Comprehensive Approach to Improve Medicine Adherence in Pediatric Leukmia

描述(申请人提供)：急性淋巴细胞性白血病(ALL)是最常见的儿童癌症。而超过97%的ALL儿童在最初的28天诱导期后进入缓解状态，约20%的儿童在5年内复发。此外，拉美裔和非裔美国人更有可能复发--这种差异并不完全由临床或遗传因素解释。抢救很差，二线治疗有毒且昂贵。持久的首次缓解需要2年的维持阶段，其中包括每天口服6-巯基嘌呤(6MP)的自我/父母给药。在全身暴露于6MP(低红细胞水平的6MP代谢物-硫鸟苷核苷酸[TGN])的患者中，观察到复发风险增加。然而，在红细胞TGN水平中观察到的个体间差异可能是由于未能坚持处方治疗。在最近完成的一项儿童肿瘤学小组研究(AALL03N1，R01 CA96670，PI：Bhatia)中，我们证明了依从率为95%的儿童的复发风险显著更高，这使我们能够创建不遵守的定义。52%的复发可归因于不坚持。66%的非洲裔美国人、46%的西班牙裔美国人、48%的亚裔美国人和32%的非西班牙裔白人是非信徒(p&lt；0.001)。在根据依从性进行调整后，按种族划分的较差结果得到了缓解。遗漏6MP最常见的原因是健忘(无论是年龄较小的孩子的父母还是青少年患者)。此外，忠实的青少年患者及其父母强调父母警觉的重要性，将其作为克服健忘的一种策略。这些发现形成了开发综合干预方案的基础，该方案包括多媒体互动患者/家长教育，以及基于网络的用药计划，该计划转化为定制的打印计划和短信提醒，以提示指定父母的直接监督治疗(DST)。使用随机临床试验设计，我们将研究这种综合干预方案(IP)与单纯教育(EDU)对所有年龄在18岁的儿童口服6MP依从性的影响。我们将考察社会人口学/心理社会因素的修正作用，以及健康信念/知识的改变在遵循干预措施的情况下对变化的中介作用，并建立确定干预对所有人复发的影响的基础设施。拟议的干预措施解决了一个临床上相关的问题--即与ALL儿童复发风险增加相关的高不遵守率，并受到我们先前研究中确定的坚持障碍/促进者的影响。这种干预是全面的、技术复杂的、但简单的(因此是可传播的)和具有成本效益的(每年节省约1260万至3280万美元)。成功实施依从性增强干预措施不仅将提高ALL儿童的存活率，而且还可能产生深远的好处，因为现代治疗方法越来越多地将口服制剂纳入许多其他疾病，而不依从性是一个重大问题。

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.