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NEW ORLEANS -- Survivors of childhood Hodgkin lymphoma experience accelerated epigenetic aging, with higher rates of neurocognitive impairment in adulthood, compared with their peers who didn't have cancer, according to data from the St. Jude Lifetime Cohort.

The mean difference in epigenetic age between the survivors and community controls was 7.7 years (95% CI 6.8-8.5, P<0.001), reported AnnaLynn M. Williams, PhD, of the Wilmot Cancer Institute at the University of Rochester School of Medicine and Dentistry in New York, during the 2022 American Society of Hematology annual meeting.

Compared with the first tertile of epigenetic age acceleration (EAA) among survivors, the second and third tertiles were linked with worse visual-motor processing speed (P=0.005 and P<0.001, respectively), worse short-term memory (P=0.011 and P<0.001), and worse executive function (P=0.035 and P=0.036), while the third tertile of EAA was associated with worse performance in verbal learning (P=0.007) and worse long-term verbal recall (P=0.005).

"Our hope is that this biomarker [EAA] may help us identify those survivors most at risk for early-onset cognitive aging, and might actually help us gauge a preclinical response to interventions, so that we can see efficacy sooner than other endpoints," said Williams at a press briefing.

A showed that EAA was significantly higher in survivors of childhood cancer versus non-cancer controls, and was associated with specific treatment exposures, as well as chronic health conditions. And in , Williams and colleagues found that survivors of childhood and adolescent Hodgkin lymphoma were more likely to self-report problems with neurocognitive functioning compared with their siblings.

"Our hypothesis is that treatments like chest radiation and alkylators are accelerating their biologic aging, placing them on a different trajectory for these neurocognitive outcomes," Williams said. "And they are happening sooner than they would have had they never been treated for cancer in the first place, so it is more of an accumulation of damage from all of the things they have experienced."

While Williams noted that treatments for Hodgkin lymphoma have changed over the past several decades -- for example, there is less use of chest radiation -- she pointed out that these patients still receive therapies that are associated with higher EAA.

Press briefing moderator Catherine Bollard, MD, of the Children's National Research Institute in Washington, D.C., noted that "my concern is that, even today in pediatrics, we are still giving combined radiation and chemotherapy to the majority of children with the more advanced disease. And that is not what is happening for the treatment of adult Hodgkin disease. I think this chemo/radiation combination does have this build-up of effects, so that it could easily affect our epigenetic age acceleration."

With the use of immune-based therapies now available for Hodgkin lymphoma, "we may not in the future even need chemotherapy, so I would like to think that these changes [in neurocognitive function] in the next 20 years will not be the same, if we change our treatment practices as pediatric oncologists," she added.

When asked how neurocognitive decline can be mitigated in these patients, Williams suggested that efforts should first be geared towards simple interventions like cognitive behavioral therapy or increased physical activity "that can help both all of these aging parameters and neurocognitive function" in high-risk patients.

The study included 215 survivors of childhood and adolescent Hodgkin lymphoma who had been treated at St. Jude Children's Research Hospital in Memphis, Tennessee, as well as 282 healthy community controls. Mean age among survivors was 39 years, 50% were women, and all were a mean of 25 years from diagnosis. Mean age among controls was 36 years, and 51% were women.

All participants underwent a neuropsychological assessment and provided blood samples.

Williams noted that the study was limited by the fact that it only included patients of European ancestry. He said that there are plans to profile the rest of the St. Jude cohort of pediatric cancer survivors in order to get a more diverse sample.

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