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American Transplant Congress 2007

San Francisco, California / May 5-9, 2007

The objective of the SYMPHONY study was to identify an effective, low-toxicity regimen based on daclizumab induction, mycophenolate mofetil and steroids plus either low-dose cyclosporine, low-dose tacrolimus or low-dose sirolimus. The control arm consisted of standard-dose cyclosporine plus mycophenolate mofetil and steroids, with no induction. At 12 months’ post-transplantation, renal function—the primary end point of the trial—was best preserved in the low-dose tacrolimus group where the calculated glomerular filtration rate (GFR) was 65.4 mL/min compared with 59.4 mL/min for the low-dose cyclosporine group, 57.1 mL/min for normal-dose cyclosporine and 56.7 mL/min for low-dose sirolimus (Table 1).

Table 1. SYMPHONY: Results at 12 Months

The overall incidence of biopsy-proven acute rejection (BPAR) during the first 12 months was also lowest in the low-dose tacrolimus group at 12.3% vs. the other regimens (Table 1). Graft survival at one year was improved in the low-dose tacrolimus group as well. In contrast, patient survival at one year was excellent and similar across all four groups.

In a series of subsequent analyses of the SYMPHONY data set presented here, investigators made a number of clinically relevant observations that could affect transplantation practice.

When borderline rejection was included in BPAR results, the rates themselves only increased by about 2% in each treatment group, and by 5% to 7% when all suspected acute and treated rejections were included in the analysis. Rates were significantly lower at 17% in the low-dose tacrolimus group compared with 29% in the low-dose cyclosporine group, 33% in the normal-dose cyclosporine group and 43% in the low-dose sirolimus group. “Acute rejection occurred mostly during the first six months’ post-transplant,” reported Dr. Ulrich Frei, Charité Campus Virchow-Klinikum, Berlin, Germany.

The proportion of Banff grade I rejections was higher in low-dose sirolimus patients compared with other groups, but for the more serious grades II and III rejections, the highest number occurred in the low-dose cyclosporine group at 35% vs. 31% in normal-dose cyclosporine patients and 28% and 27% for low-dose tacrolimus and sirolimus, respectively. The highest number of treated episodes occurred in the normal-dose cyclosporine group.

Not unexpectedly, GFR at 12 months was approximately 15% lower in rejecters vs. non-rejecters but low-dose tacrolimus patients still had the highest GFRs, even when they had evidence of rejection. Both low-dose sirolimus (hazard ratio [HR] of 1.44) and pre-existing diabetes (HR 1.39) emerged as significant factors associated with the risk of developing an acute rejection.

A considerable amount of attention was also given to drug levels achieved in the four SYMPHONY arms and whether early drug exposure predicted acute rejection or improved renal function 12 months later. As described by Dr. Herwig-Ulf Meier-Kriesche, University of Florida, Gainesville, the correlation between drug levels and the probability of acute rejection was “relatively weak” for all treatment arms but particularly for low-dose tacrolimus. He remarked, “Investigators should be reassured by these data, as there does not seem to be a striking risk for acute rejection in the low-tacrolimus exposure group.” In contrast, no significant improvement in renal function was observed among patients with early low drug exposure for the two cyclosporine-containing arms, “so keeping lower cyclosporine exposure does not necessarily translate into better renal function at one year,” he added.

Early low sirolimus exposure similarly did not improve subsequent renal function over that seen in patients with early high drug exposure levels, he noted. Regarding the actual concentrations of cyclosporine and sirolimus achieved in the study, only 46% of patients in the normal-dose cyclosporine arm were within target levels (150 to 300 ng/mL) within the first week, although this increased to 67% by week 8. In the low-dose cyclosporine arm, 43% of patients were within target levels (50 to 100 ng/mL) within the first week, though this again increased to 51% by week 8, as noted by Dr. Henrik Ekberg, Department of Nephrology and Transplantation, Lund University, Malmö, Sweden. For low-dose tacrolimus, values were more stable, in that more than 50% of patients were within targets (3 to 7 ng/mL) from week 1 to 8, with similar numbers of patients within target levels (4 to 8 ng/mL) on low-dose sirolimus.

The actual levels of cyclosporine, tacrolimus and sirolimus achieved by 75% of SYMPHONY patients consistently during weeks 1 to 8 were “somewhat higher,” mostly closer to the upper level than planned in the protocol, Dr. Ekberg cautioned, findings which “may have important implications for clinical practice.”

Donor Quality

Several other parameters known to affect transplantation outcomes were also evaluated, including the effect of donor quality and subsequent outcomes. Donor quality was categorized as either a living donor, a standard criteria donor or an expanded criteria donor. Stratifying the cohort to patients with a GFR either above or below 60 mL/min, there was no difference in the slope of GFR between deceased donor and living transplant recipients in either the high or low GFR groups. Neither was there a significant difference between expanded and standard criteria donors for patients with a low GFR at one month, although among expanded criteria donors with a higher GFR, the decline in GFR was significantly more rapid. No significant interaction between donor quality and regimen used was observed in either the low or high GFR groups. Interestingly, progression of renal function was not impaired following delayed graft function and early acute rejection in the SYMPHONY study as long as renal function was restored.

In an analysis of the effect of early adverse events on renal function at one year, patients were again stratified by GFR levels at one month (40 to 50 mL/min and >50 mL/min) and rates of GFR progression between those with early adverse events and those without were compared. Patients with delayed graft function in the first month had an 11.1 mL/min lower GFR at one month vs. those who did not, while those who experienced acute rejection in the first month had an 11.9 mL/min lower GFR at one month compared with those who did not. However, at 12 months, GFR among those with delayed graft function at one month and with a GFR of between 40 and 50 mL/min was 54 mL/min vs. 51 mL/min for patients who did not have delayed graft function with the same GFR. Similarly, patients with GFRs of at least 50 mL/min at one month had GFRs of 72 mL/min at 12 months, compared with 72 mL/min for those with the same GFR at one month but who did not have delayed graft function. An almost identical pattern was seen among patients who developed acute rejection for both categories of GFR, investigators added. Results were similar for living and deceased donor transplants and for the different immunosuppressive regimens used in the SYMPHONY study.

Toxicity and Other Adverse Events

Regarding the adverse-event (AE) profiles for each of the regimens, Dr. Ekberg found that 49% of patients in the low-dose sirolimus arm withdrew from the study vs. 30% of the normal-dose cyclosporine group, 28% of the low-dose cyclosporine patients and 20% of the low-dose tacrolimus. AEs related to the blood and lymphatic system were seen in about one-third of patients in all groups, but infections were more frequent in the normal-dose cyclosporine group while gastrointestinal disorders were more common in low-dose tacrolimus patients. Serious AEs including hospitalization were more common in the low-dose sirolimus group at 53% compared with about 44% in the other three groups.

Despite the low dosages used in SYMPHONY, all three immunosuppressants retained their distinct toxicity profiles, Dr. Ekberg observed, although no association between observed drug levels and specific AEs could be identified.

By isolating elderly patients over the age of 60 in SYMPHONY, investigators also observed an age-dependent decrease in renal function as well as an age-dependent decrease in patient survival, although age had no effect on graft survival, BPAR or delayed graft function. The elderly were also found to be at higher risk for infections, wound healing problems and new-onset diabetes than their younger counterparts.

Across all age groups, low-dose tacrolimus retained improved efficacy over the other three SYMPHONY treatment arms in terms of better renal function, fewer BPARs and improved graft survival.