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

Abstract

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.

Randomized Trial of Immunosuppressive Regimens in Renal Transplantation

“…Thus, the analyses of renal function (serum Cr and eGFR) at various times post-transplant were based on comparing patients who were still alive with functioning grafts at those times. While imputation of an arbitrarily chosen low value for eGFR (say, 10 ml/min) was considered for patients who previously experienced GF, [25][26] the results were quite similar to those found without using imputation and will therefore not be shown.…”

“…However, the impact of these differences were smaller by 3 yr post-transplant. [25][26] In conclusion, the excellent outcome in the TAC/MMF arm, as observed in the ELITE-Symphony Study, [25][26] was achieved using reduced trough levels for TAC, with mean levels ranging from 8 -10 ng/ml initially and 5-8 ng/ml beyond the first year post-transplant. While the combination of TAC/ MMF (with or without steroid avoidance) is currently the most widely used maintenance regimen in kidney transplantation, 27 nephrotoxicity due to long-term use of TAC is still a potential problem, and new immunosuppressive strategies designed to dramatically improve long-term graft survival are still required.…”

Long-Term Cancer Risk of Immunosuppressive Regimens after Kidney Transplantation

“…One recent publication reported a possible reduction in cancer risk at 24 months of follow-up with sirolimus, 12 but this has not been confirmed by other trials 13 or a meta-analysis. 14 Apart from the association of anti-CD3 mAbs with posttransplantation lymphoproliferative disease, 15 the clinical evidence for one treatment regimen over another in reducing posttransplantation malignancy is varied and not compelling.…”

“…14 Apart from the association of anti-CD3 mAbs with posttransplantation lymphoproliferative disease, 15 the clinical evidence for one treatment regimen over another in reducing posttransplantation malignancy is varied and not compelling. This analysis suggests that longer term follow-up of recent comparative immunosuppressive trials (e.g., Efficacy Limiting Toxicity Elimination [ELITE]-Symphony Trial 13 ) could provide important data on cancer outcomes and that better markers of the degree of immunosuppression may also aid in reducing cancer risk.…”

Untitled

“…8,26 Other immunosuppressive agents that have been implicated in an increased rate of GI symptoms are calcineurin inhibitors. In the seminal Symphony study, 27 it was shown that 33% of patients who received low-dose tacrolimus reported diarrhea compared with 23% of those who received cyclosporine. Our study found a much lower rate, with prevalence of loose stools in 11% of patients who received tacrolimus and 0% of patients who received cyclosporine.…”