Should Belatacept Be the Centrepiece of Renal Transplantation?

Monika Huber; Stephan Kemmner; Lutz Renders; Uwe Heemann

Disclosures

Nephrol Dial Transplant. 2016;31(12):1995-2002. 

In This Article

Safety

All clinical studies demonstrated good tolerance of belatacept. The infusion over 30 min was well tolerated, with no reported case of anaphylaxis or hypersensitivity. The frequency of adverse events was similar between the belatacept and CNI groups and the incidence of cancer and infection did not differ between the groups. The BENEFIT analysis at year 7, for example, calculated a similar risk for the cumulative frequency of serious adverse events (70.8% MI, 68.6% LI, 76% cyclosporine), serious infection (10.6 MI, 10.7 LI, 13.3 cyclosporine per 100 person-years of exposure) and cancer (2.1 MI, 1.8 LI, 2.6 cyclosporine per 100 person-years of exposure).[15]

In a pooled analysis (n = 1425) from the phase II and III trials comparing belatacept with cyclosporine with a median follow-up of 2.4 years, the risk of serious infections (37% MI, 32% LI, 36% cyclosporine) and death (7% MI, 5% LI, 7% cyclosporine) was lowest in the LI group compared with MI and CsA.[21]

In the previously mentioned clinical trials, belatacept was associated with more acute and higher-grade rejections within 6 months following initiation of therapy. Surprisingly, this was not associated with worse graft outcome. As belatacept is also associated with less antibody formation and the induction of tolerance (at least in animal models), one might speculate whether all of these rejections are really aggressive modes of destruction or might be a process of tolerance acquisition with an enhanced influx of lymphocytes into the graft necessary for the induction of tolerance. Histologically, both pictures look alike and thus cannot be distinguished from each other. In case of initial low donor-reactive T cell precursor frequency, the T cells have an increased requirement for CD28- and CD154-mediated co-stimulation and therefore CD28/CD154 blockade was associated with long-term graft survival in a model of allogenic tissue transplantation.[22]

On the other hand, there is evidence that T cell populations resistant to CD28-dependent co-stimulation blockade, such as pre-existing CD57+ CD4 T cells[23] and alloreactive memory T cells might mediate this rejection. Donor-reactive T cells primed at high frequency predicted graft rejection despite CD28/CD154 blockade.[22,24]

One major safety concern is the numerical increase of early PTLD in belatacept-treated patients, especially in patients with EBV-negative serology at baseline and with the MI regimen of belatacept. In the pooled analysis, PTLD occurred in 16 patients (8 MI, 6 LI, 2 cyclosporine), with 9 cases of PTLD including the central nervous system (6 MI, 3 LI).[21] PTLD is a well-recognized complication after solid organ transplantation, with a cumulative 10-year incidence of ~1.6% and the highest incidence in the first year.[25] For early PTLD (within the first year after solid organ transplantation), primary EBV infection, T cell–depleting antibodies, young age at transplantation and CMV mismatch or CMV disease are described as risk factors. Late PTLD (>12 months after transplantation) occurs more commonly in elderly recipients and is associated with the duration of immunosuppression.[26] Given the increased risk of PTLD in EBV-negative patients, belatacept is approved for use in EBV-positive recipients only.

However, whether or not belatacept really increases the risk of developing PTLD is unclear. While the numbers in the belatacept groups were higher than in controls in the first trial, they were still very low. Given the spontaneous frequency of occurrence (1.6%), 14 cases in about 1000 patients is not unexpectedly high. In order to be on the safe side, the company argues for an exclusion of EBV-negative recipients, as these have a higher frequency in general. Whether this exception is really needed is a matter of debate.[27]

One analysis investigated the health-related quality of life using BENEFIT and BENEFIT-EXT. Belatacept was associated with a reduced side-effect experience and higher health-related quality of life through improved renal function.[28]

Given the very similar effects of the MI and LI regimens, it was concluded that the LI regimen would suffice (Table 2).

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