ACCELERATE: An Efficient and Innovative Natural History Study Addressing Unmet Needs in Castleman Disease

项目概要/摘要： Castleman病（CD）描述了一组罕见且知之甚少的血液系统疾病， 特征性组织病理学改变、淋巴结病和全身性炎症，但病因不同， 病理学、治疗和结局。大约有2,000名各年龄段的人被诊断患有CD 每年在美国。单中心CD（UCD）涉及一个淋巴结肿大区域，通常较温和 炎症症状;目前公认的三种多中心CD（MCD）亚型由不同的炎症引起。 病因，但涉及全身炎症症状和危及生命的细胞因子的进行性发作， 驱动的多器官功能障碍，如肝脏、肾脏和骨髓。基本机制和 治疗靶点还不清楚。虽然经常尝试各种治疗CD，但系统性 尚未对这些治疗方法进行评估，因此不确定每种亚型的最佳治疗方法。 已知的，并且需要生物标志物来识别可能对某些治疗有反应的患者。新的治疗 还需要一些方法，但目前还没有经过验证的、以患者为中心的治疗反应标准或生物标志物， 在临床试验中不断评估有前景的治疗方法。此外，临床数据尚未得到 直到最近，才有集中的循证诊断或治疗指南。 为了解决这些障碍，我们于2016年建立了CD的国际纵向自然史研究 通过与Castleman疾病协作网络、Janssen 制药公司和宾夕法尼亚大学（牵头机构）。由一组医生开发， 研究人员和患者，ACCELERATE利用创新的患者动力研究设计， 美国和全球的患者在线自我登记，我们的研究团队获得并系统地提取完整的 医疗记录数据输入中央数据库。使用通用数据标准，严格的数据提取 每个病例的方案和专家裁定确保了数据的高质量和可解释性。我们 已经招募了500多名CD患者，并收集了大约一半的广泛的纵向数据， 已被用来描述CD的谱，支持循证治疗的发展 指导方针和先进的转化研究。 尽管取得了这些进展，但对于大多数没有接受治疗的CD患者来说， FDA批准的有效疗法不幸的是，我们为期5年的资助研究已经结束。我们正在寻求资金 为了利用我们5年合作伙伴关系收集的数据， 利益相关者合作，并继续招募和收集数据，以识别具有临床意义的患者 亚型、临床结果测量和新的治疗方法。我们提出的研究有可能 改变对CD患者的护理，克服治疗产品开发的障碍，并建立一个模型， 用于罕见疾病的自然史研究

Project Summary/Abstract: Castleman disease (CD) describes a group of rare and poorly understood hematologic disorders that share characteristic histopathologic alterations, lymphadenopathy, and systemic inflammation but vary in etiology, symptomatology, treatments, and outcomes. Approximately 2,000 individuals of all ages are diagnosed with CD each year in the US. Unicentric CD (UCD) involves one region of enlarged lymph nodes and typically milder inflammatory symptoms; the three currently-recognized subtypes of multicentric CD (MCD) result from different etiologies but involve progressive episodes of systemic inflammatory symptoms and life-threatening cytokine- driven multi-organ dysfunction, such as the liver, kidneys, and bone marrow. The underlying mechanisms and therapeutic targets are not well understood. While various treatments are often tried for CD, systematic evaluations of these treatments have not been performed, the optimal treatments for each subtype are not known, and biomarkers to identify patients likely to respond to certain treatments are needed. New treatment approaches are also needed, but no validated, patient-centric treatment response criteria or biomarkers exist to consistently evaluate promising treatment approaches in clinical trials. Further, clinical data had not been centralized and no evidence-based diagnostic or treatment guidelines existed until recently. To address these barriers, we established an international longitudinal natural history study of CD in 2016 through a 5-year collaborative partnership between the Castleman Disease Collaborative Network, Janssen Pharmaceuticals, and the University of Pennsylvania (lead institution). Developed by a team of physicians, researchers, and patients, ACCELERATE utilizes an innovative patient-powered study design whereby CD patients in the US and globally self-enroll online and our study team obtains and systematically extracts complete medical record data into a central database. The use of common data standards, rigorous data extraction protocols, and expert adjudication of each case ensure that the data is of high quality and interpretability. We have enrolled over 500 CD patients and collected extensive, longitudinal data on approximately one-half that have been leveraged to characterize the spectrum of CD, support the development of evidence-based treatment guidelines, and advance translational research. Despite these advances, significant unmet needs remain for the majority of CD patients who do not have an effective FDA-approved therapy. Unfortunately, our 5-year funded study has ended. We are seeking funding to leverage the data collected from our 5-year collaborative partnership, build upon infrastructure from this multi- stakeholder collaboration, and continue enrollment and data collection to identify clinically-meaningful patient subtypes, clinical outcome measures, and novel treatment approaches. Our proposed studies have the potential to transform care for CD patients, overcome barriers to therapeutic product development, and establish a model for rare disease natural history studies.