A Phase III Study of Belatacept‐based Immunosuppression Regimens versus Cyclosporine in Renal Transplant Recipients (BENEFIT Study)

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The phase III Belatacept Evaluation of Nephroprotection and Efficacy as First‐Line Immunosuppression Trial–Extended Criteria Donors Trial (BENEFIT‐EXT) study compared more or less intensive belatacept‐based immunosuppression with cyclosporine (CsA)–based immunosuppression in recipients of extended criteria donor kidneys. In this post hoc analysis, patient outcomes were assessed according to donor kidney subtype. In total, 68.9% of patients received an expanded criteria donor kidney (United Network for Organ Sharing definition), 10.1% received a donation after cardiac death kidney, and 21.0% received a kidney with an anticipated cold ischemic time ≥24 h. Over 7 years, time to death or graft loss was similar between belatacept‐ and CsA‐based immunosuppression, regardless of donor kidney subtype. In all three donor kidney cohorts, estimated mean GFR increased over months 1–84 for belatacept‐based treatment but declined for CsA‐based treatment. The estimated differences in GFR significantly favored each belatacept‐based regimen versus the CsA‐based regimen in the three subgroups (p < 0.0001 for overall treatment effect). No differences in the safety profile of belatacept were observed by donor kidney subtype.

Section: Discussionmentioning

confidence: 53%

Efficacy and Safety Outcomes of Extended Criteria Donor Kidneys by Subtype: Subgroup Analysis of BENEFIT-EXT at 7 Years After Transplant

Florman

Becker

Bresnahan

et al. 2017

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“…Belatacept was investigated in 2 randomized phase III studies: Belatacept Evaluation of Nephroprotection and Efficacy as First‐Line Immunosuppression Trial (BENEFIT) and BENEFIT‐Extended Criteria Donors (BENEFIT‐EXT). In these studies, patients were de novo recipients of a living or standard criteria deceased donor kidney (BENEFIT) or an extended criteria donor kidney (BENEFIT‐EXT) and randomized to receive up to 7 years of treatment with belatacept more‐intense (MI)–based, belatacept less‐intense (LI)–based, or cyclosporine‐based immunosuppression 2, 3. In an intent‐to‐treat analysis of BENEFIT undertaken at 7 years posttransplant, belatacept‐based immunosuppression was associated with a 43% reduction in the risk of death or graft loss relative to cyclosporine‐based immunosuppression (belatacept more intensive (MI) vs cyclosporine: hazard ratio [HR] 0.57, 95% confidence interval [CI] 0.35–0.95, P = .02; belatacept LI vs cyclosporine: HR 0.57, 95% CI 0.35–0.94, P = .02) 4.…”

Section: Introductionmentioning

confidence: 99%

De novo donor-specific antibodies in belatacept-treated vs cyclosporine-treated kidney-transplant recipients: Post hoc analyses of the randomized phase III BENEFIT and BENEFIT-EXT studies

Bray

Gebel

Townsend

et al. 2018

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Donor‐specific antibodies (DSAs) are associated with an increased risk of antibody‐mediated rejection and graft failure. In BENEFIT and BENEFIT‐EXT, kidney‐transplant recipients were randomized to receive belatacept more intense (MI)–based, belatacept less intense (LI)–based, or cyclosporine‐based immunosuppression for up to 7 years (84 months). The presence/absence of HLA‐specific antibodies was determined at baseline, at months 6, 12, 24, 36, 48, 60, and 84, and at the time of clinically suspected episodes of acute rejection, using solid‐phase flow‐cytometry screening. Samples from anti‐HLA‐positive patients were further tested with a single‐antigen bead assay to determine antibody specificities, presence/absence of DSAs, and mean fluorescence intensity (MFI) of any DSAs present. In BENEFIT, de novo DSAs developed in 1.4%, 3.5%, and 12.1% of belatacept MI‐treated, belatacept LI‐treated, and cyclosporine‐treated patients, respectively. The corresponding values in BENEFIT‐EXT were 3.8%, 1.1%, and 11.2%. Per Kaplan‐Meier analysis, de novo DSA incidence was significantly lower in belatacept‐treated vs cyclosporine‐treated patients over 7 years in both studies (P < .01). In patients who developed de novo DSAs, belatacept‐based immunosuppression was associated with numerically lower MFI vs cyclosporine‐based immunosuppression. Although derived post hoc, these data suggest that belatacept‐based immunosuppression suppresses de novo DSA development more effectively than cyclosporine‐based immunosuppression.

“…The additional dose in BENEFIT and BENEFIT‐EXT was administered on day 4 posttransplant to optimize saturation of CD80/CD86 ligands and blockade of CD28 activation. Despite these caveats, in analyses performed at 1 and 7 years posttransplant, rates of acute rejection were higher for belatacept‐treated vs CsA‐treated patients participating in BENEFIT12, 14, 15 and similar for belatacept‐treated vs CsA‐treated patients participating in BENEFIT‐EXT 13, 16…”

Section: Discussionmentioning

confidence: 98%

“…The comparable rates of acute rejection for belatacept‐based vs CsA‐based immunosuppression were preserved over 10 years: acute rejection rates in the belatacept treatment arms (6%‐7%) were noninferior to that observed in the CsA treatment arm (8%) at 6 months posttransplant in IM103‐100 10. Most acute rejection events in belatacept‐treated patients occur within 6 months of treatment initiation 10, 12, 13. In IM103‐100, most BPAR events in the population at first randomization were reported by month 6 (28 of 41, 68.3%).…”

Section: Discussionmentioning

confidence: 99%

“…However, it is difficult to compare the results from these phase III studies to IM103‐100 because enrollment to this phase II study was substantially lower and both the definition of acute rejection and the belatacept LI regimen administered were different. With regard to the latter, patients allocated to belatacept LI‐based immunosuppression in IM103‐100 received 5 doses of belatacept 10 mg/kg during the induction phase, while patients randomized to belatacept LI in BENEFIT12 and BENEFIT‐EXT13 received 6 induction doses of belatacept 10 mg/kg. The additional dose in BENEFIT and BENEFIT‐EXT was administered on day 4 posttransplant to optimize saturation of CD80/CD86 ligands and blockade of CD28 activation.…”

Section: Discussionmentioning

confidence: 99%

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Ten-year outcomes in a randomized phase II study of kidney transplant recipients administered belatacept 4-weekly or 8-weekly

Vincenti

Blancho

Dürrbach

et al. 2017

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In the phase II IM103‐100 study, kidney transplant recipients were first randomized to belatacept more‐intensive‐based (n = 74), belatacept less‐intensive‐based (n = 71), or cyclosporine‐based (n = 73) immunosuppression. At 3‐6 months posttransplant, belatacept‐treated patients were re‐randomized to receive belatacept every 4 weeks (4‐weekly, n = 62) or every 8 weeks (8‐weekly, n = 60). Patients initially randomized to cyclosporine continued to receive cyclosporine‐based immunosuppression. Cumulative rates of biopsy‐proven acute rejection (BPAR) from first randomization to year 10 were 22.8%, 37.0%, and 25.8% for belatacept more‐intensive, belatacept less‐intensive, and cyclosporine, respectively (belatacept more‐intensive vs cyclosporine: hazard ratio [HR] = 0.95; 95% confidence interval [CI] 0.47‐1.92; P = .89; belatacept less‐intensive vs cyclosporine: HR = 1.61; 95% CI 0.85‐3.05; P = .15). Cumulative BPAR rates from second randomization to year 10 for belatacept 4‐weekly, belatacept 8‐weekly, and cyclosporine were 11.1%, 21.9%, and 13.9%, respectively (belatacept 4‐weekly vs cyclosporine: HR = 1.06, 95% CI 0.35‐3.17, P = .92; belatacept 8‐weekly vs cyclosporine: HR = 2.00, 95% CI 0.75‐5.35, P = .17). Renal function trends were estimated using a repeated‐measures model. Estimated mean GFR values at year 10 for belatacept 4‐weekly, belatacept 8‐weekly, and cyclosporine were 67.0, 68.7, and 42.7 mL/min per 1.73 m2, respectively (P<.001 for overall treatment effect). Although not statistically significant, rates of BPAR were 2‐fold higher in patients administered belatacept every 8 weeks vs every 4 weeks.