Park Yongkyu, K C Nirajan, Willekens Jeremy, Patel Chadni, Savage Beth A, Lin Haiqun, Paneque Alysta, Daly Robert, Thrope Alexandra, Burns Melissa A, Welch Jennifer Jg, Kahn Justine M, Kelly Kara M, Tran Thai-Hoa, Michon Bruno, Gennarini Lisa, Silverman Lewis B, Sands Stephen A, Cole Peter D
Rutgers Cancer Institute, New Brunswick, NJ, United States.
Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, United States.
Cancer Epidemiol Biomarkers Prev. 2025 Sep 4. doi: 10.1158/1055-9965.EPI-25-1058.
Survivors of childhood acute lymphoblastic leukemia (ALL) frequently exhibit treatment-related neurocognitive impairment, although there is substantial interpatient variability in this outcome. Analysis of biomarkers that reflect the impact of chemotherapy during the two years of treatment for ALL offers the potential to identify children who have subclinical treatment-related neurotoxicity at a time when a protective intervention could prevent the development of persistent impairment.
We prospectively measured markers indicative of oxidative stress (8-hydroxydeoxyguanosine; 8OHdG) and neurodegeneration (total tau) in cerebrospinal fluid (CSF) collected at five timepoints before and during the first year of chemotherapy for ALL among 529 patients enrolled on DFCI ALL Consortium protocol 16-001 (NCT03020030).
CSF 8OHdG and total tau change significantly over time, with parallel increases emerging during intensive phases of therapy, especially following repeated doses of intrathecal chemotherapy. A concordant increase in both markers was observed in 50% of patients; a concordant decrease was seen in a smaller subset (15%). In multivariable analysis, higher CSF tau was significantly associated with White race and non-Hispanic ethnicity.
Analysis of CSF collected prospectively in a large cohort of children treated for ALL demonstrated significant changes in markers of oxidative stress and neurodegeneration within three months of treatment initiation.
The clinical relevance of the putative biomarkers reported here will be validated by testing whether they are predictive of treatment related cognitive decline. These biomarkers may then serve as surrogate markers for testing the efficacy of protective interventions designed to protect against treatment-induced neurotoxicity and cognitive decline.
儿童急性淋巴细胞白血病（ALL）幸存者经常出现与治疗相关的神经认知障碍，尽管患者间在这一结果上存在很大差异。分析反映ALL治疗两年期间化疗影响的生物标志物，有可能在保护性干预可预防持续性损伤发生时，识别出有亚临床治疗相关神经毒性的儿童。
我们前瞻性地测量了529例参加DFCI ALL联盟方案16 - 001（NCT03020030）的患者在ALL化疗第一年之前和期间五个时间点采集的脑脊液（CSF）中指示氧化应激（8 - 羟基脱氧鸟苷；8OHdG）和神经变性（总tau蛋白）的标志物。
CSF中8OHdG和总tau蛋白随时间显著变化，在强化治疗阶段出现平行升高，尤其是在多次鞘内化疗后。50%的患者观察到两种标志物一致升高；较小比例的亚组（15%）观察到一致降低。在多变量分析中，较高的CSF tau蛋白与白人种族和非西班牙裔显著相关。
对一大群接受ALL治疗的儿童前瞻性采集的CSF进行分析显示，在治疗开始后三个月内氧化应激和神经变性标志物有显著变化。
此处报告的假定生物标志物的临床相关性将通过测试它们是否能预测治疗相关的认知下降来验证。这些生物标志物随后可作为替代标志物，用于测试旨在预防治疗引起的神经毒性和认知下降的保护性干预措施的疗效。
