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Yes There Is Benefit to BENEFIT

In their letter, Drs. Midtvedt and Holdaas (1) suggest that the target levels of cyclosporine account for the difference in the GFR between cyclosporine and belatacept in the phase II and III trials (2–4). The dosage and levels of cyclosporine utilized in the belatacept trials were clearly appropriate as the rejection rate in the cyclosporine treated patients in the phase II and III trials was low. In the Benefit trial, cyclosporine treated patients had a rejection rate of 7%. The authors referred to the Symphony trial suggesting that the lower cyclosporine target level of 100 ng/mL in that trial was sufficient to produce a good outcome (5). However in the Symphony trial both the regular dose of cyclosporine (without induction therapy) and the low-dose cyclosporine (with induction therapy) treatment arms were associated with high rejection rates. The CNI minimization approach advocated by the Symphony trial may appear to benefit patients in the short term but could lead to inappropriately low exposure of immunosuppression in the long term and result in chronic alloimmune rejection. Several recent trials, including the recently published Dekaf study, show that the most common cause of late graft failure is immunologic (6). Thus CNI minimization strategies may be misguided, and rather than improving GFR for the long term, may accelerate graft loss. Belatacept therapy, of course, has to demonstrate its long-term benefit but both the recently published 5 years’ outcome of patients in the phase II study and the demonstration of persistent increase in GFR (actually a positive GFR slope in the Benefit trial) in the phase III trials at 2 years may signal an increased long-term graft survival (7). The data on cyclosporine levels in the phase III trials were omitted from the paper because of word limitation. At 12 months the median cyclosporine levels were 167 and 154 ng/mL in the Benefit and Benefit-EXT, respectively. To better define the relationship between cyclosporine levels and measured GFR, patients were divided into four quartiles based on cyclosporine concentrations. In the Benefit the quartiles were as follows: