Abstract T071

The Genomic Landscape of Pediatric High-Risk Hodgkin Lymphoma: A Liquid Biopsy Study of COG AHOD1331

Background: Pediatric classic Hodgkin lymphoma (cHL) has excellent survival, yet risk stratification relies on baseline clinical and imaging features that incompletely capture disease biology. We hypothesized that circulating tumor DNA (ctDNA) level and derived genomic subtypes, defined at baseline before therapy, are associated with disease burden, and could inform risk.

Methods: We studied patients ≥2-<22 years with newly diagnosed high-risk cHL enrolled in COG study AHOD1331 with available blood specimens. Baseline plasma was profiled using CAPP-Seq to detect tumor-derived somatic mutations and quantify ctDNA levels. Baseline ctDNA was dichotomized into high vs low levels using a previously defined threshold (2.5log10 hGE/mL) and classified into genomic subtypes (H1 and H2) using an established algorithm (Alig et al, Nature 2024). Univariate associations between genomic subtype, somatic mutation features, and clinical characteristics including age, stage, and centrally reviewed PET-derived total metabolic tumor volume [TMTV] were evaluated.

Results: 323 patients (55%) from the eligible trial cohort had evaluable samples, with median age of 15.7 years (range 3.4-22), 54% male, and stage distribution representative of the overall trial (20.1% bulky IIB, 21.4% IIIB, 28.8% IVA, 29.7% IVB; p=0.86). All patients (100%) had detectable ctDNA at baseline, varying across a broad range (4-23622 hGE/mL, median 129 hGE/mL). Higher pretreatment ctDNA levels were significantly associated with higher TMTV (P<0.001, Fig. 1A), bulky disease (P=0.018, Fig. 1B), large mediastinal adenopathy (LMA; P<0.05, Fig. 1C), B-symptoms (P=0.017, Fig. 1D), and erythrocyte sedimentation rate (ESR; P<0.05, Fig. 1E). Children had significant enrichment of H1 subtype (68.1% in AHOD1331) when compared to adults older than 60 (37.2% in Rossi et al ICML2025, p<0.001, Fig. 1F). H1 tumors harbored significantly higher somatic SNV/Indel counts than H2 counterparts (p<0.001, Fig. 1H). Key genetic alterations had expected recurrence frequencies (Fig. 1G).

Conclusion: In the largest genomic study of pediatric cHL to date, we establish the universal detection of baseline ctDNA and enrichment of H1 subtype. We confirm significant associations with key clinical indicators of tumor burden, including baseline TMTV, known to be significantly associated with EFS in this trial. Ongoing analyses of ctDNA at interim and end of therapy are being used to develop a dynamic radiogenomic risk prediction model.