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. 

 

Abstract and Introduction

Abstract

Belatacept was developed to minimize cardiovascular risk and nephrotoxicity associated with calcineurin inhibitor (CNI)–based immunosuppression. Recently, 7-year data from the Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial (BENEFIT), a phase III study comparing belatacept with cyclosporine, have been published. While during the first year of belatacept the risk of acute rejection episodes was elevated, this seemingly had marginal consequences for long-term graft survival and function as well as patient survival.

For patients at a low-immunological risk, this drug seems to be a safe and effective alternative to CNI-based immunosuppression. Whether the higher rates of acute rejection episodes in the first year outweigh the gain in long-term graft function is still debated. In particular, the lower incidence of donor-specific antibodies indicates that belatacept should not be considered as lower intensity immunosuppression over the long term.

Therefore, should belatacept be the centrepiece of immunosuppression for renal patients?

All randomized trials so far have focussed on patients at a low immunological risk. Furthermore, cyclosporine A (CsA), the comparator of belatacept in BENEFIT and the Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial-EXTended criteria donors (BENEFIT-EXT), is not the CNI of choice in modern transplantation. Furthermore, while at Year 7 the rate of cancer and infections was comparable with the CsA group, long-term data are missing on safety issues for a large number of patients. Thus, currently belatacept may be the drug of choice for a select group of patients, but not for everyone.

This review highlights the benefits and uncertainties of the use of belatacept in kidney transplantation.

Introduction

The leading cause of mortality after renal transplantation is cardiovascular disease and may partly be due to increased cardiovascular risk factors such as hypertension, dyslipidaemia and glucose intolerance, or new onset of diabetes after transplantation (NODAT) as side effects of calcineurin inhibitors (CNIs), glucocorticoids and/or mammalian target of rapamycin (mTOR) inhibitors.[1–3]

An interesting new therapeutic concept as part of immunosuppressive therapy after renal transplantation is the selective co-stimulation blockade of T cell activation with the fusion protein belatacept.[4] Recently, a number of publications suggested markedly improved long-term patient and graft outcomes in patients treated with belatacept. Thus, we asked the question whether belatacept should be the centre piece of immunosuppression in renal transplantation. The purpose of this review is to outline the published evidence regarding the effectiveness and possible advantages, but also the safety aspects and limitations, of selective co-stimulation blockade with belatacept.

 
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Table 1.  Comparison between the five big clinical trials
Belatacept study phase II trial [4] (belatacept versus cyclosporine) Benefit study phase III trial [8] (first-line immunosuppression trial) Benefit EXT study phase III trial [9] (first-line immunosuppression trial) Switching from CNI to belatacept [10] (phase II trial) Belatacept with a steroid-free regimen [11] (phase II trial)
n 218 660 543 173 89
Included patients Low immunological risk:
  • 89% with first allograft history

  • PRA < 20%

  • At no increased risk for rejection considered by an investigator

  • Adults ≥18 years

  • Receiving a living donor or standard criteria deceased donor kidney transplant

  • Cold ischaemia time <24 h 'Standard criteria donors'

Adults ≥18 years
  • Receiving an ECD allograft

ECD criteria:
  • Donors ≥60 years

  • Donors ≥50 years with at least two other risk factors (cerebrovascular accident, hypertension, sCr >1.5 mg/dL)

  • Cold ischaemia time ≥24 h

  • Donation after cardiac death

  • Adult recipients (≥18 years) from deceased or living donor

  • 6–36 month after NTX

  • Stable dose of CNI-based immunosuppression since at least one month

  • cGFR: 35–75 mL/min/1.72 m2

  • Adult recipients ≥18 years

  • Receiving allograft from a non-human leukocyte antigen (HLA)–identical living or standard criteria deceased donor

  • Cold ischaemia time <24 h

Exclusion criteria
  • Possible recurring underlying renal disease in allograft

  • Positive crossmatch

  • Active hepatitis B, C or HIV

  • (History of) cancer

  • History of drug or alcohol abuse, psychotic disorder

  • Previous treatment with basiliximab

  • Donor age >60 years or <6 years

  • Not heart beating donor at time of nephrectomy

  • Cold ischaemia time >36 h

  • Recipients of 'ECD kidneys'

  • Donors >60 years

  • Donor ≥50 years with at least two other risk factors (cerebro-vascular accident, hypertension, sCr >1.5 mg/dL)

  • Cold ischaemia time >24 h,

  • Donation after cardiac death (non-heart beating donor)

  • Prior or concurrent non-renal solid organ transplants

High-immunological risk
  • PRA ≥50%

  • PRA ≥30% in retransplants

  • History of graft loss due to acute rejection

  • Positive crossmatch

  • Possible recurring underlying renal disease in allograft

  • Active hepatits B, C or HIV

  • Active TB

  • Standard criteria donors

  • Positive crossmatch

  • Active hepatitis B, C or HIV

  • Subjects receiving a concurrent solid organ or cell transplant

  • History of substance abuse

  • History of cancer in last 5 years

  • Active TB

  • History of graft loss due to acute rejection

  • History of recent (<3 months)

  • Recurrent or

  • Severe (>BANFF IIA) rejection in the present allograft

  • C4d-positive biopsy

  • Recent >30% serum-creatinine increase

  • Positive crossmatch

  • Possible recurring underlying renal disease in allograft

  • Current infection

  • History of cancer in past 5 years

  • Recipients of 'ECD kidneys'

  • Donors >60 years

  • Donors ≥50 years with at least two other risk factors (cerebrovascular accident, hypertension, sCr >1.5 mg/dL)

  • Cold ischaemia time ≥24 h

  • Donation after cardiac death

  • Prior or concurrent non-renal solid organ transplants

  • PRA ≥50% in first time

  • PRA ≥30% in retransplants

  • History of graft loss due to acute Rejection

  • Possible recurring underlying renal disease in allograft

  • EBV-seronegative patients

  • Hepatitis B, C or HIV

  • Latent tuberculosis

  • History of cancer in last 5 years

  • BMI >35 kg/m2

Treatment Induction therapy with basiliximab (20 mg on days 0 and 4), MMF (200 mg daily) and glucorticosteroids (initiated 500 mg and tapered to no less than 2.5 mg/day by day 15) Adjunctive immunosuppressive treatment (e.g. MMF) were maintained
  • Thymoglobulin 1.5 mg/kg i.v. on days 1, 2, 3, 4 (lymphocytes >100/mm2) and not to extend past day 10

  • MPS (tapered from day 1 to 10)

→ Arm 1 More intensive (MI) regimen belatacept (Dosage Table 2) Belatacept 5 mg/kg at day 1, 15, 29, 43, 57 and then every 28 days Betalacept (Table 1)/MMF (2 g/day)
→ Arm 2 Less intensive (LI) regimen belatacept (Dosage Table 2) Belatacept (Table 1)/SRLc
→ Control, CsA (initial 4–10 mg/kg), 0–1 month adjusted to 150–300 (400) ng/mL, 2–12 month adjusted to 100–250 (300) ng/mL CNI (CsA or TAC) TACb/MMF (2 g/d)
Rejection within 6 months
  • MI belatacept: 6%

  • LI belatacept: 7%

  • CsA: 8%

  • MI belatacept: 22%a

  • LI belatacept: 17%a

  • CsA: 7%a

  • MI belatacept: 17.9%a

  • LI belatacept: 17.7%a

  • CsA: 14%a

  • Belatacept: 7%a

  • CNI: 0%a

  • Belatacept–MMF: 12%

  • Belatacept–SRL: 4%

  • TAC–MMF: 3%

n, number of patients; CsA, cyclosporine A; TAC, tacrolimus; MMF, mycophenolate mofetil; SRL, sirolimus; MPS, methylprednisolone; PRA, panel reactive antibodies; ECD, extended criteria donor.
aNearly all rejection episodes occurred within 6 months.
bTAC adjusted to 8–12 ng/mL in first months, to 5–10 ng/mL thereafter.
cSRL adjusted to 7–12 ng/mL from day 3 to 6 month, to 5–10 ng/mL thereafter.

Table 2.  The more intensive and less intensive belatacept regimens in BENEFIT and BENEFIT-EXT
Belatacept more intensive regimen Months 0–6 After 6 months
   10 mg/kg    5 mg/kg
   days 1 and 5    every 4 weeks
   then weeks 2, 4, 6, 8, 10, 12, 16, 20 and 24
Belatacept less intensive regimen Months 0–3 After 3 months
   10 mg/kg    5 mg/kg
   days 1 and 5    every 4 weeks
   then weeks 2, 4, 8 and 12

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Authors and Disclosures

Monika Huber, Stephan Kemmner, Lutz Renders and Uwe Heemann

Department of Nephrology, Technical University of Munich, Ismaninger Street 22, Munich 81675, Germany

Correspondence and offprint requests to
Uwe Heemann; E-mail: uwe.heemann@lrz.tum.de

Conflict of Interest Statement
U.H. has served as advisor and given lectures on behalf of Astellas, Chiesi, Hexal, MSD, Novartis, Pfizer and Teva. L.R. has served as advisor and given lectures on behalf of Astellas.

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