Imaging Disease Heterogeneity and Response to Therapy in Myelofibrosis

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，其特征是骨髓纤维化的进行性进展。 骨髓，导致严重贫血，肝脾肿大，虚弱的体质症状， 恶病质治疗选择仍然非常有限，因为目前只有一种FDA批准的药物用于 MF。这种药物可以减少脾肿大和全身症状，但只能最低限度地减少纤维化或 大量的恶性HSC，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预后持续不良的主要原因，5年生存率约为40%。肿瘤学家目前 依靠骨髓活检和通过体格检查或解剖MRI测量的脾脏大小来评估 MF的疾病状态和对治疗的反应。虽然被认为是分析骨骼的黄金标准 骨髓活检作为一种已知具有广泛免疫缺陷的疾病状态的测试具有几个基本的局限性。 造血骨髓不同解剖部位的异质性。活组织检查样本只有一小块骨头 骨髓来自一个部位髂嵴在骨髓广泛纤维化的患者中， 不能回收任何组织（“干抽”），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。作为一种侵入性的，痛苦的手术，患者只能忍受有限的数量 骨髓活组织检查。脾脏体积的测量是无创的，易于执行，但无法 解决病理学的根本原因和部位，骨髓中的进行性纤维化。为了推进预- 临床研究的病理生理学MF，药物开发，并最终临床肿瘤学，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。我们会评估骨头 使用临床批准的MRI序列进行细胞结构（脂肪/水，狄克逊 方法）、水的扩散（DWI）和大分子结构（磁化转移饱和，MTS）。我们 将通过参数响应映射（PRM）分析成像数据，该映射捕获空间和时间变化 在同一个病人的多项研究的成像数据中。PRM显著改善了早期效应的检测 并预测多种类型恶性肿瘤患者的长期结局。为了推进骨头 骨髓MRI作为MF的影像学标志物，我们将实现以下目标：1）MRI定量 MF小鼠模型中骨髓的指标; 2）量化对已建立的和研究性的 在具有遗传驱动突变的小鼠中进行的治疗反映了患者;以及3）进行前瞻性的初始临床研究， 使用定量MRI监测MF治疗反应的试验。我们希望这项研究能表明， 定量骨髓MRI检测MF对治疗的反应，允许非侵入性测量 疾病异质性和评估逆转骨髓纤维化的药物。相关性：能够 通过成像跟踪疾病在整个骨骼中的异质性代表了一种变革性的进步， 骨髓活检，最终将改善生活质量和照顾MF患者。

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.