Development of quantitative bone marrow magnetic resonance imaging biomarkers to assess efficacy of novel molecularly targeted agents for myelofibrosis

University Of Michigan At Ann Arbor, Ann Arbor MI

Investigators

Abstract

PROJECT SUMMARY/ABSTRACT Myelofibrosis is a chronic, ultimately fatal neoplasm caused by malignant hematopoietic stem cells. Pathologic expansion of blood cells, debilitating constitutional symptoms, massive enlargement of liver and spleen due to extramedullary hematopoiesis (formation of blood cells in organs other than bone marrow) and progressive fibrosis of bone marrow are common in patients with MF. Monitoring of treatment response currently relies on spleen volume by physical examination or imaging. However, limitations of spleen size include treatment response metric changes are very slow (6-12 months). Assessment of MF patients using bone marrow biopsy/aspiration, a painful, invasive test which samples only a single site in the iliac crest. Current use of biopsies and spleen size changes cannot evaluate skeletal marrow-specific heterogeneity or treatment associated changes as a treatment response metric. MF is a systemic disease thus analyzing a single bone marrow site provides limited information about overall disease status and response to therapy and blood tests only provide for a global assessment of disease and have been shown to be of limited utility as predictors of treatment efficacy. We propose development of an novel MRI diagnostic noninvasive imaging signature to monitor bone marrow changes to serve as a transformational improvement in patient management. Advanced specialized MRI sequences and image analysis metrics will be applied to capture key aspects of bone marrow disease phenotypes in MF mouse models. Quantitative Dixon technique for monitoring changes in proportions of fat and hematopoietic cells in bone marrow (PDFF) will be used along with diffusion-weighted imaging (DWI), quantified as apparent diffusion coefficient (ADC) for cellularity changes along with magnetization transfer imaging (MTR) for detection of changes in macromolecular fibrotic structures. Image processing approaches will be employed using voxel-by-voxel alignment (i.e., parametric response mapping) to enhance MR image sensitivity for detection of disease phenotypes and treatment response to develop a robust, multiparametric diagnostic biomarker. Primary driver mutations in MF converge on constitutive activation of the JAK pathway resulting in progressive fibrosis with disruption of bone marrow architecture along with massive enlargement of liver and spleen due to extramedullary hematopoiesis (formation of blood cells in organs other than bone marrow). As currently approved JAK2 inhibitors do not provide for long-term remission in patients and offer modest if any, disease-modifying effects, we propose new urgently needed treatment strategies and along with MRI assess treatment response. Novel inhibitors will be evaluated for targeting key downstream JAK-activated pathways including MAPK and PI3K. Our recently developed compound (LP-182) simultaneously targeted these pathways and MRI was found to detect marrow treatment responses in MF mouse models including a reduction in fibrosis along with improved survival. This integrated, multidisciplinary approach is poised to advance an MRI companion diagnostic for MF patients in tandem with reducing cancer-related mortality to improve outcomes.