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.

项目摘要/弃权 骨髓纤维化（MF）是一种慢性，最终致命的血液学恶性肿瘤，其特征是进行性纤维化 骨髓，导致严重的贫血，肝肾上腺全瘤，并使宪法符号使人衰弱 卡希克西亚。治疗方案仍然非常有限，因为目前仅存在一种FDA批准的药物 MF。这种药物可能会减少脾肿大和宪法症状，但最少会降低纤维化或 恶性HSC的抽象，疾病的主要驱动因素。无法逆转纤维化和恶性肿瘤 克隆是MF持续预后较差的主要原因，五年生存率约为40％。目前 依靠通过体格检查或解剖学MRI测量的骨髓活检和散布尺寸来评估 MF中的疾病状况和对治疗的反应。尽管被认为是分析骨骼的黄金标准 骨髓，活检有几个基本局限性，以测试已知广泛的疾病的状态 造血骨髓不同解剖部位的异质性。活检样本仅一小卷骨头 来自一个地点的骨髓，即iLiac Crest。在骨髓中广泛纤维化的患者中，活检经常 无法恢复任何组织（“干tap”），使患者和医生没有有关骨髓的信息 疾病的组成和严重程度。作为一种侵入性，痛苦的手术，患者只能容忍有限的人数 骨髓活检。 Sleen体积的测量无创，易于执行，但无法 解决病理学的基本原因和部位，骨髓的进行性纤维化。促进前 MF，药物开发和最终临床肿瘤学的病理生理学的临床研究，我们将研究 定量骨髓MRI作为疾病状况和对治疗反应的生物标志物。我们将评估骨头 使用临床批准的MRI序列进行细胞（脂肪/水，Dixon），骨髓组成和体系结构 方法），水的扩散（DWI）和大分子结构（磁化转移满意度，MTS）。我们 将通过参数响应映射（PRM）分析成像数据，该数据捕获空间和临时变化 在多个研究中来自同一患者的数据中。 PRM明显改善了早期效应的检测 多种类型恶性肿瘤患者的治疗和预测长期预后。促进骨头 MROW MRI作为MF中的成像生物标志物，我们将完成以下目的：1）验证定量MRI MF小鼠模型中骨髓的指标； 2）量化对已建立和研究的反应 具有遗传驱动突变的小鼠疗法反映了患者； 3）进行前瞻性初始临床 使用定量MRI来监测MF治疗的反应。我们希望这项研究表明 定量骨髓MRI检测对MF治疗的反应，允许对 疾病异质性和药物评估以逆转骨髓纤维化。相关性：能够 在整个骨骼中通过成像跟踪疾病的异质性，代表了超越的变革性进步 骨髓活检最终将改善MF患者的生活质量和护理。