Bone Marrow MRI Captures Relevant Measures of Disease in Myelofibrosis

Myelofibrosis (MF) is a fatal, hematopoietic stem cell (HSC) malignancy characterized by dysregulated blood cell production, destruction of the hematopoietic niche, progressive bone marrow fibrosis, and eventual bone marrow failure. Historically, drug approvals for MF treatment focus on two major endpoints, reducing both splenomegaly and severe constitutional symptoms. While addressing these manifestations of disease improves patient quality of life, reductions in spleen volume and symptoms do not significantly alter disease trajectory. Recently, the focus of treatment in MF has shifted toward restoration of healthy bone marrow architecture and a functional hematopoietic niche rather than focusing solely on alleviating symptoms. However, clinical evaluation of bone marrow relies on biopsy, a painful, invasive procedure that fails to capture heterogeneity of disease in bone marrow and cannot be repeated frequently in clinical oncology. Thus, accomplishing the new drug development goal of bone marrow disease modification requires novel approaches to monitor spatial and temporal bone marrow changes in both preclinical and clinical settings. This dissertation focuses on the initial steps of validating noninvasive magnetic resonance imaging (MRI) for evaluation of bone marrow in MF. To assess disease extent, progression, and response to therapy, we selected three quantitative MRI metrics for bone marrow: 1) apparent diffusion coefficient (ADC), 2) proton density fat fraction (PDFF), and 3) magnetization transfer ratio (MTR). PDFF and ADC respectively assess fat content and water movement and are useful for probing marrow hematopoietic composition. MTR probes changes in macromolecular structure, such as those observed with changing cellularity and extracellular matrix in MF. Using these three MRI metrics, we demonstrate an MRI framework for noninvasively evaluating bone marrow during disease progression and early treatment in a mouse model of MF. Importantly, we show MRI detects bone marrow heterogeneity as validated by histopathology. Next, we assess the capability of this MRI framework at meaningfully capturing treatment induced changes in progressive, myelofibrotic murine bone marrow. Using different treatments, we show that ADC, MTR, and PDFF distinguish between cases of effective and ineffective bone marrow treatment. Additionally, MRI identifies regional variations in bone marrow treatment efficacy, which were previously unobservable. Lastly, we evaluate the efficacy of MRI at characterizing bone marrow in patients with MF. We demonstrate that bone marrow MRI distinguishes between healthy and MF bone marrow and is consistent with bone marrow biopsy findings. Additionally, we show MRI evaluates regional and anatomic bone marrow differences that cannot be detected by bone marrow biopsy. Together, we present a robust MRI framework for evaluating preclinical and clinical bone marrow manifestations of MF. New methods for bone marrow evaluation are needed, and we believe these multiparametric MRI techniques set the stage for future drug development and mechanistic studies that will be vital to furthering research and clinical care in MF.PHDBiomedical EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/178035/1/robisont_1.pd