Use of Alemtuzumab and Tacrolimus Monotherapy for Cadaveric Liver Transplantation: With Particular Reference to Hepatitis C Virus

Abstract

We have proposed that the mechanisms of alloengraftment and variable acquired tolerance can be facilitated by minimum posttransplant immunosuppression. It was further suggested that the efficacy of minimalistic treatment could be enhanced by preoperative recipient conditioning with an antilymphoid antibody preparation. A total of 76 adults (38 hepatitis C virus [HCV], 38 HCV) were infused with 30 mg alemtuzumab before primary cadaveric liver transplantation and maintained afterward on daily monotherapy unless breakthrough rejection mandated additional agents. In stable patients, the intervals between tacrolimus doses were lengthened ("spaced weaning") after approximately 4 months. Eighty-four contemporaneous nonlymphoid-depleted liver recipients (58 HCV, 26 HCV) were treated with conventional postoperative immunosuppression. The overall incidence of rejection was similar with the two strategies of immunosuppression. With follow-ups of 14 to 22 months, patient and primary graft survival in HCV cases are 97% and 90%, respectively, with alemtuzumab depletion plus minimal immunosuppression versus 71% and 70%, respectively, under conventional immunosuppression. In HCV recipients, current patient and graft survival in the alemtuzumab-pretreated group are 71% and 70% versus 65% and 54%, respectively, under conventional treatment. With both strategies of immunosuppression, the adverse effect of preexisting HCV on survival parameters and graft function already was significant at the 1-year milestone, but its extent was not evident until the second year. With or without HCV, 62% of the 64 surviving lymphoid-depleted patients are on spaced immunosuppression, and four patients receive no immunosuppression. Lymphoid depletion with alemtuzumab and minimalistic maintenance immunosuppression is a practical strategy of liver transplantation in HCV recipients but not HCV recipients.

Early immunosuppression withdrawal after living donor liver transplantation and donor stem cell infusion

“…Indeed, in the absence of preparative therapy, infusion of donor bone marrow cell has been shown to have no significant effect in LT on either the need for maintenance IS or the rate of rejection, despite an increased rate of donor chimerism. 11,12 It has been proposed also that posttransplant IS using antilymphoid antibodies like antithymocyte globulin 13 or Alemtuzumab 14 without donor cell infusion may have a tolerogenic effect, allowing a significant proportion of patients to discontinue IS during long-term follow-up. The hypothesis was that such depletive IS regimen may allow progressive engraftment of graft-derived donor cells, leading to donor specific tolerance.…”

“…The hypothesis was that such depletive IS regimen may allow progressive engraftment of graft-derived donor cells, leading to donor specific tolerance. 13,14 In these trials, however, IS minimization or discontinuation was scheduled several months after LT, and the majority of patients still required minimal IS. 13,14 It should also be noted that spontaneous tolerance may occur in approximately 20% of liver recipients, independent of the posttransplant immunosuppressive regimen.…”

Overview of immunosuppression in liver transplantation

“…Although patients who received alemtuzumab had less renal dysfunction and acute rejection in the first two months post-transplant, the overall incidence of rejection was not significantly different between the two groups. Similarly, Marcos et al [103] proposed that alemtuzumab, in conjunction with minimal CNI use, is a successful treatment strategy in liver transplant recipients, improving overall graft and patient survival, especially in HCVinfected subjects.…”

Liver biopsy interpretation for causes of late liver allograft dysfunction

“…Lymphoid depletion followed by rapid withdrawal of immunosuppression can precipitate aggressive HCV recurrence. 38 Biopsy interpretation should include an assessment of adequacy, systematic examination, and thorough clinicopathological correlation. Adequacy is ultimately the subjective opinion of the pathologist, but in general, at least 6 small portal tracts should be sampled.…”