Racial/ethnic disparities in acute myeloid leukemia survival in the novel therapy era: an exploration of the underlying mechanisms and potential targets for intervention

新疗法时代急性髓系白血病生存的种族/民族差异：探索潜在机制和潜在干预目标

• 批准号: 10751435
• 负责人: Xin Wang
• 金额: $ 9.68万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-06 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10751435
• 关键词: Acute Myelocytic Leukemia; Address; Adoption; Allogenic; Award; Azacitidine; BCL2 gene; Biological; Biology; Biometry; Black Populations; Black race; Cancer Center; Caring; Chi-Square Tests; Clinical Trials; Cytogenetics; Data; Data Mart; Data Set; Databases; Development; Diagnosis; Disease; Disease remission; Disparity; Electronic Health Record; Epidemiology; Ethnic Origin; European; FLT3 gene; Genetic; Hematology; Hematopoietic Stem Cell Transplantation; Hispanic; Hispanic Populations; Inferior; Insurance Coverage; Intervention; Isocitrate Dehydrogenase; Knowledge; Mediating; Mediation; Mediator; Mentorship; Methodology; Methods; Modernization; Modification; Molecular; Molecular Target; Monitor; Myeloproliferative disease; Neoadjuvant Therapy; Newly Diagnosed; Not Hispanic or Latino; Oncology; Outcome; Outpatients; Pathogenesis; Pathologic; Pathway interactions; Patients; Pattern; Pennsylvania; Quality of life; Race; Regression Analysis; Relative Risks; Reporting; Research Personnel; Retrospective cohort study; Risk; Social support; Socioeconomic Status; Structural Models; Structural Racism; Testing; Therapeutic Agents; Therapy-Related Acute Myeloid Leukemia; Time; Toxic effect; Training; Universities; biological heterogeneity; black patient; clinical center; clinical epidemiology; cohort; ethnic disparity; genetic profiling; hazard; improved; improved outcome; insight; leukemia; leukemia treatment; new therapeutic target; novel; novel therapeutics; patient population; precision medicine; racial disparity; racial minority population; racial population; response; skills; survival disparity; therapeutic target; therapy development

PROJECT SUMMARY The approval of venetoclax/azacitidine frontline therapy in November 2018 shifted the long-lived paradigm of “7+3”-based induction therapy and marks the new era of modern AML care. The development of novel targeted therapies substantially improves the outcomes for some patients and offers less intense treatment options to many in the outpatient and/or local setting. Along with the revolutionary changes in management strategies, the impact of racial/ethnic disparities has been increasingly recognized in AML, which may potentially be related to the differences in disease biology, but also due to disparity in socioeconomic status and the long-term impact of structural racism. New challenges on appropriate testing, response/toxicity monitoring, therapy adjustment and social support arise with the wide adoption of novel therapeutic agents, threatening to further widen the disparities in AML care. Currently, little is known about the magnitude and mechanisms of the impact of racial/ethnic disparities on AML survival in the novel therapy era. To begin to address these knowledge gaps, we will perform a retrospective cohort study using data from Flatiron Enhanced Datamart, a nationwide database uniquely featuring a diverse patient population, comprehensive pathological and molecular data, and excellent data recency. In our first Aim, we will assess the disparities in overall survival (OS) between 1) NHB and NHW patients and 2) Hispanic and NHW patients with newly diagnosed AML in the pre- and post-novel therapy era, respectively, to demonstrate the previously unknown OS disparities specifically in modern AML care. In our second Aim, we will assess the mechanisms of OS disparities in modern AML care by decomposing the total effects and exploring the causal pathway of racial/ethnic disparities in AML OS using modern causal mediation analysis. In Aim 2a, we will first perform a descriptive analysis to assess the differences of baseline AML genetic profiling across racial groups. Finding(s) in Aim 2a, along with other biological and non-biological variables, will then be evaluated as potential mediators of AML OS disparities in Aim 2b. Ultimately, the second Aim will provide important insight into the observed OS disparities in modern AML care and help identify potential targets for intervention to make more meaningful advances towards the mitigation of such disparities. These results will help understand the disparities and highlight the specific challenges racial minority groups are facing in modern AML care so that subsequent studies and interventions can be improved for this patient population. In addition, the training provided by this award will afford the applicant with skills important for her development into an independent investigator in the field of leukemia and myeloid malignancies. The proposed training plan includes advanced epidemiologic and biostatistical coursework in the Center for Clinical Epidemiology and Biostatistics at the University of Pennsylvania, as well as mentorship from researchers in epidemiology, biostatistics, and the Division of Hematology/Oncology.

项目摘要 2018年11月批准的维奈托克/阿扎胞苷一线治疗改变了 “7+3”为基础的诱导治疗，标志着现代AML护理的新时代。有针对性的小说发展 治疗大大改善了一些患者的预后，并提供了强度较低的治疗选择， 许多是在门诊和/或当地环境中。沿着管理战略的革命性变化， 在反洗钱中，种族/族裔差异的影响越来越被认识到，这可能与以下因素有关： 疾病生物学的差异，但也由于社会经济地位的差异和长期影响， 结构性种族主义在适当的检测、反应/毒性监测、治疗调整和 随着新型治疗药物的广泛采用，社会支持出现，有可能进一步扩大治疗范围。 AML护理的差异。目前，人们对气候变化的影响程度和机制知之甚少。 新疗法时代AML生存率的种族/民族差异。 为了开始解决这些知识差距，我们将使用Flatiron的数据进行回顾性队列研究 增强型数据集市，一个全国性的数据库，独特地具有多样化的患者人群，全面的 病理学和分子学数据，以及出色的数据时效性。在我们的第一个目标中，我们将评估 1）NHB和NHW患者与2）西班牙裔和NHW患者之间的总生存期（OS） 分别在新型治疗前和新型治疗后诊断的AML，以证明之前未知的OS 特别是在现代AML护理中的差异。在我们的第二个目标中，我们将评估OS差异的机制 在现代AML护理中，通过分解总效应并探索种族/民族的因果途径， 使用现代因果中介分析的AML OS差异。在目标2a中，我们将首先执行描述性的 分析，以评估不同种族群体之间基线AML基因谱的差异。目标2a中的发现， 沿着其他生物学和非生物学变量，然后将其作为AML OS的潜在介质进行评价 目标2b中的差异。最后，第二个目标将为观察到的OS差异提供重要的见解 并帮助确定潜在的干预目标，以取得更有意义的进展 减少这种差距。 这些结果将有助于理解差异，并突出少数民族群体面临的具体挑战 面对现代AML护理，以便为该患者改善后续研究和干预措施 人口此外，该奖项提供的培训将为申请人提供对其重要的技能。 发展成为白血病和骨髓恶性肿瘤领域的独立研究者。拟议 培训计划包括临床中心的先进流行病学和生物统计学课程， 宾夕法尼亚大学流行病学和生物统计学，以及来自 流行病学、生物统计学和血液学/肿瘤学分部。