Belatacept, a selective blocker of T-cell costimulation, offers an alternative to calcineurin inhibitor (CNI)-based immunosuppression, avoiding CNI-associated nephrotoxicity. Despite evidence of improved long-term graft function associated with belatacept, widespread use has been limited by concerns regarding increased incidence and severity of acute cellular rejection and caveat that landmark randomized controlled trials (RCT) compared belatacept to cyclosporine, a CNI widely replaced with tacrolimus.1,2
High immunological risk recipients (with panel reactive antibody [PRA] ≥50% [first transplant] or ≥30% [retransplant]) were ineligible for the BENEFIT (Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial) study, which reported improved renal function and reduced mortality and graft loss at 7 years despite increased incidence of acute rejection, in kidney transplant recipients receiving de-novo belatacept compared to those receiving cyclosporine, alongside basiliximab, mycophenolate, and glucocorticoids.2 Although the BENEFIT-EXT (Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial-EXTended criteria donors) study in recipients of expanded criteria deceased-donor kidneys only excluded those with a positive T-cell lymphocytotoxic crossmatch, over 90% of subjects had PRA <20%. Improved renal function was observed in belatacept-treated patients compared to those receiving cyclosporine, with no difference in mortality or graft loss at 7 years, emphasizing the dangers of generalizing RCT results.1 BELACOR (Belatacept in Renal Transplant Recipient with Mild Immunologic Risk Factor) reported on belatacept use in 49 renal transplant recipients with low level preformed donor-specific antibodies (DSA) (maximal mean fluorescence intensity 500–3000) alongside thymoglobulin/steroid induction. No cases of antibody-mediated rejection were observed following belatacept, with similar outcomes compared to a historical control group, despite increased T-cell-mediated rejection.3 RCT comparing belatacept conversion with remaining on CNI show improved estimated glomerular filtration rate (eGFR) slope following belatacept conversion, despite increases in acute rejection4,5 but due to limited inclusion of sensitized patients, it remains uncertain whether belatacept is a safe or efficacious alternative to CNI-based immunosuppression in sensitized patients.
In this issue, Sethi et al report the Cedars-Sinai Medical Center experience of converting from CNI-based immunosuppression to belatacept in 29 HLA-sensitized (HS) individuals, with comparison to a cohort of 79 non-HS patients (Figure 1).6 Conversion was prompted by impaired allograft function related to CNI or CNI-associated side effects at the discretion of the treating physician. Small numbers were included with declining allograft function and biopsy findings of moderate-severe interstitial fibrosis and tubular atrophy in the absence of acute rejection. Reasons for conversion were similar in both groups, with no differences in the distribution of interstitial fibrosis and tubular atrophy.
Over a 5-year follow-up, there were no differences in rejection-free survival, graft or patient survival between the groups. Subgroup analysis of those converted in the first year posttransplant showed reduced rejection-free survival in the HS group compared to the non-HS group. Average eGFR slope improved post conversion in the non-HS group, but declined in the HS group, driven by those experiencing rejection post conversion, all of whom converted in the first year posttransplant. The eGFR slope remained stable in those HS recipients not experiencing rejection. In the non-HS group, 6 of 8 rejections developed in those converted in the first posttransplant year; eGFR was stable among rejectors and improved post conversion in nonrejectors. Belatacept conversion in HS patients was associated with reductions in preexisting DSA and absence of de novo DSA development in keeping with other reports;3,7 however, the use of additional immunomodulatory therapy including intravenous immunoglobulin, rituximab, and tocilizumab complicates interpretation.
The study is observational and limited by lack of an ideal comparator group—HS patients remaining on CNI-based therapy. CNI levels at conversion and details of dose reductions employed before conversion are not reported. Inherent difficulties comparing HS and non-HS groups include different expected long-term outcomes and confounding effects of differing induction protocols.
The HS group incorporates a wide range of immunological risk. The non-HS group all had 0% PRA, with neither reflecting populations studied in RCT. Positive crossmatch at transplant, presence of DSA at transplant, and conversion within the first posttransplant year but not HS status were associated with increased hazard of rejection post conversion. Presence of DSA at the time of conversion and eGFR ≤30 mL/min/1.73 mw, but not HS status, were associated with increased risk of death-censored graft-failure. Classification based on these factors may better stratify the cohort enabling identification of those at risk of rejection and eGFR decline following belatacept conversion.
The Cedar-Sinai experience identifies a group of sensitized patients with poor outcomes following belatacept conversion, not recognized in other observational studies. The largest of these, a multicenter European retrospective analysis of outcomes in 219 patients converted to belatacept posttransplant, including 35 with DSA at time of conversion, concluded that conversion was safe in sensitized patients with circulating DSA.8 Conversion before 3 months posttransplantation was a risk factor for rejection and the main predictive factor for a significant increase in eGFR; however, these patients were converted because of very poor kidney function and/or histological findings of severe acute tubular necrosis with severe vascular or tubular and interstitial chronic lesions, with lower eGFR than the Cedars-Sinai cohort. Average eGFR improved among the subset with DSA with only 4 of 35 patients experiencing acute rejection. Eight experienced graft loss not associated with acute rejection; in 6 cases related to progressive transplant dysfunction following belatacept conversion late after transplantation (median 45.6 [23.4–127] mo posttransplant) prompted by advanced graft dysfunction associated with chronic antibody-mediated rejection. Baseline characteristics specific to the DSA subgroup are not provided, hindering comparison between studies.
In the absence of RCT in sensitized individuals, best practice remains unclear; therefore, we must try to learn from real-world data, with careful interpretation of data derived from small subgroups within retrospective observational studies with multiple inherent confounders. Although conversion to belatacept may be safe in some HS individuals, particular care should be taken in subjects at high risk of developing rejection, with consideration of the indication driving change, timing posttransplant, rate of CNI tapering and alternative management strategies available, weighing up risks and benefits of all treatment options. Experimental medicine studies providing better understanding of the impact of immunotherapy combinations on the alloimmune response9 may better define those at increased risk of adverse outcomes and guide design of studies to define best treatment strategies.10
1. Durrbach A, Pestana JM, Florman S, et al. Long-term outcomes in belatacept- versus cyclosporine-treated recipients of extended criteria donor kidneys: final results from BENEFIT-EXT, a phase III randomized study. Am J Transplant. 2016; 16:3192–3201
2. Vincenti F, Rostaing L, Grinyo J, et al. Belatacept and long-term outcomes in kidney transplantation. N Engl J Med. 2016; 374:333–343
3. Leibler C, Matignon M, Moktefi A, et al. Belatacept in renal transplant recipient with mild immunologic risk factor: a pilot prospective study (BELACOR). Am J Transplant. 2019; 19:894–906
4. Grinyó JM, Del Carmen Rial M, Alberu J, et al. Safety and efficacy outcomes 3 years after switching to belatacept from a calcineurin inhibitor in kidney transplant recipients: results from a phase 2 randomized trial. Am J Kidney Dis. 2017; 69:587–594
5. Rostaing L, Massari P, Garcia VD, et al. Switching from calcineurin inhibitor-based regimens to a belatacept-based regimen in renal transplant recipients: a randomized phase II study. Clin J Am Soc Nephrol. 2011; 6:430–439
6. Sethi S, Najjar R, Peng A, et al. Outcomes of conversion from calcineurin inhibitor to belatacept-based immunosuppression in HLA sensitized kidney transplant recipients. Transplantation. 2020; 104:1500–1507
7. Bray RA, Gebel HM, Townsend R, et al. 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. Am J Transplant. 2018; 18:1783–1789
8. Darres A, Ulloa C, Brakemeier S, et al. Conversion to belatacept in maintenance kidney transplant patients: a retrospective multicenter European study. Transplantation. 2018; 102:1545–1552
9. Banham GD, Flint SM, Torpey N, et al. Belimumab in kidney transplantation: an experimental medicine, randomised, placebo-controlled phase 2 trial. Lancet. 2018; 391:2619–2630
10. Geissler EK, Hutchinson JA. Immunological investigations empower transplant drug trials. Lancet. 2018; 391:2578–2579