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.

摘要 本申请是为了响应被标识为NOT-CA的特别利益通知（NOSI）而提交的- 23-038.酪氨酸激酶抑制剂（TKI），如伊马替尼，用于治疗慢性 髓性白血病（CML）显著提高了患者的预期寿命。在高收入国家， 慢性粒细胞白血病患者的期望值接近一般人群。虽然高收入国家 朝着允许在完全缓解的情况下停止TKI的治疗模式发展， 遗憾的是，在坦桑尼亚没有观察到同样的结果，尽管TKI很容易获得CML 通过建立患者援助计划。我们的团队之前已经证明， 具有晚期疾病特征的诊断和表现有助于观察到的不良反应 在坦桑尼亚的慢性粒细胞白血病患者中。最近的研究表明，慢性粒细胞白血病的晚期诊断与 更多遗传病变的累积积累，随后可能导致治疗失败，疾病 进展，最终死亡。这些突变最常见于表观遗传修饰基因 例如ASXL 1、DNMT 3A、TET 2、IDH 1和IDH 2。我们假设治疗效果不佳 在坦桑尼亚的CML患者中观察到的这种突变是由于当时这些髓系白血病突变的高负担 诊断。因此，本研究旨在更好地了解TKI耐药的机制， 这些骨髓相关突变。我们将对新诊断的慢性粒细胞白血病进行前瞻性队列研究 在达累斯萨拉姆的海洋路癌症研究所开始伊马替尼治疗后， 坦桑尼亚，萨拉姆。存在骨髓白血病相关突变（ASXL 1、DNMT 3A、TET 2、IDH 1和 IDH 2）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（Illumina，San Diego，USA）上的市售骨髓性白血病组。广义 估计方程（GEE）将用于研究诊断时突变状态对 根据欧洲白血病网络指南的定义，在治疗的前12个月内的分子反应。 其他变量，包括性别、年龄和诊断时的索卡尔评分，将被视为模型中的协变量。 确定治疗耐药的预测因子对于改善CML治疗指南具有很大的潜力， 坦桑尼亚和撒哈拉以南非洲广泛，根据来自非洲人口的科学证据。