to patients with high PK risk (HR 0.377, 95%CI 0.19–0.75, p = 0.005), but not with low and intermediate PK risk (p > 0.05). Patients in the Tac group had better GVHD relapse-free survival (HR = 0.659, p = 0.01) and comparable overall survival (p > 0.05). In conclusion, PK risk should be accounted for in comparisons of GVHD prophylaxis regimens with calcineurin inhibitors, and Tac was superior to CsA in patients with high, but not intermediate and low PK risk.
Similar content being viewed by others
References
Storb R, Deeg HJ, Farewell V et al (1986) Marrow transplantation for severe aplastic anemia: methotrexate alone compared with a combination of methotrexate and cyclosporine for prevention of acute graft-versus-host disease. Blood 68:119–125
Ruutu T, van Biezen A, Hertenstein B et al (2012) Prophylaxis and treatment of GVHD after allogeneic haematopoietic SCT: a survey of centre strategies by the European Group for Blood and Marrow Transplantation. Bone Marrow Transplant 47(11):1459–1464
Fay JW, Wingard JR, Antin JH et al (1996) FK506 (tacrolimus) monotherapy for prevention of graft-versus-host disease after histocompatible sibling allogenic bone marrow transplantation. Blood 87(8):3514–3519
Uberti JP, Silver SM, Adams PT, Jacobson P, Scalzo A, Ratanatharathorn V (1997) Tacrolimus and methotrexate for the prophylaxis of acute graft-versus-host disease in allogeneic bone marrow transplantation in patients with hematologic malignancies. Bone Marrow Transplant 19(12):1233–1238
Ratanatharathorn V, Nash RA, Przepiorka D et al (1998) 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 92(7):2303–2314
Hiraoka A, Ohashi Y, Okamoto S et al (2001) Phase III study comparing tacrolimus (FK506) with cyclosporine for graft-versus-host disease prophylaxis after allogeneic bone marrow transplantation. Bone Marrow Transplant 28(2):181–185
Inamoto Y, Flowers ME, Appelbaum FR et al (2011) A retrospective comparison of tacrolimus versus cyclosporine with methotrexate for immunosuppression after allogeneic hematopoietic cell transplantation with mobilized blood cells. Biol Blood Marrow Transplant 17(7):1088–1092
Yanada M, Emi N, Naoe T et al (2004) Tacrolimus instead of cyclosporine used for prophylaxis against graft-versus-host disease improves outcome after hematopoietic stem cell transplantation from unrelated donors, but not from HLA-identical sibling donors: a nationwide survey conducted in Japan. Bone Marrow Transplant 34(4):331–337
Martin P, Bleyzac N, Souillet G et al (2003) 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(8):777–784
Ganetsky A, Shah A, Miano TA et al (2016) Higher tacrolimus concentrations early after transplant reduce the risk of acute GvHD in reduced-intensity allogeneic stem cell transplantation. Bone Marrow Transplant 51(4):568–572
Mori T, Kato J, Shimizu T et al (2012) Effect of early posttransplantation tacrolimus concentration on the development of acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation from unrelated donors. Biol Blood Marrow Transplant 18(2):229–234
Kanda Y, Kobayashi T, Mori T et al (2016) A randomized controlled trial of cyclosporine and tacrolimus with strict control of blood concentrations after unrelated bone marrow transplantation. Bone Marrow Transplant 51(1):103–109
Luznik L, O’Donnell PV, Symons HJ et al (2008) HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide. Biol Blood Marrow Transplant 14(6):641–650
Mehta RS, Saliba RM, Chen J et al (2016) Post-transplantation cyclophosphamide versus conventional graft-versus-host disease prophylaxis in mismatched unrelated donor haematopoietic cell transplantation. Br J Haematol 173(3):444–455
Maschan M, Shelikhova L, Ilushina M et al (2016) TCR-alpha/beta and CD19 depletion and treosulfan-based conditioning regimen in unrelated and haploidentical transplantation in children with acute myeloid leukemia. Bone Marrow Transplant 51(5):668–674
Holtick U, Chemnitz JM, Shimabukuro-Vornhagen A et al (2016) OCTET-CY: a phase II study to investigate the efficacy of post-transplant cyclophosphamide as sole graft-versus-host prophylaxis after allogeneic peripheral blood stem cell transplantation. Eur J Haematol 96(1):27–35
Tutschka PJ, Copelan EA, Klein JP (1987) Bone marrow transplantation for leukemia following a new busulfan and cyclophosphamide regimen. Blood 70(5):1382–1388
Nagler A, Aker M, Or R et al (2001) Low-intensity conditioning is sufficient to ensure engraftment in matched unrelated bone marrow transplantation. Exp Hematol 29(3):362–370
Bacigalupo A, Locatelli F, Lanino E et al (2005) Fludarabine, cyclophosphamide and anti-thymocyte globulin for alternative donor transplants in acquired severe aplastic anemia: a report from the EBMT-SAA Working Party. Bone Marrow Transplant 36(11):947–950
Holtan SG, DeFor TE, Lazaryan A et al (2015) Composite end point of graft-versus-host disease-free, relapse-free survival after allogeneic hematopoietic cell transplantation. Blood 125(8):1333–1338
Przepiorka D, Weisdorf D, Martin P et al (1995) 1994 Consensus conference on acute GVHD grading. Bone Marrow Transplant 15(6):825–828
Filipovich AH, Weisdorf D, Pavletic S et al (2005) National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant 11(12):945–956
Dellinger RP, Levy MM, Rhodes A et al (2013) Surviving sepsis campaign: International Guidelines for Management of Severe Sepsis and Septic Shock, 2012. Intensive Care Med 39(2):165–228
De Pauw B, Walsh TJ, Donnelly JP et al (2008) Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Clin Infect Dis 46(12):1813–1821
McDonald GB, Hinds MS, Fisher LD et al (1993) Veno-occlusive disease of the liver and multiorgan failure after bone marrow transplantation: a cohort study of 355 patients. Ann Intern Med 118(4):255–267
Cho BS, Yahng SA, Lee SE, Eom KS, Kim YJ, Kim HJ (2010) Validation of recently proposed consensus criteria for thrombotic microangiopathy after allogeneic hematopoietic stem-cell transplantation. Transplantation 90(8):918–926
Gooley TA, Leisenring W, Crowley J, Storer BE (1999) Estimation of failure probabilities in the presence of competing risks: new representation of old estimators. Stat Med 18(6):695–706
Lin G, So Y, Johnston G (2012) Analyzing survival data with competing risks using SAS software, Proceedings of the SAS Global Forum 2012 Conference. SAS Global Forum. Vol. 2102. SAS Institute Inc, Cary
Pollock-Barziv SM, Finkelstein Y, Manlhiot C et al (2010) Variability in tacrolimus blood levels increases the risk of late rejection and graft loss after solid organ transplantation in older children. Pediatr Transplant 14(8):968–975
Huang CT, Shu KH, Ho HC, Wu MJ (2016) Higher variability of tacrolimus trough level increases risk of acute rejection in kidney transplant recipients. Transplant Proc 48(6):1978–1980
Pizzo HP, Ettenger RB, Gjertson DW et al. Sirolimus and tacrolimus coefficient of variation is associated with rejection, donor-specific antibodies, and nonadherence. Pediatr Nephrol. 2016 Jun 10
Kohnert KD, Heinke P, Fritzsche G, Vogt L, Augstein P, Salzsieder E (2013) Evaluation of the mean absolute glucose change as a measure of glycemic variability using continuous glucose monitoring data. Diabetes Technol Ther 15(6):448–454
Mori T, Aisa Y, Kato J, Nakamura Y, Ikeda Y, Okamoto S (2009) Drug interaction between voriconazole and calcineurin inhibitors in allogeneic hematopoietic stem cell transplant recipients. Bone Marrow Transplant 44(6):371–374
Mihara A, Mori T, Aisa Y et al (2008) Greater impact of oral fluconazole on drug interaction with intravenous calcineurin inhibitors as compared with intravenous fluconazole. Eur J Clin Pharmacol 64(1):89–91
Mori T, Aisa Y, Nakazato T, Yamazaki R, Ikeda Y, Okamoto S (2005) Tacrolimus-azithromycin interaction in a recipient of allogeneic bone marrow transplantation. Transpl Int 18(6):757–758
Page RL, Klem PM, Rogers C (2005) Potential elevation of tacrolimus trough concentrations with concomitant metronidazole therapy. Ann Pharmacother 39(6):1109–1113
Bernard E, Goutelle S, Bertrand Y, Bleyzac N (2014) Pharmacokinetic drug-drug interaction of calcium channel blockers with cyclosporine in hematopoietic stem cell transplant children. Ann Pharmacother 48(12):1580–1584
Bleyzac N, Kebaili K, Mialou V, Bertrand Y, Goutelle S (2014) Pharmacokinetic drug interaction between cyclosporine and imatinib in bone marrow transplant children and model-based reappraisal of imatinib drug interaction profile. Ther Drug Monit 36(6):724–729
Aoudjhane M, Labopin M, Gorin NC et al (2005) 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 19(12):2304–2312
Crawley C, Szydlo R, Lalancette M et al (2005) Outcomes of reduced-intensity transplantation for chronic myeloid leukemia: an analysis of prognostic factors from the Chronic Leukemia Working Party of the EBMT. Blood 106(9):2969–2976
Kuypers DR, Claes K, Evenepoel P, Maes B, Vanrenterghem Y (2004) Clinical efficacy and toxicity profile of tacrolimus and mycophenolic acid in relation to combined long-term pharmacokinetics in de novo renal allograft recipients. Clin Pharmacol Ther 75(5):434–447
Keown P, Landsberg D, Halloran P et al (1996) A randomized, prospective multicenter pharmacoepidemiologic study of cyclosporine microemulsion in stable renal graft recipients. Report of the Canadian Neoral Renal Transplantation Study Group. Transplantation 62(12):1744–1752
Kuypers DR, de Jonge H, Naesens M, Lerut E, Verbeke K, Vanrenterghem Y (2007) CYP3A5 and CYP3A4 but not MDR1 single-nucleotide polymorphisms determine long-term tacrolimus disposition and drug-related nephrotoxicity in renal recipients. Clin Pharmacol Ther 82(6):711–725
Acknowledgements
The reported study was supported by The Russian Foundation for Basic Research, according to the research project no. 16-34-60142 mol_а_dk.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflicts of interest.
Electronic supplementary material
Supplementary Figure 1
(DOCX 20 kb)
Supplementary Figure 2
(DOCX 20 kb)
Supplementary Figure 3
(DOCX 23 kb)
Supplementary Figure 4
(DOCX 23 kb)
Supplementary Figure 5
(DOCX 23 kb)
Supplementary Figure 6
(DOCX 23 kb)
Rights and permissions
About this article
Cite this article
Moiseev, I.S., Burmina, E.A., Muslimov, A.R. et al. Pharmacokinetic comparison of cyclosporin A and tacrolimus in graft-versus-host disease prophylaxis. Ann Hematol 96, 935–942 (2017). https://doi.org/10.1007/s00277-017-2975-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00277-017-2975-0