Ferumoxytol: Another Exciting Addition to the Growing Field of Bone Marrow Imaging

HomeRadiology: Imaging CancerVol. 5, No. 2 PreviousNext CommentaryFree AccessFerumoxytol: Another Exciting Addition to the Growing Field of Bone Marrow ImagingJennifer Holter-Chakrabarty , Joshua GloverJennifer Holter-Chakrabarty , Joshua GloverAuthor AffiliationsFrom the Stephenson Cancer Center (J.H.C., J.G.), University of Oklahoma, 800 NE 10th St, Oklahoma City, OK 73104.Address correspondence to J.H.C. (email: [email protected]).Jennifer Holter-Chakrabarty Joshua GloverPublished Online:Mar 31 2023https://doi.org/10.1148/rycan.230015MoreSectionsPDF ToolsImage ViewerAdd to favoritesCiteTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinked In See also the article by Rashidi et al in this issue.Jennifer Holter-Chakrabarty, MD, is a professor of medicine in the section of hematology/oncology at the University of Oklahoma Health Sciences Center. She is also an adjunct associate professor of radiation oncology. Her research interests focus on leukemia, hematopoietic stem cell transplantation and cellular therapy, and imaging of bone marrow failure syndromes. In these endeavors, she has been funded locally and has collaborated with the National Cancer Institute to move her benchwork to the bedside.Download as PowerPointOpen in Image Viewer Joshua Glover, MD, is undergoing training in hematology/oncology at the University of Oklahoma Health Sciences Center. He is active in research on marrow transplantation and the complications following transplantation.Download as PowerPointOpen in Image Viewer Innovations in medical imaging technology have abounded ever since the first radiograph in 1895. With recent improvements in targeted molecules, the ability to precisely identify and target specific tissue with sensitivity and specificity has helped improve diagnosis and treatment decisions. With the development of novel radioisotopes, nanoparticles, diagnostics, and therapeutics, the scope of imaging options continues to expand. The landscape is akin to the advancements made when flow cytometry and molecular diagnostics changed the paradigm in hematology. The new era of targeted and disease-specific imaging is pushing forward advancements in more precise diagnosis and improving disease monitoring and identification of response versus failure.Despite major advances in the imaging of solid tumor malignancies, the ability to use precise imaging in marrow-borne diseases has been much more limited and less clinically adopted. Early adoption of PET/CT in hematologic malignancies held promise for staging, but this enthusiasm was tempered by low sensitivity secondary to inflammatory overlap (1). MRI has become the standard for the identification of metastatic lesions in marrow, but identification is limited by a chemotherapy effect. Dual-phase CT attempts to further help differentiate active red marrow from decreased proliferative fat, with some success (2). The selection of appropriate diagnostic imaging methods depends on timing and the patient population of interest. In a recent article published in this issue of Radiology: Imaging Cancer entitled, “Improved Detection of Bone Metastases in Children and Young Adults with Ferumoxytol-enhanced MRI,” Rashidi et al (3) propose methods to identify low-burden metastatic disease within the bone marrow of pediatric patients that could allow for improved stratification and therapeutic choices.The use of ferumoxytol as a contrast agent is not new; its MRI contrast-enhancing properties have been known since its U.S. Food and Drug Administration approval in 2009. Since then, it has been used in a myriad of clinical settings. It has been used in the setting of central nervous system disorders, especially in the visualization of lesions and the delineation of primary brain tumors. It also shows promise in other areas, including cardiac pathologic conditions, vascular pathologic conditions, and most relevant to this article, the staging of malignant tumors. In the therapeutic space, ferumoxytol has the added benefit of treating iron deficiency, a complication in both malignant and nonmalignant hematologic disorders. In patients with cancer with absolute iron deficiency or functional iron deficiency, ferumoxytol imaging of the marrow space could afford both diagnostic and therapeutic effects.The authors posit that the benefit of using ferumoxytol to identify bone marrow metastasis lies in its properties as iron oxide nanoparticles. Specifically, they identify that iron oxide nanoparticles are taken up by normal hypercellular bone marrow but not by focal bone marrow lesions. As observed in the abovementioned study and prior studies, iron oxide nanoparticles are phagocytosed by macrophages, which ultimately causes "dark (negative) contrast enhancement of normal reticuloendothelial system (RES) tissues at T2-weighted MRI" (4). Bone marrow exhibits fatty infiltration and other changes as a person progresses in age. Red marrow, containing hematopoietic stem cells, red blood cells, white blood cells, and platelets, also contains a high number of macrophages. In contrast, yellow marrow contains a high concentration of adipocytes and mesenchymal stem cells. With age, red marrow decreases and yellow marrow increases. As this study was performed in children and young adults, it stands to reason that there may be an age-related difference in the ability of ferumoxytol to help differentiate normal marrow from metastatic disease. The study showed that the use of ferumoxytol as a contrast agent resulted in the ability to identify lesions greater than 5 mm in size at 96% sensitivity. These properties, coupled with the pathophysiology of metastatic conversion of bone marrow, emphasize the benefits of ferumoxytol-enhanced MRI in this setting, especially in younger children.The study provides a well-reasoned argument for the selection of ferumoxytol as a contrast agent and the importance of this body of research. First, the authors note that gadolinium chelates have been studied for detecting bone marrow metastases, but to date, there have been few studies evaluating the use of iron oxide nanoparticles. They note previous studies in which ferumoxytol improved the detection of tumor lesions in the liver, lymph nodes, and the dura and make a reasonable hypothesis that this method of imaging enhancement may have value in bone marrow imaging. Additionally, Rashidi et al identify studies in which iron oxide becomes phagocytosed by macrophages and causes negative contrast enhancement at T2-weighted MRI. Finally, they show that chemotherapy can cause yellow-to-red marrow reconversion, complicating the differentiation of normal marrow from metastatic disease. They reason that ferumoxytol could be used in this setting to increase the contrast between this hypercellular marrow and cancers.Ferumoxytol is not without limitations. As with any new agent used in marrow detection, it must be used in the right scenario at the right time. Sensitivity may be hampered as the cellularity of marrow changes from proliferative to fat as we age. This may dampen the ability of ferumoxytol to detect marrow abnormalities, as contrast with fat would not be ideal. Furthermore, the patients studied represent a population that has low rates of metastatic disease to the marrow. In addition, the half-life of ferumoxytol is long, and the additive effects of repeated imaging must be considered when designing further studies. Last, in patients undergoing repeated imaging, multiple doses of iron could lead to iatrogenic iron overload. Further studies must be precise in the question to be answered, and additional studies in cancers in which metastatic disease is common would add strength regarding its use.We are currently in an era of medical imaging in which new, unique, and exciting imaging techniques are being developed at a high rate, especially in the setting of cancer imaging. Innovations occur frequently that change the way we diagnose, treat, and monitor malignancies of the marrow. Examples include fluorine 18 (18F)–labeled prostate-specific membrane antigen PET/CT for the identification of metastatic prostate cancer, use of gallium 68 for the identification of leukemia burden, and use of 18F-fluorothymidine for the identification of marrow disease and recovery (5–8). Furthermore, diagnostic imaging can now assist with radiation planning and help distinguish functional marrow from marrow with radiation aplasia (9). The exciting new use of FDG PET imaging following chimeric antigen therapy may lead to early differentiation of responders from nonresponders (10). These imaging modalities and contrast enhancement techniques are just a few of the many advancements made recently that have potential to enhance malignancy detection.In conclusion, the landscape of cancer imaging and treatment is ever-changing. Our increasing understanding of tumor biology has led to a steep rise in the ability to treat cancer. Even in the metastatic setting, new chemotherapeutic options such as immunotherapy have led to longer life expectancies and even potential for cure in some cancers. Thus, accurate cancer staging can allow for the implementation of optimal treatment that substantially reduces disease burden. Patients with cancer are living longer and better than ever before thanks to improved detection, treatment, and monitoring of cancer. Rashidi et al have added to the growing list of emerging imaging modalities that may provide patients with accurate treatment via correct cancer staging.Disclosures of conflicts of interest: J.H.C. No relevant relationships. J.G. No relevant relationships.Authors declared no funding for this work.References1. Asenbaum U, Nolz R, Karanikas G, et al. Evaluation of [18F]-FDG-based hybrid imaging combinations for assessment of bone marrow involvement in lymphoma at initial staging. PLoS One 2016;11(10):e0164118. Crossref, Medline, Google Scholar2. Magome T, Froelich J, Holtan SG, et al. Whole-body distribution of leukemia and functional total marrow irradiation based on FLT-PET and dual-energy CT. Mol Imaging 2017;16:1536012117732203. Crossref, Google Scholar3. Rashidi A, Baratto L, Theruvath AJ, et al. Improved Detection of Bone Metastases in Children and Young Adults with Ferumoxytol-enhanced MRI. Radiol Imaging Cancer 2023;5(2):e22008.0 Google Scholar4. Storey P, Arbini AA. Bone marrow uptake of ferumoxytol: a preliminary study in healthy human subjects. J Magn Reson Imaging 2014;39(6):1401–1410. Crossref, Medline, Google Scholar5. Agool A, Schot BW, Jager PL, Vellenga E. 18F-FLT PET in hematologic disorders: a novel technique to analyze the bone marrow compartment. J Nucl Med 2006;47(10):1592–1598. Medline, Google Scholar6. Williams KM, Chakrabarty JH. Imaging haemopoietic stem cells and microenvironment dynamics through transplantation. Lancet Haematol 2020;7(3):e259–e269. Crossref, Medline, Google Scholar7. Williams KM, Holter-Chakrabarty J, Lindenberg L, et al. Imaging of subclinical haemopoiesis after stem-cell transplantation in patients with haematological malignancies: a prospective pilot study. Lancet Haematol 2018;5(1):e44–e52. Crossref, Medline, Google Scholar8. Yassin MA, Nehmeh SA, Nashwan AJ, et al. Assessing bone marrow activity with [18F]FLT PET in patients with essential thrombocythemia and prefibrotic myelofibrosis: a proof of concept. Technol Cancer Res Treat 2022;21:15330338221086396. Crossref, Google Scholar9. Agool A, Slart RH, Thorp KK, et al. Effect of radiotherapy and chemotherapy on bone marrow activity: a 18F-FLT-PET study. Nucl Med Commun 2011;32(1):17–22. Crossref, Medline, Google Scholar10. Holland EM, Yates B, Ling A, et al. Characterization of extramedullary disease in B-ALL and response to CAR T-cell therapy. Blood Adv 2022;6(7):2167–2182. Crossref, Medline, Google ScholarArticle HistoryReceived: Feb 20 2023Revision requested: Feb 24 2023Revision received: Mar 2 2023Accepted: Mar 6 2023Published online: Mar 31 2023 FiguresReferencesRelatedDetailsAccompanying This ArticleImproved Detection of Bone Metastases in Children and Young Adults with Ferumoxytol-enhanced MRIMar 31 2023Radiology: Imaging CancerRecommended Articles RSNA Education Exhibits RSNA Case Collection Vol. 5, No. 2 Metrics Altmetric Score PDF download