Predictors of Systemic Exposure to Oral 6MP During Maintenance in Adolescentsand Young Adults with Acute Lymphoblastic Leukemia

项目总结/摘要 年龄在15- 39岁之间的诊断为癌症的患者在生存率方面没有同样的改善。 与诊断为儿童（<15岁）的患者相比。这些病人被特别指定为 由NCI作为青少年和年轻人（AYA），伴随着解决这些结果的任务 差距。急性淋巴细胞白血病（ALL）是这种现象的缩影， 继续落后于儿童（5年总生存率：1- 14年：86%; 15-21年：56%; 22-29年：42%; 30-39年：35%）。跨 儿童启发和成人风格的治疗方案，ALL治疗包括一个长期（约2年）维持期 化疗需要每天口服6-巯基嘌呤（6 MP）。一项大型调查最近证实， 全身暴露于6 MP不足与复发风险增加相关;为了测量全身6 MP 暴露，这种综合方法评估了6 MP代谢物（硫鸟嘌呤核苷酸[TG]）的水平 插入DNA（DNA-TG）。几种AYA特异性因素可能导致全身6 MP暴露， 还没有被系统地研究过。这些因素可能与AYA患者（6 MP依从性） 和医疗保健（疾病管理，由提供者处方的6 MP剂量强度[DI]反映），以及 这些领域中的障碍和促进因素。我们假设全身暴露于6 MP将与 同时具有6 MP依从性（在患者领域）和疾病管理，如提供者所代表的- 规定的6 MP DI（在医疗保健领域）。我们将研究DNA-TG水平与 6 MP依从性和6 MP DI，调整药物遗传学。然后，我们将确定障碍/促进因素， 6 MP依从性和疾病管理，使用混合方法收敛平行研究设计， 定量确定依从性和6 MP DI的预测因子，并定性描述 患者和医疗服务提供者的信息。我们将使用AYA的前瞻性队列进行这项研究 在由多种类型设施组成的全国14个研究中心联盟中接受ALL维持治疗的患者， 肿瘤学实践。每例患者6个月，将以电子方式监测6 MP依从性，并每月进行一次DNA- 将跟踪TG水平（外周血）。患者问卷将收集自我报告的障碍， 依从性的促进者以及社会人口统计学;机构层面的问卷将收集医疗保健 因素这项研究的结果有可能确定患者相关和医疗保健相关的目标 适合干预，有可能减轻ALL AYA患者的AYA结局差异。 此外，这项研究建立了基础设施，以继续跟踪这一队列的复发，并进行 在一个以AYA为重点的新联盟中，通过这项拟议试验进行干预。

PROJECT SUMMARY / ABSTRACT Patients diagnosed with cancer between the ages of 15-39y have not seen the same improvement in survival when compared with patients diagnosed as children (<15y). These patients have received special designation by the NCI as adolescents and young adults (AYA), accompanied by a mandate to address these outcome disparities. Acute lymphoblastic leukemia (ALL) epitomizes this phenomenon, where survival rates in AYA continue to lag behind children (5y overall survival: 1-14y: 86%; 15-21: 56%; 22-29: 42%; 30-39: 35%). Across pediatric-inspired and adult-style therapy regimens, ALL therapy includes a prolonged (~2y) maintenance phase of chemotherapy requiring daily oral 6-mercaptopurine (6MP). A large investigation recently confirmed that inadequate systemic exposure to 6MP is associated with an increased risk of relapse; to measure systemic 6MP exposure, this comprehensive approach assessed the levels of a 6MP metabolite (thioguanine nucleotide [TG]) incorporated into DNA (DNA-TG). Several AYA-specific factors likely contribute to systemic 6MP exposure and have not been examined systematically. These factors are likely related to both the AYA patient (6MP adherence) and healthcare (disease management, reflected by the provider-prescribed 6MP dose intensity [DI]), as well as the barriers and facilitators within these domains. We hypothesize that systemic exposure to 6MP will correlate with both 6MP adherence (in the patient domain) and disease management, as represented by provider- prescribed 6MP DI (in the healthcare domain). We will examine these associations between DNA-TG levels and both 6MP adherence and 6MP DI, adjusting for pharmacogenetics. We will then identify barriers/ facilitators to both 6MP adherence and disease management, using a mixed methods convergent parallel study design, both quantitatively determining the predictors of adherence and 6MP DI, and qualitatively describing the perspectives of both the patients and healthcare providers. We will conduct this study using a prospective cohort of AYA patients in ALL maintenance therapy across a national 14-site consortium of multiple types of facilities and oncology practices. For 6 months per patient, 6MP adherence will be monitored electronically and monthly DNA- TG levels will be followed (peripheral blood). Patient questionnaires will capture self-reported barriers and facilitators of adherence as well as sociodemographics; institution-level questionnaires will capture healthcare factors. Findings from this study have the potential to identify both patient-related and healthcare-related targets amenable to interventions with the potential to mitigate AYA outcome disparities in AYA patients with ALL. Furthermore, this study establishes the infrastructure to continue to follow this cohort for relapse, and conduct intervention(s) informed by this proposed trial within a novel AYA-focused consortium.