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

Clinical Trials

In kidney transplantation, the effects of belatacept-based immunosuppression were analysed in five large randomized clinical trials (Table 1) and some smaller ones.

Belatacept Versus Cyclosporine (Phase II)

The initial phase II study (n = 218) compared more intensive (MI) and less intensive (LI) regimens of belatacept with cyclosporine in adult recipients of living or deceased donor renal allografts (Table 2).[4] This trial focussed on patients with a very low immunological risk [first allograft, history of panel-reactive antibody (PRA) <20%] and considered to be at no increased risk for acute rejection by the investigator (Table 1). In this trial, the rate of acute rejection was similar, while the measured GFR (mGFR) (mGFR in mL/min/1.73 m2: 66.3 MI, 62.1 LI, 53.5 cyclosporine) as well as the incidence of chronic allograft nephropathy (29% MI, 20% LI, 44% cyclosporine) differed significantly between groups at month 12.

There were some cases of post-transplant lymphoproliferative disorder (PTLD), mainly cases involving the central nervous system, in the belatacept-treated patients (one case within 1 year, two cases after discontinuation of belatacept after 1 year, all in the MI belatacept regimen), all associated with either primary EBV infection or treatment with a T cell–depleting antibody. The frequency of infection (73% belatacept, 75% cyclosporine) and cancer (3% belatacept, 3% cyclosporine) was similar among groups.[4]

In the extended follow-up of 5 years (n = 128), renal function remained stable in the belatacept group and the incidence for acute rejection, graft loss or death was low. Fortunately, after the initially higher rates of PTLD in the belatacept group (three cases between 3 and 13 months), only one further PTLD case was reported in the CsA group and none in the belatacept arm.[12]

BENEFIT and BENEFIT-EXT (Phase III)

The Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial (BENEFIT)[8] and Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial-EXTended criteria donors (BENEFIT-EXT)[9] were multicentre, international, randomized, active-controlled, parallel-group phase III trials on low-risk patients (Table 1).

While BENEFIT focussed on recipients of regular criteria grafts, in BENEFIT-EXT the same protocol was applied to recipients of extended criteria grafts.

In BENEFIT, belatacept was associated with a higher number of early acute rejection episodes, partly with higher severity (≥Banff IIA) at month 12 (22% MI, 17% LI, 7% cyclosporine), while graft and patient survival was equal. There was a better eGFR in the belatacept groups during the first 3 months. However, the decrease in renal function between 3 and 12 months was similar between the groups.

In BENEFIT-EXT, rejection rates were similar, but there was a numerical increase in higher-grade rejections associated with belatacept. Nearly all rejections occurred within the first 6 months.[9,13,14] Again, eGFR was lower in the belatacept arms, but the functional decline from months 3 to 12 was similar.

In protocol biopsies at month 12, the incidence of chronic allograft nephropathy was lowest in the belatacept groups, both in BENEFIT (18% MI, 24% LI, 32% cyclosporine)[8] as well as in BENEFIT-EXT (45% MI, 46% LI, 52% cyclosporine).[9] This may be explained by the significantly less pronounced development of donor-specific antibodies in the belatacept groups (BENEFIT Year 7: 1.9% MI, 4.6% LI, 17.8% cyclosporine; BENEFIT-EXT Year 3: 7% MI, 6% LI, 15% cyclosporine).[14,15] Furthermore, it is possible that the improvement in cardiovascular risk factors, e.g. better blood pressure control, led to a better function of the graft. Last but not least, CsA has been accused of direct and indirect nephrotoxicity.

In BENEFIT and BENEFIT-EXT, a higher risk for the development of PTLD was reported in patients that were EBV seronegative at baseline (BENEFIT year 7: 3 MI, 2 LI, 2 CsA, BENEFIT-EXT year 5: 2 MI, 6 LI, 1 CsA).[13–16]

In the 7-year follow-up of patients included in BENEFIT (n= 447), a 43% reduction in risk of death or graft loss for both belatacept regimens compared with CsA was observed (rate of death or graft loss: 12.7% MI, 12.8% LI, 21.7% cyclosporine). In contrast, patients who had participated in BENEFIT-EXT revealed similar rates of death and graft loss after 5 years.

In both studies, the mean eGFR (in mL/min/1.73 m2) increased over the years, while it declined in the CsA regimen (BENEFIT Year 7: 70.4 MI, 72.1 LI, 44.9 cyclosporine; BENEFIT-EXT Year 5: 55.9 MI, 59.0 LI, 44.6 cyclosporine).[13,15]

Switching Trials

A randomized multicentre phase II study (n = 173) investigated whether belatacept might be a treatment option for patients on a CNI-based [CsA or tacrolimus (TAC)] maintenance therapy.[10] Patients were switched to belatacept between months 6 and 36 following transplantation, the control group continued the CNI treatment. At month 12, the renal function was higher in the belatacept-treated patients compared with the CNI group (mean eGFR in mL/min/1.72 m2: 60.5 belatacept, 56.5 CNI; increase from baseline in mL/min/1.72 m2: 7.0 belatacept, 2.1 CNI). The main part of eGFR improvement was directly after the switch, but the eGFR further continued to increase during the follow-up period.

There was a higher rate of acute rejections with belatacept (7% belatacept, 0% CNI); however, all resolved without allograft loss. In the extended follow-up at 2 years (n = 162) the trend towards improved renal function continued (mean eGFR in mL/min/1.72 m2: 62.0 belatacept, 55.4 CNI; mean change from baseline: +8.8 belatacept, +0.3 CNI). At year 2, the frequency of acute rejection episodes was similar (5% belatacept, 4% CsA), there were no additional acute rejection episodes from month 6 to 24 in the belatacept group.[18] Patient survival, graft survival and the overall safety profile were similar. No case of PTLD was reported.[10,18]

A retrospective observational study with a follow-up over 2 years reported 25 cases [24 extended criteria donor (ECD) kidneys among them] of conversion from a CNI-based maintenance therapy to belatacept within the first 6 months after transplantation due to suspected nephrotoxicity, intolerance to CNIs or prolonged delayed graft function. At the time of conversion from CNI to belatacept, 13 of 25 patients displayed an eGFR <15 mL/min, including 7 patients on dialysis. In 19/25 patients, renal function improved with belatacept from eGFR 18.3 ± 12.3 to 35.6 ± 13.6 mL/min, while 3 did not recover renal function and 3 died. In this observation, one acute rejection was observed that completely recovered.[19]

Another small retrospective study presented successful conversion from TAC to belatacept in six highly sensitized patients with presumed CNI toxicity and/or interstitial fibrosis and tubular atrophy. A high immunological risk profile was defined as the presence of one or more of the following criteria: PRA >80%, re-transplant status, positive crossmatch and history of antibody-mediated rejection <3 months before switching. The renal function significantly improved within a mean follow-up of 16.5 months (eGFR in mL/min/1.72 m2: 23.8 ± 12.9 to 42 ± 12.5) and no new rejection occurred.[20]

First-line Treatment With Belatacept–Mycophenolate, Belatacept–Sirolimus Versus TAC–Mycophenolate (Phase II)

In a randomized controlled phase II study (n = 89) over 12 months, two belatacept-based regimens, belatacept–mycophenolate (MMF) and belatacept–sirolimus (SRL), were compared with a TAC–MMF-based steroid-avoiding regimen in adult recipients of living or standard criteria deceased donor grafts (Table 1).[11] The acute rejection rate was highest in the belatacept–MMF regimen (15% belatacept–MMF, 4% belatacept–SRL, 3% TAC–MMF). But the renal function was better in both belatacept regimens when compared with TAC–MMF (mean eGFR in mL/min/1.73 m2: 64 belatacept–MMF, 62 belatacept–SRL, 54 TAC–MMF). The overall safety was comparable between groups. No case of PTLD was reported.[11] The belatacept–SRL regimen was associated with a similar rejection rate and a better renal function when compared with TAC–MMF.

Alemtuzumab–Belatacept With or Without Donor Bone Marrow Transplantation

Another small clinical trial evaluated a regimen with alemtuzumab induction and maintenance belatacept and sirolimus without maintenance glucocorticoids in adult living donor kidney recipients (n = 20).[17] The patients were randomized 1:1 to receive or not receive unfractionated donor bone marrow. This regimen successfully prevented allograft rejection and preserved renal function (mean serum creatinine months 12 and 36: 1.1 mg/dL and 1.13 mg/dL; eGFR months 12 and 36: 89 mL/min and 88 mL/min) irrespective of bone marrow infusion. Alemtuzumab with depletion of lymphocytes resulted in a repertoire of lymphocytes with more naive T and B cells and fewer differentiated CD28 T cells and memory B cells, which are targeted by belatacept.[17]

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