PO.CL12.03 · 临床研究

评估黑人急性髓系白血病患者中基因突变的分子图谱

Evaluating the molecular landscape of genetic mutations among Black patients with acute myeloid leukemia

编号 5301 展板 21 时间 4/21 09:00–12:00 区域 Section 44 主讲 Eno-obong Udoh, BS

分会场 Epigenetics, Cytogenetics, and Clinical Molecular Genetics

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作者与单位 Authors & Affiliations

Eno-obong B. Udoh¹, Xiaoying (Nicole) Chen², Sarah J. Philip³, Yazeed Sawalha⁴, Yazan F. Madanat⁵, Ameera Rose⁶, Teodora Kuzmanovic⁶, John C. Molina⁷, Moaath K. Mustafa Ali⁷, Akriti G. Jain⁷, Abhay Singh⁷, Sophia Balderman⁷, Babal Kant Jha⁸, Ronald Sobecks⁷, Betty K. Hamilton⁷, Sudipto Mukherjee⁷, Aaron Gerds⁷, Hetty Carraway⁷, Jaroslaw P. Maciejewski⁸, Mikkael Sekeres⁹, Anjali Advani⁷

¹Cleveland Clinic Lerner College of Medicine, Cleveland, OH,²Department of Quantitative Health Sciences, Cleveland Clinic Lerner Research Institute, Cleveland, OH,³Division of Medical Oncology & Malignant Hematology, Houston Methodist Hospital, Houston, TX,⁴Division of Hematology, The Ohio State University, Columbus, OH,⁵Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX,⁶Cleveland Clinic Foundation, Cleveland, OH,⁷Department of Hematology and Medical Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH,⁸Department of Translational Hematology and Oncology Research, Cleveland Clinic Lerner Research Institute, Cleveland, OH,⁹Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL

摘要 Abstract

中文摘要

引言：急性髓系白血病（AML）是一种由破坏造血功能的遗传学改变所驱动的侵袭性血液肿瘤。其特点是生存率低，三分之二的患者在5年内死亡。尽管具有低危细胞遗传学和更年轻年龄等有利疾病因素，非西班牙裔黑人AML患者的死亡率仍高于白人患者。通过纳入下一代测序（NGS）等工具于AML预后评估，AML的风险分层已大为改善。然而，对于黑人AML患者中突变的分子图谱及预后相关性知之甚少。本研究刻画了克利夫兰诊所黑人AML患者的遗传学特征。方法：这项回顾性、单中心队列研究纳入了2002年至2022年间诊断为AML的患者。临床数据从电子病历中获取并安全存储。分子数据来自AML中常见突变基因的NGS平台。总生存期（OS）仅限于接受强化诱导化疗的患者，采用Kaplan-Meier法估计。结果：总体而言，在我们1,264例AML患者队列中有118例（9.34%）黑人患者。这些患者中55%为男性，诊断时中位年龄为62岁。核型分析显示大多数（68%）黑人患者具有异常核型，主要由8三体（23.0%）、-7或del(7q)（17.6%）或-5或del(5q)（16.2%）异常所驱动，其中后两者代表不良风险疾病。这些患者中大多数（65%）接受了强化诱导化疗，其中30%（n=23）接受了骨髓移植。49.1%（n=58）的黑人患者可获得NGS结果，显示DNA甲基化相关基因突变占主导：DNMT3A（24%，n=14）和TET2（21%，n=12）。中位OS为24个月（95% CI：14-46个月），5年OS率为27%（95% CI：18-40%），低于全国平均水平32.9%。在单变量分析中，较大年龄（>60岁）、不良风险细胞遗传学、非强化化疗、TET2及ASXL1与较差生存相关（p<0.05）。在校正预后变量后，仅不良风险细胞遗传学仍具有显著性（p=0.02）。结论：在本队列中，DNMT3A和TET2突变在黑人AML患者中最为常见，其频率与人群研究相似。这些基因见于克隆性造血，提示是白血病发生的早期事件。其预后意义仍未明确，但可能为未来通过更好的风险分层和靶向治疗开发来解决结局差异的研究提供参考。研究局限性包括样本量小、NGS可得性以及自我报告的种族/民族。需要与白人患者进行比较分析，并开展带有遗传血统检测的前瞻性研究。

查看英文原文 English abstract

Introduction: Acute myeloid leukemia (AML) is an aggressive blood cancer driven by genetic changes that disrupt hematopoiesis. It is characterized by poor survival, with two-thirds of patients dying within 5 years. Non-Hispanic Black patients with AML have higher mortality rates compared to White patients despite favorable disease factors like low-risk cytogenetics and younger age. Risk stratification in AML has been greatly improved by the inclusion of tools such as next generation sequencing (NGS) in the prognostication of AML. However, little is known about the molecular landscape and prognostic relevance of mutations in Black patients with AML. This study characterizes the genetic profiles of Black patients with AML at the Cleveland Clinic. Method: This retrospective, single-center, cohort study included patients diagnosed with AML between 2002 and 2022. Clinical data were obtained from electronic medical records and stored securely. Molecular data were obtained from NGS platforms of genes frequently mutated in AML. Overall survival (OS) was limited to patients receiving intensive induction chemotherapy and estimated using Kaplan-Meier method. Results: Overall, there were 118 (9.34%) Black patients among our cohort of 1,264 AML patients. 55% of these patients were male and the median age at diagnosis was 62 years. Karyotype analysis revealed that majority (68%) of Black patients had an abnormal karyotype driven by trisomy 8 (23.0%), -7 or del (7q) (17.6%), or -5 or del (5q) (16.2%) abnormalities, of which the latter two represent adverse risk disease. Most of these patients (65%) were treated with intensive induction chemotherapy and of these 30% (n=23) underwent a bone marrow transplant. NGS was available for 49.1% (n = 58) of Black patients and revealed a predominance of mutations in genes involved in DNA methylation: DNMT3A (24%, n=14) and TET2 (21%, n=12). Median OS was 24 months (95% CI: 14-46months) with a 5-year OS rate of 27% (95% CI:18-40%), lower than the national average of 32.9%. Older age (>60), poor risk cytogenetics, non-intensive chemotherapy, TET2 , and ASXL1 were associated with worse survival in univariable analysis (p<0.05). Upon adjusting for prognostic variables, only poor risk cytogenetics remained significant (p=0.02). Conclusion: DNMT3A and TET2 mutations were most observed in Black patients with AML in this cohort at similar frequencies compared to population studies. These genes are observed in clonal hematopoiesis indicating early events in leukemogenesis. Their prognostic significance remains undefined but may inform future studies addressing outcome disparities through better risk stratification and the development of targeted therapies. Study limitations include small sample size, NGS availability and self-reported race/ethnicity. Comparative analysis with White patients and prospective studies with genetic ancestry testing are needed.

利益披露 Disclosure

E. B. Udoh, None.. X. Chen, None.. S. J. Philip, None. Y. Sawalha, BeiGene ). Genmab ). AbbVie ). ADC Other, Consulting. Genmab Other, Consulting. Genentech Other, Honorarium. Y. F. Madanat, None.. A. Rose, None.. T. Kuzmanovic, None. J. C. Molina, Autolus g., Board of Directors, non-salaried role), Other, Consultancy, Honoraria. Jazz g., Board of Directors, non-salaried role), Other, Consultancy, Honoraria. Amgen Other, Consultancy, Honoraria. Sobi Other, Consultancy, Honoraria. AstraZeneca Other, Consultancy, Honoraria. M. K. Mustafa Ali, None. A. G. Jain, Takeda g., Board of Directors, non-salaried role). Novartis g., Board of Directors, non-salaried role), Other, Consultancy. Sobi g., Board of Directors, non-salaried role). Servier g., Board of Directors, non-salaried role). Geron Other, Speaking. Rigel Other, Speaking. A. Singh, None.. S. Balderman, None.. B. K. Jha, None. R. Sobecks, CareDx g., Board of Directors, non-salaried role). B. K. Hamilton, None.. S. Mukherjee, None.. A. Gerds, None.. H. Carraway, None.. J. P. Maciejewski, None. M. Sekeres, Bristol Myers Squibb g., Board of Directors, non-salaried role), ). Kurome g., Board of Directors, non-salaried role). Schroedinger g., Board of Directors, non-salaried role). A. Advani, Amgen ). MD Education Other, Honoraria. Pfizer ), Other, Manuscript help, honoraria/consulting. AstraZeneca Other, Honoraria, Consulting. Glycomimetics ). BEAM ). OBI ). Incyte ). Immunogen ). Seattle Genetics ). Macrogenics ). Servier ). Kura ). Novartis ), Other, Consultancy. Emmes Other, Honoraria. PER Other, Honoraria. WebMD Other, Honoraria. Wolters Kluwer Other, Honoraria. Kite ), Other, Consultancy. MJH Life Other, Honoraria.

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