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

患有急性淋巴细胞白血病的青少年和年轻人在维持期间全身暴露于口服 6MP 的预测因子

• 批准号: 10576861
• 负责人: Julie Anna Wolfson
• 金额: $ 64.98万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-24 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10576861
• 关键词: 6-Mercaptopurine; Acute Lymphocytic Leukemia; Address; Adherence; Adolescent and Young Adult; Adult; Adult Acute Lymphocytic Leukemia; Age; Behavioral Sciences; Biometry; Caring; Child; Childhood; DNA; Diagnosis; Diagnostic; Disease Management; Disease remission; Disparity; Dose; Enrollment; Exposure to; Geography; Health Personnel; Health Services Research; Healthcare; Individual; Inferior; Infrastructure; Institution; Intervention; Interview; Investigation; Knowledge; Leukocytes; Maintenance; Maintenance Therapy; Malignant Neoplasms; Measures; Methods; Modeling; Monitor; Nucleotides; Oncology; Oral; Outcome; Outcomes and Health Services Research; Patient Care; Patient Self-Report; Patients; Pharmacogenetics; Pharmacology; Phase; Population; Process; Prospective cohort; Provider; Psychosocial Factor; Qualitative Research; Questionnaires; Recurrent disease; Regimen; Relapse; Research Design; Role; Services; Site; Social support; Structure; Survival Rate; System; Thioguanine; Time; chemotherapy; cohort; drug metabolism; health belief; health care delivery; improved; innovation; leukemia treatment; medication compliance; novel; oncology service; outcome disparities; peripheral blood; public health relevance; relapse risk; sociodemographics; young adult

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.

项目摘要 /摘要 15-39岁时诊断出患有癌症的患者的存活率没有相同的改善 与被诊断为儿童的患者相比（<15y）。这些患者已获得特殊名称 由NCI作为青少年和年轻人（AYA），并伴随着解决这些结果的授权 差异。急性淋巴细胞白血病（ALL）表现出这种现象，其中AYA中的存活率 继续落后于儿童（总体生存率5岁：1-14岁：86％； 15-21：56％； 22-29：42％； 30-39：35％）。穿过 小儿风格和成人风格的治疗方案，所有疗法均包括长时间的维持阶段 需要每天口服6-羟基肽（6MP）的化学疗法。最近的一项大型调查证实 系统性暴露不足6MP与复发风险增加有关；测量系统性6MP 暴露于这种全面的方法评估了6MP代谢产物（硫代氨酸核苷酸[TG]）的水平 掺入DNA（DNA-TG）中。几个AYA特异性因素可能导致全身6MP暴露和 尚未系统地检查。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 这些领域内的障碍和促进者。我们假设全身暴露于6MP将相关 具有6MP的依从性（在患者领域）和疾病管理，由提供者代表 规定了6MP DI（在医疗领域）。我们将研究DNA-TG水平和 6MP依从性和6MP DI，以调整药物遗传学。然后，我们将确定障碍/促进者 6MP依从性和疾病管理，使用混合方法收敛并行研究设计 定量确定依从性和6MP DI的预测因子，并定性地描述了这些观点 在患者和医疗保健提供者中。我们将使用AYA的前瞻性队列进行这项研究 全国14个地点联盟中的所有维护疗法中的患者多种类型的设施和 肿瘤学实践。每位患者6个月，将通过电子和每月的DNA进行6MP依从性。 将遵循TG水平（外周血）。患者问卷将捕获自我报告的障碍，并 坚持和社会人口统计学的促进者；机构级问卷将占据医疗保健 因素。这项研究的发现有可能识别与患者有关的和医疗有关的靶标 可以接受干预措施，有可能减轻所有患者AYA患者的AYA结果差异。 此外，这项研究确立了基础设施，以继续遵循此同类的复发和进行 这项拟议试验在一个新型以AYA为中心的联盟中拟议的干预措施。