Everolimus and early calcineurin inhibitor withdrawal: 3-year results from a randomized trial in liver transplantation

M Sterneck, G M Kaiser, N Heyne, N Richter, F Rauchfuss, A Pascher, P Schemmer, L Fischer, C G Klein, S Nadalin, F Lehner, U Settmacher, P Neuhaus, D Gotthardt, M Loss, S Ladenburger, E M Paulus, M Mertens, H J Schlitt, M Sterneck, G M Kaiser, N Heyne, N Richter, F Rauchfuss, A Pascher, P Schemmer, L Fischer, C G Klein, S Nadalin, F Lehner, U Settmacher, P Neuhaus, D Gotthardt, M Loss, S Ladenburger, E M Paulus, M Mertens, H J Schlitt

Abstract

The feasibility of de novo everolimus without calcineurin inhibitor (CNI) therapy following liver transplantation was assessed in a multicenter, prospective, open-label trial. Liver transplant patients were randomized at 4 weeks to start everolimus and discontinue CNI, or continue their current CNI-based regimen. The primary endpoint was adjusted estimated GFR (eGFR; Cockcroft-Gault) at month 11 post randomization. A 24-month extension phase followed 81/114 (71.1%) of eligible patients to month 35 post randomization. The adjusted mean eGFR benefit from randomization to month 35 was 10.1 mL/min (95% confidence interval [CI] -1.3, 21.5 mL/min, p = 0.082) in favor of CNI-free versus CNI using Cockcroft-Gault, 9.4 mL/min/1.73 m(2) (95% CI -0.4, 18.9, p = 0.053) with Modification of Diet in Renal Disease (four-variable) and 9.5 mL/min/1.73 m(2) (95% CI -1.1, 17.9, p = 0.028) using Nankivell. The difference in favor of the CNI-free regimen increased gradually over time due to a small progressive decline in eGFR in the CNI cohort despite a reduction in CNI exposure. Biopsy-proven acute rejection, graft loss and death were similar between groups. Adverse events led to study drug discontinuation in five CNI-free patients and five CNI patients (12.2% vs. 12.5%, p = 1.000) during the extension phase. Everolimus-based CNI-free immunosuppression is feasible following liver transplantation and patients benefit from sustained preservation of renal function versus patients on CNI for at least 3 years.

Keywords: Calcineurin inhibitor; everolimus; liver transplantation; long-term; withdrawal.

© 2014 The Authors. American Journal of Transplantation Published by Wiley Periodicals, Inc. on behalf of American Society of Transplant Surgeons.

Figures

Figure 1
Figure 1
Patient disposition.
Figure 2
Figure 2
eGFR from the time of randomization to month 35 after randomization according to (A) Cockcroft-Gault, (B) Nankivell and (C) MDRD4 formulae in patients randomized to everolimus or CNI therapy. Values are shown as mean (SD). CNI, calcineurin inhibitor; eGFR, estimated GFR; MDRD4, Modification of Diet in Renal Disease (four-variable).
Figure 3
Figure 3
Mean change in adjusted estimated GFR (eGFR) from baseline to months 11, 23 and 35 postrandomization according to (A) Cockcroft-Gault, (B) Nankivell and (C) MDRD4 formulae in patients randomized to everolimus or CNI therapy. The between-group differences in the adjusted change from baseline at each time point are indicated above the bars. p-Values refer to the comparison between groups. Values below the graphs show mean trough (C0) concentrations of everolimus in the everolimus group and tacrolimus or cyclosporine (CsA) in the CNI cohort at each time point. CNI, calcineurin inhibitor; MDRD4, Modification of Diet in Renal Disease (four-variable).

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Source: PubMed

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