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

项目摘要/摘要 年龄在15-39岁之间被诊断为癌症的患者并没有看到同样的生存改善。 与被诊断为儿童(15岁)的患者相比。这些患者已获得特殊称号。 NCI作为青少年和年轻人(Aya)，并伴随着解决这些结果的任务 差距。急性淋巴细胞性白血病(ALL)就是这种现象的缩影，Aya的存活率 继续落后于儿童(5年总体存活率：1-14年：86%；15-21：56%；22-29：42%；30-39：35%)。横穿 受儿童启发和成人风格的治疗方案，所有治疗包括延长(~2年)的维持期 每天需要口服6-巯基嘌呤(6MP)的化疗。最近的一项大规模调查证实， 全身性暴露于6MP不足与复发风险增加有关；衡量全身性6MP 暴露后，这一综合方法评估了一种6MP代谢物(硫代鸟嘌呤核苷酸[TG])的水平。 掺入DNA(DNA-TG)。几个特定于Aya的因素可能导致系统性6MP暴露和 没有经过系统的检查。这些因素可能与AYA患者(6MP依从性)有关 和医疗保健(疾病管理，由提供者规定的6MP剂量强度[DI]反映)，以及 这些领域中的障碍和促进者。我们假设系统性暴露于6MP会与 具有6MP遵从性(在患者领域)和疾病管理，由提供商代表- 处方6MP DI(在医疗保健领域)。我们将研究DNA-TG水平和 6MP依从性和6MP DI，根据药物遗传学进行调整。然后，我们将确定障碍/推动者 6MP依从性和疾病管理，使用混合方法收敛平行研究设计，两者 定量确定依从性和6MP DI的预测因素，并定性描述前景 无论是病人还是医疗服务提供者。我们将使用Aya的前瞻性队列进行这项研究 在一个由多种类型的设施和设备组成的全国14个地点的联盟中接受所有维持治疗的患者 肿瘤学实践。在每名患者6个月的时间里，6MP依从性将通过电子和每月DNA- 将跟踪甘油三酯水平(外周血)。患者问卷将记录自我报告的障碍和 遵守的促进者以及社会人口统计学；机构级调查问卷将涵盖医疗保健 各种因素。这项研究的发现有可能确定与患者相关和与医疗保健相关的目标 有可能减轻急性淋巴细胞白血病AYA患者的AYA结局差异的干预措施。 此外，这项研究建立了基础设施，以继续跟踪该队列的复发，并进行 干预(S)在一个新的以AYA为重点的财团内进行这项拟议的试验。

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.