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Keywords:

  • Belatacept;
  • cyclosporine;
  • extended criteria donor;
  • kidney;
  • renal function

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References
  9. Supporting Information

Recipients of extended criteria donor (ECD) kidneys are at increased risk for graft dysfunction/loss, and may benefit from immunosuppression that avoids calcineurin inhibitor (CNI) nephrotoxicity. Belatacept, a selective costimulation blocker, may preserve renal function and improve long-term outcomes versus CNIs. BENEFIT-EXT (Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial—EXTended criteria donors) is a 3-year, Phase III study that assessed a more (MI) or less intensive (LI) regimen of belatacept versus cyclosporine in adult ECD kidney transplant recipients. The coprimary endpoints at 12 months were composite patient/graft survival and a composite renal impairment endpoint. Patient/graft survival with belatacept was similar to cyclosporine (86% MI, 89% LI, 85% cyclosporine) at 12 months. Fewer belatacept patients reached the composite renal impairment endpoint versus cyclosporine (71% MI, 77% LI, 85% cyclosporine; p = 0.002 MI vs. cyclosporine; p = 0.06 LI vs. cyclosporine). The mean measured glomerular filtration rate was 4–7 mL/min higher on belatacept versus cyclosporine (p = 0.008 MI vs. cyclosporine; p = 0.1039 LI vs. cyclosporine), and the overall cardiovascular/metabolic profile was better on belatacept versus cyclosporine. The incidence of acute rejection was similar across groups (18% MI; 18% LI; 14% cyclosporine). Overall rates of infection and malignancy were similar between groups; however, more cases of posttransplant lymphoproliferative disorder (PTLD) occurred in the CNS on belatacept. ECD kidney transplant recipients treated with belatacept-based immunosuppression achieved similar patient/graft survival, better renal function, had an increased incidence of PTLD, and exhibited improvement in the cardiovascular/metabolic risk profile versus cyclosporine-treated patients.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References
  9. Supporting Information

Kidney transplantation is the treatment of choice for selected patients with ESRD and is associated with improved patient survival and quality of life compared with dialysis (1,2), but the waiting list for renal transplantation is larger than the availability of organs. Because of the growing discrepancy between kidney supply and demand, there is tremendous pressure to utilize all available kidneys for transplantation, many of which come from extended criteria donors. The definition of extended criteria donor varies by country, but usually includes older donors and donors with health issues that increase risk of graft loss or dysfunction (3). This is reflected in lower 1-year allograft survival rates for extended criteria donor kidneys versus nonextended criteria donors deceased donor kidney transplants (4), and allograft survival declines even further over time, primarily due to chronic allograft injury (5).

In addition, extended criteria donor transplant recipients are challenging to immunosuppress, as they tend to be older and are at increased risk for cardiovascular events and mortality compared with nonextended criteria donor recipients (6–8). Although calcineurin inhibitors remain a cornerstone of immunosuppression, they are nephrotoxic and exacerbate cardiovascular and metabolic risk factors that can limit graft and patient survival. Furthermore, kidneys from extended criteria donors are more susceptible to the adverse effects of calcineurin inhibitors (9). Impaired kidney function at 1 year is associated with reduced long-term graft survival (10–12) and is an independent cardiovascular risk factor (12). Immunosuppressive regimens that avoid the renal and nonrenal toxicities of calcineurin inhibitors may make extended criteria donor transplants more attractive, might improve long-term patient and graft survival and could enable more patients to benefit from transplantation (13).

Belatacept is a first-in-class costimulation blocker that selectively blocks T-cell activation (14). A Phase II study demonstrated that belatacept-based regimens were associated with a similar incidence of acute rejection and better renal function and structure compared with a cyclosporine-based regimen (15).

The Phase II study results suggested that belatacept-based regimens could provide adequate immunosuppressive efficacy while avoiding the renal toxicity associated with calcineurin inhibitors and the chronic nonrenal effects of calcineurin inhibitors that can negatively impact patient/graft survival. Thus, the objective of this global Phase III study, the largest conducted to date in an extended criteria donor patient population, was to assess whether treatment with belatacept would result in similar patient/graft survival and superior renal function versus cyclosporine in patients receiving an extended criteria donor kidney transplant. The study endpoints also included cardiovascular/metabolic assessments, and the incidence of chronic allograft nephropathy and of acute rejection episodes. The study was prospectively designed to continue beyond the 12-month primary endpoint reported here, to a total of 3 years, to assess longer-term efficacy and safety of the belatacept-based regimens.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References
  9. Supporting Information

BENEFIT-EXT (Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial—EXTended criteria donors) is a 3-year, randomized, multicenter study in adult patients who received a kidney transplant from an extended criteria donor. Primary outcomes were assessed at 12 months posttransplant. The study, which started in March 2005, is still ongoing at 79 centers worldwide. A data and safety monitoring board assessed cumulative safety and efficacy data on a regular basis throughout the trial. The study was conducted in accordance with the ethical principles that have their origin in the current Declaration of Helsinki, and was consistent with International Conference on Harmonization Good Clinical Practice and applicable regulatory requirements. The study protocol and any amendments were reviewed and approved by the Institutional Review Board/Independent Ethics Committee for each site prior to initiation of the study. This trial is registered with ClinicalTrials.gov (id: NCT00114777).

Patients

BENEFIT-EXT included men and women ages 18 and older receiving an extended criteria donor kidney transplant. The definition of extended criteria donor was as follows: donors ≥60 years old; or donors ≥50 years old and who had at least two other risk factors (cerebrovascular accident, hypertension or serum creatinine >1.5 mg/dL); or an anticipated cold ischemia time of ≥24 h; or donation after cardiac death. All patients signed informed consent.

Interventions

Patients were randomized 1:1:1, using an interactive voice response system and stratified by study site, to receive a more intensive (MI) regimen of belatacept, a less intensive (LI) regimen of belatacept or cyclosporine for primary maintenance immunosuppression (Figure 1). The study was blinded to patients and study personnel with respect to belatacept dose regimen assignment and open-label with respect to allocation to belatacept or cyclosporine, primarily due to the need for therapeutic dose monitoring in cyclosporine-treated patients. Each patient was treated with basiliximab induction (20 mg i.v. on Day 1 and Day 5), mycophenolate mofetil (2 g/day p.o. in divided doses) and corticosteroids (tapered ≥2.5 mg/day). T-cell depleting therapy was permitted for anticipated delayed graft function (DGF) in cyclosporine patients only, and for the treatment of rejection in both belatacept and cyclosporine patients.

image

Figure 1. Patient disposition.

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Patients with acute rejection ≤Grade IIA (Banff’97 classification) (16) were treated with pulses of methylprednisolone, whereas patients with acute rejection ≥Grade IIB could be treated with T-cell-depleting therapy at the investigator's discretion. Antiviral prophylaxis was recommended to all patients for at least 3 months posttransplant, and for 3 months upon initiating T-cell-depleting agents, as well as 6 months of prophylaxis against pneumocystis.

Outcomes

The primary objectives of the BENEFIT-EXT study were to assess each belatacept-based regimen compared with the cyclosporine-based regimen on two primary outcomes at 12 months: (1) composite patient and graft survival and (2) composite renal impairment. Causes of graft loss and death were adjudicated by committees blinded to the patient assignments. The composite renal impairment endpoint was defined as the percent of patients exhibiting a measured glomerular filtration rate <60 mL/min/1.73 m2 at Month 12, or a decrease in measured glomerular filtration rate ≥10 mL/min/1.73 m2 from Month 3 to Month 12. The measured glomerular filtration rate was assessed by measuring clearance of subcutaneously administered cold iothalamate (17).

Secondary outcomes

Secondary outcomes at Month 12 included measured glomerular filtration rate, calculated glomerular filtration rate using the modification of diet in renal disease (MDRD) equation (18,19), prevalence of biopsy-proven chronic allograft nephropathy (Banff ’97 classification) (16) and incidence and severity of clinically suspected, biopsy-proven acute rejection at Months 6 and 12. The incidence and severity of acute rejection was utilized as a secondary outcome in BENEFIT-EXT because of concern that the increased incidence of anticipated DGF would skew acute rejection rates and confound comparison of belatacept and cyclosporine, because cyclosporine patients, and not belatacept patients, could receive lymphocyte-depleting therapy for DGF. Scheduled (protocol) allograft biopsies were performed at implantation and Week 52. In addition, biopsies were performed in patients with clinical suspicion of acute rejection defined as unexplained rise of serum creatinine ≥25% from baseline, unexplained decrease in urine output, fever and graft tenderness or serum creatinine that remained elevated within 14 days posttransplantation. The diagnosis and grade of acute rejection was confirmed by a central pathologist blinded to the patient assignments. The decision to treat acute rejection was based on the local biopsy reading. Cardiovascular and metabolic endpoints at Month 12 included mean systolic and diastolic blood pressure, the incidence of new-onset diabetes after transplantation (NODAT) and mean changes in serum lipids. Patients were determined to have NODAT if they received an antidiabetic medication for ≥30 days, or had ≥2 fasting plasma glucose tests ≥126 mg/dL. The primary dyslipidemia assessment was the change in non-high-density lipoprotein (non-HDL) cholesterol (total cholesterol minus HDL cholesterol) from baseline to Month 12. Intensity of medication use for the treatment of hypertension and hyperlipidemia was also assessed. Patients were assessed for DGF by determining whether they had been treated with dialysis within the first week posttransplantation.

Statistical methods

All analyses were conducted on the intent-to-treat (ITT) population, which was defined as randomized patients who received a transplant. A sequential testing procedure was employed for testing the coprimary and key secondary hypotheses (20), and the testing hierarchy was as follows: (1) patient and graft survival at 12 months using a 10% noninferiority margin, (2) the superiority test of the composite renal impairment endpoint at 12 months and (3) the superiority test on chronic allograft nephropathy at 12 months. A primary measure was tested between a particular belatacept arm and the cyclosporine arm only if the test between that belatacept arm and the cyclosporine arm was statistically significant in favor of the belatacept arm for all preceding measures. To account for multiple comparisons, the nominal Type I error rate was set at 2.7% (two-sided) for each belatacept treatment arm versus the cyclosporine arm, and at 5% overall for the entire study.

Primary efficacy outcomes were assessed between treatment groups using 97.3% confidence intervals. For composite patient/graft survival, if the lower bound of the confidence interval (belatacept–cyclosporine) was >−10%, then the corresponding belatacept regimen was considered as noninferior to cyclosporine. The 10% noninferiority margin for composite patient/graft survival was chosen based on precedent in other trials of tacrolimus and mycophenolate (21,22). For the coprimary composite renal impairment endpoint, a continuity-corrected chi-square test was performed to assess the difference between each belatacept regimen and cyclosporine regimen. Imputation methodology for missing data in both primary outcomes is listed in the supporting information.

Measured glomerular filtration rate at Month 12 was analyzed using an ANOVA model with factor for treatment to assess the difference between each of the belatacept treatment groups and cyclosporine. The prevalence of chronic allograft nephropathy at 12 months was summarized between treatment groups using point estimates and 97.3% confidence intervals. In addition, a continuity corrected chi-square test was performed to assess the difference between each belatacept regimen and cyclosporine treatment. The analyses of chronic allograft nephropathy used biopsies that were obtained at 12 months, together with the imputed information for missing assessments on the basis of available biopsy information and graft function. Acute rejection was assessed by generating 97.3% confidence intervals, and if the upper bound of the confidence interval (belatacept–cyclosporine) was <20%, then the corresponding belatacept regimen was considered as noninferior to cyclosporine.

The 20% noninferiority margin for acute rejection was based on an estimate of the smallest effect size of cyclosporine from several studies (23–25). Based on these available clinical data, selection of a 20% noninferiority margin preserves approximately 50% of the estimated cyclosporine effect and is not greater than the estimated smallest effect size of cyclosporine used with similar background therapy.

Sample size

Assuming the true subject and graft survival rate is 80% for the cyclosporine regimen and 83% for each belatacept regimen at 12 months, a sample size of 180 subjects per arm would be required to detect a noninferiority margin of 10% between each belatacept regimen and the cyclosporine regimen with 83% power, and ensures that the absolute rate of subject and graft survival could not differ between belatacept and cyclosporine by more than 0.5% and still satisfy the noninferiority margin. For the renal function endpoint, 180 subjects per group will afford 98% power to detect a decrease of 25% in the proportion of subjects meeting the composite renal endpoint for each belatacept regimen compared to the cyclosporine regimen, assuming 75% of cyclosporine subjects meet this endpoint with 25% dropouts per group. Overall, a sample size of 180 patients per treatment group would have an 80% power to detect one belatacept regimen that met all coprimary endpoints with overall Type I error controlled at the 0.05 significance level (Dunnett adjustment for multiplicity).

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References
  9. Supporting Information

Characteristics and disposition of patients

A total of 578 patients were randomized; 543 of these patients were transplanted (n = 184 belatacept MI; n = 175 belatacept LI; n = 184 cyclosporine) and comprised the ITT efficacy population (Figure 1). Of the patients who discontinued study drug, 20/50 patients in the MI group, 17/45 in the LI group and 17/54 in the cyclosporine group were switched to tacrolimus.

Demographic characteristics among recipient treatment groups were balanced at baseline (Table 1). The mean donor age was 56.2 years. The primary cause of donor mortality was cerebrovascular accident (69.8%). The mean cold ischemia time was 20 h. Across all treatment groups, donors were classified as follows: age ≥60 (49%), age 50–59 with ≥2 other risk factors (22%), anticipated cold ischemia time ≥24 h (42%) and donor with cardiac death (10%). Donors could qualify under more than one extended criteria donor category. The percentage of patients with DGF was similar between groups (MI: 47%; LI: 47%; cyclosporine: 49%), as was the prevalence of CAN (interstitial fibrosis/tubular atrophy) at baseline (MI: 7%; LI: 9%; cyclosporine: 10%).

Table 1.  Demographic and baseline characteristics
Recipient characteristicBelatacept MI (n = 184)Belatacept LI (n = 175)Cyclosporine (n = 184)
  1. 1Donors could meet more than one ECD criteria.

Mean age (years) (SD)56.7 (13)  56.1 (12)  55.7 (12)  
Donor ECD category, n (%)1
 Age ≥6094 (51)79 (45)93 (51)
 Age 50–59 w/complications34 (19)43 (25)40 (22)
 Anticipated cold ischemia time ≥24 h71 (39)76 (43)80 (44)
 Donor w/cardiac death18 (10)19 (11)18 (10)
 Non-ECD3 (2)3 (2)1 (1)
Gender (%)
 Male657463
Race (%)
 White757775
 Black/African American141412
 Other121014
Geographic region (%)
 North America272325
 South America252727
 Europe484948
 Other 1 1 0
Reported cause of ESRD (%)
 Glomerulonephritis222618
 Diabetes141120
 Polycystic kidneys171917
 Hypertensive nephrosclerosis191517
 Tubular and interstitial diseases 7 4 6
 Other reasons212422
>3 HLA mismatches (%)515058
Categorized PRA (%)
 <20969491
 ≥20 0 1 3
History of diabetes (%)211629

Corticosteroid usage was similar across treatment groups over time. The median daily dose of corticosteroids during Week 1–Month 1 was 22 mg, 21 mg and 21 mg in the MI, LI and CsA groups, respectively, and was 7 mg, 5 mg and 5 mg during Months 9–12.

Patient and graft survival

Each belatacept regimen (MI and LI) was demonstrated to be noninferior to cyclosporine on the primary endpoint of patient and graft survival at 1 year at the prespecified margin of 10% (Table 2). Information on patient/graft survival (coprimary outcome) was available for 98% of all randomized and transplanted patients at Month 12.

Table 2.  Outcomes: Patient/graft survival, renal function and structure and acute rejection
Month 12 endpointsBelatacept MI (n = 184)Belatacept LI (n = 175)Cyclosporine (n = 184)
Patient/graft survival
Patients surviving w/functioning graft, n (%)159 (86)155 (89)156 (85)
 95% CI81.5–91.483.9–93.379.6–90.0
 Difference from cyclosporine (97.3% CI)1.6 (−6.6, 9.9)3.8 (−4.3, 11.9)
Graft loss or death, n (%)25 (14)20 (11)28 (15)
 Graft loss17 (9)16 (9)20 (11)
 Death8 (4)4 (2)8 (4)
 Death w/functioning graft6 (3)3 (2)5 (3)
 Imputed as graft loss or death, n (%)2 (1)1 (1)3 (2)
Renal function and structure
Measured GFR <60 mL/min/1.73 m2 or decrease124 (70.5)130 (76.5)151 (84.8)
 month 3–12 ≥10 mL/min/1.73 m2, n (%)
   95% CI63.7–77.270.1–82.879.6–90.1
   Difference from cyclosporine (97.3% CI)−14.4 (−24.0, −4.7)−8.4 (−17.8, 1.0)
   p-value0.00180.0656
Mean measured GFR, mL/min/1.73 m2 (SD)52.1 (21.9)49.5 (25.4)45.2 (21.1)
 Estimated difference from cyclosporine (97.3% CI)6.9 (1.1, 12.7)4.3 (−1.5, 10.1)
 p-value0.00830.1039
CAN, n (%[95%CI])82 (45 [37.6–52.0])80 (46 [38.6–53.4])95 (52 [44.4–58.9])
 Difference from cyclosporine (97.3% CI)−6.8 (−18.2, 4.7)−5.7 (−17.2, 6.0)
   Mild CAN (Stage I), n (%)45 (25)40 (23)49 (27)
   Moderate CAN (Stage II), n (%)10 (6)14 (8)13 (7)
   Severe CAN (Stage III), n (%)8 (4)7 (4)12 (7)
Acute rejection
Acute rejection, n (%)33 (17.9)31 (17.7)26 (14.1)
 95% CI12.4–23.512.1–23.49.1–19.2
 Difference from cyclosporine (97.3% CI)3.8 (−4.7, 12.4)3.6 (−5.0, 12.3)
Banff grade, n (%)
 Mild acute (1A)4 (2)2 (1)
 Mild acute (1B)7 (4)2 (1)2 (1)
 Moderate acute (IIA)10 (5)17 (10)17 (9)
 Moderate acute (IIB)16 (9)8 (5)5 (3)
 Severe acute (III)

The proportion of patients surviving with a functioning graft at Month 12 was similar among groups. Acute rejection as an adjudicated cause of graft loss was reported in 2% of patients in the belatacept MI group, 1% of patients in the LI group and 3% of patients in the cyclosporine group. Primary graft thrombosis as a cause of graft loss was reported for 4% of patients each in the MI and LI group, and 1% of patients in the cyclosporine group. Graft loss due to primary nonfunction or other technical causes occurred in 3% of patients in the MI group, 1% of patients in the LI group and 3% of patients in the cyclosporine group.

Renal function and structure

Patients receiving belatacept had better renal function than those receiving cyclosporine, as assessed by the coprimary composite renal impairment endpoint. Significantly fewer patients in the belatacept MI group reached the renal impairment endpoint compared with the cyclosporine group (Table 2). The measured glomerular filtration rate was significantly higher in the belatacept MI group compared with cyclosporine (Table 2). The results for the renal impairment endpoint and measured glomerular filtration rate did not reach statistical significance for the LI regimen versus cyclosporine. The calculated glomerular filtration rate was consistently 6–8 mL/min higher from Month 1 to Month 12 for each of the belatacept MI and LI regimens compared with cyclosporine (Figure 2) despite a similar proportion of patients with DGF among treatment groups (47% MI, 47% LI and 49% cyclosporine). At Month 12, the prevalence of biopsy-proven chronic allograft nephropathy was similar between groups (45% MI; 46% LI; 52% cyclosporine), and most cases of chronic allograft nephropathy were mild. Severe chronic allograft nephropathy occurred in 4%, 4% and 7% of patients in the belatacept MI, LI and cyclosporine groups, respectively. Protocol biopsy data was available at Month 12 for 73% of all patients, and for 94% of patients with an acute rejection episode. Additional information on renal function and structure can be found in Supporting Table 1.

image

Figure 2. Calculated (MDRD) glomerular filtration rate over time. Calculated glomerular filtration rate (based on the MDRD formula) (18,19) was assessed in the ITT population at months 1, 3, 6, 9 and 12.

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Acute rejection

The incidence of acute rejection episodes was similar between the belatacept and cyclosporine groups at Month 12, and the 20% noninferiority margin was achieved (Table 2). More Grade IIb acute rejections were reported in the belatacept groups compared with cyclosporine. Eighty-one percent of acute rejection episodes occurred within the first 3 months, and nearly all occurred within 6 months. More patients in the belatacept MI group (n = 5) experienced more than one episode of acute rejection compared to the LI (n = 1) and cyclosporine groups (n = 2), although the number of patients with repeat episodes was small. The most common treatment for acute rejection was corticosteroids, whereas initial T-cell-depleting therapy was used in 13, 5 and 4 patients in the belatacept MI, LI and cyclosporine groups, respectively. Twenty-seven (15%) patients in the cyclosporine group were treated with lymphocyte-depleting therapy for anticipated DGF, whereas no patients in the belatacept groups were permitted to receive such treatment. Of the 27 cyclosporine patients treated with lymphocyte-depleting therapy for anticipated DGF, 2 (7%) had an episode of acute rejection, compared with 15% of those cyclosporine patients who were not treated with lymphocyte depleting therapy for anticipated DGF. Centrally read biopsies were available for 94% of patients with clinically suspected acute rejection.

Cardiovascular and metabolic outcomes

Cardiovascular and metabolic endpoint results were generally better in patients treated with belatacept compared to patients treated with cyclosporine (Table 3). Mean systolic and diastolic blood pressure at Month 12 was lower in the belatacept groups compared with cyclosporine, in spite of more patients in the cyclosporine arm (52%) being treated with three or more antihypertensive medications compared with belatacept-treated patients (39–43%). The mean changes from baseline in non-HDL cholesterol and triglycerides (Table 3) were significantly different in the belatacept groups compared with cyclosporine, whereas the mean change in LDL and HDL cholesterol levels was similar among the three treatment arms (data not shown). A similar proportion of patients across treatment groups used ≥1 hyperlipidemic medication at Month 12. The incidence of new-onset diabetes mellitus at Month 12 was lower in the belatacept MI group (2%; p = 0.0308 vs. cyclcosporine) compared with cyclosporine (9%).

Table 3.  Cardiovascular/metabolic outcomes
Month 12 endpointsBelatacept MI (n = 184)Belatacept LI (n = 175)Cyclosporine (n = 184)
Incidence of NODAT, n (%)3 (2)7 (5)11 (9)
 Difference from cyclosporine (97.3% CI)−7.1 (−15.0, −0.6)−4.2 (−12.5, 3.2)
 p-value0.03080.2946 
Serum lipids
 Non-HDL cholesterol
   Mean change from baseline (mg/dL) (SE)12.6 (3.6)11.2 (3.6)29.3 (3.8)
   Estimated difference (97.3% CI)−16.7 (−28.3, −5.0)−18.1 (−29.7, −6.5)
   p-value0.00160.0006
 Triglycerides
   Mean change from baseline (mg/dL) (SE)−1.0 (9.5)−18.2 (9.2)34.5(10.0)
   Estimated difference (97.3% CI)−35.5 (−66.1, −4.8)−52.7 (−83.1, −22.3)
   p-value0.01060.0001 
Blood pressure (mmHg)
 Mean systolic BP141141150
 Mean diastolic BP787882

Safety

The most common (>20%) adverse events included anemia, graft dysfunction, constipation and diarrhea, and occurred with a similar frequency between groups (Table 4). Thrombotic and embolic adverse events were reported in 12% of patients in each of the belatacept MI and LI groups, and in 11% of patients in the cyclosporine group. The incidence of serious adverse events was similar between the treatment groups. Acute infusion-related adverse events (within first hour of infusion) were reported by seven (4%) and nine (5%) patients in the belatacept MI and LI groups, respectively. Except for one serious event of severe prolonged hypotension, all acute infusion-related adverse events were not serious, were mild to moderate in intensity and did not lead to study therapy discontinuation.

Table 4.  Most common (>20%) adverse events, serious adverse events (≥3%) and most common (≥4%) infections
 Belatacept MI (n = 184)Belatacept LI (n = 175)Cyclosporine (n = 184)Total (n = 543)
  1. 1Excluding infections.

  2. Some patients had >1 event.

Adverse events, n (%)1
 Anemia87 (47)85 (49)92 (50)264 (49)
 Graft dysfunction70 (38)67 (38)89 (48)226 (42)
 Constipation52 (28)57 (33)73 (40)182 (34)
 Diarrhea54 (29)58 (33)47 (26)159 (29)
 Hypertension41 (22)40 (23)61 (33)142 (26)
 Nausea42 (23)37 (21)41 (22)120 (22)
 Leukopenia44 (24)30 (17)49 (27)123 (23)
 Pyrexia41 (22)42 (24)39 (21)122 (23)
 Hyperkalemia38 (21)42 (24)35 (19)115 (21)
Serious adverse events, n (%)
 Urinary tract infection13 (7)15 (9)11 (6)39 (7)
 CMV infection12 (7)14 (8)12 (7)38 (7)
 Serum creatinine increased7 (4)8 (5)14 (8)29 (5)
 Graft dysfunction8 (4)6 (3)10 (5)24 (4)
 Pyrexia10 (5)7 (4)7 (4)24 (4)
 Lymphocele2 (1)5 (3)10 (5)17 (3)
Infectious adverse events, n (%)
 Urinary tract infection55 (30)57 (33)62 (34)174 (32)
 CMV infection21 (11)24 (14)24 (13)69 (13)
 Nasopharyngitis21 (11)12 (7)13 (7)46 (9)
 Bronchitis14 (8)13 (7)11 (6)38 (7)
 Upper respiratory tract infection11 (6)11 (6)14 (8)36 (7)
 Oral candidiasis7 (4)5 (3)12 (7)24 (4)
 Eschericia urinary tract infection7 (4)4 (2)12 (7)23 (4)
 Gastroenteritis3 (2)8 (5)10 (5)21 (4)
 Pneumonia8 (4)7 (4)5 (3)20 (4)

Four patients (2%) in the belatacept MI group, four (2%) in the LI group and six (3%) in the cyclosporine group developed malignancies (excluding nonmelanoma skin cancer) during the first 12 months. The malignancies included one case each of Kaposi's sarcoma, breast and colon cancer in the MI group; one case each of myelodysplastic syndrome and prostate cancer in the LI group and one case each of breast cancer, renal neoplasm, thyroid neoplasm and transitional cell carcinoma in the cyclosporine group. Two patients in the cyclosporine group developed Kaposi's sarcoma. One patient (0.5%) in the belatacept MI group and two patients (1%) in the LI group developed posttransplant lymphoproliferative disorder (PTLD) during the 12-month period and one additional patient in each belatacept group developed PTLD after Month 12. Four of the five cases involved the central nervous system, and two of five (both of the post-Month 12 cases) had cytomegalovirus (CMV) disease. No patients on cyclosporine developed PTLD. Three of the five PTLD patients had negative Epstein-Barr virus (EBV) serology pretransplant. No patients who developed PTLD in this study had used lymphocyte-depleting therapy. As of March 2009, three of the five PTLD patients had died (n = 2 MI; n = 1 LI) and one belatacept LI patient was alive but lost the allograft due to nephrectomy.

The overall frequency of infection and the incidence of bacterial, CMV, BK virus and fungal infections were similar between groups. Six serious fungal infections were reported: one case each of pneumocystis jiroveci pneumonia, esophageal candidiasis and fungal respiratory tract infection in the belatacept MI group, one case of pneumocystis jiroveci pneumonia in the belatacept LI group and one case each of fungal infection and fungal pneumonia in the cyclosporine group. A single case of progressive multifocal leukoencephalopathy (PML) was reported after Month 12 in a patient who received belatacept (MI), basiliximab, mycophenolate mofetil and corticosteroids. Tuberculosis was reported in four patients; two patients each in the belatacept MI and LI groups. Three of the tuberculosis cases occurred in an endemic area, of which two were from a single site. No patients in the cyclosporine group developed tuberculosis.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References
  9. Supporting Information

Renal transplantation has significantly improved patient survival, including for patients transplanted with extended criteria donor kidneys. The BENEFIT-EXT study addresses two key concerns in extended criteria donor kidney recipients: impaired renal function and adverse cardiovascular risk profile. We showed that belatacept use resulted in better renal function, similar patient/graft survival, comparable acute rejection and an improved cardiovascular/metabolic profile versus cyclosporine, and an increase in the number of cases of PTLD. Longer-term data may provide valuable information regarding the overall therapeutic profile of belatacept in kidney transplant recipients.

BENEFIT-EXT included not only extended criteria donor transplants according to a United Network for Organ Sharing (UNOS) definition in the US, but other high-risk transplants (i.e. anticipated cold ischemia time ≥24 h and donors with cardiac death). The use of extended criteria donor kidneys to meet demands for allografts is increasing and represents an increasing proportion of allocated kidneys (4). However, the life expectancy and renal function of kidneys from extended criteria donors are inferior compared with nonextended criteria donor kidneys. Renal biopsies of these extended criteria donor kidneys frequently show interstitial fibrosis and vascular lesions that can be worsened by calcineurin inhibitor regimens. In BENEFIT-EXT, the belatacept-based regimens demonstrated superior renal function soon after transplantation (measured glomerular filtration rate was 4–7 mL/min/1.73 m2 higher in the belatacept groups compared with cyclosporine at 12 months), whereas DGF was similar in the posttransplant period. The renal benefit in the belatacept groups was maintained through the 1-year follow-up. Improved kidney function at 1 year is a marker that is associated with better long-term outcomes, suggesting the importance of the renal function benefit of belatacept at 1 year (10–12,26). These results compare favorably with smaller studies of calcineurin inhibitor-avoiding regimens conducted in kidney transplant recipients receiving allografts from older donors (27–29). The acute rejection rates were similar between the belatacept and cyclosporine groups, despite the use of lymphocyte-depleting agents to treat DGF in the cyclosporine group. The increased risk of graft failure associated with extended criteria donor kidneys reinforces the importance of evaluating calcineurin-avoiding regimens for potential preservation of renal function (5,30–32).

The impact of cardiovascular risk factors in renal-transplanted patients is important because cardiovascular events are the most common cause of death with a functioning graft, especially in older patients (33). A retrospective analysis of kidney transplant patients found that each 10 mmHg increase in posttransplant blood pressure was associated with increased risk for graft failure and death (34). In BENEFIT-EXT, the lower blood pressure observed in patients receiving belatacept occurred despite less use of antihypertensive drugs. Elevated serum triglycerides are indicative of a more atherogenic lipid profile, and may contribute to the increased risk for coronary heart disease and death (35–37). Patients receiving belatacept had decreased concentrations of serum triglycerides, in contrast to cyclosporine patients, whose triglyceride levels rose. Of note, some of the differences in serum lipid concentrations, as well as other cardiovascular/metabolic risk factors, could have been influenced by the greater incidence of diabetes in the cyclosporine group compared to the belatacept groups at baseline. However, the overall differences in cardiovascular risk factors in BENEFIT-EXT are similar to those in BENEFIT, where there was no significant difference in the baseline incidence of diabetes between treatment groups. NODAT has become an important issue for transplanted patients, and has been shown to be exacerbated by calcineurin inhibitors. There was significantly less NODAT in the belatacept MI regimen and a trend towards reduced NODAT in the belatacept LI regimen. It may be informative to compare belatacept with calcineurin inhibitors other than cyclosporine in future studies targeting NODAT.

Primary graft thrombosis as the adjudicated cause of graft loss occurred more frequently in the belatacept groups. Examination of recipient and donor characteristics did not reveal any common cause or suggestion of a hypercoagulable state in subjects treated with belatacept. Rates of graft loss due to primary graft thrombosis in belatacept-treated subjects were consistent with published data in the overall transplant population (38,39). Furthermore, graft thrombosis as an adjudicated cause of graft loss did not occur more frequently in the BENEFIT study (n = 1 each MI and LI; n = 3 cyclosporine at Month 12) or in the Phase II study (15). The overall rate of thrombotic adverse events in BENEFIT-EXT was similar between groups (11–12%).

Treatment with belatacept-based regimens was generally safe. Acute infusion-related adverse events were infrequent and mild or moderate in nature. There was no increase in the overall rate of serious adverse events, malignancies, serious infections or opportunistic infections compared with cyclosporine.

Although the overall rate of malignancies in the study was low and most types of malignancies occurred in only one patient, PTLD occurred in three patients in the belatacept groups through Month 12, and has occurred in one additional patient each in the MI and LI group after Month 12. Four of the five cases involved the central nervous system. The rates of PTLD reported in the literature for renal transplant recipients range from 0.4% to 2.3%, and PTLD localized in the central nervous system constitutes 11–22% of all PTLD cases among renal transplant recipients (40–44). Although the incidence of central nervous system PTLD was higher in the belatacept arms, it occurred in patients who had known risk factors such as EBV negative status and CMV disease (45–48). Minimizing use of belatacept in patients with EBV negative status, providing prophylaxis for CMV disease and limiting the use of T-cell-depleting therapy may lead to reduced incidence of PTLD.

In conclusion, BENEFIT-EXT evaluated recipients of extended criteria donor kidneys, a population with increased concerns regarding allograft survival, as well as cardiovascular morbidity. These 1-year results of BENEFIT-EXT demonstrate that belatacept provides better renal function and similar immunosuppressive efficacy versus cyclosporine, results in improved cardiovascular risk profile, and is well tolerated. There were no clinically meaningful differences in efficacy or safety between the MI and LI regimen in this study. The incidence of PTLD was higher in belatacept-treated patients. Three of the five PTLD patients had EBV negative serology. Avoidance of belatacept in EBV-naïve patients may reduce this risk of PTLD in belatacept-treated patients. Outcomes from this 3-year study in ECD kidney recipients will continue to be assessed to help determine the overall immunosuppressive profile of belatacept-based regimens.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References
  9. Supporting Information

Funding source: The BENEFIT-EXT study was supported by Bristol-Myers Squibb. Dr Pearson has received research support from Bristol-Myers Squibb and Roche. Dr Vincenti has received research support from Bristol-Myers Squibb, Pfizer, Novartis, Astellas, Genzyme, Genentech and Roche. Dr Campistol has participated in Speaker's Bureaus for Wyeth and Novartis. Dr Rial has participated in Speaker's Bureaus for Wyeth and Novartis. Drs Block, Di Russo, Xing and Garg are employees of Bristol-Myers Squibb. Dr Grinyo has participated as an Advisory Board member for Bristol-Myers Squibb.

The authors thank the writing and editorial assistance of Brian Atkinson, PhD, Bristol-Myers Squibb.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References
  9. Supporting Information

Supporting Information

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References
  9. Supporting Information

Table S1: Additional detail regarding renal function and structure

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FilenameFormatSizeDescription
AJT_3016_sm_TableS1.pdf167KSupporting info item

Please note: Wiley Blackwell is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.