Abstract
<title>Abstract</title> <p> <bold>Background</bold> Classical Hodgkin lymphoma (cHL) is a microenvironment-driven malignancy in which soluble immune mediators may provide minimally invasive biomarkers of relapse risk beyond conventional clinical variables and interim PET/CT (iPET/CT). <bold>Methods</bold> We performed longitudinal plasma cytokine profiling of 30 cytokines in patients across baseline (T1), early on-treatment (T2) and after completion of therapy (T3/iPET/CT-aligned) to identify reproducible immune biomarkers associated with progression-free survival (PFS). Associations with progression-free survival (PFS) were assessed using differential expression, survival analyses, composite cytokine scores, and longitudinal trajectory modelling. Cytokine-derived biomarkers were also evaluated in combination with iPET/CT response. <bold>Results</bold> Baseline analyses showed that Eotaxin, MIP-1alpha, IL-6 and IL-2Ralpha differed between patients who later relapsed and those who remained relapse-free. Survival analyses identified Eotaxin, IL-6 and MCP-1 as prognostically relevant, with a baseline IL-6 + Eotaxin score providing the strongest baseline discrimination. At the early on-treatment timepoint (T2), several cytokines were associated with subsequent relapse, with the strongest signals observed for IL-7, IL-2Ralpha and Basic FGF. The T2 IL-7 + Basic FGF score yielded the best overall prognostic performance. In contrast, no significant differences were observed at the later T3/iPET/CT-aligned timepoint when absolute cytokine levels were considered. Longitudinal analyses identified IL-6 dynamics as the most consistent treatment-associated cytokine trajectory, with more pronounced IL-6 decreases from baseline associated with inferior PFS. In analyses integrating iPET/CT response, cytokine-derived biomarkers provided additional prognostic information. Among patients achieving CMR on iPET/CT, ΔIL-6 T1→T2 showed the strongest residual-risk stratification (HR per SD, 0.33; 95% CI, 0.15–0.75; p = 0.008; C-index, 0.72), while the T2 IL-7 + Basic FGF score was also associated with subsequent relapse (HR per SD, 2.49; 95% CI, 1.15–5.37; p = 0.020; C-index, 0.67). <bold>Conclusions</bold> Cytokine-derived biomarkers improved prognostic modelling beyond iPET/CT response and, importantly, retained prognostic value among patients achieving iPET/CT CMR, suggesting that early immune trajectories may reveal residual biological risk despite favorable metabolic imaging. These findings support multiplex plasma cytokine profiling as a discovery strategy to define biologically informed biomarkers that may complement PET-adapted risk stratification in cHL. </p>