Three-Year Outcomes From BENEFIT-EXT: A Phase III Study of Belatacept Versus Cyclosporine in Recipients of Extended Criteria Donor Kidneys
Abstract
Recipients of extended-criteria donor (ECD) kidneys have poorer long-term outcomes compared to standard-criteria donor kidney recipients. We report 3-year outcomes from a randomized, phase III study in recipients of de novo ECD kidneys (n = 543) assigned (1:1:1) to either a more intensive (MI) or less intensive (LI) belatacept regimen, or cyclosporine. Three hundred twenty-three patients completed treatment by year 3. Patient survival with a functioning graft was comparable between groups (80% in MI, 82% in LI, 80% in cyclosporine). Mean calculated GFR (cGFR) was 11 mL/min higher in belatacept-treated versus cyclosporine-treated patients (42.7 in MI, 42.2 in LI, 31.5 mL/min in cyclosporine). More cyclosporine-treated patients (44%) progressed to GFR <30 mL/min (chronic kidney disease [CKD] stage 4/5) than belatacept-treated patients (27–30%). Acute rejection rates were similar between groups. Posttransplant lymphoproliferative disorder (PTLD) occurrence was higher in belatacept-treated patients (two in MI, three in LI), most of which occurred during the first 18 months; four additional cases (3 in LI, 1 in cyclosporine) occurred after 3 years. Tuberculosis was reported in two MI, four LI and no cyclosporine patients. In conclusion, at 3 years after transplantation, immunosuppression with belatacept resulted in similar patient survival, graft survival and acute rejection, with better renal function compared with cyclosporine. As previously reported, PTLD and tuberculosis were the principal safety findings associated with belatacept in this study population.
Abbreviations:
-
- BENEFIT-EXT
-
- belatacept evaluation of nephroprotection and efficacy as first-line immunosupression trial-EXTended criteria donors
-
- CI
-
- confidence interval
-
- CNS
-
- central nervous system
-
- DCD
-
- donation after cardiac death
-
- ECD
-
- extended criteria donor
-
- LI
-
- less intensive
-
- MI
-
- more intensive
-
- PTLD
-
- posttransplant lymphoproliferative disorder
-
- UNOS
-
- United Network for Organ Sharing
Introduction
The use of extended criteria donor (ECDs) kidneys is becoming more common because of the increased number of patients awaiting transplant and the limitation of available standard criteria donor organs. Recipients of ECD kidneys are at increased risk for graft failure and have decreased life expectancy and poorer renal function compared with recipients of non-ECD kidneys (1–7). ECD recipients are also at increased risk for cardiovascular events and mortality compared with non-ECD recipients (3,4,7).
Calcineurin inhibitors provide excellent short-term outcomes for organ transplantation. Their intrinsic nephrotoxicity, however, contributes to declining renal function and graft fibrosis and may accelerate graft loss (8–10), although other mechanisms may also contribute to these outcomes (11). In addition, nonrenal toxicities of calcineurin inhibitors (i.e. diabetes, hypertension and hyperlipidemia) increase cardiovascular risk, which contributes to further impairment of renal function (12,13). Recipients of ECD kidneys, which by definition are of compromised tissue quality, are particularly vulnerable to the renal toxicities associated with calcineurin inhibitors (10,14–16). Therefore, immunosuppressive strategies that achieve similar rates of acute rejection, but avoid the nephrotoxicity of the calcineurin inhibitors may improve outcomes in recipients of ECD kidneys.
Belatacept, a first-in-class selective costimulation blocker that prevents T-cell activation, is designed to provide effective immunosuppression while avoiding both the renal and nonrenal toxicities associated with calcineurin inhibitors (17). Previously published results from two pivotal, phase III clinical trials assessing a more intensive (MI) and less intensive (LI) regimen of belatacept versus cyclosporine in adult kidney transplant recipients demonstrated that belatacept enabled avoidance of calcineurin inhibitors, resulting in similar rates of patient and graft survival, significantly better renal function and an improved cardiovascular/metabolic profile at both 1 and 2 years (18–20). There were more cases of posttransplant lymphoproliferative disorder (PTLD), primarily central nervous system (CNS) PTLD, in belatacept-treated patients, particularly in those who were seronegative for Epstein–Barr virus at the time of transplantation (18,20,21).
The BENEFIT-EXT study (Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosupression Trial-EXTended criteria donors) is the largest phase III trial to date conducted in de novo recipients of ECD kidneys. We report the longer term safety and efficacy from this 3-year study comparing belatacept to cyclosporine.
Methods
Study design
Details of the BENEFIT-EXT study design and primary results have been published (18). In brief, BENEFIT-EXT was a 3-year, multicenter, randomized, partially blinded, parallel-group study in de novo adult recipients of ECD renal allografts who were randomly assigned (1:1:1) to receive the MI belatacept regimen, the LI belatacept regimen, or cyclosporine (Figure 1). ECD for this trial was defined as donors aged ≥60-years old; donors aged 50–59 years and who had at least two other risk factors, including cerebrovascular accident, hypertension or serum creatinine >1.5 mg/dL (UNOS definition); plus patients with anticipated cold ischemia time (CIT) of ≥24 h; or donation after cardiac death (DCD). All patients received basiliximab induction (20 mg IV on days 1 and 5), mycophenolate mofetil (2 g/day in divided doses) and corticosteroids (tapered to ≥2.5 mg/day by day 15).
Patient disposition through year 3. Follow-up occurred after treatment discontinuation such that vital status was available for 99% of patients. Patient disposition at years 1 and 2 have been previously reported (17,18).
Outcomes
Primary outcomes were assessed at 12 months after transplantation (18). Outcomes assessed at 3 years included the proportion of patients surviving with a functioning graft, renal allograft function, acute rejection and overall safety. Patient and graft survival, graft loss and causes of graft loss and death were adjudicated by independent committees blinded to treatment assignment.
Renal function was assessed by calculated GFR (cGFR) using the MDRD equation (22,23) and the proportion of patients reaching a defined CKD stage at 3 years. These stages correspond with degrees of renal impairment, as defined by the kidney disease outcomes quality initiative for CKD stages, with cGFR <30 mL/min/1.73m2 considered to be advanced renal dysfunction (24). Given the association between advanced renal dysfunction and subsequent graft loss or death, a post hoc analysis assessing the time (Kaplan–Meier plot) to the first occurrence of cGFR <30 mL/min/1.73m2, graft loss or death was also performed.
The incidence and characteristics of protocol-defined acute rejection (clinically suspected, biopsy proven) were assessed as previously described (18). In brief, protocol-defined acute rejection included histologically confirmed rejection on the basis of protocol-defined reasons for clinical suspicion (such as increased serum creatinine, fever, tenderness of the graft or decreased urine output) or treated acute rejection with other reasons for clinical suspicion. The incidence of biopsy-proven acute rejection, defined as centrally adjudicated acute rejection on the basis of biopsies performed for any reason (including 12-month protocol biopsies), not just clinical suspicion, was also evaluated. Donor-specific antibodies were characterized as previously described (20). Finally, a post hoc analysis of biopsy-proven acute rejection, death, graft loss or lost to follow-up was performed to further characterize the combined effect of key outcomes.
Statistical analyses
All analyses at 3 years were conducted on the intent-to-treat population (ITT), defined as all randomized patients who received a transplant. Additional analyses were performed on the on-treatment population, defined as all randomized, transplanted patients who remained on assigned therapy. The proportion of patients surviving with a functioning graft up to year 3 was summarized using point estimates and the corresponding 95% confidence intervals (CI) within treatment groups and using two-sided 97.3% CI for the difference between each belatacept regimen and cyclosporine. Mean cGFR was calculated using an imputation method, (i.e. cGFR = 0 for missing GFR values because of death or graft loss) and two-sided 97.3% CI was used for the difference between each belatacept regimen and cyclosporine. A linear mixed model was used to analyze changes in cGFR over time for each belatacept regimen and cyclosporine with treatment group as a fixed effect and month as a random effect; population mean slopes were estimated for each treatment group. Safety was summarized using data up to 36 months. The median duration of exposure to belatacept was approximately 3.2 (MI)–3.4 years (LI) and for cyclosporine it was 3.0 years.
Results
Five hundred forty-three randomly assigned patients received an ECD kidney transplant (n = 184 MI; n = 175 LI; n = 184 cyclosporine) and comprised the ITT; 323 patients (n = 109 MI; n = 114 LI; n = 100 cyclosporine) remained on study treatment for 3 years (Figure 1). As previously reported, demographic and baseline characteristics were well balanced among treatment groups (18). Between years 1 and 3, cyclosporine trough levels were stable (mean ∼140–160 ng/mL) and within the protocol-specified range of 100–250 ng/mL from day 5 to year 3.
On average, the percentage of patients with cyclosporine trough values between 100 ng/mL and 250 ng/mL after month 12 exceeded 70%. When trough levels occurred outside the protocol-specified range, the tendency was for more patients to have trough values lower than the protocol-specified range (>20%), whereas the proportion of patients with trough levels >250 ng/mL ranged from approximately 5% to 10%.
Most discontinuations from treatment occurred during the first year (27% MI, 26% LI and 30% cyclosporine; Ref. 17). The cumulative discontinuation rate remained lowest in the belatacept LI group (35%) through year 3, compared with the belatacept MI group (40%) and the cyclosporine group (44%). The main reason for discontinuation in all treatment groups was adverse events (Figure 1).
Patient and graft survival
Outcomes on vital status (patient and graft survival) were available for all but one belatacept MI, one belatacept LI and five cyclosporine patients, all of whom were lost to follow-up. In the intent-to-treat analysis, the proportion of patients surviving with a functioning graft at 3 years was 80% (95% CI 74.7–86.2), 82% (76.6–87.9) and 80% (74.1–85.7) in the MI, LI and cyclosporine groups, respectively. By year 3, graft loss (death-censored) occurred in 18 (9.8%) patients in the MI group, 21 (12.0%) in the LI group and 23 (12.5%) in the cyclosporine group. Most graft losses occurred in the first 12 months. By year 3, 22 (12.0%) patients in the MI group, 15 (8.6%) in the LI group and 17 (9.2%) in the cyclosporine group died. The most common cause of death in all groups was infections. The on-treatment analysis showed comparable rates of patient and graft survival across treatment groups (data not shown).
Renal function
As was observed at months 12 and 24 (18,19), cGFR was higher in belatacept-treated patients than in cyclosporine-treated patients by year 3, with a mean estimated difference of 11 mL/min for both belatacept groups versus the cyclosporine group. Mean cGFR over time is shown in Figure 2. At 3 years, mean cGFR (±SD) in the ITT was 42.7 ± 27.6 mL/min/1.73m2 (MI), 42.2 ± 25.2 mL/min/1.73m2 (LI) and 31.5 ± 22.1 mL/min/1.73m2 (cyclosporine). The on-treatment analysis also demonstrated sustained improvements in renal function at 3 years, with estimated differences ranging from 12 mL/min/1.73m2 to 13 mL/min/1.73m2: 55.7 ± 17.2 mL/min/1.73m2 (MI), 54.8 ± 14.3 mL/min/1.73m2 (LI) and 42.5 ± 15.3 mL/min/1.73m2 (cyclosporine). The slope of the cGFR curves from 3 months to 36 months in the ITT showed a lower rate of decline in the belatacept groups (MI: –0.9 mL/min/1.73m2/year, 95% CI: –1.94, 0.23; LI; –0.6 mL/min/1.73m2/year LI-95% CI: –1.68, 0.48), compared with cyclosporine (–1.9 mL/min/1.73m2/year, 95% CI: –2.94, –0.77).
Calculated GFR (95% CI) over time: intent-to-treat population. Mean calculated GFR (cGFR; 95% CI) over time in the ITT population (with imputation for missing values (i.e. patients with graft loss or death; GFR=0). cGFR was calculated using the modification of diet in renal disease (MDRD; Ref. 21,22). At month 36, a total of 449 of 543 patients (83%) had a GFR value; 351 patients had a serum creatinine value to assess cGFR: 118 (64.1%) in the belatacept MI group; 124 (70.9%) in belatacept LI group; and 109 (59.2%) in cyclosporine group; and 98 patients were imputed (GFR=0) for death or graft loss: 34 (18.5%) belatacept MI patients; 30 (17.1%) belatacept LI patients; and 34 (18.5%) cyclosporine patients. Missing GFRs because of other reasons were not imputed.
CKD stages at month 36: Compared with cyclosporine, both belatacept regimens had more patients with cGFR values within CKD stages 1 and 2 (31% MI and 22% LI vs. 8% cyclosporine) and fewer patients within stages 4 and 5 (30% MI and 27% LI vs. 44% cyclosporine; Figure 3). Results from the post hoc analysis of the time to progression of cGFR <30 mL/min/1.73m2, graft loss or death demonstrated separation of both belatacept groups from cyclosporine beginning at month 3 and increasing over time, with 50% of cyclosporine-treated patients versus 25% of belatacept-treated patients meeting this endpoint by year 3 (Figure 4). The primary determinant of the difference between belatacept and cyclosporine was the number of patients with cGFR <30 mL/min/1.73m2.
Chronic kidney disease stages (renal function) at 3 years. Percentage of patients at chronic kidney disease stages (renal function) at 3 years (with imputation for missing values [i.e. patients with graft loss or death] GFR =0). stage 1: cGFR ≥ 90; stage 2: 60 ≤ cGFR < 90; stage 3: 30 ≤ cGFR < 60; stage 4: 15 ≤ cGFR < 30; stage 5: cGFR < 15 or dialysis (cGFR measured in mL/min/1.73m2).
Estimated time to cGFR<30 mL/min/1.73m2, graft loss or death through year 3.
Acute rejection
One patient in each treatment group experienced an acute rejection episode after year 2. By 3 years, the rate of acute rejection was 18% for MI, 19% for LI and 16% for cyclosporine. The rate of biopsy-proven acute rejection (which included subclinical acute rejection detected on protocol biopsies at 12 months in addition to the clinically suspected acute rejection) through year 3 was 22% (MI), 24% (LI) and 23% (cyclosporine). By 3 years, the proportion of patients who experienced the composite endpoint of biopsy-proven acute rejection, death, graft loss or lost to follow-up was 38%, 36% and 37% for belatacept MI, belatacept LI and cyclosporine, respectively.
At baseline, the presence of donor-specific antibodies was similar and low across treatment groups (6% MI, 5% LI and 8% cyclosporine). Incremental increase in donor-specific antibodies was observed with lower frequency in belatacept-treated versus cyclosporine-treated patients by year 3 (7% in MI, 6% in LI, 15% in cyclosporine). Among patients who experienced a rejection episode, the frequency of donor-specific antibodies was higher in the cyclosporine group (26%) than in the belatacept MI (9%) or LI (6%) groups; in patients without acute rejection, the frequency of donor-specific antibodies was 13%, 7% and 7%, respectively.
Outcomes by donor type
The protocol-specified definition of ECD encompassed the UNOS definition of ECD (25) as well as additional criteria, including CIT ≥24 h and DCD. Therefore, outcomes were analyzed by these donor subtypes. The results of the subgroup analyses were generally consistent with the overall ITT findings (Table 1). The number of patients in the CIT ≥24 h and DCD subgroups, however, was small and therefore needs to be interpreted with caution. Of note, many ECD with CIT ≥24-h and DCD also met UNOS-defined criteria.
| Belatacept MI | Belatacept LI | Cyclosporine | |
|---|---|---|---|
| (n = 184) | (n = 175) | (n = 184) | |
| Patient/graft survival, n (%; overall) | 148 (80) | 144 (82) | 147 (80) |
| UNOS ECD (a) | 103 (80) | 97 (80) | 103 (77) |
| CIT ≥24 h (a) | 39 (78) | 46 (81) | 40 (78) |
| DCD (a) | 14 (78) | 19 (100) | 13 (72) |
| Mean cGFR, mL/min/1.73m2 (overall) | 43 | 42 | 32 |
| UNOS ECD (b) | 40 | 39 | 27 |
| CIT ≥24 h (b) | 45 | 44 | 38 |
| DCD (b) | 41 | 56 | 27 |
| Acute rejection through year 3, n (%; (overall) | 33 (18) | 33 (19) | 29 (16) |
| UNOS ECD (a) | 26 (20) | 26 (21) | 20 (15) |
| CIT ≥24 h (a) | 6 (12) | 10 (18) | 8 (16) |
| DCD (a) | 2 (11) | 4 (21) | 4 (22) |
- UNOS ECD = United Network for Organ Sharing Extended Criteria Donor; CIT = cold ischemia time; DCD = donation after cardiac death.
- 1The number of patients in each treatment donor subtype group are given below in footnotes (a) for patient/graft survival and acute rejection and (b) for GFR:
- (a) UNOS ECD: n = 129 (MI), n = 122 (LI), n = 133 (cyclosporine); CIT ≥ 24 h: n = 50 (MI), n = 57 (LI), n = 51 (cyclosporine); DCD: n = 18 (MI), n = 19 (LI), n = 18 (cyclosporine) for outcomes of patient/graft survival and acute rejection.
- (b) UNOS ECD: n = 107 (MI), n = 108 (LI), n = 100 (cyclosporine); CIT ≥ 24 h: n = 42 (MI), n = 49 (LI), n = 46 (cyclosporine); DCD: n = 13 (MI), n = 17 (LI), n = 14 (cyclosporine) for mean cGFR.
Cardiovascular and metabolic endpoints
Similar to the trends observed at both 1 and 2 years, mean systolic and diastolic blood pressures at year 3 were lower (about 6 mmHg and 2 mmHg, respectively) in the belatacept groups versus the cyclosporine group. Furthermore, somewhat fewer belatacept-treated patients used multiple (≥3) antihypertensive medications (41–46%) compared with cyclosporine-treated patients (55%). There were no significant differences across treatment groups in the total, non-HDL, HDL and LDL cholesterol and triglyceride levels. The proportion of patients using lipid-lowering drugs was somewhat lower in belatacept-treated (46–52%) versus cyclosporine-treated (61%) patients. These data should be interpreted with caution, however, because about 50% of the ITT population did not have lipid measurements at year 3. The incidence of new-onset diabetes after transplant was numerically lower in the belatacept MI group (5%) compared with the belatacept LI (10%) and cyclosporine (9%) groups.
Safety
The overall safety profile of belatacept at 3 years was consistent with that observed at both 1 and 2 years (18,21). By year 3, 22 (12.0%), 15 (8.6%) and 17 (9.2%) patients died in the MI, LI and cyclosporine groups, respectively. Adverse events occurred with a similar frequency across treatment groups (98.9–100%), the most common of which included anemia, graft dysfunction, urinary tract infection, diarrhea, constipation, peripheral edema, pyrexia and hypertension. Nausea and leukopenia were more frequently reported in the belatacept MI and cyclosporine groups and vomiting was more common in the belatacept LI group. The overall frequency of serious adverse events was similar among treatment groups (81% MI, 79% LI and 79% cyclosporine). The most common serious adverse events included urinary tract infection (10.3% in MI, 12.6% in LI, 9.8% in cyclosporine) and cytomegalovirus (9.2% in MI, 9.1% in LI, 6.5% in cyclosporine).
The overall rates of malignancies were similar across treatment groups and remained low over time (9% in MI, 9% in LI, 10% in cyclosporine). The most common malignancies are shown in Table 2. By 3 years, PTLD was reported in two MI and three LI patients; four cases involved the CNS and one case (LI) involved the renal allograft and lymph nodes. Four additional cases of PTLD (three LI and one cyclosporine) occurred after 3 years; one case involved the CNS (LI), one involved the renal allograft (LI), one involved the gastrointestinal tract (LI) and the other involved bone marrow (cyclosporine). Seven of the nine patients with PTLD (two MI, four LI, one cyclosporine) died.
| n (%) | Belatacept MI (n = 184) | Belatacept LI (n = 175) | Cyclosporine (n = 184) |
|---|---|---|---|
| All malignancies | 16 (8.7) | 15 (8.6) | 19 (10.3) |
| PTLD1 | 2 (1.1) | 3 (1.7) | 0 |
| Most common malignancies2 | |||
| Basal cell carcinoma | 5 (2.7) | 2 (1.1) | 6 (3.3) |
| Squamous cell carcinoma of skin | 5 (2.7) | 1 (0.6) | 4 (2.2) |
| Kaposi's sarcoma | 1 (0.5) | 1 (0.6) | 3 (1.6) |
| Prostate | 0 | 3 (1.7) | 0 |
| Viral infections | 73 (39.7) | 68 (38.9) | 70 (38.0) |
| Cytomegalovirus infections | 32 (17.4) | 27 (15.4) | 31 (16.8) |
| BK polyomavirus | 12 (6.5) | 7 (4.0) | 9 (4.9) |
| Polyomavirus-associated nephropathy | 5 (2.7) | 2 (1.1) | 2 (1.1) |
| BK virus infection | 4 (2.2) | 3 (1.7) | 4 (2.2) |
| Polyomavirus test positive | 3 (1.6) | 1 (0.6) | 3 (1.6) |
| Human polyomavirus infection | 1 (0.5) | 1 (0.6) | 1 (0.5) |
| Progressive multifocal leukoencephalopathy | 1 (0.5) | 0 | 0 |
| Herpes infections | 32 (17.4) | 29 (16.6) | 25 (13.6) |
| Herpes zoster | 21 (11.4) | 11 (6.3) | 9 (4.9) |
| Oral herpes | 7 (3.8) | 12 (6.9) | 7 (3.8) |
| Herpes virus infection | 3 (1.6) | 2 (1.1) | 5 (2.7) |
| Genital herpes | 3 (1.6) | 2 (1.1) | 4 (2.2) |
| Herpes simplex | 2 (1.1) | 3 (1.7) | 3 (1.6) |
| Fungal infections | 45 (24.5) | 24 (13.7) | 43 (23.4) |
| Oral candidiasis | 11 (6.0) | 7 (4.0) | 12 (6.5) |
| Onchomycosis | 8 (4.3) | 1 (0.6) | 3 (1.6) |
| Candidiasis | 7 (3.8) | 2 (1.1) | 6 (3.3) |
| Fungal infection | 6 (3.3) | 4 (2.3) | 8 (4.3) |
| Tinea versicolour | 2 (1.1) | 3 (1.7) | 7 (3.8) |
| Tuberculosis | 2 (1.1) | 4 (2.3) | 0 |
- 1After 3 years, three additional cases of PTLD were reported in the belatacept LI group and 1 was reported in the cyclosporine group. EBV-negative serostatus at the time of transplantation was strongly associated with PTLD in the belatacept clinical trials (17,19,20).
- 2Malignancies occurring in ≥2 patients in any treatment group, reported by MedDRA preferred terms; “PTLD” includes multiple individual terms, including “EBV-associated PTLD”, “B-cell lymphoma”, “CNS lymphoma” and “lymphoma”.
Infections were observed with similar frequency across treatment groups by 3 years (79% in MI, 82% in LI, 82% in cyclosporine). The most common infections included urinary tract infections, nasopharyngitis and cytomegalovirus infections. Serious infections were observed in 48% (MI), 41% (LI) and 46% (cyclosporine) of patients and included urinary tract and cytomegalovirus infections and pyelonephritis. The frequency of viral and fungal infections decreased over time in all treatment groups and by year 3 the reported incidence of cytomegalovirus, polyomavirus and herpes was comparable across treatment groups (Table 2). There were more cases of tuberculosis reported in belatacept-treated patients (1.1% in MI, 2.3% in LI and 0% in cyclosporine), most of which occurred in endemic areas (n = 4 Brazil; n = 2 France).
Discussion
The BENEFIT-EXT study is the largest multicenter, randomized phase III trial conducted to evaluate outcomes in transplant recipients of ECD kidneys. The longer term results from BENEFIT-EXT demonstrated similar rates of patient survival, graft survival and acute rejection between treatment groups with no new safety signals at 3 years posttransplant. Our findings show that the higher GFR in belatacept-treated versus cyclosporine-treated patients seen at years 1 and 2 (18,19) were not only maintained by 3 years after transplant, but showed a widening difference over time: 8 mL/min at 12 months, 8–10 mL/min at 24 months and 11 mL/min at 36 months. Belatacept-treated patients showed less decline in renal function over time, which may provide additional years of allograft longevity in ECD recipients.
The impact of the renal-sparing effects of belatacept on critical patient outcomes was further demonstrated in the post hoc analysis of time to renal failure (cGFR < 30 mL/min), death or graft loss. The survival curves demonstrated a marked advantage for patients receiving belatacept, driven primarily by more rapid progression to advanced renal insufficiency in cyclosporine-treated patients. These results are consistent with long-term data from a phase II trial of belatacept in kidney transplant recipients as well as the phase III data in living and standard criteria donor kidneys (19,20,26). Collectively, these data demonstrate that preservation of renal function translates into a clinically meaningful difference in the rate of progression to CKD stages 4 or 5 and potential avoidance of the mounting morbidity and mortality that accompanies advanced renal failure. On the basis of a validated graft survival prediction model that included various donor/recipient characteristics, cGFR and acute rejection at 3 years posttransplant in the BENEFIT-EXT trial (27), the projected median survival with graft function was 9 years and 9 months for belatacept LI patients compared to 7 years and 11 months for cyclosporine patients, a difference of 22 months (28; see also Supporting Information). The utility of renal function as a predictor for renal allograft loss has been previously questioned by some (30) and supported by others (14,31,32). We acknowledge the limitations inherent in any study based on projections in the absence of long-term data.
Although rates of acute rejection in the BENEFIT study were higher in belatacept-treated patients compared with cyclosporine-treated patients (19,20), the acute rejection rates in this study were comparable among treatment groups throughout the entire 3-year study period. Most events occurred early and generally did not recur. A lower incidence of donor-specific antibodies was observed in belatacept-treated patients, regardless of rejection status.
These findings are especially important in view of recent publications highlighting the compromised outcomes in patients receiving kidneys from suboptimal donors. In a recent cohort analysis of outcomes among 9134 recipients of cardiac-death and brain-death donor kidneys, donor age ≥60 years was identified as a risk factor for graft failure and reduced long-term renal function. Summers et al. found that graft survival and renal function decrease as the age of the donor increases, with recipients of these ECD kidneys having twice the risk of graft failure compared with recipients of younger donor kidneys (33). Pascual et al. performed a comprehensive systematic review of kidney transplants from ECDs and concluded that management protocols for this patient population need to be based on nephron-protecting strategies (34). These reports further underscore the importance of the 3-year findings from BENEFIT-EXT, which suggest that belatacept may better preserve renal function for recipients of ECD kidneys.
Limitations of this study include the reduced or imbalanced participation in the cyclosporine group at 3 years. More belatacept patients remained on-therapy at 3 years than did cyclosporine-treated patients, which may limit interpretation and extrapolation of data. However, data collection on patient and graft survival was available for 99% of patients at 3 years, providing added reassurance on the robustness of the data and the durability of results from year 1 to year 3. A second limitation of the study is the potential underestimation of subclinical rejection because protocol biopsies were only required at year 1. Finally, the study was conducted using cyclosporine as the comparator, which was standard at the time the study was initiated and the data may not necessarily be extrapolated to other calcineurin inhibitors.
In conclusion, the 3-year results from this study demonstrated comparable patient and graft survival, sustained improvements in renal function over time, with no new safety issues identified in patients receiving belatacept. The consistency and durability of preservation of renal function at 3 years after transplantation suggest that these higher risk donor organs may be used more efficaciously. To our knowledge, this is the first study to demonstrate a persistent benefit in renal function in a population of patients receiving high-risk transplanted kidneys.
Acknowledgments
The BENEFIT-EXT study was supported by Bristol–Myers Squibb and is registered with ClinicalTrials.gov (ID: NCT00114777). The authors thank Elizabeth Proszynski for protocol management and Susan A. Nastasee for medical writing and editorial assistance; both are employees of Bristol–Myers Squibb.
Funding source: This study was sponsored by Bristol–Myers Squibb.
Disclosure
The authors of this manuscript have conflicts of interest to disclose as described by the American Journal of Transplantation. YV has been an advisory board member for Astellas; TB has received honoraria for advisory board membership meetings and has received compensation for travel expenses for presentation at scientific congresses from Bristol–Myers Squibb; JC has received compensation for consultancy and advisory board membership for Astellas, Novartis and Pfizer; SF and his institution have received support from Bristol–Myers Squibb for clinical trial research; NK has received honoraria from Astellas, Genzyme, Novartis, Pfizer and Roche and received compensation for consultancy from Novartis; PL's institution has received research grants from Bristol–Myers Squibb; RCM and his institution have received support from Bristol–Myers Squibb for clinical trial research; PM and his institution have received support from Bristol–Myers Squibb for clinical trial research; MDCR has received fees for expert testimony from Astellas, Bristol–Myers Squibb, Novartis and Pfizer/Wyeth and Roche and has received payment for development of educational presentations from Novartis and Pfizer/Wyeth; MS has received a grant for a research study and compensation for consultancy from Bristol–Myers Squibb; SV has received compensation from Bristol–Myers Squibb for advisory board membership; TD, AB and MBH are employees of Bristol–Myers Squibb and MBH and holds stock options; AD has received support from Bristol–Myers Squibb for data monitoring and for travel expenses related to scientific congresses and his spouse is an employee of Bristol–Myers Squibb. There are no other conflicts of interest to disclose.
