Abstract P130

Second-Generation Epigenetic Clocks Reveal Accelerated Biological Aging in Relapsed/Refractory Hodgkin Lymphoma

Background: Relapsed/refractory (R/R) Hodgkin lymphoma (HL) is associated with poor clinical outcomes arising from multiple contributing factors. Biological aging has recently emerged as an area of interest; however, its role in driving R/R HL is not well defined. Epigenetic age acceleration (EAA), derived from DNA methylation-based clocks, may capture treatment- and disease-related aging processes in HL. First-generation epigenetic clocks predict chronological age, whereas second-generation clocks are designed to reflect biologic aging and health-related outcomes. Thus, we conducted a single-center study comparing EAA in R/R HL patients to that of healthy individuals.

Methods: EAA was evaluated in 20 patients with R/R HL diagnosed from 2020 to 2022, and 60 healthy, non-cancer controls. Pre-banked peripheral blood samples collected at the time of relapse were obtained and processed using the Illumina EPIC v2 array to generate DNA methylation data. Methylation data were analyzed to calculate EAA using first-generation (Horvath, Hannum) and second-generation (PhenoAge, GrimAge2) epigenetic clocks. Comparisons were performed between R/R HL patients and controls, as well as across patient subgroups stratified by clinical characteristics.

Results: Second-generation clocks demonstrated statistically significant increases in EAA in R/R HL patients compared with controls (PhenoAge: p = 0.0009; GrimAge2: p = 0.035). Additionally, R/R HL patients showed higher median EAA than control patients (median PhenoAge acceleration: 10.89 [IQR, 15.31] vs −3.17 [IQR, 5.36]; median GrimAge acceleration: 3.21 [IQR, 7.47] vs −1.84 [IQR, 3.60]). Among first-generation clocks, Horvath’s clock demonstrated significant age deceleration in relapsed HL patients compared with controls (median age acceleration: -3.16 vs 0.69, p = 0.007) whereas Hannum’s clock showed no significant difference. EAA did not differ significantly according to ethnicity, cHL status or treatment exposure (p > 0.05 for all comparisons).

Conclusion: In this single-center analysis, we observed that second-generation epigenetic clocks detected significantly increased biological aging in patients with R/R HL. These findings support a potential association between biological aging and R/R HL, indicating that EAA may represent a biomarker of underlying disease biology and treatment-related aging. Further studies are needed to clarify the prognostic and clinical impact of accelerated epigenetic aging in HL.