Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, Tennessee.
Department of Neurology, St Jude Children's Research Hospital, Memphis, Tennessee.
JAMA Oncol. 2018 Jul 12;4(7):e180089. doi: 10.1001/jamaoncol.2018.0089.
Little is known about treatment-related neurotoxic mechanisms in children with acute lymphoblastic leukemia (ALL) treated with chemotherapy only.
To examine concentration of cerebrospinal fluid (CSF) biomarkers of brain injury at ALL diagnosis and during cancer therapy and to evaluate associations with long-term neurocognitive and neuroimaging outcomes and relevant genetic polymorphisms.
DESIGN, SETTING, AND PARTICIPANTS: This prospective cohort study included 235 patients with ALL who received a chemotherapy-only protocol. Patients provided CSF samples after diagnosis and throughout treatment. At 5 or more years after the diagnosis, 138 (69.7%) of 198 eligible survivors participated in long-term follow-up assessments. Children were treated from June 1, 2000, through October 31, 2010. Follow-up was completed on October 21, 2014, and data were analyzed from August 1, 2015, through September 30, 2016.
Plasma concentration of high-dose intravenous methotrexate sodium and number of triple intrathecal chemotherapy injections.
The CSF samples were assayed at 5 points from diagnosis to reinduction for biomarkers of myelin degradation (myelin basic protein [MBP]), neuronal damage (nerve growth factor [NGF] and total and phosphorylated tau protein), astrogliosis (glial fibrillary acidic protein [GFAP]), and neuroinflammation (chitotriosidase). DNA was genotyped for polymorphisms in drug metabolism, oxidative stress, and neurodevelopment. Leukoencephalopathy was evaluated by brain imaging. At 5 or more years after the diagnosis, survivors completed neurocognitive testing and brain imaging of white matter integrity.
Among the 235 patients with CSF samples (120 boys [51.1%] and 115 girls [48.9%]; mean [SD] age at diagnosis, 6.8 [4.7] years), MBP and GFAP levels were elevated at baseline and through consolidation. The number of intrathecal injections was positively correlated with NGF level increase at consolidation (r = 0.19; P = .005). Increases in GFAP (risk ratio [RR], 1.23; 95% CI, 1.09-1.40), MBP (RR, 1.06; 95% CI, 1.01-1.11), and total tau (RR, 1.76; 95% CI, 1.11-2.78) levels were associated with a higher risk for leukoencephalopathy and higher apparent diffusion coefficient in frontal lobe white matter 5 years after diagnosis (standardized estimate, 0.05; P < .001). Increase in total tau at consolidation was associated with worse attention (omissions z score estimate, -0.20; P = .04).
Glial injury may be present at diagnosis of ALL. Neuronal injury was associated with intrathecal chemotherapy. The CSF biomarkers may be useful in identifying individuals at risk for worse neurologic outcomes, particularly those with genetic susceptibility to poor brain function.
对于仅接受化疗治疗的急性淋巴细胞白血病（ALL）患儿，人们对其治疗相关的神经毒性机制知之甚少。
检测 ALL 患儿在诊断时和癌症治疗期间脑脊液（CSF）中脑损伤生物标志物的浓度，并评估其与长期神经认知和神经影像学结局以及相关遗传多态性的相关性。
设计、环境和参与者：本前瞻性队列研究纳入了 235 名接受单纯化疗方案治疗的 ALL 患儿。患者在诊断后和治疗期间提供 CSF 样本。在诊断后 5 年或以上时，198 名符合条件的幸存者中有 138 名（69.7%）参加了长期随访评估。患儿于 2000 年 6 月 1 日至 2010 年 10 月 31 日接受治疗。随访于 2014 年 10 月 21 日结束，数据分析于 2015 年 8 月 1 日至 2016 年 9 月 30 日进行。
大剂量静脉注射甲氨蝶呤钠的血浆浓度和三次鞘内化疗注射的次数。
从诊断到再诱导的 5 个时间点检测 CSF 样本中的髓鞘降解生物标志物（髓鞘碱性蛋白[MBP]）、神经元损伤生物标志物（神经生长因子[NGF]和总tau蛋白及磷酸化 tau 蛋白）、星形胶质细胞损伤生物标志物（胶质纤维酸性蛋白[GFAP]）和神经炎症生物标志物（几丁质酶）。对药物代谢、氧化应激和神经发育的基因多态性进行 DNA 基因分型。通过脑成像评估白质脑病。在诊断后 5 年或以上时，幸存者完成了神经认知测试和白质完整性的脑成像。
在 235 名有 CSF 样本的患儿中（120 名男孩[51.1%]和 115 名女孩[48.9%]；诊断时的平均[标准差]年龄为 6.8[4.7]岁），MBP 和 GFAP 水平在基线和巩固治疗期间升高。鞘内注射次数与巩固治疗时 NGF 水平升高呈正相关（r = 0.19；P = .005）。GFAP（风险比[RR]，1.23；95%CI，1.09-1.40）、MBP（RR，1.06；95%CI，1.01-1.11）和总 tau（RR，1.76；95%CI，1.11-2.78）水平升高与白质脑病和诊断后 5 年额叶白质表观扩散系数升高的风险增加相关（标准化估计值，0.05；P < .001）。巩固治疗时总 tau 水平升高与注意力下降相关（遗漏 z 评分估计值，-0.20；P = .04）。
ALL 患儿在诊断时可能存在神经胶质损伤。神经元损伤与鞘内化疗有关。CSF 生物标志物可能有助于识别神经结局较差的个体，尤其是那些具有大脑功能不良遗传易感性的个体。
