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，Venetoclax/Azacitidine前线疗法的批准改变了长期的范式 基于“ 7+3”的诱导疗法，标志着现代AML护理的新时代。新颖针对性的发展 疗法大大改善了某些患者的结果，并提供了较少的治疗选择 许多在门诊和/或本地设置中。以及管理策略的革命性变化， 种族/族裔差异的影响在AML中越来越多地认识到，这可能与 疾病生物学的差异，这也是由于社会经济地位的差异以及长期影响 结构性种族主义。适当测试，反应/毒性监测，治疗调整和 通过广泛采用新颖的治疗剂，社会支持引起 AML护理的差异。目前，关于影响的大小和机制知之甚少 在新疗法时代，AML生存的种族/种族差异。 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dataMart是一个全国性的数据库，其独特的数据库，具有潜水员的群体，全面 病理和分子数据，以及出色的数据新颖性。在我们的第一个目标中，我们将评估 1）NHB和NHW患者之间的总生存率（OS）以及2）新的和NHW患者 分别在推荐前和后疗法时期诊断为AML，以证明先前未知的OS 专门针对现代AML护理的差异。在第二个目标中，我们将评估OS分布的机制 在现代AML护理中，通过分解全面影响并探索种族/种族的因果途径 使用现代因果中介分析中AML OS的差异。在AIM 2A中，我们将首先执行描述性 分析以评估种族群体基线AML基因分析的差异。在AIM 2A中发现， 再加上其他生物学和非生物变量，将评估为AML OS的潜在介体 最终，第二个目标将为观察到的OS分布提供重要的见解 在现代AML护理中，并有助于确定潜在的干预目标，以取得更有意义的进步 朝着这种差距缓解。 这些结果将有助于了解差异，并强调种族少数群体的具体挑战 面对现代AML护理，因此可以改善此患者的研究和干预措施 人口。此外，该奖项提供的培训将为申请人提供对她重要的技能 发展成为白血病和髓样恶性菌领域的独立研究者。提议 培训计划包括临床中心的高级流行病学和生物统计学课程 宾夕法尼亚大学的流行病学和生物统计学，以及研究人员的指导 流行病学，生物统计学和血液学/肿瘤学分裂。