Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS - American Transplant Congress 2010

San Diego, California / May 1-5, 2010

In the CONCEPT study, kidney transplant recipients either switched from cyclosporine (CsA), mycophenolate mofetil (MMF) and steroids to sirolimus (SRL), MMF and steroids three months’ post-transplantation or continued with their original regimen (Am J Transplant 2009;9:1115-23). Steroids were withdrawn from the majority of patients at 8 months. An intent-to-treat (ITT) analysis at 12 months showed that the mean creatinine clearance (CrCl) estimated according to Cockcroft and Gault was significantly higher with the mammalian target of rapamycin (mTOR) inhibitor SRL at 68.9 mL/min than with CsA at 64.4 mL/min (P=0.017). Similar results were observed for estimated glomerular filtration rates (eGFR) calculated by the MDRD formula.

As reported at last year’s ATC meeting by Prof. Yvon Lebranchu, Université François-Rabelais, Tours, France, the 30-month ITT analysis continued to demonstrate better renal function with SRL. At 30 months, eGFRs were still higher at 58.8 mL/min/1.73 m2 and 52.6 mL/min/1.73 m² for SRL and CsA, respectively. Among patients who had remained on treatment, results were even more pronounced with a 20% difference in renal function in favour of the SRL-containing arm (64.4 mL/min/1.73 m² vs. 53.8 mL/min/1.73 m²).

Early Conversion: A CONCEPT Follow-Up

At 48 months, “renal function benefits were maintained in the SRL group in the ITT population,” Prof. Lebranchu reported at this year’s meeting. Specifically, the eGFR in the ITT cohort was 58.2 mL/min/1.73 m² for the SRL arm vs. 49.8 mL/min/1.73 m² for the CsA arm.

On-treatment renal values at 48 months were even more impressive, Pr.of Lebranchu added, at eGFRs of 66.1 mL/min/1.73 m² for the mTOR inhibitor arm compared with 51.4 mL/min/1.73 m2 for the CNI arm. “We observed a progressive deterioration in renal function over time in patients on CsA, with a 30% difference [in renal function] at four years between the two groups,” Prof. Lebranchu confirmed.

Graft and patient survival were excellent in both arms, with only two deaths in each group at month 48. At the same time point, there had been two graft losses in the SRL group and one in the CsA group. At 48 months, there were only two additional biopsy-proven acute rejection episodes in both groups from those reported at 12 months, he added. Approximately equal numbers of patients were also steroid-free at four years—69% of SRL patients and 64% of CsA recipients. Steroid withdrawal eight months’ post-transplantation was part of the planned protocol.

Because SRL has such potent antiproliferative activity, malignancy rates have consistently been lower over long-term follow-up. At 48 months, three patients in the mTOR inhibitor arm had developed a malignancy compared with nine in the CsA arm. Three additional patients who were originally converted to SRL but who then went back to the CNI also developed cancer by month 48.

Systolic blood pressure was 5 mm Hg lower in the SRL arm at four years than in the CsA arm; proteinuria was similar throughout the study group in both arms (0.39 g/day in the SRL cohort vs. 0.37 g/day in the CsA group). Lipids at year 4 were also similar.

SPIESSER Study Long-term Follow-Up

In a previously published report, Büchler et al. reported that eGFR, the primary end point of the SPIESSER study, was not significantly different at 12 months between patients who were randomized to either SRL or CsA (Am J Transplant 2007;7:2522-31). All patients received anti-thymocyte globulin (rabbit) for five days, plus MMF and steroids initially, although steroids were withdrawn at month 6. Patients received SRL within 48 hours after transplantation, at a loading dose of 15 mg for two days, followed by 10 mg/day, with target maintenance trough levels of 10 to 15 ng/mL. Patients similarly began CsA within 48 hours after transplantation at a dose of 6 to 8 mg/kg/day. Target trough levels were maintained between 150 and 250 ng/mL for the next three months, then reduced to between 75 and 150 ng/mL from the fourth month onward.

Of 133 patients still living with a functional graft at 12 months in the SPIESSER trial, 130 patients (63 in the SRL arm and 67 in the CsA arm) were enrolled in a follow-up study. Renal function was estimated according to Nankivell formula.

Poster data on the 36-month results (poster 1642) showed that patients were receiving SRL at a dose of 2.8 mg/day, with trough levels of 9.5 ng/mL. CNI patients were receiving CsA at a dose of 209 mg/day, trough levels being 113 ng/mL. At three years, patient and graft survival remained excellent in both groups with two deaths occurring in the mTOR inhibitor arm and one graft loss in each arm after the 12-month follow-up point. Nankivell estimates of renal function in the ITT population remained virtually identical from month 12 and 36 in both arms at 66.3 mL/min for SRL patients and 60.9 and 59.8 mL/min for the CsA arm, respectively.

The percentage of patients with good renal function (=60 mL/min) in the ITT analysis was significantly greater in the mTOR inhibitor arm at both month 12 and 36 (75% and 67%, respectively) compared with 52% and 44% for the CNI arm, respectively. As was seen in the four-year follow-up data from CONCEPT, on-treatment Nankivell renal function values were again impressively different at 36 months in the SPIESSER cohort at 70.7 mL/min for SRL recipients vs. 59.8 mL/min for their CsA counterparts (P<0.05).

At 36 months, mean proteinuria levels were higher for SRL patients at 0.56 g/day vs. 0.32 g/day for CsA patients. This is in contrast to the CONCEPT study where there was no difference in proteinuria between the two treatment groups at any point during the study. However, as Prof. Lebranchu explained, patients with proteinuria >1 g/day were not eligible for randomization into CONCEPT.

When SRL is introduced de novo as it was in the SPIESSER study, proteinuria is only increased in patients with delayed graft function and not among those with immediate graft function, he added. Virtually identical percentages of patients in the SPIESSER study were on antihypertensive medication at 36 months but more patients on SRL were on a statin than those on CsA.

Approximately 70% of patients in both arms were steroid-free at 36 months. As in CONCEPT, there were fewer malignancies in the mTOR inhibitor arm at 3% vs. 10% for the CNI arm. “This is another cohort but they reached the same conclusions as we did in CONCEPT, namely, that renal function is better and there are fewer cancers with SRL than with CsA,” Prof. Lebranchu observed.

Prednisone-free Regimen: Interim Results

Conversion from a CNI-based immunosuppressive regimen to an mTOR inhibitor-based regimen does not increase acute rejection rates, graft loss or compromise patient survival. This was demonstrated by interim results presented here at the ATC from a prospective study in which kidney transplant recipients initially maintained on a prednisone-free regimen with tacrolimus (Tac)/MMF for six to 24 months were randomized to SRL conversion or to continue on Tac/MMF. With 104 patients thus far enrolled, patient and graft survival at 12 months have been excellent at 100%, with no difference in acute rejection rates during the post-transplantation period; no rejection occurred following conversion to SRL/MMF. Renal function expressed as eGFR has not differed significantly between the two groups.

However, as noted by co-investigator Dr. Lorenzo Gallon, Assistant Professor of Medicine, Northwestern University, Chicago, Illinois, “All of our kidney transplant recipients received a living donor kidney and these kidneys are healthier overall, so we expect to see a difference in kidney function between the two groups with longer-term follow-up.”

Summary

Excellent patient and graft survival are now the norm following receipt of a donor kidney, at least over the short term. These successful outcomes are the result of improved maintenance immunosuppressive regimens that preserve graft function over time and cause minimal toxicity. There is a growing body of research showing that CNI-sparing or –avoidance regimens with early introduction of the mTOR inhibitor sirolimus preserves renal function over the long term and reduces malignancies while providing excellent immunosuppression.