Time to relapse in chronic lymphocytic leukemia and DNA-methylation-based biological age

Chronic lymphocytic leukemia (CLL) is a mature B cell neoplasm with a predilection for older individuals. While previous studies have identified epigenetic signatures associated with CLL, whether age-related DNA methylation changes modulate CLL relapse remains elusive. In this study, we examined the association between epigenetic age acceleration and time to CLL relapse in a publicly available dataset. DNA methylation profiling of 35 CLL patients prior to initiating chemoimmunotherapy was performed using the Infinium HumanMethylation450 BeadChip. Four epigenetic age acceleration metrics (intrinsic epigenetic age acceleration [IEAA], extrinsic epigenetic age acceleration [EEAA], PhenoAge acceleration [PhenoAA], and GrimAge acceleration [GrimAA]) were estimated from blood DNA methylation levels. Linear, quantile, and logistic regression and receiver operating characteristic curve analyses were conducted to assess the association between each epigenetic age metric and time to CLL relapse. EEAA ( p = 0.011) and PhenoAA ( p = 0.046) were negatively and GrimAA ( p = 0.040) was positively associated with time to CLL relapse. Simultaneous assessment of EEAA and GrimAA in male patients distinguished patients who relapsed early from patients who relapsed later ( p = 0.039). No associations were observed with IEAA. These findings suggest epigenetic age acceleration prior to chemoimmunotherapy initiation is associated with time to CLL relapse. Our results provide novel insight into the association between age-related DNA methylation changes and CLL relapse and may serve has biomarkers for treatment relapse, and potentially, treatment selection.