Comprehensive Approach to Improve Medicine Adherence in Pediatric Leukmia

描述（申请人提供）：急性淋巴细胞白血病（ALL）是最常见的儿童癌症。超过97%的ALL患儿在最初的28天诱导期后进入缓解期，约20%的患儿在5年内复发。此外，西班牙裔和非裔美国人更容易复发——这种差异不能完全用临床或遗传因素来解释。抢救效果很差，二线治疗有毒且昂贵。持久的首次缓解需要2年的维持期，包括每日口服6-巯基嘌呤（6MP）。在低系统性暴露于6MP （6MP代谢物-硫鸟嘌呤核苷酸[TGN]的低红细胞水平）的患者中观察到复发的风险增加。然而，红细胞TGN水平的个体间差异可能是由于未能坚持规定的治疗。在最近完成的一项儿童肿瘤组研究（AALL03N1, R01 CA96670, PI: Bhatia）中，我们证明了依从率<95%的儿童复发风险显着更高，从而允许我们创建非依从性（依从性<95%）的定义。52%的复发可归因于不坚持治疗。66%的非裔美国人、46%的西班牙裔美国人、48%的亚洲人和32%的非西班牙裔白人没有依从性（p<0.001）。在调整依从性后，种族差异的较差结果有所缓解。缺失6MP最常见的原因是健忘（对年幼儿童的父母以及青少年患者而言）。此外，坚持青少年患者和他们的父母强调父母警惕作为一种克服健忘的策略的重要性。这些发现为开发综合干预方案奠定了基础，该方案包括多媒体互动式患者/家长教育、基于网络的药物安排（可转换为定制的印刷时间表和短信提醒，以提示指定家长直接监督治疗（DST））。采用随机临床试验设计，我们将研究综合干预方案（IP）与单独教育（Edu）对18岁ALL患儿口服6MP依从性的影响。我们将研究社会人口统计学/心理社会因素的调节作用，以及健康信念/知识改变对干预依从性变化的中介作用，并建立基础设施，以确定干预对ALL复发的影响。建议的干预措施解决了一个与临床相关的问题——即，ALL患儿不依从性的高患病率与复发风险增加有关，并且在我们之前的研究中发现了依从性的障碍/促进因素。干预措施全面，技术复杂，但简单（因此可推广）且具有成本效益（每年节省约1260万至3280万美元）。依从性增强干预的成功实施不仅将提高ALL患儿的生存率，而且还可能产生深远的益处，因为当代治疗方法越来越多地在许多其他疾病中纳入口服药物，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.