Comprehensive Approach to Improve Medicine Adherence in Pediatric Leukemia

急性淋巴细胞白血病（ALL）是最常见的儿童癌症。超过97%的儿童 ALL在最初的28天诱导期后进入缓解期，约20%在5年内复发。此外，委员会认为， 西班牙裔和非洲裔美国人更容易复发--这种差异不能完全解释为 临床或遗传因素。抢救效果不佳，二线治疗有毒且昂贵。耐用第一 缓解期需要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 (low 6 MP代谢物-硫鸟嘌呤核苷酸[TGN]的红细胞水平）。然而，个体间的变异性 在红细胞TGN水平中观察到的异常可能是由于未能坚持处方治疗。在最近完成的 儿童肿瘤组研究（AALL 03 N1，R 01 CA 96670，PI：Bhatia），我们证明， 在依从率<95%的儿童中，复发率显著较高，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 未粘附（p<0.001）。调整依从性后，种族的不良结局减轻。 错过6 MP的最常见原因是健忘（年幼孩子的父母都是如此， 青少年患者）。此外，青少年患者及其父母强调， 父母警惕作为克服健忘的策略的重要性。这些发现构成了 开发一个综合干预包，包括多媒体互动病人/家长 教育和基于网络的药物安排，转化为定制的打印时间表和文本- 消息提醒，以提示由指定父母进行的直接监督治疗（DST）。采用随机 临床试验设计，我们将研究这种综合干预包（IP）与教育的影响 在参与研究时年龄<18岁的ALL儿童中单独（Edu）口服6 MP的依从性。我们将研究 社会人口/心理社会因素的修正作用和健康变化的中介作用 信念/知识的变化，坚持干预，并建立基础设施，以确定 干预对急性淋巴细胞白血病复发影响。拟议的干预措施解决了一个临床相关的问题- 也就是说，与ALL儿童复发风险增加相关的高不依从率， 并通过我们先前研究中确定的依从性障碍/促进因素进行了了解。述干预 全面、技术先进、简单（因此可推广）和成本效益高（节省 约1260万美元至3280万美元/年）。成功实施提高依从性的干预措施不仅 提高ALL儿童的生存率，但也可能有深远的好处，因为当代疗法 越来越多地将口服药物用于许多其他疾病，并且不依从性是一个重要的问题。

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.