The Use of Ferumoxytol in CMRV Procedures

Since gadolinium-based contrast agents (GBCAs) were first introduced more than three decades ago, they’ve become a critical component of MRI, with an estimated 30 million GBCA studies conducted annually.

In recent years, the safety of GBCAs has come under increased scrutiny, particularly due to its association with nephrogenic systemic fibrosis (NSF) and reports of gadolinium deposition, where gadolinium can accumulate in the brain, bone, and other tissues. As researchers have explored other contrast alternatives, ferumoxytol has been viewed as a potential alternative to GBCAs.

Ferumoxytol is an iron replacement product used to treat iron deficiency anemia in adult patients with chronic kidney disease (CKD) and in patients unable to take oral iron.

It was originally designed more than 20 years ago as a bolus injectable blood pool agent for MRI and was briefly explored for first-pass contrast-enhanced MR angiography (MRA) and for MR venography. However, the manufacturers decided to pursue a therapy, rather than a diagnostic label. In 2009, the United States Food and Drug Administration (FDA) approved ferumoxytol for the treatment of iron deficiency anemia in adult patients with CKD.

Ferumoxytol is an ultrasmall, superparamagnetic iron oxide (USPIO) nanoparticle with “remarkable MRI properties and pharmacokinetics,” according to research by J. Paul Finn, MD, Professor of Radiology in the David Geffen School of Medicine at UCLA.

“If you use ferumoxytol in patients with renal disease, you don't have to worry about NSF and you don't have to worry about any deposits. I think this is a superior vascular imaging agent,” says Dr. Finn.

Femumoxytol Mechanics

According to the FDA ferumoxytol injection label, ferumoxytol consists of a superparamagnetic iron oxide that is coated with a carbohydrate shell. 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 of the liver, spleen, lymph nodes and bone marrow. Incorporation into body iron stores ranges from three days to 11 months.

When used for MR imaging, ferumoxytol starts out with a higher relaxivity than other GBCAs, delivering more signal per unit dose throughout the body during the MRI scan. It stays strictly within blood vessels and doesn’t diffuse into soft tissues, so it maintains high contrast between what's inside the blood vessel and what's outside the blood vessel. For this reason, it can be used successfully in its steady state distribution, particularly for venography.

“We generally infuse ferumoxytol slowly and image in the steady state distribution, when it enhances all vessels (arteries and veins), to the same extent.  The enhancement persists unchanged for hours, so we can assess the patency of pretty much every vessel in the chest, abdomen and pelvis.  In these areas, arterial and venous anatomy is distinctive, so we don’t have a problem distinguishing arteries from veins”, says Dr. Finn, noting that patent vessels enhance.

“With steady state imaging, we don’t have to worry about bolus timing or even whether patients hold their breath properly at the first attempt.  If they don’t we can simply repeat the breath hold and, if necessary, make adjustments to the imaging parameters to shorten the breath hold.  We can even recall the patient hours later if the radiologist requires supplemental imaging.  These attributes make ferumoxytol a uniquely powerful vascular imaging agent,” he says.

Off-label Use of Ferumoxytol

In an article published in the Journal of Magnetic Resonance Imaging (JMRI), Dr. Finn writes that ferumoxytol is opening up new vistas in clinical applications. Researchers have explored the use of ferumoxytol for imaging brain tumors, lymph nodes and myocardial inflammation, with the potential for use as a vascular agent to image dialysis fistulae and renal transplant vascularity. He notes that ferumoxytol has been leveraged to generate high-resolution, steady-state 4D images of dynamic anatomy and blood flow in children with congenital heart disease (CHD).

It’s important to note that ferumoxytol is approved to treat iron deficiency anemia, and does not have an FDA-approved imaging indication for MRI. And in March of 2015, the FDA issued a Black Box warning noting rare but serious hypersensitivity reactions in postmarketing surveillance of ferumoxytol.

However, published imaging studies are reporting outstanding results with its use for MRI Imaging. Dr. Finn notes that in more than 4,000 ferumoxytol injections and 3,000 closely monitored subjects, there were no serious adverse events and the rate of minor adverse events was lower than that quoted in the package inserts for the macrocyclic gadolinium agents.

“We use it so often because it is clinically powerful and our referring physicians and surgeons specifically request it.  And from a research perspective, it's got huge potential,” he says. “We were extremely impressed with its clinical performance and with the consistent results we obtained.”

Dr. Finn’s staff uses an electronic MR injector to slowly infuse the Ferumoxytol over 7-8 minutes, using a dosage rate of 4 milligrams per kilogram of patient weight. This is in keeping with updated FDA guidelines for infusion of a therapeutic dose over 15 minutes. 

Out of approximately 800 injections, Dr. Finn has seen only a handful of patients experience mild side effects, such as flushing, back pain and nausea. If a patient experiences discomfort, he simply pauses the infusion, waits for the side effects to pass, then continues slowly if no further ill effects.

Pausing an infusion doesn’t affect uptake or image quality because Ferumoxytol stays in the bloodstream for hours, unlike other contrast agents. “Once you inject it, the patient could have lunch or dinner and come back and you’d still get pretty much the same images. Not that we recommend that!” he says. “In this regard, it's completely different than the other MR contrast agents.”

Ferumoxytol and Cardiovascular Magnetic Resonance Venography

Because the vascular anatomy is well defined with the use of ferumoxytol, Dr. Finn and his team also evaluated the diagnostic performance of 3-dimensional (3D) ferumoxytol-enhanced cardiovascular magnetic resonance venography (FE-CMRV) for suspected central venous occlusion in patients with renal failure.

They concluded that 3D 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.”

Dr. Finn says 3D FE-CMRV will be applicable as he and his staff are called to provide venous imaging for more patients. “This is the new gold standard for venography, that's no doubt in my mind,” he says.

Future Applications of Ferumoxytol

There are some challenges, such as ferumoxytol’s lack of FDA approval for MRI, the need for more safety data, and the high cost and limited availability compared to other diagnostic agents. But as clinicians search for options beyond gadolinium-based agents, ferumoxytol will add real clinical value to radiology imaging.

“I honestly think this agent stands to transform the way we do vascular MR imaging in general, and for several applications it can complement or outperform CTA” says Dr. Finn. “I think this agent has a very, very bright future.”

In his article, Dr. Finn describes data indicating that ferumoxytol prompts tumor-associated macrophages to destroy cancer cells in a mouse model. He writes, “The implications in human cancer are profound, highlighting the potential status of ferumoxytol as a multifaceted, true theranostic agent.”

Editor’s note: Kieran Anderson, publisher of Applied Radiology, spoke with J. Paul Finn, MD, a Professor of Radiology at the David Geffen School of Medicine at UCLA, about the use of ferumoxytol in contrast-enhanced MRI studies. This article is based on their discussion.

This article is found in Applied Radiology’s MR Digital Community.

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