Randomized trial investigating the utility of a liver tissue transcriptional biomarker in identifying adult liver transplant recipients not requiring maintenance immunosuppression.
Vionnet, J., et al.American Journal of Transplantation 2024 [record in progress].
Aims
They aim to assess whether a previously derived 5-gene liver tissue transcriptional biomarker accurately identifies stable adult liver transplant (LT) recipients who can safely discontinue maintenance immunosuppression (IS) without rejection—referred to as operational tolerance.
Interventions
Divided into two arms: Arm A (Non-biomarker-based): All participants underwent a gradual IS weaning protocol, regardless of biomarker results. Arm B (Biomarker-based): Participants first underwent a liver biopsy, which was tested using the 5-gene “tolerance” biomarker: Arm B+ (biomarker-positive): Proceeded to the same IS weaning protocol as in arm A. Arm B– (biomarker-negative): Continued baseline IS with no weaning.
Participants
116 adult, stable LT recipients, at least 3 years post-transplant if age >50 or ≥6 years if age ≤50, with normal allograft function, no active viral disease/autoimmune condition, no recent rejection. Arm A: 58 patients and Arm B: 58 patients (24 biomarker-positive, 34 biomarker-negative).
Outcomes
1. Primary Outcome: Operational tolerance at 1-year post–IS withdrawal, defined by (i) successful IS discontinuation for ≥12 months, (ii) normal liver function, and (iii) absence of rejection or inflammation on protocol biopsy. 2. Secondary Outcomes: Rate, severity, and timing of acute rejection; histologic changes on protocol biopsies; formation of donor-specific antibodies; biomarker performance (sensitivity, specificity, predictive values); immune characterisation (circulating T- and B-cell subsets, RNA-seq of liver tissue, immunohistochemistry measures of immune synapses).
Follow-up
At least 1 year after cessation of IS (with a 1-year protocol biopsy). Some participants had extende
CET Conclusions
The authors present the LIFT trial, a phase IV, open-label, prospective, multi-centre, randomised controlled trial assessing transcriptional biomarkers for operational tolerance in liver transplantation. Stable livers transplant patients were randomised into one of Arm A, where IS was progressively weened regardless of biomarker status or Arm B, in which biomarker positive patients were offered IS withdrawal and those who were biomarker negative remained on baseline IS. Over all the biomarker, the 5-gene liver transcriptional test, failed to predict who would tolerate IS withdrawal (sensitivity 54%, specificity 42%, positive predictive value ~16%). They found a low prevalence of operational tolerance, at only 16% (13/80) of patients fully weaned off IS at 1-year post-withdrawal met histologic criteria for operational tolerance. They found that indicators of tolerance to be longer time since transplant and older recipient age, and circulating exhausted/senescent CD8+ T cells. Whereas De novo donor-specific antibodies were strongly associated with failure of IS withdrawal. The trial found comparable rates of true operational tolerance (~16%) with the OPTIMAL trial, which had a near identical protocol. They ended recruitment early when interim analysis indicated the biomarker’s positive predictive value was unlikely to meet pre-specified criteria, while ethically justified and common in futility analyses, it reduced the final sample size and power, especially for the low-prevalence outcome of operational tolerance. Operational tolerance was adjudicated mainly at 1 year post-IS withdrawal with a follow-up biopsy. Some participants with mild inflammation at 1 year remained off immunosuppression and eventually stabilized on subsequent histologic checks, meaning the “final” tolerance outcomes might not be fully captured in a single 12-month time point, which given the low overall event rate, could be relevant. The minor methodological concerns revolve around the open-label design, the premature closure of recruitment, and the inherent difficulty of studying an event that is both rare and histologically stringent such as operational tolerance. These factors constrain the ultimate power and precision in estimating the biomarker’s predictive value. Nevertheless, the study’s careful design, protocol harmonization with the OPTIMAL trial, and robust immunologic/histologic analyses make a strong case for the likely negative utility of the 5-gene liver tissue transcriptional biomarker.
Data analysis
Per protocol analysis
Trial registration
ClinicalTrials.gov - NCT024989977; ISRCTN - 47808000; EudraCT - 2014-004557-14