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Telomere content may predict slow post-treatment recovery in children with AML
Telomere length at the end of induction may identify pediatric patients with acute myeloid leukemia who are at high risk for delayed bone marrow recovery after receiving therapy, according to a report from the Children’s Oncology Group.
“Telomeres are protective caps on chromosome ends that keep DNA from fraying as you age, much like the plastic end of a shoelace prevents it from unraveling,” Maria M. Gramatges, MD, PhD, assistant professor of pediatric oncology at Baylor College of Medicine, said in a press release. “We were interested in telomere length as a marker for blood count recovery, because defects in telomere maintenance are known risks for bone marrow failure and anaplastic anemia. “We know that up to 15% to 20% of children can take 2 months or longer to recover their blood counts after a course of AML chemotherapy,” Gramatges added. “Our goal was to understand if these children had an underlying genetic predisposition associated with an impaired capacity for recovery.”
The analysis included data from 115 children and young adults aged 1 month to 29.99 years with de novo AML who enrolled in Children’s Oncology Group study AAML0531.
The researchers used quantitative polymerase chain reaction to measure telomere content from available remission bone marrow samples (n = 97) obtained after the second induction chemotherapy course.
A significantly delay in neutrophil recovery following chemotherapy — defined as more than one standard deviation above the mean for at least two chemotherapy courses — occurred in 53 patients.
Telomere content decreased with patient age. However, the comparison of mean telomere content between patients with and without delayed neutrophil recovery did not reach statistical significance (0.66 ± 0.13 vs. 0.7 1 ± 0.15).
To further examine the association between telomere content and hematopoietic recovery, researchers categorized patients into quartiles. Twenty-four patients in quartile one had the least telomere content (range, 0.43-0.59; mean, 0.52).
Patients in quartile one were significantly more likely than patients in quartiles two through four to experience prolonged neutropenia after the fourth (P < .001) and fifth (P = .002) chemotherapy cycles. This difference was especially apparent with the fourth chemotherapy cycle, after which mean time to absolute neutrophil count recovery was 53.8 days (range, 27-92) among patients in quartile one compared with 42.7 days (range, 20-91) in all other patients.
The association between less telomere content and delayed neutrophil recovery persisted in analyses adjusted for age after the fourth (P = .002) and fifth (P = .009) chemotherapy cycles.
However, 5-year OS appeared comparable among patients with less and more telomere content (87% ± 14% vs. 90% ± 7%).
A DNA analysis for germline mutations in four telomere maintenance genes did not reveal enrichment of rare or novel variants among patients with delayed recovery.
“A significant proportion of children with AML suffer from treatment-related toxicities, with some succumbing to complications of the therapies we give, rather than from the actual cancer itself,” Gramatges said. “We hope this research will help identify those who are at a higher risk for delayed recovery and use this knowledge to reduce the morbidity and mortality associated with AML treatment.” – by Cameron Kelsall
Disclosure: Gramatges reports no relevant financial disclosures. Please see the full study for a list of all other researchers’ relevant financial disclosures.