Ferumoxytol vs. Gadolinium agents for contrast‐enhanced MRI: Thoughts on evolving indications, risks, and benefits

When gadolinium contrast was first described for human use in magnetic resonance imaging (MRI) over three decades ago,1 many doubted the need for it. After all, the promise of MRI was that inherent soft-tissue contrast could be tweaked in limitless ways without the type of pharmaceutical fuel that was essential for computed tomography (CT). As things transpired, the clinical and commercial impact of gadolinium-based contrast agents (GBCAs) has been enormous. Recent estimates put the number of GBCA studies at 30 million annually,2 fueling a multibillion dollar global market. By the mid 2000s, five extracellular GBCA formulations had been introduced in the United States and for many years these agents enjoyed a blemish-free reputation, even for patients with renal impairment. In the mid 2000s, the association between GBCA and nephrogenic systemic fibrosis (NSF) sent shock waves through the community.3, 4 Since the initial FDA (Food and Drug Administration) Black Box warning about NSF,5 two new macrocyclic GBCAs, which are less associated with NSF, have been launched in the US: Gadavist (gadobutrol)6 and Dotarem (gadoterate).7 In the past decade, NSF has been virtually eradicated, albeit with substantial changes to practice guidelines,8 and an uneasy peace has settled on the landscape of GBCA use in renal failure. It seemed we had identified patients with renal failure as one specific group with a particular vulnerability to GBCA and had a management plan for them. Then, in 2014, the first reports of gadolinium retention in the brains of patients with normal renal function following repeated dosing with GBCA appeared.9, 10 No clinical sequelae have yet been linked to this phenomenon, which appears to be more common with linear than with macrocyclic agents, but which has been detected with all classes of GBCA.11, 12 Most recently, gadolinium brain deposition has been reported in children13 and the quest for a magnetic metal alternative to gadolinium has taken on a new sense of urgency. Whereas gadolinium is a heavy metal with no known role in normal metabolism, iron is an essential biologic nutrient for normal cellular function and maintenance of health. We focus this Commentary on ferumoxytol as a potential MR contrast agent and the reader is directed to other reviews for in-depth discussions on other forms of ultrasmall superparamagnetic iron oxide nanoparticles.14-16 Ferumoxytol (Feraheme, AMAG Pharmaceuticals, Waltham, MA) is an ultrasmall, superparamagnetic iron oxide (USPIO) nanoparticle with remarkable MRI properties and pharmacokinetics. It is a potent T1 and T2 relaxation agent with an intravascular half-life of more than 15 hours and it can support a plethora of applications and workflows beyond those available with GBCA. Ironically, ferumoxytol does not have an FDA-approved imaging indication and has been something of a sleeping giant. Once in the bloodstream, and over the course of several days, ferumoxytol is taken up by macrophages, which expose the elemental iron at its core for incorporation into the body iron store via the reticuloendothelial system (liver, spleen, lymph nodes, bone marrow).17 Clearance ranges from 3 days to 11 months.18 Ferumoxytol was originally designed more than 20 years ago as a bolus injectable blood pool agent for MRI19 and was briefly explored for first-pass contrast-enhanced MR angiography (MRA)20 and for MR venography.21 However, the manufacturers decided to pursue a therapy, rather than a diagnostic label, and in 2009 AMAG obtained FDA approval to market ferumoxytol for bolus parenteral treatment of anemia in adults with chronic kidney disease.22 In the meantime, researchers explored the use of ferumoxytol for imaging brain tumors,23 lymph nodes,24 and myocardial inflammation,25, 26 but its potential as a vascular agent did not resurface again until Sigovan et al27 and Bashir et al28, 29 studied ferumoxytol to image dialysis fistulae and renal transplant vascularity. These articles garnered immediate attention and reports of ferumoxytol-enhanced MRA in children followed quickly afterwards.30, 31 To date, all of the published imaging studies have reported outstanding results, with no safety concerns; albeit, these studies were in small patient populations, with the largest study encompassing 217 patients.32 Multicenter pooled analysis of safety data relating to the diagnostic use of ferumoxytol is underway. In March of 2015, the FDA issued a Black Box warning noting rare but serious hypersensitivity reactions in the postmarketing surveillance of ferumoxytol.33 There were reports of 79 anaphylactoid type reactions, mostly in patients undergoing ferumoxytol therapy in dialysis clinics, 18 of which were associated with a fatal outcome. Over the observation period, approximately 1.2 million doses had been dispensed (personal communication, AMAG Pharmaceuticals). Although this reported serious adverse event (SAE) rate is lower than the 0.02% reported in the largest clinical trial involving the therapeutic use of ferumoxytol,34 it is possible that not all SAEs were reported during postmarketing surveillance. Mechanisms of adverse events associated with all intravenous iron products include free-iron release and immune-mediated reactions. However, because ferumoxytol has a large carbohydrate shell, the amount of labile iron release is lower.35 Free-iron release may also be addressed by infusing slowly. While an immune-mediated mechanism of anaphylaxis has been demonstrated for older,36 high molecular weight iron dextran products, an IgE-mediated pathway has not been shown in newer intravenous (IV) iron products.37 Due to confounding factors including unclear definitions of hypersensitivity reactions and voluntary reporting, specific pathways for rare SAE are often difficult to define in the postmarketing surveillance period. Nonetheless, the FDA identified injection rate as being a potential risk modifier and warned against bolus injection of ferumoxytol. It is suggested that with bolus injection, an unspecified amount of free iron in solution may cause transient changes in blood pressure or other symptoms via unclear mechanisms. The updated therapy guidelines now call for slow infusion over 15 minutes per 500 mg, replacing the 17 seconds per 500 mg maximum rate previously approved. Lastly, while iron overload has been cited as a theoretical concern, on a practical level there are far more patients worldwide who are iron-deficient and anemia is associated with far wider adverse health outcomes.38 Further, it is widely accepted that clinical consequences due to iron overload are unlikely with total body iron less than 10 g in an adult.38 It is estimated that, in aggregate, about 2000 diagnostic studies have been performed with ferumoxytol, for a variety of applications and with widely varying dosages and injection schemes (personal communication, Ferumoxytol Working Group, ISMRM 2015, Toronto, Canada). It should be noted that the therapy dose of ferumoxytol is greater than the typical diagnostic dose used for MRI. To date, relatively few published studies address the topic of safety with ferumoxytol for MRI, but this should now be regarded as a high priority. Muehe et al40 reported on 68 patients aged 5–25 years and Ning et al39 reported on 86 subjects aged 1 day to 34 years and noted no SAE. Most recently, Nguyen et al32 found no SAE with the use of ferumoxytol for MRI in 217 patients aged 3 days to 94 years. Although their sample size was still small for a safety study, it represents the largest series to date on the diagnostic use of ferumoxytol. While the benefit-to-risk ratio was not evaluated by Nguyen et al, when considered in the context of the results of other studies, the pretest likelihood of benefit was considered to greatly exceed the likelihood of harm in the appropriate clinical setting. All three studies listed cardiorespiratory parameters including blood pressure, heart rate, oxygenation, and end-tidal carbon dioxide levels, as well as side effects related to ferumoxytol administration. Whereas the study by Nguyen et al used established definitions of adverse events defined by the National Cancer Institute, the study by Muehe et al was prospective and assessed relevant laboratory values. Indeed, if ferumoxytol were simply an alternative to GBCA in patients with renal failure, it would be a huge boon. The reality is, however, that ferumoxytol can fuel clinical applications well beyond the scope of extracellular gadolinium agents and open up new vistas in clinical practice and workflow. The stable blood pool signal of ferumoxytol has been leveraged to generate high-resolution, steady-state 4D images of dynamic anatomy41, 42 and blood flow43 in children with congenital heart disease (CHD), redefining the approach to MRI in this complex group. The 4D approach has profound implications for MRI in neonates and small infants with CHD, because it can simplify and speed the acquisition, eliminating the requirement for highly specialized technologists and physicians to perform the study. It is noteworthy that many small children and most neonates in the intensive care unit are iron deficient,44 such that ferumoxytol may serve as a true theranostic agent. Evidence for the clinical relevance of a blood pool MRI agent is the growing popularity of gadofosveset (Ablavar, Lantheus Medical Systems, North Billerica, MA), particularly for pediatric cardiovascular applications.45, 46 The recent withdrawal of Ablavar from the market caught many practitioners off guard and has created a vacuum in this clinical segment. Whereas gadofosveset provided a longer vascular time window than the extracellular agents, the kinetics of ferumoxytol are qualitatively and quantitatively different. Gadofosveset images at 30 minutes look very different to images during first pass. With ferumoxytol, the stability of the vascular signal over several hours offers multiple advantages over all other agents. The need for bolus timing is eliminated and if the patient breathes or moves during data acquisition, it can be repeated or modified until satisfactorily completed. Multiple stations encompassing chest, abdomen, and pelvis can be acquired at separate table positions, covering head to thighs in two or three breath-holds. In patients with large aneurysms, low cardiac output, or complex venous disease, bolus timing for MR or CT can be problematic. Slow bolus propagation or contrast dilution can result in partial or complete nonopacification of relevant structures on first-pass CT or MRI, resulting in diagnostic ambiguity. In steady state, ferumoxytol is distributed uniformly throughout the entire blood pool, eliminating errors due to contrast dynamics and dilution (Fig. 1). For slow processes, such as filling of varicosities or endoleaks, delayed imaging with ferumoxytol may be uniquely helpful. From a workflow perspective, the paradox is that steady-state imaging with ferumoxytol might require less table time than modern CT scanning, raising intriguing possibilities about efficiency, quality, and throughput. Steady-state, ferumoxytol-enhanced MRI in an 84-year-old claustrophobic female patient with aortic aneurysm, chest pain, and renal failure. The left panel is a thin MIP reconstruction from a breath held 3D MR angiogram and the middle panel is the volume rendered, full-thickness MR angiogram, with systemic arteries rendered in red. The right panel shows a nonbreath-held half-Fourier acquisition single-shot turbo spin-echo (HASTE) image in the same anatomic location as the left panel. Arrows point to wall thickening in the left panel, corresponding to high signal intramural hemorrhage visible in the HASTE image on the right. The detailed 3D anatomy of the aneurysmal thoracoabdominal aorta is clear on the volume rendered image. Difficulties in timing an MR or CT contrast bolus in this type of patient are obviated by imaging in steady state. All bright-blood and dark-blood images in this patient were acquired in less than 5 minutes. The applications of ferumoxytol to imaging of lymph nodes and inflammation exploit the signal loss (negative enhancement) due to its T2* effect and workers have reported success in distinguishing normal from malignant nodes.47 Negative enhancement can also serve an important complementary role in vascular imaging, because ferumoxytol turns the blood pool reliably dark on T2-weighted imaging,20 without the need for magnetization preparation or presaturation pulses. In this way, thrombus, atheroma, or intramural hemorrhage can be readily distinguished from flow artifact (Fig. 1). Whereas much research has been done on the use of ferumoxytol for brain23, 48, 49 and lymph node24, 47 imaging, much remains to be done in solid organs such as liver, kidneys, pancreas, and myocardium. The reader should note that tissue enhancement with ferumoxytol is different than with the extracellular GBCAs and images should be interpreted in this context. Ferumoxytol distribution, for at least the first 12 hours after injection, largely reflects the regional fractional blood volume. Other than under conditions of highly abnormal capillary permeability, one would not expect to see significant enhancement of the extravascular spaces. Insofar as ferumoxytol may influence signal intensity on specific sequences for days to months following diagnostic or therapeutic administration, it will be important for physicians to be aware of this possibility and to interpret the MRI findings in context. In this Commentary, we have only scratched the surface of what may be the ultimate scope of applications that ferumoxytol can support. Whether and to what extent ferumoxytol will go mainstream, and to what extent it will complement or replace GBCA in clinical practice, remains to be seen. However, data to date suggest strongly that the diagnostic use of ferumoxytol may benefit many categories of patients in unique ways and these should be explored in depth to define parameters for its safe and appropriate use. At the time of writing, an intriguing article has appeared in Nature Nanotechnology,50 reporting that ferumoxytol prompts tumor-associated macrophages to destroy cancer cells in a mouse model. The implications in human cancer are profound, highlighting the potential status of ferumoxytol as a multifaceted, true theranostic agent. J.P.F. has been a Scientific Advisory Board Participant for Bayer, Guerbet, Bracco, and AMAG Pharmaceuticals.