Advanced Search

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

Am J Transplant. 2017 Jan;17(1):180-190 doi: 10.1111/ajt.13886.
Abstract

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.

CET Conclusion
Reviewer: Mr Simon Knight, Centre for Evidence in Transplantation, The Royal College of Surgeons of England.
Conclusion: In this post-hoc analysis of the BENEFIT-EXT trial, participants are split by donor subtype (ECD, DCD or anticipated CIT > 24 hours). The benefits in GFR of belatacept over cyclosporine A are maintained in all 3 subgroups. It is not really clear what the rationale for the subgroup analysis presented here is – the authors do not speculate as to why they would expect belatacept to have a differential effect in the 3 subgroups. Given that the subgroups are quite small (only 55 patients in the DCD group) the findings are not that surprising, and this paper adds little to the current literature.
Expert Review
Reviewer: Professor Teun van Gelder, Erasmus Medical Center Rotterdam, Netherlands.
Conflicts of Interest: Teun van Gelder has received lecture fees from Roche, Chiesi and Astellas Pharma, and consulting fees from Astellas, Novartis, Teva and Sandoz.
Clinical Impact Rating 2
Review: Following the publication of the seven-year outcome results of the Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial (BENEFIT) trial [1] Florman et al have now also published the (post-hoc) 7 year follow-up results of the BENEFIT-EXT trial, that included extended (EXT) criteria donors [2]. The authors conclude that although time to death or graft loss was similar between belatacept- and CsA-based immunosuppression, eGFR was better in both belatacept-treated groups. In BENEFIT-EXT, 543 patients were randomized and transplanted, and Figure 2 shows that only 160 (29%) patients reached the 84 months time point. It is unclear why Florman et al, despite the small patient numbers, performed their analysis on three different subgroups of patients (UNOS ECD, DCD and anticipated CIT ≥24 h), as in the original publication by Durrbach et al, this subgroup analysis was not performed [3]. The original study had a 3 year follow-up and patients could continue study treatment beyond 3 years if they were still on their original study drug. As commented on previously, the groups in this long-term follow-up can therefore not be considered truly randomized [4]. An interesting finding that confirms data obtained in the BENEFIT study is that de novo DSA development occurred significantly less frequently with belatacept versus CsA-based immunosuppression. Tacrolimus is now the most frequently prescribed calcineurin inhibitor and one can only speculate on what the outcome would have been if the belatacept groups would have been compared to a tacrolimus-based regimen. In view of the small patient numbers at 7 years follow-up, and the comparison with CsA it is not expected that this publication will change prescription behaviour. References: 1. Vincenti F, Rostaing L, Grinyo J, et al. Belatacept and Long-Term Outcomes in Kidney Transplantation. N Engl J Med 2016; 374: 333-343. 2. Florman S, Becker T, Bresnahan B, et al. Efficacy and Safety Outcomes of Extended Criteria Donor Kidneys by Subtype: Subgroup Analysis of BENEFIT-EXT at 7 Years After Transplant. Am J Transplant 2017; 17(1): 180-190. 3. Durrbach A, Pestana JM, Pearson T, et al. A phase III study of belatacept versus cyclosporine in kidney transplants from extended criteria donors (BENEFIT-EXT study). Am J Transplant 2010; 10(3): 547-57. 4. Van Gelder T, Hesselink DA. Belatacept: A Game Changer? Transplantation 2016; 100(7): 1390-2.
Methodological quality
Jadad score 2
Allocation concealment YES
Data analysis MODIFIED INTENTION TO TREAT
Score based on Durrbach A, et al. A phase III study of belatacept versus cyclosporine in kidney transplants from extended criteria donors (benefit-ext study). American Journal of Transplantation. 2010
Study Details
Aims: To conduct a post-hoc analysis of the previous Belatacept Evaluation of Nephroprotection and Efficacy as First-Line Immunosuppression Trial–Extended Criteria Donors (BENEFIT-EXT) trial* to determine the efficacy and safety of belatacept at 7 years according to donor kidney subtype.
Interventions: All patients received basiliximab induction, mycophenolate mofetil and corticosteroids and were randomized to one of three groups and received either more intensive or less intensive belatacept-based immunosuppression, or CsA-based immunosuppression. Outcomes were assessed according to three donor subtypes, donation after cardiac death (DCD), expanded criteria donor (ECD) or anticipated cold ischemia time (CIT) ≥ 24 hours.
Participants: 543 de novo kidney transplant recipients aged ≥18 years who participated in the BENEFIT-EXT trial beyond 3 years.
Outcomes: Measured outcomes included patient and graft survival, renal function, acute rejection, donor-specific antibodies, and safety outcomes including adverse events, infections and malignancies.
Follow Up: 7 years (84 months)
Metadata
Funding: Industry funding
Publication type: Multicenter Study, Randomized Controlled Trial, Randomised Controlled Trial
Trial registration: ClinicalTrials.gov - NCT00114777
Organ: Kidney
Language: English
Author email: sander.florman@mountsinai.org
MeSH terms: Abatacept; Female; Follow-Up Studies; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Function Tests; Kidney Transplantation; Male; Middle Aged; Prognosis; Risk Factors; Safety; Tissue Donors; 0 (Immunosuppressive Agents); 7D0YB67S97 (Abatacept)