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

抗血管生成疗法可减少遗传性出血性毛细血管扩张症的出血并改善健康相关的生活质量

基本信息

批准号：
10642812
负责人：
Hanny T Al-Samkari
金额：
$ 19.98万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-15 至 2027-06-30
项目状态：
未结题

项目摘要

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.

项目概要/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性出血性疾病，影响五千分之一的人对于美国人来说，这是一种毁灭性的终生疾病，且尚无 FDA 批准的治疗方法。据此，有一个迫切需要有效的 HHT 全身治疗，以减少出血并改善与健康相关的质量生活（HRQOL）。 HHT 患者继发于肠道和鼻粘膜的脆弱毛细血管扩张。血管内皮生长因子（VEGF）升高。这会导致反复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/或铁剂输液）并严重降低 HRQOL。我们和其他人之前已经成功地使用了系统贝伐单抗，一种抗 VEGF 单克隆抗体，作为治疗 HHT 慢性出血的标签外药物，多中心观察研究记录了红细胞输注和铁输注减少了 70-80%，与贝伐珠单抗使用前相比，平均血红蛋白升高 3-4 g/dL，鼻出血严重程度降低 50% 治疗。然而，鉴于患者的异质性、可变性，这项观察工作的普遍性受到限制。药物剂量以及红细胞和铁给药的非标准化阈值。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II期临床对依赖铁剂输注和/或输血的成人 HHT 进行全身贝伐珠单抗试验确定贝伐珠单抗对出血和 HRQOL 的影响。主要终点将是一个复合终点红细胞输注和铁输注的测量，血液支持评分（HSS）。我们将评估贝伐珠单抗对 HHT 中 HRQOL 的影响作为次要终点，利用 PROMIS 仪器和新颖的 HHT 特定 QOL 工具。最后，我们将评估贝伐珠单抗对血管生成生物标志物的影响 HHT，更好地了解它如何影响 HHT 血管生成环境。我们的中心假设是系统性的贝伐珠单抗可显着减少 HHT 的慢性出血（通过 HSS 和 HSS 的减少来衡量）血红蛋白和 HRQOL 的改善。成功将为更大规模的最终试验铺平道路，并建立未来研究重新利用其他抗血管生成药物治疗 HHT 的蓝图。申请人 Hanny Al-Samkari 博士完全有资格执行这项研究，并致力于成为一名独立止血临床研究者，专注于 HHT 的药物再利用和生物标志物研究。他将得到 David Kuter 博士的指导，Neil Zakai 博士、Karla Ballman 博士和 Dan Duda 博士将担任联合导师。导师。每位导师都贡献了他过渡到独立 HHT NIH 所需的独特专业知识医师科学家。为了实现自己的目标，他提出了全面的五年职业发展计划与研究计划目标相协同的严格课程作业。麻省总医院血液肿瘤科因其卓越的临床试验、科学发现和指导的传统而受到国际认可，完成这些科学和职业发展目标的理想环境。

项目成果

期刊论文数量（20）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Common-sense combination therapy in refractory immune thrombocytopaenia.

难治性免疫性血小板减少症的常识性联合治疗。

DOI：
10.1111/bjh.18919
发表时间：
2023
期刊：
British journal of haematology
影响因子：
6.5
作者：
Al-Samkari,Hanny;Bussel,JamesB
通讯作者：
Bussel,JamesB

Computer vision quantitation of erythrocyte shape abnormalities provides diagnostic, prognostic, and mechanistic insight.

DOI：
10.1182/bloodadvances.2022008967
发表时间：
2023-08-22
期刊：
BLOOD ADVANCES
影响因子：
7.5
作者：
Foy, Brody H.;Stefely, Jonathan A.;Bendapudi, Pavan K.;Hasserjian, Robert P.;Al-Samkari, Hanny;Louissaint Jr, Abner;Fitzpatrick, Megan J.;Hutchison, Bailey;Mow, Christopher;Collins, Julia;Patel, Hasmukh R.;Patel, Chhaya H.;Patel, Nikita;Ho, Samantha N.;Kaufman, Richard M.;Dzik, Walter H.;Higgins, John M.;Makar, Robert S.
通讯作者：
Makar, Robert S.

Treatment of chemotherapy-induced thrombocytopenia with monotherapy versus combination therapy: the devil is in the details.