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: 9891988
• 负责人: Gary D Luker
• 金额: $ 62.07万
• 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/9891988
• 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; 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; outcome forecast; preclinical study; prospective; quantitative imaging; response; targeted treatment; 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.

项目摘要/ABSRACT 骨髓纤维化(MF)是一种慢性的、最终致命的血液系统恶性肿瘤，其特征是进行性纤维化。 骨髓，导致严重贫血，肝脾肿大，以及虚弱的体质症状 恶病质。治疗选择仍然极其有限，因为目前只有一种FDA批准的药物用于治疗 Mf.这种药物可以减轻脾肿大和躯体症状，但只能最小限度地减少纤维化或 大量的恶性肝星状细胞，疾病的主要驱动力。无法逆转纤维化和恶性 克隆性是∼患者预后持续较差的主要原因，其5年生存率为40%。目前的肿瘤学家 依靠骨髓活检和体检或解剖MRI测量的脾大小来评估 多发性骨髓瘤的疾病状态和治疗反应。尽管被认为是分析骨骼的黄金标准 骨髓活检有几个基本的局限性，作为一种已知具有广泛 造血骨髓不同解剖部位的异质性。活组织检查只有少量的骨头样本 骨髓来自单一部位，即髂骨。对于骨髓广泛纤维化的患者，经常进行活组织检查 无法恢复任何组织(“干水龙头”)，使患者和医生对骨髓一无所知 疾病的构成和严重程度。作为一种侵入性的、痛苦的手术，患者只能耐受有限的数量。 骨髓活组织检查。脾体积的测量是非侵入性的，很容易进行，但无法 阐述骨髓进行性纤维化的根本原因和病理部位。推进预研-- 在MF的病理生理学、药物开发和最终临床肿瘤学方面的临床研究，我们将调查 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密度磁共振序列(脂肪/水，Dixon)的骨髓成分和结构 方法)、水的扩散(DWI)和大分子结构(磁化传递饱和度，MTS)。我们 将通过捕捉空间和时间变化的参数响应映射(PRM)来分析成像数据 同一患者在多项研究中的成像数据。PRM显著提高了对早期效应的检测 并预测多种类型恶性肿瘤患者的长期结果。推进骨骼 骨髓MRI作为多发性骨髓瘤的影像生物标志物，我们将完成以下目标：1)验证定量MRI MF小鼠模型的骨髓指标；2)对已建立的和研究的反应进行量化 对带有基因驱动突变的小鼠的治疗反映了患者的情况；以及3)进行前瞻性的初始临床 应用定量核磁共振监测治疗多发性骨髓瘤的疗效。我们希望这项研究能证明 定量骨髓MRI检测MF的治疗反应，允许非侵入性测量 疾病异质性与逆转骨髓纤维化药物的评价。相关性：能够 通过成像跟踪整个骨骼中疾病的异质性代表着一项变革性的进步 骨髓活检最终将改善MF患者的生活质量和护理。