Infusion Of Ferumoxytol Research Articles

Quiescent frame, contrast-enhanced coronary magnetic resonance angiography reconstructed using limited number of physiologic frames from 5D free-running acquisitions

Background5D, free-running imaging resolves sets of 3D whole-heart images in both cardiac and respiratory dimensions. In an application such as coronary imaging when a single, static image is of interest, computationally expensive offline iterative reconstruction is still needed to compute the multiple 3D datasets. PurposeEvaluate how the number of physiologic bins included in the reconstruction affects the computational cost and resulting image quality of a single, static volume reconstruction. Study typeRetrospective. Subjects15 pediatric patients following Ferumoxytol infusion (4 mg/kg). Field strength/Sequence1.5 T/Ungated 5D free-running GRE sequence. AssessmentThe raw data of each subject were binned and reconstructed into a 5D (x-y-z-cardiac-respiratory) images. 1, 3, 5, 7, and 9 bins adjacent to both sides of the retrospectively determined cardiac resting phase and 1, 3 bins adjacent to the end-expiration phase are used for limited frame reconstructions. The static volume within each limited reconstruction was compared with the corresponding full 5D reconstruction using the structural similarity index measure (SSIM). A non-linear regression model was used to fit SSIM with the percentage of data used compared to full reconstruction (% data). A linear regression model was used to fit computation time with % raw data used. Coronary artery sharpness is measured on each limited reconstructed images to determine the minimal number of cardiac and respiratory bins needed to preserve image quality. Statistical testsThe coefficient of determination (R2) is computed for each regression model. ResultsThe % of data used in the reconstruction was linearly related to the computational time (R2 = 0.99). The SSIM of the static image from the limited reconstructions is non-linearly related with the % of data used (R2 = 0.80). Over the 15 patients, the model showed SSIM of 0.9 with 18% of data, and SSIM of 0.96 with 30% of data. The coronary artery sharpness of images reconstructed using no less than 5 cardiac and all respiratory phases is not significantly different from the full reconstructed images using all cardiac and respiratory bins. Data conclusionReconstruction using only a limited number of acquired physiological states can linearly reduce the computational cost while preserving similarity to the full reconstruction image. It is suggested to use no less than 5 cardiac and all respiratory phases in the limited reconstruction to best preserve the original quality seen on the full reconstructed images.

A case of severe anaphylactic reaction after administration of diagnostic-dose ferumoxytol in a pediatric patient

We describe a case of anaphylaxis during administration of intravenous (IV) ferumoxytol as a magnetic resonance imaging (MRI) contrast agent in a 4-year-old patient with complicated past medical history including YARS genetic mutation with resultant liver failure and deceased donor liver transplantation, stage IV chronic kidney disease (CKD), and hypertension. The patient was noted to have labored breathing 4 min after initiation of ferumoxytol infusion and was subsequently rapidly intubated and returned to the intensive care unit (ICU) for monitoring. Anaphylactic reactions to therapeutic doses of ferumoxytol led to issuance of a black box warning by the FDA in 2015. Adverse reactions to lower-dose ferumoxytol used in diagnostic imaging, however, are rare and there has been a paucity of documented anaphylactic reactions in the literature.

Abstract 17723: Non-Contrast Cardiac Magnetic Resonance BOOST Whole Heart Acquisition to Evaluate Coronaries in Children and Young Adults

Introduction: Cardiac magnetic resonance (CMR) coronary evaluation remains challenging in teenagers and young adults using conventional respiratory navigation strategies due to irregular respiratory patterns. Motion correction strategies have shown promise in improving efficiency and quality. We sought to evaluate a non-contrast 3D whole-heart sequence with bright-blood (BB) and dark-blood (DB) phase sensitive inversion recovery (BOOST) using image-based navigation (iNAV) and a variable-density cartesian spiral profile order trajectory (VD-CASPR). Hypothesis: BOOST acquisitions improves delineation of coronary origins and proximal courses. Methods: Pts undergoing clinically indicated CMRs were prospectively enrolled and scanned at 1.5T (AVANTO FIT, Siemens) using 2 different imaging methods: 1) BOOST research sequence employing either T2 or magnetization transfer preparation at 1.0-1.4 mm isotropic resolution. When clinically indicated, 2) a standard navigated inversion recovery gradient echo sequence (IR-FLASH) acquired after gadolinium or ferumoxytol infusion. Both coronary imaging methods were rated on a 1-4 scale: 1=non-diagnostic, 2=coronary origins with significant image degradation, 3=mild image degradation, and 4=sharp delineation of the proximal coronaries. A composite BOOST score (highest score between BB and DB images) was compared to IR-FLASH. Group comparisons used a paired t-test (two-tailed, p<0.05). Results: 18 pts, mean age 18.8 years (range=10-31) underwent BOOST imaging. 15 had an IR-FLASH for comparison. BOOST acquisition times were 7-12 minutes. Three pts had coronary anomalies (2 with right coronary from the left sinus, 1 single coronary). Coronary origins were delineated on all BOOST exams with a mean score=3.6 for BB BOOST and 2.9 for DB compared to 3.1 for the IR-FLASH, neither of which was significantly different. The composite BOOST mean score was 3.8, which was significantly higher than IR-FLASH. Conclusions: In our series in children and young adults, contrast-free BOOST imaging delineated coronary origins in all pts, even in challenging cases of anomalous origins. When utilizing both BB and DB BOOST images, image quality exceeded that of a conventional post-contrast IR-FLASH sequence.

Ferumoxytol magnetic resonance imaging detects joint and pleural infiltration of bone sarcomas in pediatric and young adult patients.

The diagnosis of joint infiltration by a malignant bone tumor affects surgical management. The specificity of standard magnetic resonance imaging (MRI) for diagnosing joint infiltration is limited. During our MRI evaluations with ferumoxytol nanoparticles of pediatric and young adult patients with bone sarcomas, we observed a surprising marked T1 enhancement of joint and pleural effusions in some patients but not in others. To evaluate if nanoparticle extravasation differed between joints and pleura with and without tumor infiltration. We retrospectively identified 15 pediatric and young adult patients (mean age: 16±4years) with bone sarcomas who underwent 18 MRI scans at 1h (n=7) or 24h (n=11) after intravenous ferumoxytol infusion. Twelve patients also received a gadolinium-enhanced MRI. We determined tumor invasion into the joint or pleural space based on histology (n=11) and imaging findings (n=4). We compared the signal-to-noise ratios (SNR) and contrast-to-noise ratios (CNR) of the joint or pleural fluid for tumors with and without invasion using a Mann-Whitney U test. MRI scans 24h after intravenous ferumoxytol infusion demonstrated a positive T1 enhancement of the effusion in all joints and pleural spaces with tumor infiltration and no joint or pleural space without infiltration. Corresponding SNR (P=0.004) and CNR (P=0.004) values were significantly higher for joints and pleural spaces with tumor infiltration than without. By contrast, unenhanced MRI, gadolinium-enhanced MRI and 1-h post-contrast ferumoxytol MRI did not show any enhancement of the joint or pleural effusion, with or without tumor infiltration. This pilot study suggests that 24-h post-contrast ferumoxytol MRI scans can noninvasively differentiate between joints with and without tumor infiltration.

Implementing total-dose ferumoxytol in lieu of split-dose ferumoxytol

BackgroundFerumoxytol is Food and Drug Administration–approved as two 510 mg infusions. Retrospective and prospective reviews have established that a single 1020 mg infusion is as efficacious and safe as two 510 mg infusions. ObjectivesTo transition our preferred intravenous iron infusion practice from two 510 mg infusions to a single 1020 mg ferumoxytol infusion. Practice descriptionThis is a prospective process improvement study conducted at Tripler Army Medical Center, a large academic medical center. Practice innovationWe set up an evidence-based project to transition and monitor our preferred iron treatment of ferumoxytol from 2 doses to 1 dose. Evaluation methodsWe collected efficacy and safety data for 188 unique patients receiving 228 infusions, of which 62 were single 1020 mg doses, and 166 were two 510 mg doses. ResultsComparing the 1020 mg dose in 62 patients with 166 patients treated with two 510 mg infusions, we found no increase in the rate of infusion reactions (4.8 % vs. 4.8 %) and comparable improvement in ferritin and hemoglobin (144 ng/mL vs. 140 ng/mL; P value = 0.874, and 1.8 g/dL vs. 1.9 g/dL; P value = 0.721, respectively). ConclusionThus, we were able to successfully transition to total-dose ferumoxytol for iron-deficient anemia, effectively reducing patient treatment visits without any difference in safety or efficacy. Ferumoxytol 1020 mg infused intravenously over 30 minutes in 250 mL normal saline single dose is a viable, safe, and effective treatment for iron-deficiency anemia.

Safety and efficacy of a single total dose infusion (1020 mg) of ferumoxytol.

Purpose:Iron deficiency anemia (IDA) is the most common type of anemia. A single dose infusion of intravenous (IV) iron is a convenient treatment option. Ferumoxytol is an IV formulation of iron that is typically given in two doses of 510 mg each. Utilizing a single dose of 1020 mg over 15 min has previously been described as safe and effective. In July 2018, we began to administer a single 1020 mg dose of ferumoxytol to patients needing IV iron replacement at the North Florida/South Georgia Veterans Health System. To evaluate the impact of this change, a utilization review was conducted.Methods:Outcomes of all patients who received ferumoxytol injections in the 6 months prior to and after the dosing strategy change were analyzed. A total of 140 patients, who received 270 separate IV ferumoxytol infusions, were included in the analysis.Results:No significant difference in safety was observed, with one infusion reaction occurring in each group (p = 1.00). Efficacy also appeared equivalent with no significant difference between the change in hemoglobin for those who received a single 1020 mg dose versus those who received two 510 mg doses (p = 0.764). As expected, those who received a single total dose infusion of 1020 mg had less clinic utilization (p < 0.0001).Conclusion:In summary, ferumoxytol administered as a 1020 mg single dose infusion was more convenient and should be considered a safe and effective treatment option for IDA.

Estimation of fractional myocardial blood volume and water exchange using ferumoxytol-enhanced magnetic resonance imaging.

Fractional myocardial blood volume (fMBV) estimated using ferumoxytol-enhanced magnetic resonance imaging (MRI) (FE-MRI) has the potential to capture a hemodynamic response to myocardial hypoperfusion during contrast steady state without reliance on gadolinium chelates. Ferumoxytol has a long intravascular half-life and its use for steady-state MRI is off-label. The aim of this prospective study was to optimize and evaluate a two-compartment model for estimation of fMBV based on FE-MRI. Nine healthy swine and one swine with artificially induced single-vessel coronary stenosis underwent MRI on a 3.0 T clinical magnet. Myocardial longitudinal spin-lattice relaxation rate (R1) was measured using the 5(3)3(3)3 modified Look-Locker inversion recovery (MOLLI) sequence before and at contrast steady state following seven ferumoxytol infusions (0.125-4.0 mg/kg). fMBV and water exchange were estimated using a two-compartment model. Model-fitted fMBV was compared to simple fast-exchange fMBV approximation and percent change in pre- and postferumoxytol R1. Dose undersampling schemes were investigated to reduce acquisition duration. Variation in fMBV was assessed using one-way analysis of variance. Fast-exchange fMBV and ferumoxytol dose undersampling were evaluated using Bland-Altman analysis. Healthy normal swine showed a mean mid-ventricular fMBV of 7.2 ± 1.4% and water exchange rate of 11.3 ± 5.1 s-1 . There was intersubject variation in fMBV (p < 0.05) without segmental variation (p=0.387). fMBV derived from eight-dose and four-dose sampling schemes had no significant bias (mean difference=0.07, p=0.541, limits of agreement -1.04% [-1.45, -0.62%] to 1.18% [0.77, 1.59%]). Pixel-wise fMBV in one swine model with coronary artery stenosis showed elevated fMBV in ischemic segments (apical anterior: 11.90 ± 4.00%, apical septum: 16.10 ± 5.71%) relative to remote segments (apical inferior: 9.59 ± 3.35%, apical lateral: 9.38 ± 2.35%). A two-compartment model based on FE-MRI using the MOLLI sequence may enable estimation of fMBV in studies of ischemic heart disease. LEVEL OF EVIDENCE: 2. TECHNICAL EFFICACY STAGE: 2.

Revealing vascular abnormalities and measuring small vessel density in multiple sclerosis lesions using USPIO

Background and PurposeMultiple Sclerosis (MS) is a progressive, inflammatory, neuro-degenerative disease of the central nervous system (CNS) characterized by a wide range of histopathological features including vascular abnormalities. In this study, an ultra-small superparamagnetic iron oxide (USPIO) contrast agent, Ferumoxytol, was administered to induce an increase in susceptibility for both arteries and veins to help better reveal the cerebral microvasculature. The purpose of this work was to examine the presence of vascular abnormalities and vascular density in MS lesions using high-resolution susceptibility weighted imaging (SWI). MethodsSix subjects with relapsing remitting MS (RRMS, age = 47.3 ± 11.8 years with 3 females and 3 males) and fourteen age-matched healthy controls were scanned at 3 T with SWI acquired before and after the infusion of Ferumoxytol. Composite data was generated by registering the FLAIR data to the high resolution SWI data in order to highlight the vascular information in MS lesions. Both the central vein sign (CVS) and, a new measure, the multiple vessel sign (MVS) were identified, along with any vascular abnormalities, in the lesions on pre- and post-contrast SWI-FLAIR fusion data. The small vessel density within the periventricular normal-appearing white matter (NAWM) and the periventricular lesions were compared for all subjects. ResultsAveraged across two independent raters, a total of 530 lesions were identified across all patients. The total number of lesions with vascularity on pre- and post-contrast data were 287 and 488, respectively. The lesions with abnormal vascular behavior were broken up into following categories: small lesions appearing only at the vessel boundary; dilated vessels within the lesions; and developmental venous angiomas. These vessel abnormalities observed within lesions increased from 55 on pre-contrast data to 153 on post-contrast data. Finally, across all the patients, the periventricular lesional vessel density was significantly higher (p < 0.05) than that of the periventricular NAWM. ConclusionsBy inducing a super-paramagnetic susceptibility in the blood using Ferumoxytol, the vascular abnormalities in the RRMS patients were revealed and small vessel densities were obtained. This approach has the potential to monitor the venous vasculature present in MS lesions, catalogue their characteristics and compare the vascular structures spatially to the presence of lesions. These enhanced vascular features may provide new insight into the pathophysiology of MS.

Ferumoxytol-enhanced three-dimensional magnetic resonance imaging of carotid atheroma- a feasibility and temporal dependence study

Ferumoxytol is an ultrasmall super paramagnetic particles of iron oxide (USPIO) agent recently used for magnetic resonance (MR) vascular imaging. Other USPIOs have been previously used for assessing inflammation within atheroma. We aim to assess feasibility of ferumoxytol in imaging carotid atheroma (with histological assessment); and the optimum MR imaging time to detect maximum quantitative signal change post-ferumoxytol infusion. Ten patients with carotid artery disease underwent high-resolution MR imaging of their carotid arteries on a 1.5 T MR system. MR imaging was performed before and at 24, 48, 72 and 96 hrs post ferumoxytol infusion. Optimal ferumoxytol uptake time was evaluated by quantitative relaxometry maps indicating the difference in T2* (ΔT2*) and T2 (ΔT2) between baseline and post-Ferumoxytol MR imaging using 3D DANTE MEFGRE qT2*w and iMSDE black-blood qT2w sequences respectively. 20 patients in total (10 symptomatic and 10 with asymptomatic carotid artery disease) had ferumoxytol-enhanced MR imaging at the optimal imaging window. 69 carotid MR imaging studies were completed. Ferumoxytol uptake (determined by a decrease in ΔT2* and ΔT2) was identified in all carotid plaques (symptomatic and asymptomatic). Maximum quantitative decrease in ΔT2* (10.4 [3.5–16.2] ms, p < 0.001) and ΔT2 (13.4 [6.2–18.9] ms; p = 0.001) was found on carotid MR imaging at 48 hrs following the ferumoxytol infusion. Ferumoxytol uptake by carotid plaques was assessed by histopathological analysis of excised atheroma. Ferumoxytol-enhanced MR imaging using quantitative 3D MR pulse sequences allows assessment of inflammation within carotid atheroma in symptomatic and asymptomatic patients. The optimum MR imaging time for carotid atheroma is 48 hrs after its administration.

Efficacy and Safety of Low Molecular Weight Iron Dextran (LMWID) Vs. Ferumoxytol in Treating Iron Deficiency Anemia

Introduction: Iron deficiency anemia is the most common form of anemia and hematologic problem worldwide. Treatment options include oral or intravenous (IV) iron replacement. Although oral iron is commonly employed as first-line therapy, many studies suggest that IV iron more effective and associated with better quality of life when compared to oral iron. Yet, adverse infusion reactions are possible. Several forms of IV iron are used in clinical practice, including low molecular weight iron dextran (LMWID), ferumoxytol, ferric gluconate, iron sucrose, and ferric carboxymaltose. We sought to compare the efficacy and safety of LMWID and ferumoxytol, the two most frequently used products at our center. Methods: A retrospective cohort analysis was conducted using internal pharmacy records. Adults with an ICD-10 diagnosis of iron deficiency anemia treated with LMWID or ferumoxytol from 2018 to 2019 were identified. Records were reviewed for demographics, comorbidities, allergies, type and frequency of iron administered. Outcomes of interest were comparisons of baseline and post-treatment hemoglobin [Hgb] and ferritin levels and adverse events (AEs) following infusion. Results: In total 55 patients received one of the two included iron preparations. Of the 40 cases of iron deficiency treated with LMWID, only 4 patients (10%) received a second dose. Of the first LMWID infusions (dose of 1000 mg), all patients demonstrated an increase in Hgb from a mean of 12.21 to 13.15 within an average of 2.75 months. Mean ferritin levels went from 28.34 pre-treatment to 231.14 post-treatment, within an average of 3.26 months. 2 patients (5%) received premedication, one with diphenhydramine or promethazine, based on prior history of an AE. AEs were documented in 3 patients (7.5%) and included arm swelling, dysphagia with globus sensation, and nausea. No patients received premedication prior to ferumoxytol infusion. Those receiving ferumoxytol demonstrated an increase in hemoglobin from a mean of 10.25 to 12.17 within an average of 4.2 months. Ferritin increased from baseline 75.93 to 150.33 within 3 months. AE of diarrhea and nausea were reported in only one patient (6.67%) upon second infusion of ferumoxytol. No patient in either group experienced AEs requiring hospitalization, nor did any patient develop severe hypersensitivity reactions, hypotension, or hypophosphatemia. Discussion: In our retrospective cohort, LMWID or ferumoxytol for treatment of iron deficiency were well tolerated with minimal AEs, limited to arm swelling, dysphagia and nausea in 3 patients. Those treated with ferumoxytol experienced similarly few AEs, with only one patient developing transient diarrhea and nausea. Hesitancy to utilize IV iron has persisted due to concerns for potential side effects including anaphylaxis. Our encouraging results provide additional evidence for the efficacy and safety of LMWID and furomoxytol, and should help to assuage fears that IV iron might be poorly tolerated or ineffective. Disclosures Shatzel: Aronora, Inc.: Consultancy.

Safety and Efficacy of 1020 Mg Total Dose Infusion of Ferumoxytol in a Veterans Health System

Background Ferumoxytol (Feraheme) is an intravenous (IV) formulation of iron that can be infused quickly, making it a convenient choice. It is typically given in two doses of 510 mg. Auerbach and colleagues previously described utilizing a single dose of 1020 mg over 15 minutes safely and effectively (Am J Hematol 2013). A total dose infusion of 1020 mg has been described by experts in the field as the "maximum safe dose" (Auerbach and Adamson, Am J Hematol 2016). There exists very little published literature about the safety and efficacy of this off-label dosing, however it is an attractive administration schedule due to convenience of the one-time dose. In July 2018, we began to administer a single 1020 mg dose of feumoxytol to patients diagnosed with iron deficiency at the North Florida/South Georgia Veterans Health System (NF/SG VHS). The purpose of this review is to evaluate the impact of the use of the 1020 mg ferumoxytol dose to ensure safe, effective and efficient utilization in the management of iron deficiency anemia. Methods A retrospective chart review was conducted on patients who received ferumoxytol from February 1st, 2018 to January 31st, 2019 to capture approximately 6 months of data prior to and after the dosing strategy change. Patients were excluded from review if they had received IV iron within 3 months prior to the study period. Parameters collected included pre and post hemoglobin, iron saturation and ferritin concentrations, dose of iron given, frequency and number of infusions, post infusion monitoring time and hypersensitivity reactions. Our primary outcome was assessing safety, particularly the rate of infusion reactions for the entire cohort of patients. Secondary outcomes included efficacy and clinic utilization. Number of clinic visits, baseline and change in hemoglobin, ferritin and iron saturation following 1 dose of 1020 mg or 2 doses of 510 mg were compared using paired t tests. Rate of infusion reactions was compared between all patients who received either dose using Fisher's exact test. Results A total of 212 patients were screened and 140 included in analysis. 270 total doses of iron were given during the study period. Fifty nine patients (42%) received only 510 mg doses, 60 (43%) received only 1020mg doses and were included in the efficacy analysis. An additional 21 patients (15%) received both 510 mg and 1020 mg doses and were included in the analysis of reaction rate. Baseline characteristics were similar between the groups (see Table 1). Response to iron infusions were not significantly different between the dosing strategies. Mean change in hemoglobin was 1.96 g/dL for 510 mg group and 2.00 g/dL for the 1020 mg group (p=0.726). Mean change in ferritin was 114 ng/ml and 120 ng/ml, respectively(p=0.8203). Likewise, mean change in iron saturation was 13.6% and 14.3% (p=0.7808). The rate of infusion reactions was not increased with the higher dose (see Table 2), with only 1 reaction occurring in each group (0.57 % and 1.04 %, p=1.00). Both infusion reactions were able to be treated on an outpatient basis and the patients were discharged from the infusion clinic on the same day. Utilizing the 1020 mg dose significantly reduced the number of infusion room visits required, with an average of 2 visits for 510 mg patients and 1 visit for 1020 mg patients (p&amp;lt;0.0001). Conclusion Implementation of a total dose infusion of 1020 mg of ferumoxytol reduced the number of infusion room visits without increasing infusion reactions or compromising efficacy. This strategy could be considered at other institutions to improve infusion room access, patient convenience, and reduce costs. OffLabel Disclosure: Off label discussion concerns use of a one time dose of 1020mg of ferumoxytol as opposed to the labeled dose of 510 mg followed by a second dose 3 to 8 days later.

Multicenter Safety and Practice for Off-Label Diagnostic Use of Ferumoxytol in MRI.

Background Ferumoxytol is approved for use in the treatment of iron deficiency anemia, but it can serve as an alternative to gadolinium-based contrast agents. On the basis of postmarketing surveillance data, the Food and Drug Administration issued a black box warning regarding the risks of rare but serious acute hypersensitivity reactions during fast high-dose injection (510 mg iron in 17 seconds) for therapeutic use. Whereas single-center safety data for diagnostic use have been positive, multicenter data are lacking. Purpose To report multicenter safety data for off-label diagnostic ferumoxytol use. Materials and Methods The multicenter ferumoxytol MRI registry was established as an open-label nonrandomized surveillance databank without industry involvement. Each center monitored all ferumoxytol administrations, classified adverse events (AEs) using the National Cancer Institute Common Terminology Criteria for Adverse Events (grade 1-5), and assessed the relationship of AEs to ferumoxytol administration. AEs related to or possibly related to ferumoxytol injection were considered adverse reactions. The core laboratory adjudicated the AEs and classified them with the American College of Radiology (ACR) classification. Analysis of variance was used to compare vital signs. Results Between January 2003 and October 2018, 3215 patients (median age, 58 years; range, 1 day to 96 years; 1897 male patients) received 4240 ferumoxytol injections for MRI. Ferumoxytol dose ranged from 1 to 11 mg per kilogram of body weight (≤510 mg iron; rate ≤45 mg iron/sec). There were no systematic changes in vital signs after ferumoxytol administration (P > .05). No severe, life-threatening, or fatal AEs occurred. Eighty-three (1.9%) of 4240 AEs were related or possibly related to ferumoxytol infusions (75 mild [1.8%], eight moderate [0.2%]). Thirty-one AEs were classified as allergiclike reactions using ACR criteria but were consistent with minor infusion reactions observed with parenteral iron. Conclusion Diagnostic ferumoxytol use was well tolerated, associated with no serious adverse events, and implicated in few adverse reactions. Registry results indicate a positive safety profile for ferumoxytol use in MRI. © RSNA, 2019 Online supplemental material is available for this article.

High resolution, 3-dimensional Ferumoxytol-enhanced cardiovascular magnetic resonance venography in central venous occlusion

BackgroundAlthough cardiovascular magnetic resonance venography (CMRV) is generally regarded as the technique of choice for imaging the central veins, conventional CMRV is not ideal. Gadolinium-based contrast agents (GBCA) are less suited to steady state venous imaging than to first pass arterial imaging and they may be contraindicated in patients with renal impairment where evaluation of venous anatomy is frequently required. We aim to evaluate the diagnostic performance of 3-dimensional (3D) ferumoxytol-enhanced CMRV (FE-CMRV) for suspected central venous occlusion in patients with renal failure and to assess its clinical impact on patient management.MethodsIn this IRB-approved and HIPAA-compliant study, 52 consecutive adult patients (47 years, IQR 32–61; 29 male) with renal impairment and suspected venous occlusion underwent FE-CMRV, following infusion of ferumoxytol. Breath-held, high resolution, 3D steady state FE-CMRV was performed through the chest, abdomen and pelvis. Two blinded reviewers independently scored twenty-one named venous segments for quality and patency. Correlative catheter venography in 14 patients was used as the reference standard for diagnostic accuracy. Retrospective chart review was conducted to determine clinical impact of FE-CMRV. Interobserver agreement was determined using Gwet’s AC1 statistic.ResultsAll patients underwent technically successful FE-CMRV without any adverse events. 99.5% (1033/1038) of venous segments were of diagnostic quality (score ≥ 2/4) with very good interobserver agreement (AC1 = 0.91). Interobserver agreement for venous occlusion was also very good (AC1 = 0.93). The overall accuracy of FE-CMRV compared to catheter venography was perfect (100.0%). No additional imaging was required prior to a clinical management decision in any of the 52 patients. Twenty-four successful and uncomplicated venous interventions were carried out following pre-procedural vascular mapping with FE-CMRV.Conclusions3D FE-CMRV is a practical, accurate and robust technique for high-resolution mapping of central thoracic, abdominal and pelvic veins and can be used to inform image-guided therapy. It may play a pivotal role in the care of patients in whom conventional contrast agents may be contraindicated or ineffective.

Macrophage Imaging of Cerebral Aneurysms with Ferumoxytol: an Exploratory Study in an Animal Model and in Patients

The purpose of this study is to assess the validity and feasibility of macrophage imaging using an ultrasmall superparamagnetic iron oxide nanoparticle, ferumoxytol, in the cerebral aneurysmal wall in an animal model and in humans. Engulfment of ferumoxytol by primary culture of macrophages and RAW264.7 cells was assessed. Uptake of ferumoxytol was evaluated histologically in a cerebral aneurysmal model in rats. In an exploratory clinical study of magnetic resonance macrophage imaging, 17 unruptured aneurysms in 17 patients were imaged using thin-slice gapless magnetic resonance images of 2D-gradient-recalled echo (2D-GRE) and 3D-T1-fast-spin echo sequences on day 0 and of the same sequences with infusion of ferumoxytol 24 hours after the first imaging. Pre- and postinfusion images were evaluated independently by 2 medical doctors. Engulfment of ferumoxytol was confirmed in vitro, but the amount of ferumoxytol uptake was independent of the activation state or the differentiation state. Ferumoxytol uptake in CD68-positive cells was observed in the cerebral arterial walls of 4 out of 15 (26.7%) experimentally induced aneurysms in rats. In a clinical study, 17 aneurysms were enrolled and 2 aneurysms were not assessed because of incomplete images. Eleven aneurysms without oral intake of recent anti-inflammatory agents of the remaining 15 aneurysms showed ferumoxytol uptake on 2D-GRE subtraction images, and the size of the aneurysms was significantly related to positive images. Ferumoxytol uptake was confirmed in cultured macrophages and in the cerebral aneurysmal wall in rats. Thin-slice gapless magnetic resonance imaging with ferumoxytol in human cerebral aneurysmal walls may reflect macrophages in the cerebral aneurysmal wall, but its application to small-sized lesions may be restricted.

Intravenous Ferumoxytol in Pediatric Patients With Iron Deficiency Anemia.

Iron deficiency anemia (IDA) is common in children. Limited data exist on the efficacy and safety of ferumoxytol in children. To assess the efficacy of 10 mg/kg dose given over 15-60 minutes in correcting IDA and report any adverse drug reactions (ADRs). We conducted a retrospective review of all patients who received ferumoxytol infusions for the management of IDA by the Pediatric Blood Management Program between October 2010 and March 2015. A total of 110 infusions were given to 54 patients. Compared with baseline preinfusion hemoglobin (Hb; 9.2 ± 1.9 g/dL), a significant rise was seen at 1 week and 4 weeks postinfusion (11.5 ± 1.5 and 11.8 ± 1.7 g/dL, respectively, P < 0.001). Also, a significant rise in serum ferritin at 1 week and 4 weeks postinfusion was seen (51 ± 71 vs 192 ± 148 and 89 ± 135 ng/mL, P < 0.001 and <0.035, respectively). Patients who concomitantly received erythropoietin had a significantly larger Hb rise from baseline than those who did not at 4 weeks (2.7 ± 2.2 vs 1.6 ± 1.1 g/dL, P < 0.017). ADRs included pruritus (n = 1), urticaria (n = 1), and multisymptom episodes (n = 3) that included shortness of breath, chest tightness, back pain, and epigastric cramping that responded to therapy with IV diphenhydramine and methylprednisolone. Ferumoxytol was effective in treating IDA in our small study. Slow infusion rate and close monitoring allowed early detection of the infrequent ADRs.

MRI with ferumoxytol: A single center experience of safety across the age spectrum.

PurposeTo summarize our single‐center safety experience with the off‐label use of ferumoxytol for magnetic resonance imaging (MRI) and to compare the effects of ferumoxytol on monitored physiologic indices in patients under anesthesia with those of gadofosveset trisodium.Materials and MethodsConsecutive patients who underwent ferumoxytol‐enhanced (FE) MRI exams were included. Adverse events (AEs) were classified according to the Common Terminology Criteria for Adverse Events v4.0. In a subgroup of patients examined under general anesthesia, recording of blood pressure, heart rate, oxygen saturation, and end‐tidal CO2 was performed. A comparable group of 23 patients who underwent gadofosveset‐enhanced (GE) MRI under anesthesia with similar monitoring was also analyzed.ResultsIn all, 217 unique patients, ages 3 days to 94 years, underwent FE‐MRI. No ferumoxytol‐related severe, life‐threatening, or fatal AEs occurred acutely or at follow‐up. Two patients developed ferumoxytol‐related nausea. Between‐group (FE‐ vs. GE‐MRI) comparisons showed no statistical difference in heart rate (P = 0.69, 95% confidence interval [CI] 96–113 bpm), mean arterial blood pressure (MAP) (P = 0.74, 95% CI 44–52 mmHg), oxygen saturation (P = 0.76, 95% CI 94–98%), and end‐tidal CO2 (P = 0.73, 95% CI 31–37 mmHg). No significant change in MAP (P = 0.12, 95% CI 50–58 mmHg) or heart rate (P = 0.25, 95% CI 91–105 bpm) was noted between slow infusion of ferumoxytol (n = 113) vs. bolus injection (n = 104).ConclusionIn our single‐center experience, no serious AEs occurred with the diagnostic use of ferumoxytol across a wide spectrum of age, renal function, and indications. Because of the limited sample size, firm conclusions cannot be drawn about the generalizability of our results. Thus, vigilance and monitoring are recommended to mitigate potential rare adverse reactions. Level of Evidence: 2J. Magn. Reson. Imaging 2017;45:804–812.

Abstract OT3-02-14: A phase 1 study in patients with metastatic breast cancer to evaluate the feasibility of magnetic resonance imaging with ferrumoxytol as a potential biomarker for response to treatment with nanoliposomal irinotecan (nal-IRI, MM-398)

Abstract Background: Nal-IRI (MM-398, nanoliposomal irinotecan) is designed for extended circulation relative to free irinotecan and to exploit leaky tumor vasculature for enhanced drug delivery to tumors. Tumor deposition of nal-IRI and subsequent conversion to SN-38 in both neoplastic cells and tumor associated macrophages (TAM) may positively correlate with response to therapy. In phase I studies of nal-IRI, activity has been shown in metastatic breast cancer (MBC), pancreatic and colorectal cancer. Ferumoxytol (FMX) is an iron-oxide superparamagnetic nanoparticle that has been used off-label for its MRI contrast properties. FMX has long-circulating pharmacokinetics and is taken up by TAMs with similar distribution patterns to nal-IRI in preclinical models. A single site pilot study established the feasibility of performing quantitative FMX MRI. Thirteen patients with advanced cancer (3 with ER/PR+ MBC) were imaged with FMX MRI and treated with nal-IRI. Median tumor lesion FMX uptake in the pilot study was 32.6 and 34.5 μg/mL at 1 h and 24 h, respectively. Lesions with FMX uptake above the median were associated with greater reductions in tumor size following treatment with nal-IRI as determined by CT lesion measurements. The relationship between FMX levels in tumor lesions and nal-IRI activity may serve as a potential biomarker for nal-IRI deposition and response in solid tumors. This study has been expanded to include additional MBC patients to further evaluate the technical feasibility of FMX MRI at multiple study sites, and to evaluate activity of nal-IRI in patients with MBC. Trial Design: Three cohorts of 10 patients with MBC in the following categories will be enrolled: ER and/or PR positive/HER2-negative, triple negative (TNBC) and MBC with brain metastases. An imaging phase will be followed by a treatment phase. The imaging phase consists of a baseline MRI scan, FMX infusion, and follow-up MRI scans at 1-4 and 24 h after infusion. The treatment phase begins 1-6 days after imaging and consists of nal-IRI 80 mg/m2 q2w. A pretreatment biopsy is required for correlative studies. Study Objectives: The primary objective of this multisite expansion is to investigate the feasibility of FMX quantitation in tumor lesions at multiple lesion sites in breast cancer. The secondary objective is to characterize the efficacy of nal-IRI in patients with metastatic breast cancer. Eligibility Criteria: The key inclusion criteria include patients with MBC, ECOG 0 or 1 with adequate bone marrow reserve and no prior topoisomerase 1 inhibitor or anti-VEGF treatment. ER and/or PR positive/HER2-negative and TNBC patients must have had 1-3 prior lines of chemotherapy in the metastatic setting and have at least 2 measurable lesions. Patients with brain metastasis must be neurologically stable and have new or progressive brain metastases after prior radiation therapy with at least one lesion measuring ≥ 1 cm in longest diameter on gadolinium-enhanced MRI. Status: This trial is currently recruiting patients. Citation Format: Sachdev JC, Ramanathan RK, Raghunand N, Anders C, Munster P, Minton S, Northfelt D, Blanchette S, Campbell K, Lee H, Klinz SG, Hendriks BS, Moyo V, Fitzgerald JB, Korn RL. A phase 1 study in patients with metastatic breast cancer to evaluate the feasibility of magnetic resonance imaging with ferrumoxytol as a potential biomarker for response to treatment with nanoliposomal irinotecan (nal-IRI, MM-398). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT3-02-14.

Ferumoxytol-Contrasted MRI for Macrophage Imaging of Inflammation in Human Osteomyelitis, a Feasibility Study

Diabetic foot infections have a 15-25% lifetime incidence in diabetics, and account for more than half of all non-traumatic lower extremity amputations. Currently, the most accurate means of non-invasively diagnosing osteomyelitis in patients with foot infections is with gadolinium-enhanced MRI. However, gadolinium has limited specificity, as it not only enhances infection but also neuropathic changes and other forms of sterile inflammation. Also, safety concerns about gadolinium have recently been raised given the recent discovery that gadolinium (a molecule that some animal studies suggest is a neurotoxin) deposits in the brains in some patients with normal renal function. Making the correct diagnosis of osteomyelitis is paramount, as an MRI that is falsely positive for osteomyelitis may lead to unnecessary bone biopsies, prolonged antibiotic courses, or even amputation. Ferumoxytol is a superparamagnetic iron oxide nanoparticle (SPION) that is FDA approved for iron replacement in patients with chronic kidney disease. Ferumoxytol is also widely studied as a contrast agent for MRI imaging. Ferumoxytol is taken up by macrophages, and thus provides contrast in areas of active infection, manifested as negative enhancement (eg hypo-enhancement) on T2/T2* sequences. In this prospective feasibility study, ferumoxytol was used as an MRI contrast agent in patients with osteomyelitis.We included non-septic patients with suspected osteomyelitis who had a baseline MRI using standard sequences. Patients without a contra-indication to gadolinium also were imaged with standard T1 sequences after gadolinium administration. Ferumoxytol was then administered, and ferumoxytol contrasted images were then obtained 12-24 hours after ferumoxytol infusion. When available, resected tissue was analyzed for iron content and macrophages by immunohistochemistry.To date we have enrolled 8 patients with possible osteomyelitis. Because this was a feasibility study, statistical analysis is not meaningful in this small cohort of patients. Two patients had strong contrast-enhanced evidence of osteomyelitis on both gadolinium and ferumoxytol imaging. Osteomyelitis was confirmed by histology of the amputated digits for both patients. Representative images from a patient with biopsy confirmed osteomyelitis is shown in Figure 1. Another patient had images that did not demonstrate hypo-enhancement on ferumoxytol imaging, but did have evidence of osteomyelitis on gadolinium-enhanced imaging. This patient underwent an amputation after antibiotics failed to heal this patient's wound, and the pathology came back negative for osteomyelitis. Five other patients did not have tissue available as a reference standard with which to analyze the accuracy of the ferumoxytol enhanced images.In conclusion, macrophage imaging using ferumoxytol-contrasted MRI merits further study for use in the diagnosis of osteomyelitis. [Display omitted] DisclosuresOff Label Use: ferraheme is for iron replacement, and we are using it as a contrast agent..

Abstract P5-01-06: Characterization of metastatic breast cancer lesions with ferumoxytol MRI and treatment response to MM-398, nanoliposomal irinotecan (nal-IRI)

Abstract Introduction Irinotecan has known activity in metastatic breast cancer (MBC). MM-398, nanoliposomal irinotecan (nal-IRI), is designed to exploit leaky tumor vasculature for enhanced drug delivery to tumors. Tumor deposition of nal-IRI and subsequent conversion to SN-38 in both neoplastic cells and tumor associated macrophages (TAM) may positively correlate with activity. Predictive biomarkers to measure tumor deposition could identify patients likely to benefit from nal-IRI. Ferumoxytol (FMX), an iron-oxide superparamagnetic nanoparticle with MRI contrast properties, is taken up by TAMs with similar distribution patterns to nal-IRI in preclinical models. Our previous work has shown the feasibility of quantitative FMX MRI (Fe-MRI) of tumor lesions, and we developed a quantitative mechanistic PK model of FMX deposition (AACR 2014, abstract #CT224). Here we report nal-IRI activity and FMX levels in MBC patients on the study. Patients and methods Patients (n=15) with refractory solid tumors and at least two metastatic lesions &amp;gt;2 cm accessible for percutaneous biopsy were enrolled in a Phase 1 study. Fe-MRI scans were performed using T2* iron sensitive sequences prior to and following FMX infusion (1 h, 24 h, 72 h). T2* signal was used to calculate FMX levels in total lesions by comparison to a standard curve. Comparison of quantified FMX lesion uptake with a mechanistic PK model previously indicated that tissue permeability to FMX contributed to early Fe-MRI signals at 1 h and 24 h, while FMX binding contributed at 72 h. Patients then received nal-IRI (80 mg/m2 q2w) until progression. Core biopsies were obtained 72 h after both FMX and nal-IRI infusions. RECIST evaluation was done by CT every 8 weeks. Results FMX was well tolerated, and adverse events to nal-IRI were consistent with previous studies. Three of the 13 patients receiving nal-IRI had ER/PR+ MBC (median # of prior Rx: 8 compared to 4 for all study patients). Thirteen liver lesions (4-5/pt) were evaluated by FMX-MRI and CT for these 3 patients. Average lesion size: 26.9±11.2 mm diameter and 8.1±11.3 cm3 (median 4.7 cm3). Time on treatment for the 3 patients was 57, 126 and 256 days (study median 57 days). Best overall response was 1 stable disease (SD) and 1 partial response (PR) in these 3 patients. The patient with a PR had an average lesion size reduction of 44.5%, while the patient with SD had an average lesion size increase of 12.5% at final evaluation. Lesions that shrank after nal-IRI showed higher early levels of FMX compared to the study median (median 39.6 vs. 32.6 mcg/mL at 1 h; median 37.7 vs. 34.5 mcg/mL at 24 h). This relationship between lesion response and FMX levels was consistent with the lesion behavior in the full data set (n=31 lesions/9 patients across 7 indications) of the study. Conclusions Clinical activity of nal-IRI was observed in a subset of heavily treated ER/PR+ MBC patients. The relationship between FMX levels in tumor lesions and nal-IRI activity suggests that lesion permeability to FMX may be a useful biomarker for nal-IRI deposition and tumor response in MBC and potentially other indications. A multi-institution expansion of this study in HER2-negative MBC is planned to confirm these findings. Citation Format: Jasgit C Sachdev, Ramesh K Ramanathan, Natarajan Raghunand, Jaeyeon Kim, Stephan G Klinz, Eliel Bayever, Jonathan B Fitzgerald, Ronald L Korn. Characterization of metastatic breast cancer lesions with ferumoxytol MRI and treatment response to MM-398, nanoliposomal irinotecan (nal-IRI) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-01-06.

Abstract CT224: Pilot study in patients with advanced solid tumors to evaluate feasibility of ferumoxytol (FMX) as tumor imaging agent prior to MM-398, a nanoliposomal irinotecan (nal-IRI)

Abstract Introduction MM-398, a stable nanoliposomal irinotecan (nal-IRI), is designed to exploit leaky tumor vasculature for enhanced drug delivery to tumors. Tumor deposition of nal-IRI and subsequent irinotecan conversion by CES enzymes in both neoplastic cells and tumor associated macrophages (TAM) may positively correlate with activity. Predictive biomarkers to measure tumor deposition could identify patients likely to benefit from nal-IRI. FMX is a 30nm iron-oxide, superparamagnetic nanoparticle with MRI contrast properties. The particle size, its propensity for uptake by TAMs and similar distribution patterns to nal-IRI in preclinical models led to a clinical study evaluating the feasibility of correlating FMX-based MRI (Fe-MRI) acquisition with tissue drug metabolite levels and other biomarkers to estimate drug delivery to tumor. Patients and methods Eligible patients (n=12) with refractory solid tumors with at least two metastatic lesions &amp;gt;2cm accessible for a percutaneous biopsy were enrolled from one institution. Fe-MRI scans were performed on a 1.5T MRI using T2* iron sensitive sequences prior to and following FMX infusion (0.5h, 24h, 72h). MR images were used to direct biopsies at 72h to FMX high or low regions, permitting intra- and inter-patient comparisons of FMX and nal-IRI tumor levels. Patients continued on nal-IRI at 80mg/m2 q2w until progression. Tissue iron and TAM distribution were assessed by IHC, tissue-bound metabolite levels by mass-spectrometry. T2* signal was used to calculate FMX levels in total lesions along with FMX estimates on biopsy images derived from fused MRI-CT biopsy images. The first 9 patients (2M 7F; median age 57 years, range 28-71 years) are reported. Results There were no safety-related or other potential interactions with nal-IRI and FMX. Adverse events of nal-IRI were consistent with previous studies. FMX levels, quantified in 36 tumor lesions from the first 9 subjects, showed mean FMX accumulation of 37.9 mcg/mL [3.3-101.2 mcg/mL] and 13.2 mcg/mL [0.1-41.0 mcg/mL] at 24h and 72h, respectively. Lesions were localized mostly in liver (67%) and lymph nodes/peritoneal sites (25%). A mechanistic PK model indicated that tissue permeability to FMX contributed to Fe-MRI signals at 24h, while FMX binding contributed at 72h. Levels of irinotecan and SN-38 were 3.59mcg/g [2.29-4.89mcg/g] and 11.43ng/g [4.04-18.8ng/g], respectively, at 72h in biopsies from the first 6 patients. Conclusions This study is one of the first to measure active metabolite SN-38 levels in patient tumors. FMX can be used as a tumor contrast agent prior to nal-IRI treatment. T2* MRI sequences allowed for quantitation of FMX concentrations in tumor and reference tissue. A mechanistic model provided an estimation of FMX tumor tissue permeability and binding that may be useful as a predictive biomarker of nanotherapeutics such as nal-IRI. Citation Format: Ramesh K. Ramanathan, Ronald L. Korn, Jasgit C. Sachdev, Gerald J. Fetterly, Katie Marceau, Vickie Marsh, John M. Neil, Ronald G. Newbold, Natarajan Raghunand, Joshua Prey, Stephan G. Klinz, Eliel Bayever, Jonathan B. Fitzgerald. Pilot study in patients with advanced solid tumors to evaluate feasibility of ferumoxytol (FMX) as tumor imaging agent prior to MM-398, a nanoliposomal irinotecan (nal-IRI). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT224. doi:10.1158/1538-7445.AM2014-CT224