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Belatacept in Solid Organ Transplant

Review of Current Literature Across Transplant Types

Perez, Caroline P. PharmD, BCPS1; Patel, Neha PharmD1; Mardis, Caitlin R. PharmD2; Meadows, Holly B. PharmD1; Taber, David J. PharmD3,4; Pilch, Nicole A. PharmD5

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doi: 10.1097/TP.0000000000002291
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Renal transplantation has shown to improve morbidity and mortality as well as quality of life in end-stage renal disease patients.1 Calcineurin inhibitors (CNI) have been the foundation of immunosuppression for renal transplant patients since the 1980s.2-4 Long-term CNI exposure unfortunately is associated with nephrotoxicity, and depending on the agent posttransplant, diabetes mellitus, dyslipidemia, gingival hyperplasia, alopecia, and hypertension. Several of these adverse effects has contributed to increased rates of cardiovascular morbidity and mortality in this patient population, as well as decline in allograft function over time.5-8 Alternative regimens to minimize these adverse effects have become more prominent in today's practice.

The co-stimulation pathway for T-cell activation is one that has been studied in recent years. CD28 was identified as a crucial co-stimulatory molecule that was required for T-cell activation, whereas CTLA-4, its homologue, was found to attenuate T-cell activation. Both CD28 and CTL4-A bind to CD80 and CD86 that are found on antigen-presenting cells. It was hypothesized that by inhibiting CD80/86 receptors with a high affinity molecule could block costimulation and inhibition of T-cell activation. Abatacept, CTLA4-Ig fusion protein, was the first agent developed. It was shown to have promising results in managing autoimmune disorders, such as psoriasis and rheumatoid arthritis, but in animal transplant model studies was found to have an inadequate response. Belatacept, the daughter protein to abatacept, was then developed and found to have a fourfold binding affinity to CD86 and CD80 than its counterpart.9 Belatacept has shown some promising results in preserving renal function and minimizing adverse effect.10 The aim of this review is to determine belatacept's role in transplantation and discuss its use in practice.

DE NOVO BELATACEPT USE IN KIDNEY TRANSPLANTATION

Maintenance immunosuppression with CNIs improve 1-year survival but are associated with long-term adverse effects, such as cardiovascular disease, glucose homeostasis, and acute and chronic nephrotoxicity. Table 1 summarizes the de novo belatacept data in kidney transplant recipients. Vincenti and colleagues11 published the first phase 2 multicenter trial that compared the safety and efficacy of 2 dosing regimens (more or less-intensity) of belatacept to cyclosporine (CsA). All patients received induction with basiliximab 20 mg on days 0 and 4, mycophenolate mofetil (MMF) 2 g daily, and a corticosteroid taper but continued corticosteroids long-term. At 12 months, the measured glomerular filtration rate (GFR) was significantly higher in the patients that received more intensive (MI) and less intensive (LI) belatacept regimens compared to the CsA arm (66.3, 62.1, and 53.5 mL/min per m2, respectively; P = 0.01 for the comparison between intensive belatacept and CsA and P = 0.04 between the less-intensive belatacept and CsA). At month 12, the incidence of chronic allograft nephropathy was lower in belatacept groups compared with CsA.

TABLE 1
TABLE 1:
De novo belatacept use in kidney transplant

Subsequently, multiple phase 3 trials were conducted, Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial (BENEFIT), a 3-year, randomized, active-controlled, parallel group, multicenter phase 3 trial.12-15 Patients were eligible to enroll if they received a living donor or standard criteria deceased donor kidney with a PRA less than 50%. Patients were randomized to 1 of 3 groups: MI or LI belatacept versus CsA. All patients received basiliximab for induction and MMF and corticosteroids for a maintenance regimen. Belatacept dosing is shown in Table 1. Both belatacept regimens were noninferior (using 10% noninferiority margin) to CsA on the primary endpoint of patient and graft survival. At 1 year, MI, LI, and CsA treatment groups had a 95%, 97%, and 93% patient and graft survivals, respectively. The mean GFR at 1 year was significantly higher in both belatacept regimens. By year 3, belatacept-treated patients continued to have a higher GFR compared with CsA-treated group.13 At 5 and 7 years, the calculated GFR remained higher in both belatacept groups and continued to decline with the CsA regimen.14,15 The incidence of acute rejection at 12 months was higher in the belatacept group (22% in MI, 17% in LI, and 7% in CsA regimen).12 The incidence of acute rejection met the noninferiority criteria between belatacept LI and CsA group but not MI belatacept and CsA. There were no new cases of rejection in the belatacept groups from years 2 and 3.13 At year 5, there was 1 additional case of rejection in each the LI belatacept group and CsA group.14 At year 7, there were no additional cases of rejection.15 Overall, there were no differences in patient or graft survival over the 7 years in those who remained on therapy.

The second set of phase 3 trials, BENEFIT-EXTended criteria donors (BENEFIT-EXT) is a 3-year randomized, multicenter study in patients who received a kidney transplant from an extended criteria which include, donor older than 60 years; 50 years or older, and at least 2 other risk factors (CVA, hypertension, serum creatinine >1.5 mg/dL); anticipated cold ischemic time of at least 24 hours; or donation after circulatory death.16-19 All patients received basiliximab for induction and maintenance therapy with MMF and corticosteroids. Belatacept dosing was same as those used in the BENEFIT trials. Both belatacept regimens were noninferior to CsA on patient and graft survival. The mean GFR at 1 year was 52.1, 49.5, and 45.2 mL/min per m2 for the MI, LI, and CsA groups, respectively. The difference in GFR was significantly better in the MI-treated group versus CsA-treated group (P = 0.0083).16 At year 3, mean GFR remained higher in both belatacept regimens; however, the difference did not reach significance.17 At 5 years, the adjusted mean GFR was 74.1 ± 18.9, 76.4 ± 19, and 53 ± 17.2 mL/min per m2 for the MI, LI, and CsA groups, respectively (P < 0.0001 for belatacept vs CsA).18 At year 7, both belatacept regimens maintained a higher GFR compared to the CsA regimen; however, it did not reach significance.19 There was no significant difference in the incidence of acute rejection between the 3 groups at years 1, 3, 5, and 7. Patient and graft survivals were similar between all 3 groups throughout the study.16-19

Hypertension is associated with increased risk for cardiovascular disease and diminished renal function. In both the BENEFIT and BENEFIT-EXT trials, diastolic and systolic blood pressure were lower in belatacept-treated patient compared with CsA-treated patients. Similarly, changes in lipids from baseline were more significant in the CsA group, which is consistent with the known effects of CNI-based regimens.15,19 The incidence of new-onset diabetes mellitus was similar across all groups. Interestingly, there was less donor-specific antibody (DSA) development in patients who received belatacept versus CsA. The recent subanalysis by Bray and colleagues provides additional granular detail about mean fluorescence intensity between the groups, and their data further indicate that even when DSA develops in belatacept recipients, it developed at a lower level than that in patients treated with CNIs.20 These data may create additional uses for costimulatory blockade in the pretransplant period and for challenging antibody-mediated rejections posttransplant.

Adams and colleagues recently published a retrospective study of their institutional experience of using de novo belatacept versus tacrolimus. This particular study included patients who were underrepresented in clinical trials, including African Americans and higher immunological risk. They compared a standard tacrolimus-based regimen with MMF 1 gram twice daily and corticosteroids tapered to 5 mg daily by postoperative day (POD) 3 to de novo belatacept based on package insert recommendations. Belatacept was given 10 mg/kg perioperatively and on PODs 4, 14, 28, 56, and 86 with subsequent doses of 5 mg/kg given every 4 weeks. Recipients also received MMF and corticosteroids as the tacrolimus-based regimen group, and all patients in the study received basiliximab for induction therapy. An increased risk of rejection at 1 year was observed in the belatacept group versus tacrolimus (50.5% vs 20.5%, P < 0.001) as well as more severe rejection grades were noted in the belatacept group. These high rates of rejection lead to modification of their initial belatacept regimen. They overlapped tacrolimus for the first 6 months posttransplant and belatacept doses given on days 4 and 14 were eliminated. With this new regimen, initial rejection rates at 3 months were similar to the tacrolimus group (14.9% vs 17.1%), but once tacrolimus was tapered off an additional cohort of patients experienced rejection in the belatacept group (33.3% vs 20.5%, P = 0.046) and again were more severe in nature. With still unacceptable rejection rates, Adams and colleagues again modified their belatacept regimen to include a longer duration of tacrolimus that was tapered off by month 12 posttransplant. With this new cohort of belatacept/extended tacrolimus group, they found similar rates and grades of rejection when compared tacrolimus alone at 12 months (16% vs 20.5%, P = 0.90). Renal function was significantly higher in all belatacept-based regimens as compared with tacrolimus, and patient and graft survival was equivalent for all groups. Interestingly, belatacept-based regimens were associated with a significantly lower risk of DSA formation at 1 year (4.14% vs 8.82%, P = 0.04).21 This finding does confirm some of the findings seen in the BENEFIT trial as previously mentioned.

CONVERSION TO BELATACEPT FROM A CNI-BASED REGIMEN IN KIDNEY TRANSPLANT

The BENEFIT and BENEFIT-EXT de novo studies revealed the renal-protective effects of belatacept in kidney transplant recipients, but at the expense of increased rates of rejection within the first year after transplant.11-19 With this in mind, several investigators have evaluated converting to belatacept posttransplant to avoid prolonged CNI exposure (Table 2). A phase II, randomized, open-label study compared the safety and efficacy of converting stable kidney transplant patients from CNI therapy to belatacept versus remaining on CNI maintenance therapy. Patients were enrolled if they received a kidney transplant 6 months prior, on stable doses of tacrolimus or CsA, and stable renal function. At 1 year, the mean change in cGFR from baseline was higher in the belatacept group versus the CNI group (7.0 and 2.1 mL/min per 1.73 m2, respectively; P = 0.0058). There were 6 acute rejection episodes with belatacept versus none with CNIs. No grafts were lost in either group, and 1 patient died in the CNI with a functioning graft.22

TABLE 2
TABLE 2:
Belatacept conversion in kidney transplant

Two- and 3-year results from the phase II trial showed sustained improvement in renal function with belatacept.23,24 At 2 years, the mean change in cGFR was 8.8 mL/min per 1.73 m2 in the belatacept group and 0.3 mL/min per 1.73 m2 in the CNI group.23 Three-year analysis revealed a significantly higher estimated gain in mean eGFR per year with belatacept versus CNIs (1.9 and 0.07 mL/min per 1.73 m2, respectively; P = 0.1).24 There were no new acute rejection episodes in the belatacept group at 2 years while 3 patients in the CNI group did.23 The 3-year cumulative rates of acute rejection was 8.38% with belatacept and 3.6% with CNIs, with a probability of acute rejection in the belatacept group versus CNI being 2.5 (95% confidence interval, 0.65-9.65; 0.2).24 Patient and graft survival at 2 and 3 years were equivalent in both groups.23,24

There has been recent data describing early conversion to belatacept in patients with CNI toxicity or marginal renal function. Nair and colleagues25 published a retrospective cohort study of conversion to belatacept within 6 months from transplant with a median time to conversion of 81.5 days. The serum creatinine fell from a baseline of 3.9 to 2.1 mg/dL and 1.9 mg/dL at 6 and 12 months postconversion, respectively. Only 2 cases of borderline rejection occurred postconversion. Patient survival was 100%, and graft survival was 88%. Early conversion in recipients of extended-criteria donors, as defined in the BENEFIT-EXT study above, was described by Le Meur and colleagues.26 Patients were converted less than 6 months posttransplant due to CNI intolerance. cGFR had improved by 6 months postconversion from a baseline of 18.28 to 33.9 mL/min (P < 0.001) and was sustained at 1 year (34.9 mL/min; P < 0.001) and 2 years (35.6 mL/min; P = 0.001). Three of the 25 patients evaluated though did not have any renal recovery postswitch. Graft survival 6 months, 1 year, and 2 years postconversion were 88%, 83%, and 70%, respectively. Only 1 patient experienced acute rejection after conversion.

Recent reports have shown promising results in patients with prolonged delayed graft function (DGF), chronic transplant nephropathy, or significant allograft dysfunction secondary to CNI exposure. Wojciechowski and colleagues27 evaluated early conversion to belatacept in patients with prolonged DGF. Mean eGFR rose from 16 to 43.1 mL/min per 1.73 m2 within 30 days postconversion (P < 0.001) and continued to rise to 54.2 mL/min per 1.73 m2 at 1 year. Renal improvement was sustained at 2 years postconversion (53.9 mL/min per 1.73 m2). Acute rejection within 1 year posttransplant occurred in 20% of patients, and no additional episodes were seen between year 1 and 2. Graft survival was 95% by year 2. In a large retrospective analysis, Brakemeier and colleagues28 described late conversion to belatacept in kidney recipients with chronic transplant nephropathy or CNI-induced nephrotoxicity with worsening renal function. Mean time to conversion was 69 months. Mean eGFR had increased from a baseline of 26.1 to 29.7 mL/min per 1.73 m2 at 3 months (P = 0.002), 31.6 mL/min per 1.73 m2 at 6 months (P < 0.0005), and 34 mL/min per 1.73 m2 at 1 year (P < 0.0005). Proteinuria levels had decreased from 413 to 255 mg/L at 1 year postconversion. Graft survival was 93.6% and 85.6% 6 months and 1 year postconversion, respectively. Schulte and colleagues29 published results on late conversion in patients with CNI intolerance or chronic allograft dysfunction and the first to describe belatacept’s impact on acid-base handling and mineral bone metabolism. The eGFR had improved from 22.2 to 34.4, and 32.1 mL/min at 6 and 12 months, respectively. Serum bicarbonate levels increased significantly from 24.4 mmol/L to 28.7 mmol/L (P < 0.001), as well as pH from 7.34 to 7.36 (P < 0.005) after conversion. Parathyroid hormone levels decreased (125 ng/L vs 80.7 ng/L; P < 0.01), serum phosphate levels decreased (1.21 mmol/L vs 1.08 mmol/L; P < 0.05), serum albumin levels increased (3.95 g/dL vs 4.4 g/dL; P < 0.01) postconversion. Serum calcium and ionized calcium levels were equivalent preconversion and postconversion.

There are limited data using belatacept for immunologically high-risk patients, and the increased risk of rejection with belatacept in immunologically low-risk patients seen in the BENEFIT studies has lead centers to avoid its use in sensitized patients. Gupta and colleagues30 report their experience in converting highly sensitized patients to belatacept for presumed CNI toxicity and/or interstitial fibrosis and tubular atrophy. Majority of patients had a PRA >80% and were of retransplant status. Mean eGFR improved significantly from 23.8 to 42 mL/min per 1.73 m2 postconversion (P = 0.028). Two patients who had DGF had renal recovery. Postconversion biopsy results did not reveal any signs of acute rejection or worsening chronicity and new DSAs had not developed in any patient. Although this study was promising, more data is needed to determine if belatacept is safe to use in a high immunological risk population and what concomitant immunosuppression is needed.

BELATACEPT AND LIVER TRANSPLANTATION

Klintmalm and colleagues31 published the findings of the phase II exploratory trial evaluating the safety and efficacy of belatacept in liver transplant recipients. This study was the first controlled trial that demonstrated some concerns about using belatacept in liver transplant. Results failed to demonstrate safety or effectiveness (Table 3). The challenge with this study is the limited number of patients and significant number of study groups. As a result of this study the package insert continues to carry the black box language that belatacept is not recommended for use in liver transplant secondary to the risk of graft loss and death.32,33 Despite these negative results centers continue to explore avenues for use within liver transplant recipients specifically to mitigate the effects of calcineurin on renal function or neurotoxicity. LaMattina and colleagues34 evaluated Hepatitis C positive liver transplant recipients with peritransplant renal dysfunction using belatacept. They demonstrated that this agent can be used in selected patients to allow for CNI avoidance in the early posttransplant period. This study was small and subjects were converted back to a CNI-based regimen but does provide evidence that use may be beneficial in select patients.34 Schwarz and colleagues35 also postulated that belatacept would be beneficial in liver transplant recipients to facilitate maintenance immunosuppression withdrawal. Authors evaluated 8 patients who were part of a substudy of patients maintained on belatacept and MMF versus tacrolimus based regimens (Table 3). This study demonstrated that belatacept did now allow for long-term tolerance and patients were not able to be maintained on MMF monotherapy upon belatacept withdrawal without experiencing graft dysfunction.35 Despite mixed evidence in liver transplantation, belatacept is an available option for select patients who are unable to tolerate CNIs.

TABLE 3
TABLE 3:
Belatacept and liver transplant

BELATACEPT IN NONABDOMINAL, PANCREAS, AND PEDIATRIC TRANSPLANT

Data in nonabdominal organ transplant, pancreas, and pediatrics have been limited to case reports and series. Table 4 outlines the existing literature. Patients in these cases were mainly converted secondary to immunosuppression nonadherence concerns or calcineurin induced toxicity that was unable to be managed by mammalian target of rapamycin (mTOR) addition or conversion. Data in these selected patients indicate that there are several scenarios in which belatacept can be considered and safely used with the appropriate monitoring for efficacy and toxicity.

TABLE 4
TABLE 4:
Belatacept in nonabdominal transplant, pancreas, and pediatrics

BELATACEPT IN COMBINATION WITH mTOR INHIBITORS

There have been few studies that have used belatacept in combination with mTORs. Ferguson and colleagues36 evaluated 89 patients randomized to 3 treatment regimens comparing belatacept with MMF, belatacept with sirolimus, and tacrolimus with MMF in low-to-moderate risk kidney transplant recipients. All patients received antithymocyte globulin for induction and methylprednisolone for days 0 to 4 then steroids were withdrawn. One-year acute rejection rates were 15% in belatacept-MMF group, 4% in belatacept-sirolimus group, and 3% in tacrolimus-MMF group. There were 2 graft losses at 1 year in each of the belatacept groups. Mean GFR at month 12 was approximately 8 to 10 mL/min per 1.73 m2 higher in the belatacept groups. Approximately 70% of patients in the belatacept groups remained off CNIs and steroids at month 12. There were no major differences in adverse events between groups.

Kirk and colleagues37 studied the use of belatacept without CNIs and steroids in 20 low-risk kidney transplant patients. Patients received induction with alemtuzumab. Belatacept and sirolimus were initiated the following day. Nine patients received donor bone marrow infusion. There were no clinical rejections or development of DSA at 1 year, although there were 3 patients with subclinical rejection on surveillance biopsy. Estimated mean GFR remained greater than 80 mL/min for 36 months posttransplant. Seven patients were weaned successfully off oral immunosuppression to belatacept monotherapy after 1 year (2). BK viremia occurred in 10 patients, but resolved with reduction in oral immunosuppression.

The use of belatacept with mTORs in these studies shows promise. Both studies used depleting induction therapy, steroid avoidance or withdrawal and CNI avoidance with acceptable rejection rates and adverse events with excellent graft function. Most patients included in these studies were low- to moderate-risk patients. More studies are needed to define the role of mTORs with belatacept, particularly in the high-risk kidney transplant population.

ADVERSE EFFECTS ASSOCIATED WITH BELATACEPT USE

The published outcomes of the BENEFIT and BENEFIT-EXT studies all reported similar safety profiles between the LI belatacept, MI belatacept, and CsA groups, and belatacept has continued to have an acceptable safety profile in conversion trials.12,13,16,24,38,39 At month 84 of the BENEFIT study, the cumulative frequencies of serious adverse events remained comparable between arms at 68.6% (LI), 70.8% (MI), and 76.0% (CsA).39 Discontinuation of the study regimen specifically due to adverse events (excluding death or lack of efficacy) by month 84 occurred in 5% to 6% of patients in each arm.39

The most common serious safety events at 7 years of follow-up in the BENEFIT study were infectious in nature, with cumulative incidence rates of serious infections of 10.7, 10.6, and 13.3 events per 100 person-years of treatment exposure in the LI, MI, and CsA groups. Urinary tract infections and cytomegalovirus infections were most common, but no difference was observed between treatment groups.39 Adams et al21 did report a significantly higher rate of CMV viremia when belatacept was used without adjunct tacrolimus, which was attributed to the higher rates of rejection in this arm and subsequent administration of antithymocyte globulin and steroids for treatment.

One of the most significant concerns related to belatacept therapy following early published experiences were posttransplant lymphoproliferative disease (PTLD), specifically central nervous system (CNS) PTLD. At 7 years of follow-up of the BENEFIT cohort, a total of 5 patients in the belatacept arms (2 LI, 3 MI) and 2 in the CSA arm developed PTLD. Two of the 5 cases in the belatacept arms (both MI) involved the CNS. Three of the 7 cases in the study occurred in EBV-negative patients, 2 of whom also received T cell depleting therapy. Of the 4 cases which occurred in EBV-positive patients, 1 received T cell depleting therapy. All cases in belatacept-treated patients occurred within the first 24 months of therapy. Within 2 years of follow up in the BENEFIT-EXT cohort, 5 patients in the belatacept arms (3 LI, 2 MI) developed PLTD, 4 of which involved the CNS. No patients in the CsA arm of BENEFIT-EXT developed PTLD. Three of the 5 cases occurred in EBV-negative patients, and none of the cases involved T cell depleting therapies. Given the early results of the BENEFIT study, an efficacy analysis in EBV-seropositive patients was performed and was found to be similar to the overall population. Belatacept now carries a black box warning against use in EBV seronegative recipients.32 A Cochrane review in 2014 showed no difference in the risk of PTLD among patients who were EBV-negative and those who were EBV-positive, though this was attributed to selective outcome reporting.47

Acute infusion-related reactions related to belatacept are uncommon and mild-to-moderate in nature, occurring in less than 2% of patients in the BENEFIT cohort and not leading to termination of belatacept therapy. Within the BENEFIT-EXT group, 5% of patients in the low-intensity belatacept arm and 4% of patients in the moderate-intensity belatacept arm experienced infusion-related reactions, with a single patient experiencing severe prolonged hypotension.12,16 There has been 1 postmarketing report of an anaphylactic reaction within 5 minutes of initiation of belatacept infusion.32 No premedication is required before the 30-minute infusion.32

Interestingly, primary graft thrombosis revealed itself as a more frequent cause of graft loss in the belatacept arms of the BENEFIT-EXT study, though this was not observed in the BENEFIT study and was not attributed to the study drug.12,16 Data related to termination of a phase 3 trial published in 2017 revealed that enrollment in the belatacept arm (with alemtuzumab induction) was paused due to 3 allograft losses attributed to thrombosis. One case was attributed to vascular clamp injury, one to compression of the inferior vena cava by a native polycystic kidney, and one had no clear technical cause.12

BARRIERS TO USE

Belatacept is limited by formulation and should only be used in patients who are EBV seropositive at the time of initiation. De novo and early conversion regimens require frequent intravenous dosing initially with regular infusion visits. Home infusion companies are available in select areas but some patients have limited access. Also, during the initiation phase, it is desirable to observe patient tolerance and have increased laboratory monitoring to ensure efficacy. After the initial induction phase of belatacept, patients are required to maintain a 28-day infusion schedule for life of their allograft in combination with daily immunosuppression. It is important to explain the regimen and treatment goals with the patient to maximize adherence and therefore safety and efficacy.

The cost of belatacept may also limit patient's access to the medication. The acquisition cost of belatacept per year is around US $21 000, whereas tacrolimus is about US $7000 per year. Nursing time and infusion supplies would also add to the overall costs of belatacept use, though laboratory fees would be saved because belatacept does not require drug level monitoring. The package insert limits use beyond kidney transplant without significant prior approval from third-party payors. Patients with federal healthcare programs are not eligible for co-pay assistance programs. The significant out of pocket cost for patients with limited drug insurance may prohibit use. These patients must then rely on independent charitable foundations to aid with out of pocket costs. Careful consideration of use in patients with limited resources and transportation must be considered to ensure short- and long-term efficacies.

Intravenous access must also be considered. Patients with very poor peripheral access may require more invasive line placement to ensure administration. This may lead to additional infectious risk that outweighs the benefit of the agent. Centers should consider developing protocols to facilitate de novo or conversion protocols which ensure that medication access is feasible long-term. Novel biomarkers, such as graft/donor derived cell-free DNA, which has been studied in several organ groups, or CXCL9 in kidney transplant recipients may provide additional insight into ability use belatacept in more patients and minimize other agents.48-50 Considerations for use of belatacept can be seen in Figure 1.

FIGURE 1
FIGURE 1:
Considerations with belatacept use in transplant recipients.

ONGOING CLINICAL TRIALS USING BELATACEPT THERAPY

There are a significant number of ongoing or recently completed clinical trials assessing novel interventions with the use of belatacept in transplantation. Table 5 provides a summary of the trials listed in clinicaltrials.gov that are ongoing active interventions. Based on a review of these studies, as well as those that are recently completed, a number of themes emerge. Belatacept is predominately being studied in kidney transplantation, with only 1 active study in vascular composite transplant (hand). Novel regimens in kidney transplantation that are actively being investigated with belatacept include using it in combination with cytolytic induction therapy and steroid withdrawal, using it in marginal, distressed, or failing grafts (including to prevent DGF), using it in combination with mTOR therapy and using it in maintenance immunosuppression minimization strategies. For minimization strategies, use with regulatory T-cell infusions to induce tolerance and expanding infusions from every 4 weeks to every 8 weeks are actively being pursued.51

TABLE 5
TABLE 5:
Ongoing clinical trials

There are a number of recently completed studies that have yet to fully publish their results as well. These include assessing the use of belatacept therapy in immunologically high-risk recipients and the potential safety and efficacy of subcutaneously administered belatacept therapy. Subcutaneous administration has the potential to dramatically improve the logistics of using belatacept therapy, particularly if transplant recipients can conduct home-based self-administered therapy. If any of these novel strategies prove to be safe and effective, it may allow for expanded use of belatacept therapy. Finally, it should be noted that currently, based on our review, there are few, if any, ongoing studies in liver, heart, or lung transplantation.48

More trials, which aid in adherence, such as a once daily oral maintenance regimens in combination with belatacept and systematic conversion trials in pediatric or nonadherent patients, are warranted. Also, additional CNI or corticosteroid minimization and withdrawal studies may allow for expanded use in select patient populations. As more costimulatory blockers are introduced in nontransplant disease states (Lupus, rheumatoid arthritis) the use of additional costimulatory blockers in pretransplant and posttransplant recipients is inevitable especially in the setting of options needed for patients at increased risk of DSA development.52

CONCLUSIONS

Belatacept is a viable option in kidney transplant recipients who have not tolerated CNIs or have chronic allograft nephropathy. In both de novo and conversion data, belatacept has shown to have sustained renal protective effects when compared with CNIs. The risk of rejection in the optimal patient is equivocal to standard of care in clinical trials, though recent experiences in clinical practice have demonstrated increased risk of rejection within the first year posttransplant when belatacept was used for all recipients at a single center. Based on our review of the literature, more studies are needed to ensure the efficacy and safety of belatacept use in high immunological risk patients, other immunosuppressive strategies, such as combinations with mTOR inhibitors and steroid withdrawal, and other solid organ recipients.

REFERENCES

1. Wolfe RA, Ashby VB, Milford EL, et al. Comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant. N Engl J Med. 1999;341:1725–1730.
2. Hart A, Smith JM, Skeans MA, et al. OPTN/SRTR 2015 Annual data report: kidney. Am J Transplant. 2017;17(Suppl 1):21–116.
3. Halloran PF. Immunosuppressive drugs for kidney transplantation. N Engl J Med. 2004;351:2715–2729.
4. Patel PS. Overcoming the Force and Power of Immunity: A History of Immunosuppression in Kidney Transplantation. J Nephrol. 2006;19(suppl 10):S137–S143.
5. Glicklich D, Vohra P. Cardiovascular risk assessment before and after kidney transplantation. Cardiol Rev. 2014;22:153–162.
6. Naesens M, Kuypers DR, Sarwal M. Calcineurin inhibitor nephrotoxicity. Clin J Am Soc Nephrol. 2009;4:481–508.
7. Ducloux D, Motte G, Kribs M, et al. Hypertension in renal transplantation: donor and recipient risk factors. Clin Nephrol. 2002;57:409–413.
8. Mathis AS, Davé N, Knipp GT, et al. Drug-related dyslipidemia after renal transplantation. Am J Health Syst Pharm. 2004;61:565–585.
9. Larsen CP, Pearson TC, Adams AB, et al. Rational development of LEA29Y (belatacept), a high-affinity variant of CTLA4-Ig with potent immunosuppressive properties. Am J Transplant. 2005;5:443–453.
10. Hardinger KL, Sunderland D, Wiederrich JA. Belatacept for the prophylaxis of organ rejection in kidney transplant patients: an evidence-based review of its place in therapy. Int J Nephrol Renovasc Dis. 2016;9:139–150.
11. Vincenti F, Larsen C, Durrbach A, et al. Costimulation blockade with belatacept in renal transplantation. N Engl J Med. 2005;353:770–781.
12. Vincenti F, Charpentier B, Vanrenterghem Y, et al. A phase III study of belatacept-based immunosuppression regimens versus cyclosporine in renal transplant recipients (BENEFIT Study). Am J Transplant. 2010;10:535–546.
13. Vincenti F, Larsen CP, Alberu J, et al. Three-year outcomes from BENEFIT, a randomized, active-controlled, parallel-group study in adult kidney transplant recipients. Am J Transplant. 2012;12:210–217.
14. Rostaing L, Vincenti F, Grinyo J, et al. Long-term belatacept exposure maintains efficacy and safety at 5 years: results from the long-term extension of the BENEFIT study. Am J Transplant. 2013;13:2875–2883.
15. Vincenti F, Rostaing L, Grinyo J, et al. Belatacept and long-term outcomes in kidney transplantation. N Engl J Med. 2016;374:333–343.
16. 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;10:547–557.
17. Pestana JO, Grinyo JM, Vanrenterghem Y, et al. Three-year outcomes from BENEFIT-EXT: a phase III study of belatacept versus cyclosporine in recipients of extended criteria donor kidneys. Am J Transplant. 2012;12:630–639.
18. Charpentier B, Medina Pestana JO, del C Rial M, et al. Long-term exposure to belatacept in recipients of extended criteria donor kidneys. Am J Transplant. 2013;13:2884–2891.
19. 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.
20. 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.
21. Adams AB, Goldstein J, Garrett C, et al. Belatacept combined with transient calcineurin inhibitor therapy prevents rejection and promotes improved long-term renal allograft function. Am J Transplant. 2018;18:1783–1789.
22. 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.
23. Grinyo J, Alberu J, Contieri FL, et al. Improvement in renal function in kidney transplant recipients switched from cyclosporine or tacrolimus to belatacept: 2-year results from the long-term extension of a phase II study. Transpl Int. 2012;25:1059–1064.
24. 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.
25. Nair V, Liriano-Ward L, Kent R, et al. Early conversion to belatacept after renal transplantation. Clin Transplant. 2017;31:e12951.
26. Le Meur Y, Aulagnon F, Bertrand D, et al. Effect of an early switch to belatacept among calcineurin inhibitor-intolerant graft recipients of kidneys from extended-criteria donors. Am J Transplant. 2016;16:2181–2186.
27. Wojciechowski D, Chandran S, Vincenti F. Early post-transplant conversion from tacrolimus to belatacept for prolonged delyaed graft function improves renal function in kidney transplant recipients. Clin Transplant. 2017;31:e12930.
28. Brakemeier S, Kannenkeril D, Durr M, et al. Experience with belatacept rescue therapy in kidney transplant recipients. Transpl Int. 2016;29:1184–1195.
29. Schulte K, Vollmer C, Klasen V, et al. Late conversion from tacrolimus to a belatacept-based immuno-suppression regime in kidney transplant recipients improves renal function, acid-base derangement and mineral-bone metabolism. J Nephrol. 2017;30:607–615.
30. Gupta G, Regmi A, Kumar D, et al. Safe conversion from tacrolimus to belatacept in high immunologic risk kidney transplant recipients with allograft dysfunction. Am J Transplant. 2015;15:2726–2731.
31. Klintmalm GB, Lake JR, Vargas HE, et al. Belatacept-based immunosuppression in de novo liver transplant recipients: 1-year experience from a phase II randomized study. Am J Transplant. 2014;14:1817–1827.
32. Nulojix (belatacept) [package insert]. Bristol-Myers Squibb. Belatacept (NULOJIX). Prescribing information. Princeton, NJ: Bristol-Myers Squibb Company; revised April 2018.
33. Knechtle SJ, Adams AB. Belatacept: is there BENEFIT for liver transplantation too? Am J Transplant. 2014;14:1717–1718.
34. LaMattina JC, Hanish SI, Ottmann SE, et al. Safety of belatacept bridging immunosuppression in hepatitis C-positive liver transplant recipients with renal dysfunction. Transplantation. 2014;97:133–137.
35. Schwarz C, Rasoul-Rockenschaub S, Soliman T, et al. Belatacept treatment for two yr after liver transplantation is not associated with operational tolerance. Clin Transplant. 2015;29:85–89.
36. Ferguson R, Grinyo J, Vincenti F, et al. Immunosuppression with belatacept-based corticosteroid-avoiding regimens in de novo kidney transplant recipients. Am J Transplant. 2011;11:66–76.
37. Kirk AD, Guasch A, Xu H, et al. Renal transplantation using belatacept without maintenance steroids or calcineurin inhibitors. Am J Transplant. 2014;14:1142–1151.
38. Larsen CP, Grinyó J, Medina-Pestana J, et al. Belatacept-based regimens versus a cyclosporine A-based regimen in kidney transplant recipients: 2-year results from the BENEFIT and BENEFIT-EXT studies. Transplantation. 2010;90:1528–1535.
39. Vincenti F. Belatacept and long-term outcomes in kidney transplantation. N Engl J Med. 2016;374:2600–2601.
40. Enderby CY, Habib P, Patel PC, et al. Belatacept maintenance in a heart transplant recipient. Transplantation. 2014;98:74–75.
    41. Ong P, Mudambi L, Fuenteset A, et al. Belatacept as Primary Immunosuppression in a Lung Transplant Recipient. J Heart Lung Transplant. 2014;33(S4):S31.
    42. Timofte I, Terrin M, Barr E, et al. Belatacept for renal rescue in lung transplant patients. Transpl Int. 2016;29:453–463.
    43. Iasella CJ, Winstead RJ, Moore CA, et al. Maintenance Belatacept-Based Immunosuppression in Lung Transplantation Recipients Who Failed Calcineurin Inhibitors. Transplantation. 2018;102:171–177.
    44. Lerch C, Kanzelmeyer NK, Ahlenstiel-Grunow T, et al. Belatacept after kidney transplantation in adolescents: a retrospective study. Transpl Int. 2017;30:494–501.
    45. Mujtaba MA, Sharfuddin AA, Taber T, et al. Conversion from tacrolimus to belatacept to prevent the progression of chronic kidney disease in pancreas transplantation: case report of two patients. Am J Transplant. 2014;14:2657–2661.
    46. Posselt AM, Szot GL, Frassetto LA, et al. Islet transplantation in type 1 diabetic patients using CNI-free immunosuppressive protocols based on T cell adhesion or costimulation blockade. Transplantation. 2010;90:1595–1601.
    47. Masson P, Henderson L, Chapman JR, et al. Belatacept for kidney transplant recipients. Cochrane Database Syst Rev. 2014; 11:CD010699.
    48. Schütz E, Fischer A, Beck J, et al. Graft-derived cell-free DNA, a noninvasive early rejection and graft damage marker in liver transplantation: a prospective, observational, multicenter cohort study. PLoS Med. 2017;14: e1002286.
    49. Bloom RD, Bromberg JS, Poggio ED, et al. Cell-free DNA and active rejection in kidney allografts. J Am Soc Nephrol. 2017;28:2221–2232.
    50. Hricik DE, Nickerson P, Formica RN, et al. Multicenter validation of urinary CXCL9 as a risk-stratifying biomarker for kidney transplant injury. Am J Transplant. 2013;13:2634–2644.
    51. NIH U.S. National Library of Medicine. Clinical Trials website. clinicaltrials.gov. Accessed September 21, 2017.
    52. Kälble F, Schaier M, Schäfer S, et al. An update on chemical pharmacotherapy options for the prevention of kidney transplant rejection with a focus on costimulation blockade. Expert Opin Pharmacother. 2017;18:799–807.
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