Imaging Disease Heterogeneity and Response to Therapy in Myelofibrosis

骨髓纤维化的影像疾病异质性和治疗反应

• 批准号: 10360496
• 负责人: Gary D Luker
• 金额: $ 60.82万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-12 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10360496
• 关键词: Acute Myelocytic Leukemia; Address; Anatomy; Anemia; Architecture; Automobile Driving; Biological Markers; Biopsy; Biopsy Specimen; Blood Cells; Bone Marrow; Bone Marrow Diseases; Bone Tissue; Bone marrow biopsy; Cachexia; Cancer Etiology; Cellularity; Cessation of life; Chronic; Clinical; Clinical Oncology; Clinical Trials; Complication; Constitutional Symptom; Data; Diffusion; Disease; Disease Progression; Early Diagnosis; Early treatment; FDA approved; Fatty acid glycerol esters; Fibrosis; Functional disorder; Genetic; Genomics; Gold; Hematologic Neoplasms; Hematopoietic; Hematopoietic Neoplasms; Hematopoietic stem cells; Hepatosplenomegaly; Heterogeneity; Histology; Image; Inflammation; Investigational Drugs; Investigational Therapies; JAK1 gene; Magnetic Resonance Imaging; Malignant - descriptor; Malignant Neoplasms; Marrow; Measurement; Measures; Methods; Molecular Structure; Monitor; Multicenter Trials; Mus; Mutation; Myelofibrosis; Myeloproliferative disease; Oncologist; Outcome; Pain; Pathology; Patient Care; Patient imaging; Patients; Pharmaceutical Preparations; Physical Examination; Physicians; Preclinical Testing; Procedures; Profibrotic signal; Prognosis; Progressive Disease; Quality of life; Recurrent disease; Research; Sampling Errors; Serum; Severity of illness; Signal Pathway; Signal Transduction; Site; Skeleton; Spleen; Splenomegaly; Stromal Cells; Techniques; Testing; Time; Tissues; Treatment Efficacy; Water; burden of illness; clinical practice; computerized data processing; cytokine; disease heterogeneity; driver mutation; drug development; image processing; imaging biomarker; imaging modality; improved; millimeter; mouse model; novel therapeutics; preclinical study; prospective; quantitative imaging; response; targeted treatment; treatment response; water diffusion

PROJECT SUMMARY/ABSRACT Myelofibrosis (MF) is a chronic, ultimately fatal hematologic malignancy characterized by progressive fibrosis of bone marrow, leading to severe anemia, hepatosplenomegaly, and debilitating constitutional symptoms with cachexia. Treatment options remain extremely limited because only one FDA-approved drug currently exists for MF. This drug may reduce splenomegaly and constitutional symptoms but only minimally reduces fibrosis or abundance of malignant HSCs, the primary drivers of disease. The inability to reverse fibrosis and the malignant clone is a major reason for continued poor prognosis in MF with ∼40% five-year survival. Oncologists currently rely on bone marrow biopsy and spleen size measured by physical examination or anatomic MRI to assess disease status and response to therapy in MF. Although regarded as the gold standard for analyzing bone marrow, biopsy has several fundamental limitations as a test for status of a disease known to have extensive heterogeneity in different anatomic sites of hematopoietic marrow. Biopsy samples only a small volume of bone marrow from a single site, the iliac crest. In patients with extensive fibrosis in bone marrow, biopsy frequently recovers no tissue (“dry tap”), leaving patients and physicians with no information about bone marrow composition and severity of disease. As an invasive, painful procedure, patients only tolerate a limited number of bone marrow biopsies. Measurements of spleen volume are non-invasive and easy to perform but fail to address the fundamental cause and site of pathology, progressive fibrosis in bone marrow. To advance pre- clinical studies in pathophysiology of MF, drug development, and ultimately clinical oncology, we will investigate quantitative bone marrow MRI as a biomarker for disease status and response to therapy. We will assess bone marrow composition and architecture using clinically-approved MRI sequences for cellularity (fat/water, Dixon method), diffusion of water (DWI), and macromolecular structure (magnetization transfer saturation, MTS). We will analyze imaging data by parametric response mapping (PRM), which captures spatial and temporal changes in imaging data from the same patient over multiple studies. PRM markedly improves detection of early effects of therapy and predicts long-term outcome in patients with multiple types of malignancies. To advance bone marrow MRI as an imaging biomarker in MF, we will accomplish the following aims: 1) Validate quantitative MRI metrics for bone marrow in mouse models of MF; 2) Quantify response to established and investigational therapies in mice with genetic driver mutations mirroring patients; and 3) Conduct a prospective initial clinical trial using quantitative MRI to monitor response to therapy in MF. We expect this research to show that quantitative bone marrow MRI detects response to therapy in MF, allowing non-invasive measurements of disease heterogeneity and assessment of drugs to reverse bone marrow fibrosis. Relevance: The ability to track heterogeneity of disease throughout the skeleton by imaging represents a transformative advance over bone marrow biopsy that ultimately will improve quality of life and care for patients with MF.

项目概要/摘要 骨髓纤维化（MF）是一种慢性、最终致命的血液恶性肿瘤，其特征是进行性纤维化 骨髓，导致严重贫血、肝脾肿大和衰弱的全身症状 恶病质。治疗选择仍然极其有限，因为目前只有一种 FDA 批准的药物 中频。这种药物可以减轻脾肿大和全身症状，但只能最小程度地减少纤维化或 大量的恶性造血干细胞是疾病的主要驱动因素。无法逆转纤维化和恶性 克隆是 MF 预后持续不良的主要原因，五年生存率约为 40%。目前肿瘤科医生 依靠骨髓活检和体格检查或解剖 MRI 测量的脾脏大小来评估 MF 的疾病状态和治疗反应。尽管被视为分析骨骼的金标准 骨髓活检作为对已知具有广泛影响的疾病状态的测试有几个基本局限性 造血骨髓不同解剖部位的异质性。活检仅采集少量骨骼样本 骨髓来自一个部位，即髂嵴。对于骨髓广泛纤维化的患者，经常进行活检 无法恢复任何组织（“干水龙头”），使患者和医生无法获得有关骨髓的信息 疾病的组成和严重程度。作为一种侵入性、痛苦的手术，患者只能忍受有限的数量 骨髓活检。脾脏体积的测量是非侵入性的且易于执行，但无法 解决骨髓进行性纤维化的根本原因和病理部位。为推进预 MF 病理生理学、药物开发以及最终临床肿瘤学的临床研究，我们将进行调查 定量骨髓 MRI 作为疾病状态和治疗反应的生物标志物。我们将评估骨骼 使用临床批准的细胞结构 MRI 序列（脂肪/水、Dixon 方法）、水的扩散（DWI）和大分子结构（磁化转移饱和度，MTS）。我们 将通过参数响应映射（PRM）分析成像数据，捕获空间和时间的变化 来自同一患者的多项研究的影像数据。 PRM 显着改善了早期效应的检测 治疗并预测多种恶性肿瘤患者的长期结果。使骨前进 骨髓 MRI 作为 MF 的成像生物标志物，我们将实现以下目标：1）验证定量 MRI MF 小鼠模型的骨髓指标； 2) 量化对已建立的和正在研究的响应 对带有基因驱动突变的小鼠进行的治疗与患者相似； 3) 进行前瞻性初步临床 使用定量 MRI 监测 MF 治疗反应的试验。我们期望这项研究表明 定量骨髓 MRI 可检测 MF 治疗的反应，从而可以进行非侵入性测量 疾病异质性和逆转骨髓纤维化药物的评估。相关性：有能力 通过成像追踪整个骨骼疾病的异质性代表了一个革命性的进步 骨髓活检最终将改善 MF 患者的生活质量和护理。