Calcineurin Inhibitor Minimization in the Symphony Study: Observational Results 3 Years after Transplantation

Lund University, Malmö, Sweden.
American Journal of Transplantation (Impact Factor: 5.68). 07/2009; 9(8):1876-85. DOI: 10.1111/j.1600-6143.2009.02726.x
Source: PubMed


The Symphony study showed that at 1 year posttransplant, a regimen based on daclizumab induction, 2 g mycophenolate mofetil (MMF), low-dose tacrolimus and steroids resulted in better renal function and lower acute rejection and graft loss rates compared with three other regimens: two with low-doses of cyclosporine or sirolimus instead of tacrolimus and one with no induction and standard cyclosporine dosage. This is an observational follow-up for 2 additional years with the same endpoints as the core study. Overall, 958 patients participated in the follow-up. During the study, many patients changed their immunosuppressive regimen (e.g. switched from sirolimus to tacrolimus), but the vast majority (95%) remained on MMF. During the follow-up, renal function remained stable (mean change: -0.6 ml/min), and rates of death, graft loss and acute rejection were low (all about 1% per year). The MMF and low-dose tacrolimus arm continued to have the highest GFR (68.6 +/- 23.8 ml/min vs. 65.9 +/- 26.2 ml/min in the standard-dose cyclosporine, 64.0 +/- 23.1 ml/min in the low-dose cyclosporine and 65.3 +/- 26.2 ml/min in the low-dose sirolimus arm), but the difference with the other arms was not significant (p = 0.17 in an overall test and 0.077, 0.039 and 0.11, respectively, in pair-wise tests). The MMF and low-dose tacrolimus arm also had the highest graft survival rate, but with reduced differences between groups over time, and the least acute rejection rate. In the Symphony study, the largest ever prospective study in de novo kidney transplantation, over 3 years, daclizumab induction, MMF, steroids and low-dose tacrolimus proved highly efficacious, without the negative effects on renal function commonly reported for standard CNI regimens.

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Available from: Corrado Bernasconi, Sep 04, 2014
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    • "Novel immunosuppressive agents and combination therapy enabled a reduction of side effects and an increase of graft and patient survival. However, regimens that completely avoid calcineurin inhibitors (CNIs) have been associated with high rates of rejection [1, 2], poorer renal function [3] and intolerability [4, 5]. Nowadays kidney graft loss due to chronic allograft nephropathy (CAN)/interstitial fibrosis and tubular atrophy (IFTA) and death with functioning graft is observed in 3 to 5% of cases after the first year of transplantation [6, 7]. "
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    ABSTRACT: Belatacept was approved for prevention of acute rejection in adult kidney transplantation in 2011 based on two randomized, controlled, multicenter phase 3 studies. Long-term experience over 10 years with belatacept-based immunosuppression after kidney transplantation has not been reported before. Analyzed were 20 patients who had been included into a randomized multicenter phase 2 study by our institution between March 2001 and November 2002. For 10-year follow-up, three different groups could be analyzed: 1) patients with primary calcineurin inhibitor-based (CNI-based) immunosuppression (n = 5), 2) patients with early switch from a belatacept-based to a CNI-based regimen within the first 14 months (n = 8) and 3) patients with completely CNI-free belatacept immunosuppression (n = 7). Fifteen patients received primary belatacept-based immunosuppression and five patients primary cyclosporine A (CyA). Five patients are still on belatacept. Kidney function measured by serum creatinine levels worsened in the CNI group and the belatacept to CNI switch group during long-term follow-up whereas all patients receiving belatacept throughout follow-up showed stable creatinine values. Acute rejections occurred predominantly in the first 12 months after transplantation and were responsible for four of seven switches from belatacept- to CNI-based immunosuppression within the first 14 months. Five of the 20 patients died. Belatacept is effective and safe in renal transplant patients and was not associated with graft loss due to chronic allograft nephropathy. Belatacept was well tolerated in all patients and caused less nephrotoxic side effects and was well accepted in most patients.
    Journal of Clinical Medicine Research 04/2014; 6(2):98-110. DOI:10.14740/jocmr1697w
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    • "In two large kidney transplant trials, 3-year results have been reported. In the SYMPHONY study, patient and graft survival in the low-dose tacrolimus arm were 95 and 90%, respectively (9). In the belatacept trial, patient survival with functioning graft in two calcineurin-free belatacept arms and the CsA arm were 92, 92, and 89%, while graft survival rates were approximately 87, 88, and 84%, respectively (10). "
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    ABSTRACT: In a phase III, open-label, comparative, noninferiority study, 638 subjects receiving de novo kidney transplants were randomized to one of three treatment arms: tacrolimus extended-release (Astagraf XL) qd, tacrolimus (Prograf) bid, or cyclosporine (CsA) bid. All subjects received basiliximab induction, mycophenolate mofetil, and corticosteroids. Safety and efficacy follow-up data through 4 years are reported. Evaluations included patient and graft survival, study drug discontinuations, laboratory values including renal function and development of new-onset diabetes after transplantation, concomitant medications, and adverse events. At study termination, 129 Astagraf XL, 113 Prograf, and 79 CsA patients had continued follow-up. Demographic and baseline characteristics were similar in all arms. Four-year Kaplan-Meier estimates of patient survival in the Astagraf XL, Prograf, and CsA groups were 93.2, 91.2, and 91.7%, respectively, while graft survival was 84.7, 82.7, and 83.9%, respectively. At least one serious adverse event was reported in the majority of patients in each group during the study (65.9% Astagraf XL, 69.8% Prograf, and 65.6% CsA). Renal function was not significantly different between Astagraf XL and Prograf. HgbA1c levels were collected every 6 months; the 4-year Kaplan-Meier estimate for incidence of HgbA1c levels ≥6.5% was significantly higher for both tacrolimus formulations compared to CsA; 41.1% (Astagraf XL), 33.6% (Prograf), and 21.3% (CsA). In this 4-year follow-up report, patients receiving Astagraf XL and Prograf showed comparable efficacy and safety profiles, with a higher incidence of new-onset diabetes after transplantation but superior renal function compared to patients receiving CsA.
    Transplantation 02/2014; 97(6). DOI:10.1097/01.TP.0000437669.93963.8E · 3.83 Impact Factor
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    • "In the Symphony study, patients were randomised to one of four treatment groups: MMF with standard-dose CsA and corticosteroids; MMF with low-dose CsA, daclizumab and corticosteroids; MMF with low-dose tacrolimus, daclizumab and corticosteroids; or MMF with low-dose SRL, daclizumab and corticosteroids [11]. This study found that the regimen containing low-dose tacrolimus resulted in improved renal function, graft survival, and acute rejection rates compared with SRL/MMF and the other regimens, and that this was sustained over 3 years of follow up [12]. Even though the blood concentrations of SRL in these studies may have been lower than optimal, SRL/MMF would appear to be a less potent immunosuppressive combination than CNI/MMF, especially in the first few months after transplant when rejection is more likely to occur. "
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    ABSTRACT: Renal transplantation is the treatment of choice for end-stage renal failure. Although advances in immunosuppression have led to improvements in short-term outcomes, graft survival beyond 5 to 10 years has not improved. One of the major causes of late renal allograft failure is chronic allograft nephropathy, a component of which is nephrotoxicity from the use of calcineurin inhibitors (CNIs). In addition, premature patient death is a major limitation of renal transplantation and the major causes are cancer, cardiovascular disease and infection. CNI-free immunosuppressive regimens based on mammalian target of rapamycin (mTOR) inhibitors have been trial led over the last few years and have defined the rational use of these agents. Conversion from a CNI-based to an mTOR-inhibitor-based regimen has been successful at improving renal function for a number of years after conversion, although long-term survival outcomes are still awaited. The studies suggest that the safest and most effective time to convert is between 1 and 6 months after transplant. In addition, mTOR-inhibitor-based regimens have been shown to be associated with lower rates of post-transplant malignancy and less cytomegalovirus infection, which may add further to the appeal of this approach.
    11/2013; 2(Suppl 1):S4. DOI:10.1186/2047-1440-2-S1-S4
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