Background

Treatment for childhood acute lymphoblastic leukemia has evolved over the past five decades, with moderation of traditional chemotherapy and radiotherapy and the introduction of targeted immune-based and cellular-based therapies. The affect of these changes on late health outcomes has not been assessed. Using data from the The St Jude Lifetime (SJLIFE) Cohort, we aimed to characterise the magnitude of morbidity and patterns of late health outcomes among survivors of childhood acute lymphoblastic leukaemia treated over time.

Methods

The St Jude Lifetime (SJLIFE) Cohort is a retrospective cohort study with prospective follow-up and ongoing data accrual designed to facilitate longitudinal, clinically-based assessment of health outcomes among survivors of paediatric malignancies. 980 survivors included in this analysis were diagnosed with paediatric acute lymphoblastic leukaemia at St Jude Children's Research Hospital (SJCRH) between Aug 28, 1963, and July 19, 2003, were aged 18 years old and older at enrolment, had a minimum follow-up of 10 years after diagnosis, and completed an initial on-campus SJLIFE assessment as of data cutoff (June 30, 2015). 272 community control participants, matched to survivors on 5-year age blocks in each sex, were recruited for comparison. Cumulative chemotherapy and radiation dose exposures and major medical events during and after therapy were retrieved from the medical records of the survivors. History or physical examination, laboratory analysis, physical fitness, and neurocognitive testing were done. Health conditions were graded according to a modified version of the Common Terminology Criteria for Adverse Events. Neurocognitive domains of attention (Trial Making Test Part A and Conner's Continuous Performance Test-II) and executive function (Trail Making Test Part B, Controlled Oral Word Association Test, and Wechsler Adult Intelligence Scale-III Digit Span Test Backward) were measured and age-adjusted Z scores were calculated. Mean cumulative count was used to calculate the age-standardised cumulative burden of health conditions over time. This cohort study is registered at ClinicalTrials.gov, number NCT00760656.

Findings

980 survivors of acute lymphoblastic leukaemia (50% women, median age at diagnosis 5 years [IQR 3·1–9·1 years], and median time from diagnosis of 30·0 years [22·7–36·3]) had a median age of 35·8 years (29·4–42·9) at assessment compared with 35·1 years (28·7–42·6) for 272 controls. Survivors had significantly more growth hormone deficiency, hypogonadism, and neuropathy than controls. By age 30 years, survivors of acute lymphoblastic leukaemia had, on average, 5·4 (95% CI 5·1–5·8) grade 1–4 health conditions, including 3·2 (2·9–3·4) grade 2–4 health conditions, compared with 2·0 (CI 1·7–2·2) grade 1–4 and 1·2 (1·03–1·4) grade 2–4 health conditions among controls. The cumulative burden of grade 2–4 health conditions involved multiple organ systems for survivors treated on protocols between 1962–91, but after elimination of cranial radiotherapy for children with acute lymphoblastic leukaemia, conditions now predominately include musculoskeletal and endocrine disorders for survivors on protocols between 1991–2007.

Interpretation

Although changes in paediatric acute lymphoblastic leukaemia treatment protocols have improved overall survival, the burden of late morbidity remains high for these patients. We show that the pattern of late toxic effects has markedly changed over time, with survivors having a reduction in health conditions that are immediately life-threatening, however, maintaining health status and quality of life for survivors of paediatric acute lymphoblastic leukaemia requires continued medical surveillance, counselling, and lifestyle modifications.

Funding

US National Cancer Institute and the American Lebanese Syrian Associated Charities.

中文翻译：

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儿童急性淋巴细胞白血病的幸存者长期健康结局不断变化的负担：圣裘德终生队列研究的回顾性分析。

背景

在过去的五十年中，随着传统化学疗法和放射疗法的缓和以及针对性的基于免疫和基于细胞的治疗方法的引入，儿童急性淋巴细胞白血病的治疗方法得到了发展。这些变化对晚期健康结局的影响尚未评估。我们使用来自St Jude Lifetime（SJLIFE）队列的数据，旨在表征随时间推移治疗的儿童急性淋巴细胞白血病幸存者的发病率大小和后期健康结局的模式。

方法

St Jude Lifetime（SJLIFE）队列是一项回顾性队列研究，具有前瞻性随访和不断累积的数据，旨在促进纵向，基于临床的儿科恶性肿瘤幸存者健康状况评估。1963年8月28日至2003年7月19日期间，圣裘德儿童研究医院（SJCRH）将980名幸存者诊断为小儿急性淋巴细胞白血病，入组时年龄18岁以上。确诊后的10年内，截至数据截止（2015年6月30日）完成了校园内SJLIFE初始评估。招募了272位社区控制参与者，与每种性别在5岁年龄段的幸存者相匹配，以进行比较。从幸存者的病历中检索出累积的化学疗法和放射剂量以及治疗期间和治疗后的重大医疗事件。进行病史或体格检查，实验室分析，身体适应性和神经认知测试。根据《不良事件通用术语标准》的修订版对健康状况进行分级。测量了注意的神经认知领域（试制测试A部分和Conner的持续表现测试II）和执行功能（试制测试B部分，受控口语联想测试和Wechsler成人智力测验III级数字跨度测试）和年龄计算出调整后的Z分数。平均累积计数用于计算随时间推移按年龄标准化的健康状况累积负担。

发现

980名急性淋巴细胞白血病幸存者（50％妇女，诊断中位年龄为5年[IQR 3·1–9·1年]，诊断后中位时间为30·0年[22·7–36·3]）评估时的中位年龄为35·8岁（29·4–42·9），而272名对照者为35·1岁（28·7–42·6）。幸存者的生长激素缺乏症，性腺功能减退和神经病的发生率明显高于对照组。到30岁时，急性淋巴细胞白血病的幸存者平均达到1-4级的健康状况，即5·4（95％CI 5·1–5·8），包括3·2（2·9–3·4） 2–4级健康状况，而对照组的2·0（CI 1·7–2·2）1–4级和1·2（1·03–1·4）2–4级健康状况。对于1962-91年间接受治疗的幸存者，2-4年级健康状况的累积负担涉及多个器官系统，

解释

尽管小儿急性淋巴细胞白血病治疗方案的改变提高了总生存率，但这些患者的晚期发病负担仍然很高。我们显示，随着时间的流逝，晚期毒性作用的模式已发生显着变化，幸存者的健康状况有所下降，这立即威胁到生命，但是，维持小儿急性淋巴细胞白血病幸存者的健康状况和生活质量需要持续的医学监测，咨询和生活方式的改变。

资金

美国国家癌症研究所和美国黎巴嫩叙利亚联合慈善机构。