Steep Price for Surviving Childhood Lymphoma: Epigenetic Aging
NEW ORLEANS — Children with Hodgkin lymphoma can be cured with intensive chemotherapy, radiation, and other modalities, but a large majority of patients who survive into adulthood may pay a steep price years later in terms of accelerated aging and neurocognitive impairment.
The findings come from a study of nearly 500 individuals in their late 30s, of whom 215 were adult survivors of pediatric Hodgkin lymphoma (HL) and 282 were community controls.
The results show that HL survivors had a higher epigenetic age relative to their chronological age compared with controls, translating into epigenetic age acceleration over chronological age equivalent to a mean of 7.7 years
In addition, this accelerated epigenetic aging in HL survivors was accompanied by neurocognitive deficits, including declines in visual-motor processing, short-term memory, verbal learning and recall, and executive function.
Dr AnnaLynn Williams
“We found that biologic aging is associated with long-term neurocognitive impairment in Hodgkin lymphoma survivors,” commented lead author AnnaLynn M. Williams, PhD, of the Wilmot Cancer Institute at the University of Rochester School of Medicine and Dentistry, Rochester, New York. “Specifically, we see strong and consistent associations with memory impairment, which suggests that biologic aging is likely related to cognitive aging.”
Williams presented the findings here at the American Society of Hematology (ASH) annual meeting.
“Our hope is that this biomarker 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 some other endpoints,” she said in a media briefing prior to presenting the data.
“This is an area that is very near and dear to my heart,” commented ASH President Jane N. Winter, MD, from the Feinberg School of Medicine at Northwestern University in Chicago.
“Pediatricians have been very much wedded to very intensive therapies and intend to incorporate radiation more frequently in their treatment strategies for children than we do in adults,” she said. In addition, “we are very much focused on the long-term consequences of mediastinal radiation causing breast cancer in adults who were treated as young adults or children for Hodgkin lymphoma, but now we’re shedding a light on the neurocognitive deficits, which I think are underappreciated.”
It can have a significant long-term impact on a patient population “that we otherwise cure,” she commented, pointing to a study by investigators in Germany that showed high unemployment levels among adult survivors of childhood HL compared with the general population.
Dr Catherine Bollard
Also reacting to the findings, Catherine Bollard, MD, of the Center for Cancer and Immunology Research at Children’s National Research Institute in Washington, DC, said: “My concern actually is that even today, in pediatrics, we’re still giving combined chemotherapy and radiation to the majority of the children with the more advanced disease, and that is not what is happening for the treatment of adult Hodgkin disease.”
She noted that there are now many immune-based therapies available for Hodgkin lymphoma that could soon obviate the need for chemotherapy.
Williams and colleagues had previously reported that compared with their healthy siblings, long-term survivors of HL had significantly higher risk (P < .05 for all comparisons) of neurocognitive impairment, anxiety, depression, unemployment, and impaired physical/mental quality of life.
In the current study, they looked specifically at epigenetic aging, and asked all participants to complete a comprehensive neuropsychological battery of tests.
The 215 trial participants who were survivors of pediatric HL came from the St Jude Lifetime Cohort. The mean patient age was 39, and the survivors were an average of 25 years out from their initial diagnosis.
The mean age of the 282 community controls was 36 years. Both the cohort and the controls were all European ancestry.
All participants provided a blood sample. The investigators performed genome-wide methylation studies on DNA derived from peripheral blood mononuclear cells (PBMC), and used the data to calculate epigenetic age according to a biomarker called DNAm PhenoAge. Also known as “Levine’s Clock,” this is an epigenetic biomarker of aging for life span and health span developed by Morgan E. Levine, PhD, and colleagues at the University of California Los Angeles and other centers.
Williams and her team determined epigenetic age acceleration by calculating the difference between epigenetic and chronological age, with a higher epigenetic accelerated age suggesting an older biological age relative to the patient’s actual age.
As noted above, they found that HL survivors had a significantly higher epigenetic accelerated age compared with controls, equivalent to a mean difference of 7.7 years (P < .001).
More than 80% of the survivors had some degree of accelerated aging, compared with only 23% of controls.
HL survivors with higher degrees (second and third tertiles) of accelerated aging had significantly worse visual-motor processing speed compared with survivors in the first (lowest) tertile, with survivors in the second tertile performing on average 0.42 standard deviations (SD) worse (P = .005) and those in the third tertile performing 0.55 SD worse (P < .001).
In addition, relative to first tertile survivors, those in the second and third tertiles performed worse on short-term memory, with a decrease of -0.42 SD (P = .011) and 0.59 SD (P < .001), respectively.
HL survivors in the third tertile performed worse than those in the other tertiles on measures of verbal learning (P =.007) and long-term verbal recall (P = .005), and those in the second or third tertiles had an average decline of 0.4 SD compared with those in first tertile on verbal fluency, a measure of executive function.
The declines in neurocognitive measures among survivors were relatively small, but they are clinically significant, Williams said, and were likely to be troublesome for patients.
Williams said that she and her colleagues are currently compiling data on a comparison of neurocognitive scores between cohort members and control for future publication, “but I can say that in the majority of measures that are reported on, survivors do worse.”
The investigators are planning expansion of DNA methylation profiling in the St. Jude Lifetime Cohort, and will follow survivors prospectively to look for changes in epigenetic acceleration and how those changes might predict who is most at risk for neurocognitive decline.
The study was supported by grants from the National Cancer Institute. Williams, Winter, and Bollard all report no relevant financial relationships.
American Society of Hematology (ASH) 2022 Annual Meeting: Abstract 902. Presented December 12, 2022.
Neil Osterweil, an award-winning medical journalist, is a long-standing and frequent contributor to Medscape.
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