Belatacept-based immunosuppression in de novo liver transplant recipients: 1-year experience from a phase II randomized study

G B Klintmalm, S Feng, J R Lake, H E Vargas, T Wekerle, S Agnes, K A Brown, B Nashan, L Rostaing, S Meadows-Shropshire, M Agarwal, M B Harler, J-C Garcia-Valdecasas, G B Klintmalm, S Feng, J R Lake, H E Vargas, T Wekerle, S Agnes, K A Brown, B Nashan, L Rostaing, S Meadows-Shropshire, M Agarwal, M B Harler, J-C Garcia-Valdecasas

Abstract

This exploratory phase II study evaluated the safety and efficacy of belatacept in de novo adult liver transplant recipients. Patients were randomized (N = 260) to one of the following immunosuppressive regimens: (i) basiliximab + belatacept high dose [HD] + mycophenolate mofetil (MMF), (ii) belatacept HD + MMF, (iii) belatacept low dose [LD] + MMF, (iv) tacrolimus + MMF, or (v) tacrolimus alone. All received corticosteroids. Demographic characteristics were similar among groups. The proportion of patients who met the primary end point (composite of acute rejection, graft loss, death by month 6) was higher in the belatacept groups (42–48%) versus tacrolimus groups (15–38%), with the highest number of deaths and grafts losses in the belatacept LD group. By month 12, the proportion surviving with a functioning graft was higher with tacrolimus + MMF (93%) and lower with belatacept LD (67%) versus other groups (90%: basiliximab + belatacept HD; 83%: belatacept HD; 88%: tacrolimus). Mean calculated GFR was 15–34 mL/min higher in belatacept-treated patients at 1 year. Two cases of posttransplant lymphoproliferative disease and one case of progressive multifocal leukoencephalopathy occurred in belatacept-treated patients. Follow-up beyond month 12 revealed an increase in death and graft loss in another belatacept group (belatacept HD), after which the study was terminated.

Trial registration: ClinicalTrials.gov NCT00555321.

Figures

Figure 1
Figure 1
Patient disposition and dosing. All patients received corticosteroids on days 1–5, which was tapered to ≤10 mg/day by day 30 and ≤5 mg/day by day 90. Thereafter, withdrawal of corticosteroids was at the discretion of the investigator. HD, high dose; LD, low dose; MMF, mycophenolate mofetil.
Figure 2
Figure 2
Mean calculated GFR (MDRD methodology) over time (intent-to-treat analysis, as observed data with no imputation for missing values). All calculated GFR >200 were truncated at 200 mL/min. HD, high dose; LD, low dose; MMF, mycophenolate mofetil.
Figure 3
Figure 3
Serum trough levels and mean daily dosing at specified time points. Concentrations of belatacept in human serum were determined using a validated enzyme-linked immunosorbent assay (ELISA) by PPD (Richmond, VA). (A) Mean serum trough levels of belatacept. (B) Mean daily dose of MMF. (C) Mean serum trough levels of tacrolimus. (D) Mean daily dose of steroids. HD, high dose; LD, low dose; M, month; MMF, mycophenolate mofetil; W, week.
Figure 4
Figure 4
Patient disposition in LTE. HD, high dose; LD, low dose; LTE, long-term extension; MMF, mycophenolate mofetil.

References

    1. Merion RM, Schaubel DE, Dykstra DM, Freeman RB, Port FK, Wolfe RA. The survival benefit of liver transplantation. Am J Transplant. 2005;5:307–313.
    1. Ravaioli M, Grazi GL, Dazzi A, et al. Survival benefit after liver transplantation: A single European center experience. Transplantation. 2009;88:826–834.
    1. Johnston SD, Morris JK, Cramb R, Gunson BK, Neuberger J. Cardiovascular morbidity and mortality after orthotopic liver transplantation. Transplantation. 2002;73:901–906.
    1. Ojo AO, Held PJ, Port FK, et al. Chronic renal failure after transplantation of a nonrenal organ. N Engl J Med. 2003;349:931–940.
    1. Gonwa TA, Mai ML, Melton LB, et al. Renal replacement therapy and orthotopic liver transplantation: The role of continuous veno-venous hemodialysis. Transplantation. 2001;71:1424–1428.
    1. Moreno JM, Cuervas-Mons V, Rubio E, et al. Chronic renal dysfunction after liver transplantation in adult patients: Prevalence, risk factors, and impact on mortality. Transplant Proc. 2003;35:1907–1908.
    1. Gonwa TA, Mai ML, Melton LB, et al. End-stage renal disease (ESRD) after orthotopic liver transplantation (OLTX) using calcineurin-based immunotherapy: Risk of development and treatment. Transplantation. 2001;72:1934–1939.
    1. Gonwa TA, McBride MA, Mai ML, Wadei HM. Kidney transplantation after previous liver transplantation: Analysis of the organ procurement transplant network database. Transplantation. 2011;92:31–35.
    1. Pham PT, Pham PC, Wilkinson AH. Management of renal dysfunction in the liver transplant recipient. Curr Opin Organ Transplant. 2009;14:231–239.
    1. Distant DA, Gonwa TA. The kidney in liver transplantation. J Am Soc Nephrol. 1993;4:129–136.
    1. Lee JP, Heo NJ, Joo KW, et al. Risk factors for consequent kidney impairment and differential impact of liver transplantation on renal function. Nephrol Dial Transplant. 2010;25:2772–2785.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. Grinyó J, Charpentier B, Pestana JM, et al. An integrated safety profile analysis of belatacept in kidney transplant recipients. Transplantation. 2010;90:1521–1527.
    1. Demetris AJ, Batts KP, Dhillon AP, et al. Banff schema for grading liver allograft rejection: An international consensus document. Hepatology. 1997;25:658–663.
    1. Ishak K, Baptista A, Bianchi L, et al. Histological grading and staging of chronic hepatitis. J Hepatol. 1995;22:696–699.
    1. Neuhaus P, Clavien PA, Kittur D, et al. Improved treatment response with basiliximab immunoprophylaxis after liver transplantation: Results from a double-blind randomized placebo-controlled trial. Liver Transpl. 2002;8:132–142.
    1. Wiesner R, Rabkin J, Klintmalm G, et al. A randomized double-blind comparative study of mycophenolate mofetil and azathioprine in combination with cyclosporine and corticosteroids in primary liver transplant recipients. Liver Transpl. 2001;7:442–450.
    1. Shen J, Gelb JS, Townsend RM, et al. Rationale for belatacept less intensive regimen in renal transplant recipients. Am J Transplant. 2011;11:352. (Suppl S2, Abstract #1096)
    1. Sánchez-Fueyo A, Strom TB. Immunologic basis of graft rejection and tolerance following transplantation of liver and other solid organs. Gastroenterology. 2011;140:51–64.
    1. Crispe IN. Liver antigen-presenting cells. J Hepatol. 2011;54:357–365.
    1. Wekerle T, Grinyó JM. Belatacept: From rational design to clinical application. Transpl Int. 2012;25:139–150.
    1. Moreso F, Serón D, Morales JM, et al. Incidence of leukopenia and cytomegalovirus disease in kidney transplants treated with mycophenolate mofetil combined with low cyclosporine and steroid doses. Clin Transplant. 1998;12:198–205.

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