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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

基本信息

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
项目类别：
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

项目摘要

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.

项目总结/ ABSRACT