Tacrolimus (TAC) and Single Intra-Operative High-Dose of r-ATG Induction vs. Tacrolimus Monotherapy as Immunosuppression (IS) in Adult Liver Transplantation (LT): One-Year Results of an Investigator-Driven, Prospective, Randomized, Controlled Trial (RCT). (July 2018)

• Record Type: Journal Article
• Authors: Iesari, Samuele; Ackenine, Kevin; Foguenne, Maxime; Komuta, Mina; Ciccarelli, Olga; Coubeau, Laurent; Riani, Eliano Bonaccorsi; Lai, Quirino; De Reyck, Chantal; Gianello, Pierre; Lerut, Jan
• Is Part Of: Transplantation. Volume 102(2018)Supplement 7S-1
• Publication Date: 2018-07
• Subjects: Transplantation of organs, tissues, etc -- Periodicals; Transplantation immunology -- Periodicals; 617.95
• DOI: 10.1097/01.tp.0000543147.59147.7b
• Languages: English
• ISSNs: 0041-1337

Abstract

Abstract : Introduction: The role of induction therapy using anti-lymphocytic serum is poorly understood in LT as it is its utility in tolerance induction. We aimed to assess efficacy of a high-dose of rabbit anti-lymphocytic serum (r-ATG, Grafalon®, Neovii) administered intra-operatively in combination with TAC (Prograft®, Astellas) in primary adult LT. Materials and Methods: Investigator-driven, single-centre, open-label, prospective RCT stratifying pts into an intra-operative dose of 9 mg/kg r-ATG followed by TAC monotherapy maintenance IS (TAC-ATG group; n=97) and TAC monotherapy IS (TAC group, n=109).The primary endpoint was minimization of IS to monotherapy within 12 months. Safety endpoints were patient (PS) and graft survival (GS). The secondary endpoint was one-year biopsy-proven acute cellular rejection (ACR). 200 patients were required to provide a power of 80% to detect a difference of 9% in attaining TAC monotherapy within 12 mo, accepting 5% level of α error. Means were compared with t-test and proportions with Pearson's χ2 test. Time to clinical rejection, PS and GS were analysed with the Kaplan–Meier method and compared with the log-rank test. All patients had similar clinical, biochemical and histological follow-up (FU) including protocol biopsies. ACR treatment was based on concordance of Banff score > 5 and biochemical score (including bilirubin, platelet and eosinophilia) >2. Steroid-resistant rejection (SRR) was defined as absence of response to 3-5 pulses of 200 mg methylprednisolone. Mean FU for TAC-ATG and TAC groups were 87 and 95 months. Results: 78/80 (97.5%) TAC-ATG and 100/101 (99.0%) TAC pts were steroid free (p=0.429). A second immunosuppressant (steroids, mycophenolate, azathioprine or mTOR inhibitor) was administered in 29/80 (36.3%) TAC-ATG and 35/101 (34.7%) TAC pts (p=0.823). One-year mean TAC trough level was 5.19 (±3.06) mg, in TAC-ATG and 5.04 (±2.80) mg in TAC pts (p=0.738). No statistically significant differences in one-year PS (83% TAC-ATG vs. 92% TAC pts, p=0.260) and GS (76% TAC-ATG vs. 90% TAC pts, p=0.054) were observed. A 6-9 Banff score was seen in 27/107 (25.2%) TAC and 14/83 (16.9%) TAC-ATG pts (p=0.164). No difference was observed in relation to the number of treated rejection (15% TAC-ATG vs. 18% TAC pts developed steroid-sensitive rejection (SSR), p=0.449); 2% TAC-ATG and 3% TAC pts (p=0.628) developed SRR. Chronic rejection was diagnosed in 1% in TAC-ATG vs. 4% in TAC pts (p=0.307). Discussion: This first ever-done RCT comparing TAC and single intra-operative high-dose of r-ATG induction vs. TAC monotherapy as IS in adult LT did not show any benefit in relation to IS minimization nor survival. Rejection treatment based on concordance between histology and biochemistry was similar in both groups. Conclusions: The studied induction protocol did not offer short-term clinical benefit. Long-term results have to be awaited in order to analyse its' influence on tolerance induction. (EudraCT 2006-004830-34). Unrestricted grant from Neovii - Fresenius for immunological research not presented in this study.