Soluble cytokines enhance risk prediction across all stages of classical Hodgkin lymphoma.

Classical Hodgkin lymphoma (cHL) is a heterogeneous malignancy with favorable outcomes, but accurate prognostic stratification remains challenging, particularly across all disease stages. Traditional risk models are focused on advanced stages and do not account for tumor microenvironment (TME) dynamics. Soluble cytokines reflecting TME activity may offer additional prognostic value. In our prospective multicenter study, we investigated the prognostic value of pretreatment plasma levels of soluble TARC, sCD30, sCD163, and sIL-6 in 162 newly diagnosed cHL patients and developed a model incorporating these biomarkers for risk prediction across all stages. Cytokine levels were measured using ELISA, and clinical characteristics, treatment responses, and outcomes were collected. The primary endpoint was 5-year progression-free survival (PFS). Elevated levels of sIL-6 and sCD30 were associated with higher disease stage, presence of B-symptoms, extranodal involvement, and inferior 5-year PFS. A novel prognostic model incorporating age, extranodal disease, and high sCD30/sIL-6 levels outperformed IPS-3 in predicting therapy failure. Patients with both elevated sCD30 and sIL-6 levels at diagnosis had significantly worse outcomes. Integrating soluble cytokine biomarkers, particularly sIL-6 and sCD30, into prognostic models enhances risk stratification across all stages of cHL and supports future efforts toward biomarker-driven, personalized treatment strategies.