• Gene signatures reflecting tumor microenvironment composition correlate with event-free survival of patients in COG AHOD0031 trial.

  • An outcome prognostic model risk stratifies patients according to 5-year event-free survival.

Classical Hodgkin lymphoma (cHL) is a common malignancy in children and adolescents. Although cHL is highly curable, treatment with chemotherapy and radiation often come at the cost of long-term toxicity and morbidity. Effective risk-stratification tools are needed to tailor therapy. Here, we used gene expression profiling (GEP) to investigate tumor microenvironment (TME) biology, determine molecular correlates of treatment failure, and develop an outcome model prognostic for pediatric cHL. A total of 246 formalin-fixed, paraffin-embedded tissue biopsies from patients enrolled in the Children's Oncology Group trial AHOD0031 were used for GEP and compared to adult cHL data. Eosinophils, B-cells, and mast cell signatures were enriched in children, while macrophage and stromal signatures were more prominent in adults. Concordantly, a previously published model for overall survival prediction in adult cHL did not validate in pediatric cHL. Therefore, we developed a 9-cellular component model reflecting TME composition to predict event-free survival (EFS). In an independent validation cohort, we observed a significant difference in weighted 5-year EFS between high-risk and low-risk groups (75.2% vs. 90.3%; log-rank P = .0138) independent of interim response, stage, fever and albumin. We demonstrate unique disease biology in children and adolescents that can be harnessed for risk-stratification at diagnosis. ClinicalTrials.gov Identifier: NCT00025259

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