Antiangiogenic Therapy to Reduce Bleeding and Improve Health-Related Quality of Life in Hereditary Hemorrhagic Telangiectasia

项目总结/摘要 遗传性出血性毛细血管扩张症（HHT），一种常染色体显性遗传出血性疾病，影响1/5000 这是一种毁灭性的终身疾病，没有FDA批准的治疗方法。因此，有一个 HHT迫切需要有效的全身治疗，以减少出血和改善健康相关的质量， 生活质量（HRQOL）。HHT患者发生沿着肠道和鼻粘膜的脆性毛细血管扩张， 血管内皮生长因子（VEGF）升高。这会导致复发性严重鼻出血和慢性 胃肠道出血，导致缺铁性贫血（以及依赖输血和/或铁 （注）和HRQOL严重降低。我们和其他人以前曾成功地使用系统性 贝伐珠单抗，一种抗VEGF单克隆抗体，作为标签外药物治疗HHT慢性出血， 在多中心观察性研究中记录了红细胞输注和铁输注减少70-80%， 与贝伐珠单抗治疗前相比，平均血红蛋白升高3-4 g/dL，鼻衄严重程度降低50% 治疗然而，考虑到患者的异质性， 药物剂量以及红细胞和铁的施用的非标准化阈值。此外，影响 贝伐珠单抗对HRQOL和血管生成环境的影响尚不清楚。因此，我们将进行二期临床试验 在依赖铁剂输注和/或输血的HHT成人患者中进行的全身性贝伐珠单抗试验， 确定贝伐单抗对出血和HRQOL的影响。主要终点为复合终点 测量红细胞输注和铁输注，血液支持评分（HSS）。我们将评估 使用PROMIS工具和 新型HHT特定QOL工具。最后，我们将评估贝伐单抗对血管生成生物标志物的影响， HHT，以更好地了解它如何影响HHT血管生成环境。我们的核心假设是， 贝伐珠单抗可显著减少HHT患者的慢性出血， 改善血红蛋白和HRQOL。成功将为更大规模的最终试验铺平道路， 进行未来研究的蓝图，将其他抗血管生成药物重新用于HHT。 申请人Hanny Al-Samkari博士完全有资格执行这项研究，并致力于成为 独立止血临床研究者，专注于HHT中的药物再利用和生物标志物研究。 他将由大卫库特博士指导，尼尔扎凯博士，卡拉鲍尔曼博士和丹杜达博士担任共同。 导师每位导师都贡献了向独立的HHT NIH过渡所需的独特专业知识 医学科学家为了实现自己的目标，他提出了一个全面的五年职业发展计划 严格的课程，协同与研究计划的目标。MGH血液肿瘤学分部 因其卓越的临床试验、科学发现和指导的传统而获得国际认可， 为完成这些科学和职业发展目标提供理想的环境。

Project Summary/Abstract Hereditary hemorrhagic telangiectasia (HHT), an autosomal dominant bleeding disorder affecting 1 in 5000 people in the US, is a devastating lifelong condition with no FDA-approved treatments. Accordingly, there is an urgent need for efficacious systemic therapies in HHT to reduce bleeding and improve health-related quality of life (HRQOL). Patients with HHT develop fragile telangiectasias along the gut and nasal mucosa secondary to elevated vascular endothelial growth factor (VEGF). This leads to recurrent severe epistaxis and chronic gastrointestinal bleeding, resulting in iron deficiency anemia (and dependence on blood transfusions and/or iron infusions) and severely diminished HRQOL. We and others have previously successfully used systemic bevacizumab, an anti-VEGF monoclonal antibody, as an off-label agent to treat chronic bleeding in HHT, documenting in multicenter observational studies a 70-80% reduction in red cell transfusions and iron infusions, a 3-4 g/dL mean hemoglobin rise, and 50% reduction in epistaxis severity compared to before bevacizumab treatment. However, this observational work is limited in generalizability given heterogeneity in patients, variable drug dosing, and non-standardized thresholds for administration of red cells and iron. Furthermore, the impact of bevacizumab on HRQOL and the angiogenic milieu is unknown. Therefore, we will perform a phase II clinical trial of systemic bevacizumab in adults with HHT dependent on iron infusions and/or blood transfusions to determine the impact of bevacizumab on bleeding and HRQOL. The primary endpoint will be a composite measurement of red cell transfusions and iron infusions, the Hematologic Support Score (HSS). We will evaluate the impact of bevacizumab on HRQOL in HHT as a secondary endpoint utilizing PROMIS instruments and a novel HHT-specific QOL tool. Finally, we will evaluate the effect of bevacizumab on angiogenic biomarkers in HHT, to better understand how it impacts the HHT angiogenic milieu. Our central hypothesis is that systemic bevacizumab significantly reduces chronic bleeding in HHT as measured by reductions in the HSS and improvements in hemoglobin and HRQOL. Success would pave the way for a larger definitive trial and establish a blueprint for conducting future studies repurposing other antiangiogenics for HHT. The applicant, Dr. Hanny Al-Samkari, is well-qualified to execute this research and is committed to becoming an independent hemostasis clinical investigator with a focus on drug repurposing and biomarker research in HHT. He will be mentored by Dr. David Kuter, with Dr. Neil Zakai, Dr. Karla Ballman and Dr. Dan Duda serving as co- mentors. Each mentor contributes unique expertise necessary for his transition to an independent HHT NIH physician scientist. To achieve his goals, he has proposed a comprehensive five-year career development plan of rigorous coursework that synergizes with the research plan aims. The MGH Division of Hematology Oncology is internationally-recognized for its tradition of clinical trial excellence, scientific discovery and mentorship, so is an ideal environment for completion of these scientific and career development objectives.