Comprehensive Approach to Improve Medicine Adherence in Pediatric Leukmia

描述（由申请人提供）：急性淋巴细胞白血病（ALL）是最常见的儿童癌症。虽然超过97%的ALL儿童在最初的28天诱导期后进入缓解期，但约20%在5年内复发。此外，西班牙裔和非洲裔美国人更容易复发-这种差异并不完全由临床或遗传因素解释。抢救效果不佳，二线治疗有毒且昂贵。持久的首次缓解需要2年的维持期，包括每日口服自我/父母给药6-巯基嘌呤（6 MP）。在全身暴露于6 MP较低的患者中观察到复发风险增加（6 MP代谢物-硫鸟嘌呤核苷酸[TGN]的红细胞水平较低）。然而，在红细胞TGN水平中观察到的个体间变异性可能是由于未能坚持处方治疗所致。在最近完成的一项儿童肿瘤组研究（AALL 03 N1，R 01 CA 96670，PI：Bhatia）中，我们证明了依从率<95%的儿童复发风险显著更高，这使我们能够定义非依从性（依从性<95%）。百分之五十二的复发归因于不遵守。66%的非洲裔美国人、46%的西班牙裔美国人、48%的亚洲人和32%的非西班牙裔白人为非依从性（p<0.001）。调整依从性后，种族的不良结局减轻。缺失6 MP的最常见原因是健忘（年幼儿童的父母以及青少年患者）。此外，坚持青少年患者和他们的父母强调父母警惕的重要性，作为一种策略，以克服健忘。这些发现形成了开发综合干预包的基础，该综合干预包包括多媒体交互式患者/家长教育和基于网络的药物安排，该药物安排转化为定制的打印时间表和短信提醒，以提示指定家长直接监督治疗（DST）。采用随机临床试验设计，我们将研究这种综合干预包（IP）与单纯教育（Edu）对参与研究时年龄<18岁的ALL儿童口服6 MP依从性的影响。我们将研究社会人口学/心理社会因素的修正效应，以及健康信念/知识变化对干预依从性变化的中介效应，并建立基础设施以确定干预对ALL复发的影响。所提出的干预解决了临床相关问题-即，不依从性的高患病率与ALL儿童复发风险增加相关，并由我们先前研究中确定的依从性障碍/促进因素提供信息。干预措施全面、技术先进、简单（因此可推广）且具有成本效益（每年可节省约1260万至3280万美元）。成功实施增强依从性的干预措施不仅可以提高ALL儿童的生存率，而且还可能产生深远的益处，因为当代治疗越来越多地将口服药物纳入许多其他疾病，而不依从性是一个重要问题。

DESCRIPTION (provided by applicant): Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. While over 97% of children with ALL enter remission after an initial 28-day induction period, ~20% relapse within 5 years. Furthermore, Hispanics and African Americans are more likely to suffer relapse - a difference not entirely explained by clinical or genetic factors. Salvage is poor, and second-line therapies are toxic and expensive. Durable first remissions require a 2-year maintenance phase that includes daily oral self/parent-administration of 6- mercaptopurine (6MP). Increased risk of relapse is observed in patients with low systemic exposure to 6MP (low red cell levels of 6MP metabolite - thioguanine nucleotide [TGN]). However, the inter-individual variability observed in red cell TGN levels could be due to failure to adhere to prescribed therapy. In a recently completed Children's Oncology Group study (AALL03N1, R01 CA96670, PI: Bhatia), we demonstrated that the risk of relapse was significantly higher among children with adherence rates <95%, allowing us to create a definition of non-adherence (adherence <95%). Fifty-two percent of the relapses were attributable to non-adherence. Sixty-six percent of African Americans, 46% of Hispanics, 48% of Asians, and 32% of non-Hispanic whites were non-adherent (p<0.001). The worse outcome by ethnicity was mitigated after adjusting for adherence. The most common reason for missing 6MP was forgetfulness (on part of both parents of younger children as well as adolescent patients). Furthermore, adherent adolescent patients and their parents emphasized the importance of parental vigilance as a strategy to overcome forgetfulness. These findings have formed the basis for developing a comprehensive intervention package that consists of multimedia interactive patient/parent education, and web-based medication scheduling that translates into customized printed schedules and text- message reminders to prompt directly supervised therapy (DST) by a designated parent. Using a randomized clinical trial design, we will study the impact of this comprehensive intervention package (IP) vs. education alone (Edu) on adherence to oral 6MP in children with ALL who are d18 years at participation. We will examine the modifying effect of sociodemographic/ psychosocial factors and the mediating effects of change in health beliefs/knowledge on change in adherence with intervention, and establish the infrastructure to determine the impact of intervention on relapse of ALL. The proposed intervention addresses a clinically relevant problem - i.e., high prevalence of non-adherence that is associated with an increased risk of relapse in children with ALL, and is informed by the barriers/facilitators to adherence identified in our previous studies. The intervention is comprehensive, technologically sophisticated, yet simple, (hence disseminable) and cost-effective (savings of ~$12.6M to $32.8M/y). Successful implementation of the adherence-enhancing intervention will not only improve survival in children with ALL, but could also have far-reaching benefits, since contemporary therapies are increasingly incorporating oral agents in many other diseases, and non-adherence is a significant problem.