BENEFIT: Belatacept for Kidney Transplantation

In Review

Vincenti F, et al. "A phase III study of belatacept-based immunosuppression regimens versus cyclosporine in renal transplant recipients (BENEFIT study)". Am J Transplant. 2010. 10(3):535-546.
PubMed • Full text

Clinical Question

Can belatacept be used in place of cyclosporine as a de novo maintenance therapy to preserve allograft function in kidney transplant recipients?

Bottom Line

Belatacept was associated with improved renal function at 12 months when compared to cyclosporine. Despite an increased risk for acute rejection, patient and graft survival was similar.

Major Points

Calcineurin inhibitors have been the backbone of kidney transplant immunosuppression since their development, however they are well known to cause renal toxicity and allograft injury with short and long-term use. Additonally, they are know to cause metabolic adverse effects including diabetes, hypertension and dyslipidemias. Belatacept is a T-lymphocyte costimulation blocker designed to prevent renal allograft rejection while avoiding renal injury. This study was designed to evaluate the efficacy and safety of belatacept as a first-line immunosuppressant in kidney transplantation.

This multicenter, randomized controlled trial evaluated two regimens of belatacept vs cyclosporine in kidney transplant recipients treated with basiliximab induction and mycophenolate/prednisone maintenance. There were superior renal outcomes, including GFR increase in the 12 months post-transplant in the belatacept groups, while GFR decreased in the cyclosporine arm. Rejection occurred more frequently in the belatacept arms, but patient and graft survival were similar. Lipids and blood pressure were slightly better controlled in the belatacept arms, but these differences were clinically modest. There was not difference in rates of new onset diabetes after transplant. There were no advantages to using a more intense belatacept regimen over a less intense regimen. Importantly, PTLD occurred more frequently in the belatacept group, most noticeably in the more intense regimen. However, these were typically associated with known risk factors for PTLD, including EBV negative status and CMV infection.

Belatacept (less intense regimen) was FDA approved in 2011 for EBV-positive, de novo kidney transplant recipients. Subsequent analyses at 3 years and 7 years showed continued renal function improvement over time and graft survival was shown to be superior than cyclosporine at 7 years. Additionally, the development donor specific antibodies was shown to be less with belatacept. In is important to note that tacrolimus, rather than cyclosporine, has been the calcineurin inhibitor of choice for the past two decades given its superior efficacy vs. cyclosporine. Future studies will need to evaluate the efficacy of belatacept vs. tacrolimus in order to better define its place in therapy.

Guidelines

KDIGO Care of Kidney Transplant Recipients (2009)

• NOTE: These guidelines pre-date this publication.

Design

• Prospective, open-label, multicenter, phase III, randomized controlled trial
• N=666
  • Belatacept less intense (LI) group (n=226)
  • Belatacept more intense (MI) group (n=219)
  • Cyclosporine group (n=221)
• Setting: 100 centers worldwide.
• Enrollment: 2006
• Mean follow-up: 3 years
• Analysis: intention-to-treat
• Primary outcomes at 12 months vs. cyclosporine: (1) composite patient and graft survival, (2) composite renal impairment endpoint, (3) incidence of acute rejection

Population

Inclusion Criteria

• Age ≥ 18 years
• Recipient of living donor or standard criteria deceased donor kidney with an anticipated cold ischemic time <24 hours

Exclusion Criteria

• Recipients of kidneys from extended-criteria donors (ECD)
  • Donor age ≥ 60 years;
  • Donor age ≥ 50 years with at least two other risk factors (cerebral vascular accident, hypertension, serum creatinine > 1.5mg/dL)
  • Donation after cardiac death (DCD) donors
  • Cold ischemic time ≥ 24 hours
• Recipient with prior or concurrent non-renal transplant
• First-time recipients with panel reactive antibody ≥ 50% or retransplant with ≥ 30%

Baseline Characteristics

For the Belatacept LI group:

• Demographics: 65% Male; Mean age 42.6 years; 59% white, 10% black
• Previous kidney transplant: 3%
• Panel-reactive antibody ≥ 20%: 13%
• Type of donor: 42% deceased
• Donor mean age: 42 years (living), 38 years (deceased)
• Cold ischemia time: 1.4 hours (living), 16.3 hours (deceased)
• Delayed graft function: 14%

Interventions

• Less Intense (LI) Belatacept
  • 0-1 months: 10 mg/kg days 1,5, weeks 2,4
  • 2-3 months: 10 mg/kg weeks 8,12
  • 3-12 months: 5 mg/kg every 4 weeks
• More Intense (MI) Belatacept
  • 0-3 months: 10 mg/kg days 1,5, weeks 2,4,6,8,10,12
  • 4-6 months: 10 mg/kg weeks 16,20,24
  • 7-12 months: 5 mg/kg every 4 weeks
• Cyclosporine
  • Initial daily dose: 4-10 mg/kg
  • 0-1 months: dose adjusted to 150-300ng/mL
  • 2-12 months: dose adjusted to 100-250ng/mL
• All patients received basiliximab induction (20mg x2 doses), mycophenolate 2g/day, and steroids tapered to no less than 2.5mg/day by post-op day 15.

Outcomes

Comparisons are belatacept LI vs. belatacept MI vs. cyclosporine (CSA).

Primary Outcomes

Patients surviving with functioning graft

97% vs. 95% vs. 93% (difference LI vs. CSA: 3.2 (97.3% CI -1.5, 8.4); difference MI vs. CSA: 2.2 (97.3% CI -2.9, 7.5))

Measured GFR <60ml/min/1.73m2 or GFR decrease month 3-12 ≥ 10ml/min/1.73m2

54% vs. 55% vs. 78% (difference LI vs. CSA: -23.7 (97.3% CI -33.3, -13.7; P<0.0001); difference MI vs. CSA: -22.9 (97.3% CI -32.6, -12.9; P<0.0001))

Incidence of acute rejection

17% vs. 22% vs. 7% (difference LI vs. CSA: 10.0 (97.3% CI 3.3, 17.1); difference MI vs. CSA: 15.1 (97.3% CI 7.9, 22.7))

Secondary Outcomes

Mean measured GFR ml/min/1.73m2

63.4 vs. 65.0 vs. 50.4 (difference LI vs. CSA: 12.9 (97.3% CI 7.2, 18.6; P<0.0001); difference MI vs. CSA: 14.6 (97.3% CI 8.8, 20.3; P<0.0001))

Chronic allograft nephropathy

24% vs. 18% vs. 32% (difference LI vs. CSA: -8.5 (97.3% CI -17.9, 0.9); difference MI vs. CSA: -14.2 (97.3% CI -23.2, -5.0))

Adverse Events

Incidence of new onset diabetes after transplant

4% vs. 7% vs. 10% (difference LI vs. CSA: -5.7 (97.3% CI -12.6, 0.5; P=0.0687); difference MI vs. CSA: -2.8 (97.3% CI -10.2, 4.4; P=0.4825))

Change in non-HDL cholesterol from baseline, mg/dL

8.0 vs. 8.1 vs.18.3 (difference LI vs. CSA: -10.3 (97.3% CI -19.1, -1.4; P=0.0104); difference MI vs. CSA: -10.1 (97.3% CI -19.0, -1.3; P=0.0115))

Change in triglycerides from baseline, mg/dL

-21.2 vs. -17.0 vs. 6.6 (difference LI vs. CSA: -27.8 (97.3% CI -49.5, -6.1; P=0.0047); difference MI vs. CSA: -17.0 (97.3% CI -45.5, -1.8; P=0.0165))

Mean systolic blood pressure, mmHg

131 vs. 133 vs. 139 (LI vs CSA: P<0.0001; MI vs CSA: P=0.001)

Malignancies (excluding nonmelanoma skin cancer)

1.8% vs. 2.3% vs. 0.4%

Post transplant lymphoproliferative disorder (PTLD)

0.4% vs. 0.4% vs. 0%

Criticisms

• Open-label design of the study

Funding

This study was funded by Bristol-Myers Squib.