Letter: Rethinking Washout Thresholds for Immune Checkpoint Inhibitors Before Liver Transplantation

We read with interest the study by Aceituno et al. [1] demonstrating comparable post-transplant rejection rates between ICI-treated and control patients in hepatocellular carcinoma. While this work provides important safety data, the proposed 50-day washout threshold warrants further discussion. A striking finding is the dissociation between washout duration and rejection incidence. Among patients developing rejection, those receiving PD-1 inhibitors had a median washout of 38 days versus 164.5 days for PD-L1 inhibitors (p < 0.001), yet overall rejection rates were virtually identical (18.9% vs. 18.2%). Population pharmacokinetic analyses report elimination half-lives of approximately 25 days for nivolumab [2] and 27 days for atezolizumab [3]; serum drug levels should therefore be negligible in PD-L1-treated patients who rejected at a median of 164.5 days—well beyond five half-lives—indicating that drug clearance alone does not determine immunological risk. This raises the question: could rejection risk be driven less by residual drug levels and more by persistent immunological changes, such as ICI-induced expansion of effector T-cell populations that persist as alloreactive memory clones [4]? The largest individual patient data meta-analysis to date similarly found that, while longer washout was associated with reduced rejection risk, the relationship was not absolute [5]. Incorporating functional immune monitoring—such as Ki-67 expression on circulating CD8+ T cells [4]—may offer a more biologically informed approach to transplant timing than a uniform time-based threshold. The observation that none of eight patients receiving anti-thymocyte globulin (ATG) induction developed rejection, compared with 22.5% of those without ATG, is noteworthy, though not statistically significant. Could ATG-mediated T-cell depletion mitigate the heightened alloimmune priming conferred by prior ICI exposure? The small numbers and potential selection bias preclude firm conclusions. Nevertheless, a recent meta-analysis demonstrated that T-cell specific antibody induction in liver transplantation was associated with comparable rejection rates and reduced CMV infection [6], providing a mechanistic rationale warranting prospective evaluation in the ICI-to-LT setting. Finally, an important methodological consideration deserves attention. While propensity score matching was employed [7], all 144 controls were drawn from a single centre, whereas the 48 ICI-treated patients originated from ten diverse international centres. This design creates a structural confounding where centre-specific management—particularly the 16.7% vs. 0% disparity in ATG induction (p < 0.001)—is inextricably coupled with ICI exposure. Such asymmetry means the observed control rejection rate serves as an unreliable benchmark, as it reflects the practices of a single institution rather than the baseline risk of the multicentre ICI cohort. The design by Moeckli et al. [8], which utilized internal controls from the same participating centres, represents a methodologically preferable approach to mitigating these institutional biases. Given that PD-L1-treated patients developed rejection more than 160 days after their last ICI dose—far exceeding both the proposed 50-day threshold and the expected duration of drug activity—we would welcome the authors' perspective on whether a fixed time-based washout period adequately captures the immunological complexity of post-ICI transplant candidates. Heyong Liu: writing – original draft. Bin He: writing – original draft. Zhicheng Huang: writing – review and editing. The authors have nothing to report. The authors declare no conflicts of interest. This article is linked to Aceituno et al. papers. To view this article, visit https://doi.org/10.1111/apt.70528. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.