Circulating tumor DNA in Hodgkin lymphoma: biological classification, molecular residual disease, and integration with PET response

Circulating cell-free DNA (cfDNA) and its tumor-derived fraction, circulating tumor DNA (ctDNA), enable non-invasive tumor genotyping, longitudinal disease monitoring, and molecular residual disease (MRD) assessment. Classical Hodgkin lymphoma (cHL) is particularly suitable for ctDNA-based analysis because malignant Hodgkin and Reed-Sternberg cells usually constitute only a small fraction of the tumor mass, whereas plasma may contain a strong tumor-derived DNA signal. This narrative review summarizes the potential applications of cfDNA-based ctDNA analysis in hematologic malignancies, with a focused emphasis on cHL. We discuss pre-analytical and analytical requirements, including plasma processing, tumor-informed and tumor-naive sequencing, error suppression, droplet digital PCR, and control for clonal hematopoiesis. We then synthesize evidence for ctDNA as a dual-readout biomarker: a baseline tool for non-invasive biological classification and a dynamic measure of molecular response. Published studies identify cHL genomic subtypes, associations with the tumor microenvironment, and prognostic information complementary to PET and conventional risk factors. Age-specific evidence is uneven, and most studies demonstrate analytical feasibility or prognosis rather than benefit from a ctDNA-triggered intervention. ctDNA-MRD should complement FDG-PET/CT; it cannot localize disease or currently replace established staging and response criteria. Routine implementation will require harmonized sample handling, validated assays and reporting thresholds, external quality assessment, and prospective trials demonstrating that ctDNA-guided treatment improves disease control, toxicity, or quality of life.