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 May;69(5):587-594 doi: 10.1053/j.ajkd.2016.09.021.
Abstract
BACKGROUND:

In a phase 2 study, kidney transplant recipients of low immunologic risk who switched from a calcineurin inhibitor (CNI) to belatacept had improved kidney function at 12 months postconversion versus those continuing CNI therapy, with a low rate of acute rejection and no transplant loss.

STUDY DESIGN:

36-month follow-up of the intention-to-treat population.

SETTING & PARTICIPANTS:

CNI-treated adult kidney transplant recipients with stable transplant function (estimated glomerular filtration rate [eGFR], 35-75mL/min/1.73m2).

INTERVENTIONS:

At 6 to 36 months posttransplantation, patients were randomly assigned to switch to belatacept-based immunosuppression (n=84) or continue CNI-based therapy (n=89).

OUTCOMES:

Safety was the primary outcome. eGFR, acute rejection, transplant loss, and death were also assessed.

MEASUREMENTS:

Treatment exposure-adjusted incidence rates for safety, repeated-measures modeling for eGFR, Kaplan-Meier analyses for efficacy.

RESULTS:

Serious adverse events occurred in 33 (39%) belatacept-treated patients and 36 (40%) patients in the CNI group. Treatment exposure-adjusted incidence rates for serious infections (belatacept vs CNI, 10.21 vs 9.31 per 100 person-years) and malignancies (3.01 vs 3.41 per 100 person-years) were similar. More patients in the belatacept versus CNI group had any-grade viral infections (14.60 vs 11.00 per 100 person-years). No posttransplantation lymphoproliferative disorder was reported. Belatacept-treated patients had a significantly greater estimated gain in mean eGFR (1.90 vs 0.07mL/min/1.73m2 per year; P for time-by-treatment interaction effect = 0.01). The probability of acute rejection was not significantly different for belatacept (8.38% vs 3.60%; HR, 2.50 [95% CI, 0.65-9.65; P=0.2). HR for the comparison of belatacept to the CNI group for time to death or transplant loss was 1.00 (95% CI, 0.14-7.07; P=0.9).

LIMITATIONS:

Exploratory post hoc analysis with a small sample size.

CONCLUSIONS:

Switching patients from a CNI to belatacept may represent a safe approach to immunosuppression and is being further explored in an ongoing phase 3b trial.

CET Conclusion
Reviewer: Centre for Evidence in Transplantation
Conclusion: This manuscript reports the 36-month extension from a phase 2 study randomising stable kidney transplant recipients (6-36 months post-transplant) to either continue CNI or switch to Belatacept. The renal function benefit seen at earlier time-points appears to be maintained, with an acceptable safety profile in both arms. Hazard for acute rejection is increased with Belatacept (HR 2.50), but this does not reach significance due to the small size of the study. In all, these data suggest that a switch to belatacept is safe and may result in small improvements in renal function compared to CNI-based therapy. The results are made difficult to interpret as patients/investigators were given the option to switch to belatacept at month 24. 16 patients (around 18%) in the CNI arm chose to switch, which may lead to an underestimation of any efficacy benefit or additional risk posed by the use of belatacept.
Expert Review
Reviewer: Dr Claudio Ponticelli, Humanitas Clinical and Research Center, Rozzano, Milano, Italy.
Conflicts of Interest: No
Clinical Impact Rating 5
Review: In this multicenter controlled trial, 173 CNI-treated adult kidney transplant recipients with stable graft function were randomly assigned to continue therapy with CNI (89 patients) or to be converted to belatacept (84 patients) at 6-36 months after transplantation. Belatacept-treated patients showed a significantly greater increase in GFR compared to CNI (+1.9 vs 0.07 ml/min). No difference between the two arms was seen in death, graft loss, acute rejection, serious adverse events, serious infection or malignancy. However, viral infection occurred more frequently in belatacept-treated patients. This study confirms that switching patients with stable renal graft function from CNI to belatacept is safe. The fact that the mean GFR at 36 months is better in belatacept-treated patients may represent an important result. However, it is also comforting to note that no attrition of renal function was seen in patients who continued CNI up to 3 years. Of note, the concern that belatacept might increase the risk of posttransplant lymphoproliferative disorder (PTLD) seems to be limited to EBV negative patients. Indeed, no case of PTLD was observed in this trial. In conclusion, the results of this study reinforce the idea that different but equally effective treatments are now available for kidney transplant recipients and that switching from a treatment to another one seems to be feasible and relatively safe, at least in patients with stable renal graft function.
Study Details
Aims: To summarise outcomes, specifically the safety and tolerability of belatacept at 36 months post randomization of kidney transplant recipients with low immunologic risk who switched from a calcineurin inhibitor (CNI) to belatacept.
Interventions: Participants were randomized to either switch to a belatacept-based immunosuppression (5 mg/kg of belatacept intravenous on days 1, 15, 29, 43, and 57 and every 28 days thereafter) or continue with CNI-based therapy.
Participants: 173 adult stable kidney transplant recipients who were receiving CNI based maintenance immunosuppression.
Outcomes: The primary outcome measured was safety, specifically adverse events (AEs) and serious AEs. Secondary outcomes measured were estimated glomerular filtration rate, acute rejection, transplant loss, and death.
Follow Up: 36 months
Metadata
Publication type: Multicenter Study, Randomized Controlled Trial, Randomised Controlled Trial
Organ: Kidney
Language: English
MeSH terms: Abatacept; Adult; Calcineurin Inhibitors; Cyclosporine; Drug Substitution; Female; Graft Rejection; Graft Survival; Humans; Immunocompromised Host; Immunosuppressive Agents; Infections; Kidney Transplantation; Lymphoproliferative Disorders; Male; Middle Aged; Mortality; Neoplasms; Tacrolimus; Treatment Outcome; Infectionsim [Immunology]; 0 (Calcineurin Inhibitors); 0 (Immunosuppressive Agents); 7D0YB67S97 (Abatacept); 83HN0GTJ6D (Cyclosporine); WM0HAQ4WNM (Tacrolimus)