Belatacept and Long-Term Outcomes in Kidney Transplantation

Joseph Phan, Mercer University College of Pharmacy

The Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guideline for the care of kidney transplant recipients states that prolonged maintenance of immunosuppressive therapy after kidney transplantation has improved short-term outcomes in many cases, however this effect on long-term allograft survival is not known. The current standard-of-care combines calcineurin-inhibitors with antiproliferative drugs, with or without maintenance glucocorticoids. [1] According to a retrospective analysis of over 51,000 kidney transplantations, these regimens may not be adequate to preserve allograft function. [2]

Title: Belatacept and Long-Term Outcomes in Kidney Transplantation
Design International, randomized, single-blind, parallel-group study with an active control; N= 666
Objective To assess each belatacept-based regimen against a cyclosporine based regimen on patient and graft survival, renal impairment endpoint, an incidence of acute rejection
Study Groups More-intensive (MI) belatacept-based regimen

Less-intensive (LI) belatacept-based regimen

Cyclosporine-based (CsA) regimen for primary immunosuppression

MI Belatacept; n= 219 LI Belatacept; n= 226 CsA; n= 221
0 – 3 months 10 mg/kg Days 1, 5 on weeks 2, 4,6, 8, 10, 12 0 – 1 Month 10 mg/kg Days 1, 5 on weeks 2, 4 Initial daily dose 4 – 10 mg/kg
4 – 6 months 10 mg/kg Weeks 16, 20, 24 2 – 3 Months 10 mg/kg Weeks 8, 12 0 – 1 month Dose adjusted to 150- 300 ng/mL
7 – 12 months 5 mg/kg Every 4 weeks 3 – 12 Months 5 mg/kg Every 4 weeks 2 – 12 months Dose adjusted to 100- 250 ng/mL
Methods After 36 months, patients were required to continue the assigned regimen to remain in the study. Patients were randomly assigned to in a 1:1:1 ratio to a more-intensive belatacept-based regimen, a less-intensive belatacept-based regimen, or a cyclosporine-based regimen for primary immunosuppression. All patients received basiliximab induction, mycophenolate mofetil, and glucocorticoids. Patients were eligible to continue with the assigned therapy beyond 36 months if they provided written informed consent and if they received the approval of their physician.
Duration January 13, 2006, and June 14, 2007
Primary Outcome Measure The primary objective at month 12 was an assessment of the composite end point of patient and graft survival, renal function, and the incidence of acute rejection in each belatacept group as compared with the cyclosporine group.
Baseline Characteristics   MI Belatacept LI Belatacept CsA
Mean age, years 43.6 42.6 43.5
Male (%) 69 65 75
White (%) 60 59 63
Previous transplants      
0 96 97 94
1 2 2 4
2 1 0 0
History of Diabetes (%) 17 15 17
Glomerulonephritis 22 32 25
Results   MI Belatacept LI Belatacept CsA
Patient/graft survival      
Patients surviving with functional graft, n (%) 209 (95) 218 (97) 206 (93)
95% Confidence Interval (CI) 92.7- 98.2 94.1- 98.9 89.9- 96.5
Graft loss or death, n (%) 10 (5) 8 (4) 15 (7)
Renal Function and Structure      
mGFR (mean glomerular filtration rate) < 60 mL/min/1.73 m^2 or decrease 115 (55) 116 (54) 166 (78)
95% CI 48.3 – 61.8 47.5 – 60.9 72.4 – 83.5
p- value < 0.0001 < 0.0001  
Adverse Events Common Adverse Events: (MI/LI: number of events/100 person-years) urinary tract infection (1.9/2.0), pneumonia (0.7/1.1), pyelonephritis (0.7/0.7),
Serious Adverse Events: cytomegalovirus infection (1.4/1.1), sepsis (0.8/0.5), serious gastrointestinal disorder (3.9/2.2), serious cardiac disorders (2.0/1.4), serious vascular disorders (1.8/1.5), cancer of any grade (2.1/1.8)
Percentage that Discontinued due to Adverse Events: 20%
Study Author Conclusions In the present study, patients randomly assigned to either a more-intensive or a less-intensive belatacept regimen had a 43% reduction in the risk of death or graft loss at 7 years, as compared with patients randomly assigned to cyclosporine. The treatment effect was similar for each component of the composite end point (time to death and time to graft loss). The reduction in the risk of death at 7 years was 38% with the more-intensive belatacept regimen and 45% with the less-intensive regimen as compared with cyclosporine. The corresponding values for the reduction in the risk of graft loss, with censoring of data for patients who died, were 44% and 41%.

This phase III trial demonstrates that patients who were randomized to a more-intensive or a less-intensive belatacept-based regimen had a large reduction in risk of death or graft loss at 7 years as compared to patients who were treated with cyclosporine. A major limitation of the trial was that belatacept was not compared to tacrolimus, the current standard of care calcineurin inhibitor; however, outcomes of patient and graft survival are similar to those observed with cyclosporine based regimens. [3]

References

  1. Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant 2009;9:Suppl 3:S1-S155
  1. Opelz G, Döhler B. Influence of immunosuppressive regimens on graft survival and secondary outcomes after kidney transplantation. Transplantation 2009;87:795-802
  1. Vincenti F, Rostaing L, Grinyo J, et al. Belatacept and Long-Term Outcomes in Kidney Transplantation. N Engl J Med. 2016;374(4):333-343
Advertisements

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s