Development of a Pediatric Mylelodysplastic Syndrome Patient Registry

描述(由申请人提供)：本申请涉及广泛的挑战领域(07)加强临床试验和特定挑战主题07-DK-103：支持注册儿科骨髓增生异常综合征(PMDS)是一种罕见的造血系统疾病，其特征是一组不同的疾病，包括原发或新发MDS，以及先天性或获得性骨髓衰竭(BMF)综合征或细胞毒治疗后的“继发性MDS”。到目前为止，人们对导致经前抑郁症的始发事件知之甚少，因此没有针对性的治疗方法；骨髓移植是这些患者唯一的治疗选择。临床和实验室表现的异质性使得研究经前抑郁症和识别新的基因改变变得困难。到目前为止，对儿童MDS启动事件的有限知识阻碍了具有生物学相关性的分子分类。因此，该病在很大程度上仍按形态和细胞遗传学标准进行分类。与老年人的MDS不同，某些遗传疾病，如遗传性骨髓衰竭综合征，以及一级亲属中的获得性再生障碍性贫血和MDS，容易使年轻患者患上MDS。这可能为揭示经前抑郁症发病机制的独特特征提供重要的见解。为了能够系统地研究这种疾病，需要大量的样本，这些样本很好地注释了临床病史和辅助信息，如细胞遗传学。到目前为止，美国还没有这么大的样本收集。因此，我们寻求建立一个PMDS患者登记和组织储存库，使我们能够收集足够的患者材料，以便在未来对这一家族疾病进行系统和深入的分析。患者登记册将提供一个平台，通过对形态和细胞遗传学以及分子分析的标准化审查来提高MDS儿童的诊断准确性(例如，我们寻求利用该登记册进行全基因组范围的筛查方法，以确定与经前抑郁症有关的新基因)。它还将使我们能够评估不同亚型经前抑郁症的频率，以及评估HSCT后的存活率、复发率、发病率和死亡率。我们已经开始与夏洛特·尼迈耶博士领导的欧洲MDS工作组(EWOG-MDS)进行讨论，以学习他们在欧洲建立类似登记册的经验，该登记册现已存在了10年。综上所述，我们寻求在美国建立一个儿科MDS患者登记系统，不仅将通过使用标准化方法改善诊断，而且还将允许我们和其他未来的合作者对一种罕见疾病进行有意义的转化性研究，对于这种罕见疾病，往往难以收集足够数量的患者样本进行分析。最终的希望是，患者登记中出现的发现将为PMDS的发病机制和潜在的分子事件提供新的重要见解，这可能导致未来针对疾病的治疗应用。该项目将由David A.Williams博士(以其在造血干细胞和骨髓衰竭疾病方面的专业知识而闻名)和Mark D.Fleming博士(儿科血液病理学专家)共同领导，利用他们在血液学和骨髓衰竭疾病方面的临床专业知识以及他们在儿科血液病理学方面的专业知识。威廉姆斯博士和弗莱明博士将与Inga Hofmann Zhang博士一起参与这个项目，他在儿科血液学/肿瘤学和血液病理学方面的培训和背景将为执行该项目提供额外的技能。该项目将在波士顿儿童医院进行，该医院在儿科护理、研究和转化医学创新方面处于全国领先地位。波士顿儿童医院拥有庞大的转诊基础，并与其他中心建立了良好的联系。这将使我们能够扩大转介基础，以便更快地填写这一登记表。此外，儿童医院已经在临床血液学和血液病理学方面拥有完善的基础设施，这将有助于执行这项建议。在通过挑战赠款提供的资金的帮助下，我们相信，凭借我们在造血和血液病理学领域的独特专业知识，我们有能力建立一个成功的儿科MDS患者登记系统。 公共卫生相关性：儿童骨髓增生异常综合征(PMDS)是一种罕见的血液系统疾病，其特征是一组不同的疾病。到目前为止，人们对导致经前抑郁症的始发事件知之甚少，因此没有针对性的治疗方法；骨髓移植是这些患者唯一的治疗选择。我们的目标是建立一个患者登记和组织库，使我们能够实现我们的总体目标，即定义儿童MDS的遗传学并确定治疗途径，并最终将这些知识转化为改善这些儿童的结果。

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (07) Enhancing Clinical Trials and specific Challenge Topic 07-DK-103: Support for Registries Pediatric myelodysplastic syndrome (pMDS) is a rare hematopoietic disease characterized by a heterogeneous group of disorders that include primary or de novo MDS, and "secondary MDS" following congenital or acquired bone marrow failure (BMF) syndromes or cytotoxic therapy. To date, very little is known about the initiating events leading to pMDS, and thus no targeted therapies exist; bone marrow transplantation is the only therapeutic option for these patients. The heterogeneity in the clinical and laboratory presentation has made it difficult to study pMDS and to identify novel genetic alterations. Limited knowledge of initiating events in childhood MDS have to date prevented a molecular classification with biological relevance. Therefore the disease remains largely classified by morphological and cytogenetic criteria. Unlike MDS in the elderly, certain genetic conditions such as inherited bone marrow failure syndromes, as well as acquired aplastic anemia and MDS in a first-degree relative predispose young patients to MDS. This may provide important insights into the unique features of the pathogenesis of pMDS. In order to be able to study the disease systematically, a large number of samples that are well annotated with a clinical history and ancillary information such as cytogenetics are needed. To date such a large sample collection does not exist within the USA. Therefore, we seek to build a pMDS patient registry and tissue repository that will allow us to gather sufficient patient material to permit systematic and in depth analysis of this family of disorders in the future. A patient registry will provide a platform to improve accuracy of diagnosis for children with MDS by standardized review of morphology and cytogenetics and molecular analysis (for example we seek to utilize the registry to perform whole genome-wide screening approach to identify novel genes involved in pMDS). It will also allow us to evaluate the frequency of the different subtypes of pMDS, as well as assessing survival, relapse rate, morbidity and mortality after HSCT. We have already initiated discussions with the European Working Group of MDS (EWOG-MDS), led by Dr. Charlotte Niemeyer, to learn from their experience setting up a similar registry in Europe that has now been in existence for 10 years. Taken together, we seek to establish a pediatric MDS patient registry in the US that will not only improve the diagnosis by using a standardized approach, but it will also allow us and other future collaborators to perform meaningful translational research on a rare disease for which it is often difficult to collect sufficient numbers of patient samples for analysis. The ultimate hope is that the findings that will emerge from the patient registry will provide new and important insights into the pathogenesis and underlying molecular events that play a role in pMDS, which might lead to future disease-specific therapeutic applications. This project will be lead by Drs. David A. Williams (known for his expertise in hematopoietic stem cells and bone marrow failure disorders) and Mark D. Fleming, (an expert Pediatric Hematopathologist) in collaborative effort, utilizing both their clinical expertise in hematology and marrow failure disorders as well as their expertise in pediatric hematopathology. Drs. Williams and Fleming will be joined in this project by Dr. Inga Hofmann Zhang whose training and background in Pediatric Hematology/Oncology and Hematopathology will provide additional skills to execute the project. This project will be carried out at Children's Hospital Boston, a national leader in pediatric care, and innovation in research and translational medicine. Children's Hospital Boston has a large referral base and is well connected with other centers. This will permit us to expand the referral base to more quickly populate this registry. Furthermore Children's Hospital already has a well-developed infrastructure in clinical Hematology and Hematopathology that will facilitate the execution of this proposal. With the help of funds available through the challenge grants we are confident that with our unique expertise in the fields of hematopoiesis and hematopathology we are well equipped to establish a successful Pediatric MDS patient registry. PUBLIC HEALTH RELEVANCE: Pediatric myelodysplastic syndrome (pMDS) is a rare hematopoietic disease characterized by a heterogeneous group of disorders. To date very little is known about the initiating events leading to pMDS, and thus no targeted therapies exist; bone marrow transplantation is the only therapeutic option for these patients. Our objective is to establish a patient registry and tissue bank that will permit us to reach our overall goal to define the genetics of childhood MDS and identify pathways for therapy, and ultimately translate this knowledge to improve the outcome for these children.