European Project for ctDNA Detection as a Biomarker for Non-invasive Therapy Monitoring in Paediatric Classical Hodgkin Lymphoma

Despite significant advances in the management of classical Hodgkin lymphoma (cHL) in children and adolescents, a proportion of patients still relapse or exhibit primary refractory disease. This highlights a persistent limitation in current prognostic tools, particularly in identifying, at diagnosis or early during treatment, those at high risk of treatment failure. Existing stratification systems rely on clinical features and PET/CT imaging, which, although valuable, do not consistently differentiate between patients requiring intensification and those who could benefit from treatment de-escalation. To address this unmet need, the use of circulating tumor DNA (ctDNA) as a non-invasive biomarker has emerged as a promising avenue. ctDNA analysis allows real-time molecular assessment of tumor dynamics, including mutation detection and disease burden, without requiring invasive tissue biopsies. In adult cHL, ctDNA has demonstrated feasibility, prognostic relevance, and strong correlation with PET/CT results during treatment. Its early kinetics may even outperform imaging in predicting treatment outcomes, particularly in discordant PET scenarios. In pediatric cHL, ctDNA remains underexplored. The HOLY study, a French initiative nested within the EuroNet-PHL-C2 framework, was among the first to evaluate ctDNA detection in this population using a targeted panel of 18 recurrently mutated genes. Preliminary findings show a high mutation detection rate (\~85%) in baseline plasma samples. Parallel efforts in Germany (PHL-ctDNA study) use a broader panel and an alternative detection method, offering a valuable opportunity for methodological comparison and data integration. The current study proposes a binational collaborative approach involving France and Germany to: * Extend and harmonize ctDNA analyses in pediatric cHL; * Compare sequencing methodologies for sensitivity, specificity, and clinical concordance; * Integrate ctDNA dynamics with imaging and clinical outcomes to refine prognostic models. This will culminate in a prospective trial using a unified NGS panel (\~80 genes), informed by pooled retrospective analysis. ctDNA will be assessed at strategic timepoints to evaluate its added value in relapse prediction and risk-adapted therapy. Ultimately, this work seeks to validate ctDNA as a central biomarker for early response assessment, molecular monitoring, and personalized treatment planning in pediatric cHL.