Distinct Circulating Genomic Features of Classical Hodgkin Lymphoma of Older Adults

Introduction: Despite significant progress in curing younger patients with classical Hodgkin lymphoma (cHL), older patients continue to have substantially inferior outcomes. The bimodal distribution of age at cHL diagnosis has suggested distinct underlying pathogenesis in older adults. For example, among older patients where EBV+ disease is more prevalent, EBV+ status is associated with worse outcomes, unlike younger patients where it confers more favorable prognosis (Keegan, JCO 2005). The reasons for this disparity remain enigmatic. To address these challenges, we used circulating tumor DNA (ctDNA) profiling, enabling noninvasive genotyping, risk stratification, and classification into distinct molecular subtypes (Spina, Blood 2018; Alig, ASH 2022). We leveraged several non-invasive techniques to systematically characterize the genomic peculiarities of elderly cHL patients distinguishing them from younger counterparts, with special attention to EBV status. Methods: We comprehensively profiled newly diagnosed cHL patients from 3 prospective clinical trials: LYSA-PVAB (NCT02414568) for subjects ≥60 years (Ghesquières, ASH 2019), AHL2011 (NCT01358747) for patients aged 16-59 years with advanced cHL, and BIO-LYMPH (NCT04417803) for patients ≥18 years. We used age ≥60 as a threshold for stratification of older versus younger patients, a common cutoff in clinical trials. We identified somatic single nucleotide variants using CAPP-Seq (Newman et al, Nature Biotech 2016); and analyzed copy number alterations with CANARy (Chabon, Nature 2020). Patients were categorized into high vs low pretreatment ctDNA levels using a predefined threshold (2.5 log hGE/mL; Kurtz, JCO 2018). We determined EBV status using EBER and/or LMP1 staining of FFPE tumor tissue or plasma EBV levels (>32 copies/mL) by VirCAPP-Seq (Garofalo, ASH 2022). Results: A total of 215 newly diagnosed cHL patients were evaluable, with a median age of 51 years, and 35% being older (≥60 years). In this cohort, 82% had advanced stage disease, 68% had high IPS (≥3), and 57% had extra nodal involvement. At 4-year follow-up, OS and PFS were 84% and 74%, respectively. At presentation, older patients (≥60y) had more advanced stage (93% vs 73%, p