The SYMPHONY Trial: Tacrolimus

A new study has highlighted low-dose tacrolimus-based regimes as the preferred immunotherapy for renal transplant recipients. Results of the SYMPHONY trial were presented at the World Transplant Congress (WTC) in Boston, Massachusetts in July 2006, along with other new scientific and clinical information relevant to solid organ and tissue transplantation.

Organ transplantation has provided amazing revolutions in the field of medicine in the 20^th century. Patients with end-stage diseases are now able to have new functioning organs implanted to replace the functions of diseased or deficient organs. In some instances the defective organ is removed from the body (e.g. liver transplants), whilst in other instances the old organ remains in situ and the new organ is inserted at a different site (e.g kidney transplants). Organs or parts thereof, may be taken from either living or deceased donors. Organs that have been successfully transplanted include the cornea, kidney, pancreas, liver, heart and lung. However, rejection and side effects of preventing rejection have remained a key challenge. Many immunosuppressant agents are available that satisfactorily reduce rejection but their life-long use can pose serious side effects for patients. Currently research is being targeted at determining the optimal balance of immunosuppressant regimes to extend the life of the graft and the patient. Of particular interest is the role of calcineurin inhibitors such as tacrolimus and cyclosporine in prevention of kidney transplant rejections. A recent study entitled the SYMPHONY trial is the largest ever comparative trial to be conducted de novo in renal transplant patients. The study enrolled 1645 patients who underwent kidney transplantation in 15 different countries. It compared the efficacy and safety of four different triple immunosuppressive regimes over a one year period. Results of the trial were presented by Henrik Ekberg, MD, professor of medicine, Lund University, Lund, Sweden at the renowned World Transplant Congress (WTC) in Boston in 2006.In this prospective, randomised, open study, patients were assigned to receive either standard immunosuppression with conventional-dosage cyclosporine (target troughlevel 150-300ng/ml for 3 months and then 100-200ng/ml thereafter), Mycophenolate Mofetil (MMF, 1g twice daily) and corticosteroids or to one of three different regimes consisting of daclizumab (an anti-IL-2R antibody) induction and maintenance therapy with MMF and corticosteroids combined with low-dose cyclosporine, tacrolimus (3-7ng/ml) or sirolimus (4-8ng/ml). Patients were followed for one year and evaluated in terms of renal function (based on the glomerular-filtration rate, GFR), rejection rates (based on biopsy), survival rates and safety profiles. The main results showed that low-dose tacrolimus, when combined with daclizumab induction therapy, corticosteroids and MMF is superior in terms of efficacy and toxicity, compared with low-dose sirolimus, low-dose cyclosporine or standard-dose cyclosporine regimens. Differences in results met statistical significance for GFR and biopsy proven acute rejection in all four groups. The patients receiving low-dose tacrolimus achieved a glomerular filtration rate of 65.4 mL per minute, compared with 60.9 with low-dose cyclosporine, 57.3 with low-dose sirolimus, and 56.8 with standard dose cyclosporine. After 1 year, graft survival was 94.2% for the low-dose tacrolimus patients, 93.1% for the low-dose cyclosporine patients, 90% for the standard-dose cyclosporine patients, and 89.2% for the low-dose sirolimus patients. The frequency of acute rejection episodes was also lower in the low-dose tacrolimus arm, quoted as 12.3% at 12 months compared to 23.5%, 25.3% and 35.3% for the low-dose cyclosporine, standard-regimen cyclosporine and low-dose sirolimus patients respectively. The authors concluded that immunosuppression consisting of daclizumab induction, MMF, low-dose TAC and corticosteroids provides the most optimal balance between efficacy and toxicity. However, patient survival did not differ significantly between groups and the follow-up period was very short. Furthermore, researchers in this study did not explore the metabolic effects of each agent. Further research is required for example to explore whether the choice of calcineurin inhibitors influences the incidence of new-onset diabetes. However, results from this preliminary study suggest that low-dose tacrolimus offers more favourable outcomes and has already been adopted by many clinicians in the field. Source:

1. Ekberg H, Tedesco-Silva H, Demirbas A, Vitko S, Nashan B, Gurkan A, Margreiter R, Hugo C, Grinyo J, Frei U, Vanrenterghem Y, Daloze P, Halloran P: SYMPHONY: Comparing standard immunosuppression to low-dose cyclosporine, tacrolimus or sirolimus in combination with MMF, daclizumab and corticosteroids in renal transplantation [Abstract]. Am J Transplant 2006; 6 [Suppl 2]: 83.
2. Blackstock T. Tacrolimus music to transplant recipients’ ears: the SYMPHONY trial, Inpharma 2006; 1 (1554): 15-16.
3. Cravedi P, Noris M, Remuzzi G. Report of the First World Transplant Congress, Clin J Am Soc Nephrol 2007; 2: 393-400.

(Kindly reviewed by Dr Dwarakanathan, MD DM FRCP FRACP, Senior Consultant Nephrologist at Royal Brisbane & Women’s Hospital and Editorial Advisory Board Member of the Virtual Renal Centre.)