Impact of myeloid leukemia associated mutations (ASXL1, DNMT3A, TET2, IDH1 and IDH2) on treatment responses among Chronic Myeloid Leukemia (CML) patients in Tanzania

粒细胞白血病相关突变（ASXL1、DNMT3A、TET2、IDH1 和 IDH2）对坦桑尼亚慢性粒细胞白血病 (CML) 患者治疗反应的影响

• 批准号: 10846461
• 负责人: Ahlam Nasser
• 金额: $ 10.96万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-01 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10846461
• 关键词: ABL1 gene; Address; Administrative Supplement; Africa South of the Sahara; African; Age; Ally; Award; Bulky Disease; Caring; Cessation of life; Chronic Disease; Chronic Myeloid Leukemia; Collaborations; Country; Cross-Sectional Studies; DNMT3a; Development; Diagnosis; Disease Progression; Disease remission; Disparity; Doctor of Philosophy; Epigenetic Process; Equation; European; Financial Hardship; Foundations; General Population; Genes; Genetic; Genomic DNA; Genomic Instability; Goals; Guidelines; Health; Hematologic Neoplasms; Hematopoietic Neoplasms; High Prevalence; Imatinib; Income; Lead; Lesion; Life Expectancy; Malignant Neoplasms; Medical; Mentors; Mentorship; Modeling; Molecular; Molecular Abnormality; Mutation; Myelogenous; Myeloid Leukemia; Newly Diagnosed; Oceans; Oncology; Outcome; Parents; Patients; Population; Precision therapeutics; Prevalence; Prospective, cohort study; Protein Tyrosine Kinase; Quality of life; Reporting; Research; Research Personnel; Resistance; Resource-limited setting; Resources; Risk; Science; Survival Rate; Tanzania; Testing; Time; Training; Translating; Treatment Failure; Tyrosine Kinase Inhibitor; Universities; advanced disease; cancer care; care delivery; cost effective; cost effective treatment; determinants of treatment resistance; evidence base; experience; high risk; improved; interest; international partnership; leukemia; molecular diagnostics; mutational status; next generation sequencing; patient assistance; prognostic; prognostic significance; programs; response; sex; therapy resistant; treatment guidelines; treatment response

ABSTRACT This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA- 23-038. The development of tyrosine kinase inhibitors (TKIs), such as imatinib, for the treatment of chronic myeloid leukemia (CML) has dramatically improved patients’ life expectancy. In high-income nations, the life expectancy of a patient with CML approaches that of the general population. While high-income countries are moving towards a treatment paradigm that allows for TKI discontinuation in the setting of complete remission, these same outcomes are unfortunately not observed in Tanzania, despite good access of TKIs to CML patients through an established patient assistance program. Our group has previously shown that delayed diagnoses and presentations with advanced disease features contribute to the observed poor responses among patients with CML in Tanzania. Recent studies have shown that late CML diagnosis is associated with cumulative accumulation of more genetic lesions which can subsequently lead to treatment failure, disease progression, and eventual death. These mutations are most commonly identified in epigenetic modifier genes such as ASXL1, DNMT3A, TET2, IDH1, and IDH2. We hypothesize that the poor treatment responses observed in CML patients in Tanzania is due to a high burden of these myeloid leukemia mutations at the time of diagnosis. Therefore, this study aims to better understand mechanisms of TKI resistance contributed by these myeloid-associated mutations. We will conduct a prospective cohort study of newly diagnosed CML patients followed over a period of 12 months after imatinib initiation at Ocean Road Cancer Institute in Dar es Salaam, Tanzania. Presence of myeloid-leukemia associated mutations (ASXL1, DNMT3A, TET2, IDH1, and IDH2) will be assessed at diagnosis. Extracted genomic DNA (gDNA) will undergo next generation sequencing using commercially available myeloid leukemia panel on MiSeq (Illumina, San Diego, USA). Generalized Estimating Equations (GEE) will be used to investigate the influence of mutation status at diagnosis on molecular responses in the first 12 months of treatment as defined by the European Leukemia Net Guidelines. Other variables including sex, age, and Sokal score at diagnosis will be considered as covariates in the model. Identification of predictors of treatment resistance has a high potential to improve CML treatment guidelines in Tanzania and sub-Saharan Africa broadly, based on scientific evidence derived from African population.

抽象的 该申请是为了响应特殊利益通知（NOSI）而提交 23-038。酪氨酸激酶抑制剂（TKI）的发展，例如伊马替尼，用于治疗慢性 髓样白血病（CML）极大地改善了患者的预期寿命。在高收入国家，生活 患有CML的患者的期望接近普通人群。高收入国家是 朝着治疗范式迈进，该范式允许在完全缓解的情况下停用TKI 不幸的是，在坦桑尼亚没有观察到这些相同的结果，TKIS迫切地访问了CML 通过已建立的患者援助计划的患者。我们的小组以前已经表明了延迟 具有晚期疾病特征的诊断和演示导致观察到的反应不佳 在坦桑尼亚的CML患者中。最近的研究表明，晚期CML诊断与 更遗传病变的累积积累，随后会导致治疗失败，疾病 进展和最终死亡。这些突变最常见于表观遗传修饰的基因 例如ASXL1，DNMT3A，TET2，IDH1和IDH2。我们假设治疗反应不佳 在坦桑尼亚的CML患者中观察到的是由于当时这些髓样白血病突变的高燃烧 诊断。因此，本研究旨在更好地了解由 这些髓样相关突变。我们将对新诊断的CML进行前瞻性队列研究 伊马替尼在海洋路癌症研究所的伊马替尼倡议后的12个月内跟踪患者 坦桑尼亚萨拉姆。髓样白血病相关突变的存在（ASXL1，DNMT3A，TET2，IDH1和 IDH2）将在诊断时进行评估。提取的基因组DNA（GDNA）将进行下一代测序 使用Miseq（美国圣地亚哥的Illumina）上的市售骨髓白血病小组。广义 估计方程（GEE）将用于研究突变状态对诊断的影响 欧洲白血病净准则定义的治疗的前12个月，分子反应。 诊断时性别，年龄和索卡尔评分在内的其他变量将被视为模型中的协变量。 识别治疗耐药性预测因子具有改善CML治疗指南的高潜力 坦桑尼亚和撒哈拉以南非洲广泛基于非洲人口的科学证据。