Biologics in Transplantation (Anti-thymocyte Globulin, Belatacept, Alemtuzumab): How Should We Use Them?

Kahan BD. Individuality: the barrier to optimal immunosuppression. Nat Rev Immunol. 2003;3(10):831–8. Kasiske BL, Zeier MG, Chapman JR, et al. KDIGO clinical practice guideline for the care of kidney transplant recipients: a summary. Kidney Int. 2010;77(4):299–311. Ruzek MC, Neff KS, Luong M, et al. In vivo characterization of rabbit anti-mouse thymocyte globulin: a surrogate for rabbit anti-human thymocyte globulin. Transplantation. 2009;88(2):170–9. Boenisch O, Lopez M, Elyaman W, Magee CN, Ahmad U, Najafian N. Ex vivo expansion of human Tregs by rabbit ATG is dependent on intact STAT3-signaling in CD4(+) T cells and requires the presence of monocytes. Am J Transplant. 2012;12(4):856–66. Gurkan S, Luan Y, Dhillon N, et al. Immune reconstitution following rabbit antithymocyte globulin. Am J Transplant. 2010;10(9):2132–41. • Brennan DC, Flavin K, Lowell JA, et al. A randomized, double-blinded comparison of Thymoglobulin versus Atgam for induction immunosuppressive therapy in adult renal transplant recipients. Transplantation. 1999;67(7):1011–8. This is one of the few randomized double-blinded trials in transplantation and was the first to show that an induction agent, Thymoglobulin, not only delayed but decreased the incidence of acut rejection to an unprecedented level of less than 5% at one year Gaber AO, First MR, Tesi RJ, et al. Results of the double-blind, randomized, multicenter, phase III clinical trial of Thymoglobulin versus Atgam in the treatment of acute graft rejection episodes after renal transplantation. Transplantation. 1998;66(1):29–37. Popow I, Leitner J, Grabmeier-Pfistershammer K, et al. A comprehensive and quantitative analysis of the major specificities in rabbit antithymocyte globulin preparations. Am J Transplant. 2013;13(12):3103–13. Cicora F, Mos F, Paz M, Roberti J. Clinical experience with thymoglobulin and antithymocyte globulin-Fresenius as induction therapy in renal transplant patients: a retrospective study. Exp Clin Transplant. 2013;11(5):418–22. Chen GD, Lai XQ, Ko DS, et al. Comparison of efficacy and safety between rabbit anti-thymocyte globulin and anti-T lymphocyte globulin in kidney transplantation from donation after cardiac death: a retrospective cohort study. Nephrology (Carlton). 2015;20(8):539–43. Klem P, Cooper JE, Weiss AS, et al. Reduced dose rabbit anti-thymocyte globulin induction for prevention of acute rejection in high-risk kidney transplant recipients. Transplantation. 2009;88(7):891–6. Peddi VR, Bryant M, Roy-Chaudhury P, Woodle ES, First MR. Safety, efficacy, and cost analysis of thymoglobulin induction therapy with intermittent dosing based on CD3+ lymphocyte counts in kidney and kidney-pancreas transplant recipients. Transplantation. 2002;73(9):1514–8. Stevens RB, Foster KW, Miles CD, et al. A randomized 2x2 factorial trial, part 1: single-dose rabbit antithymocyte globulin induction may improve renal transplantation outcomes. Transplantation. 2015;99(1):197–209. Charpentier B, Rostaing L, Berthoux F, et al. A three-arm study comparing immediate tacrolimus therapy with antithymocyte globulin induction therapy followed by tacrolimus or cyclosporine A in adult renal transplant recipients. Transplantation. 2003;75(6):844–51. Mourad G, Garrigue V, Squifflet JP, et al. Induction versus noninduction in renal transplant recipients with tacrolimus-based immunosuppression. Transplantation. 2001;72(6):1050–5. Webster AC, Ruster LP, McGee R, et al. Interleukin 2 receptor antagonists for kidney transplant recipients. Cochrane Database Syst Rev. 2010;1:CD003897. Brennan DC, Daller JA, Lake KD, Cibrik D, Del Castillo D. Thymoglobulin induction study G. Rabbit antithymocyte globulin versus basiliximab in renal transplantation. N Engl J Med. 2006;355(19):1967–77. Brennan DC, Schnitzler MA. Long-term results of rabbit antithymocyte globulin and basiliximab induction. N Engl J Med. 2008;359(16):1736–8. Lentine KL, Schnitzler MA, Xiao H, Brennan DC. Long-term safety and efficacy of antithymocyte globulin induction: use of integrated national registry data to achieve ten-year follow-up of 10-10 Study participants. Trials. 2015;16:365. Noel C, Abramowicz D, Durand D, et al. Daclizumab versus antithymocyte globulin in high-immunological-risk renal transplant recipients. J Am Soc Nephrol. 2009;20(6):1385–92. Hellemans R, Hazzan M, Durand D, et al. Daclizumab versus rabbit antithymocyte globulin in high-risk renal transplants: five-year follow-up of a randomized study. Am J Transplant. 2015;15(7):1923–32. Schold J, Poggio E, Goldfarb D, Kayler L, Flechner S. Clinical outcomes associated with induction regimens among retransplant kidney recipients in the United States. Transplantation. 2015;99(6):1165–71. • Woodle ES, First MR, Pirsch J, et al. A prospective, randomized, double-blind, placebo-controlled multicenter trial comparing early (7 day) corticosteroid cessation versus long-term, low-dose corticosteroid therapy. Ann Surg. 2008;248(4):564–77. This randomized-double-blineded study of early steroid withdrawal was possible with Thymoglobulin but not basilixmab induction but there was an increased risk of acute and chronic rejection without significant benefit in steroid-induced side effects like weight gain, post transplant diabetes or fractures or cataracts Tanriover B, Jaikaransingh V, MacConmara MP, et al. Acute rejection rates and graft outcomes according to induction regimen among recipients of kidneys from deceased donors treated with tacrolimus and mycophenolate. Clin J Am Soc Nephrol. 2016;11(9):1650–61. Tanriover B, Zhang S, MacConmara M, et al. Induction therapies in live donor kidney transplantation on tacrolimus and mycophenolate with or without steroid maintenance. Clin J Am Soc Nephrol. 2015;10(6):1041–9. Thomusch O, Wiesener M, Opgenoorth M, et al. Rabbit-ATG or basiliximab induction for rapid steroid withdrawal after renal transplantation (Harmony): an open-label, multicentre, randomised controlled trial. Lancet. 2016. Kliem V, Fricke L, Wollbrink T, Burg M, Radermacher J, Rohde F. Improvement in long-term renal graft survival due to CMV prophylaxis with oral ganciclovir: results of a randomized clinical trial. Am J Transplant. 2008;8(5):975–83. Bustami RT, Ojo AO, Wolfe RA, et al. Immunosuppression and the risk of post-transplant malignancy among cadaveric first kidney transplant recipients. Am J Transplant. 2004;4(1):87–93. Opelz G, Naujokat C, Daniel V, Terness P, Dohler B. Disassociation between risk of graft loss and risk of non-Hodgkin lymphoma with induction agents in renal transplant recipients. Transplantation. 2006;81(9):1227–33. van Leeuwen MT, Grulich AE, Webster AC, et al. Immunosuppression and other risk factors for early and late non-Hodgkin lymphoma after kidney transplantation. Blood. 2009;114(3):630–7. Gaber AO, Matas AJ, Henry ML, et al. Antithymocyte globulin induction in living donor renal transplant recipients: final report of the TAILOR registry. Transplantation. 2012;94(4):331–7. Marks WH, Ilsley JN, Dharnidharka VR. Posttransplantation lymphoproliferative disorder in kidney and heart transplant recipients receiving thymoglobulin: a systematic review. Transplant Proc. 2011;43(5):1395–404. Kidney Disease: Improving Global Outcomes Transplant Work G. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant. 2009;9 Suppl 3:S1–155. Lim WH, Chadban SJ, Campbell S, Dent H, Russ GR, McDonald SP. Interleukin-2 receptor antibody does not reduce rejection risk in low immunological risk or tacrolimus-treated intermediate immunological risk renal transplant recipients. Nephrology (Carlton). 2010;15(3):368–76. Willoughby LM, Schnitzler MA, Brennan DC, et al. Early outcomes of thymoglobulin and basiliximab induction in kidney transplantation: application of statistical approaches to reduce bias in observational comparisons. Transplantation. 2009;87(10):1520–9. Calne R, Moffatt SD, Friend PJ, et al. Campath IH allows low-dose cyclosporine monotherapy in 31 cadaveric renal allograft recipients. Transplantation. 1999;68(10):1613–6. Vo AA, Wechsler EA, Wang J, et al. Analysis of subcutaneous (SQ) alemtuzumab induction therapy in highly sensitized patients desensitized with IVIG and rituximab. Am J Transplant. 2008;8(1):144–9. Hanaway MJ, Woodle ES, Mulgaonkar S, et al. Alemtuzumab induction in renal transplantation. N Engl J Med. 2011;364(20):1909–19. Willicombe M, Brookes P, Santos-Nunez E, et al. Outcome of patients with preformed donor-specific antibodies following alemtuzumab induction and tacrolimus monotherapy. Am J Transplant. 2011;11(3):470–7. Zachariah M, Nader ND, Brar J, et al. Alemtuzumab and minimization immunotherapy in kidney transplantation: long-term results of comparison with rabbit anti-thymocyte globulin and standard triple maintenance therapy. Transplant Proc. 2014;46(1):94–100. Farney AC, Doares W, Rogers J, et al. A randomized trial of alemtuzumab versus antithymocyte globulin induction in renal and pancreas transplantation. Transplantation. 2009;88(6):810–9. Morgan RD, O’Callaghan JM, Knight SR, Morris PJ. Alemtuzumab induction therapy in kidney transplantation: a systematic review and meta-analysis. Transplantation. 2012;93(12):1179–88. Zhang X, Huang H, Han S, Fu S, Wang L. Alemtuzumab induction in renal transplantation: a meta-analysis and systemic review. Transpl Immunol. 2012;27(2–3):63–8. Ciancio G, Gaynor JJ, Guerra G, et al. Randomized trial of three induction antibodies in kidney transplantation: long-term results. Transplantation. 2014;97(11):1128–38. Group CSC, Haynes R, Harden P, et al. Alemtuzumab-based induction treatment versus basiliximab-based induction treatment in kidney transplantation (the 3C Study): a randomised trial. Lancet. 2014;384(9955):1684–90. Saull HE, Enderby CY, Gonwa TA, Wadei HM. Comparison of alemtuzumab vs. antithymocyte globulin induction therapy in primary non-sensitized renal transplant patients treated with rapid steroid withdrawal. Clin Transpl. 2015;29(7):573–80. Chan K, Taube D, Roufosse C, et al. Kidney transplantation with minimized maintenance: alemtuzumab induction with tacrolimus monotherapy—an open label, randomized trial. Transplantation. 2011;92(7):774–80. Cannon RM, Brock G, Marvin MR, Eng M, Buell JF. Analysis of BK viral infection after alemtuzumab induction for renal transplant. Transpl Infect Dis. 2012;14(4):374–9. Theodoropoulos N, Wang E, Penugonda S, et al. BK virus replication and nephropathy after alemtuzumab-induced kidney transplantation. Am J Transplant. 2013;13(1):197–206. LaMattina JC, Mezrich JD, Hofmann RM, et al. Alemtuzumab as compared to alternative contemporary induction regimens. Transpl Int. 2012;25(5):518–26. Margreiter R, Klempnauer J, Neuhaus P, Muehlbacher F, Boesmueller C, Calne RY. Alemtuzumab (Campath-1H) and tacrolimus monotherapy after renal transplantation: results of a prospective randomized trial. Am J Transplant. 2008;8(7):1480–5. Schadde E, D’Alessandro AM, Knechtle SJ, et al. Alemtuzumab induction and triple maintenance immunotherapy in kidney transplantation from donors after cardiac death. Transpl Int. 2008;21(7):625–36. Ciancio G, Burke GW, Gaynor JJ, et al. A randomized trial of three renal transplant induction antibodies: early comparison of tacrolimus, mycophenolate mofetil, and steroid dosing, and newer immune-monitoring. Transplantation. 2005;80(4):457–65. Hall EC, Engels EA, Pfeiffer RM, Segev DL. Association of antibody induction immunosuppression with cancer after kidney transplantation. Transplantation. 2015;99(5):1051–7. Puttarajappa C, Yabes J, Bei L, et al. Cancer risk with alemtuzumab following kidney transplantation. Clin Transpl. 2013;27(3):E264–71. Vincenti F, Larsen C, Durrbach A, et al. Costimulation blockade with belatacept in renal transplantation. N Engl J Med. 2005;353(8):770–81. • 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(3):535–46. This randomized open label study of two different regimens of belatacept used in place of cyclosporine at relatively high doses and levels was associated with more rejection but a better estimated glomerular filtration rate 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. 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(1):210–7. 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(3):630–9. Vincenti F, Rostaing L, Grinyo J, et al. Belatacept and long-term outcomes in kidney transplantation. N Engl J Med. 2016;374(4):333–43. 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(11):3192–201. Ekberg H, Tedesco-Silva H, Demirbas A, et al. Reduced exposure to calcineurin inhibitors in renal transplantation. N Engl J Med. 2007;357(25):2562–75. 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