Date Published: 
Friday, 20 June, 2014

Iron therapy in haematology

Professor Michael Auerbach

Professor Michael Auerbach is a haematologist and oncologist at Auerbach Hematology and Oncology Associates, Inc. (Baltimore, USA) and a Clinical Professor of Medicine at Georgetown University School of Medicine (Washington DC). He is also a member of the Lombardi Cancer Center (Washington DC). He serves on the scientific board of the Network for Advancement of Transfusion Alternatives, and advises the Society for the Advancement of Blood Management. The recipient of two Investigational New Drug (IND) approvals from the US Food and Drug Administration (FDA), he is currently investigating the administration of a total-dose infusion of intravenous iron as a method of iron replacement across a host of conditions.  He also serves as a member of the editorial board of the American Journal of Hematology.

Why did you become interested in iron deficiency?

When I was a fellow at the Columbia Presbyterian Hospital (New York, USA), I had a patient with severe iron deficiency and pagophagia (ice craving), who did not tolerate oral iron therapy. One of my colleagues suggested administering an iron therapy infusion over several hours. The patient was given 2000 mg of intravenous iron dextran over 12 hours (the administration was conducted in 4 hours in subsequent years) and responded extremely well. However, iron administration at that time – during the 1970s – was advised against owing to serious adverse events, including anaphylactic shock and even death. In 1982 I started investigating these adverse events with intravenous iron therapy administered over both 12 and 4 hours and only one serious adverse event was observed. When I moved to Beth Israel Hospital (New York, USA) as an Assistant Professor at the Mount Sinai School of Medicine, I continued administering iron therapy regularly to patients with iron deficiency and found that patients responded well and serious adverse events did not occur.

Why is treatment of iron deficiency important?

Iron deficiency is extremely common in the general population worldwide (and especially in menstruating women). It is associated with decreased exercise performance, fatigue, dizziness, pagophagia, sleeplessness and restless leg syndrome. In pregnancy, a patient may not be checked for iron deficiency unless the woman is anaemic, despite the fact that it has been shown to cause a detriment to the growth and development of the foetus during pregnancy. Epidemiological data also indicates that iron deficiency may cause a statistically significant increment in cognitive and behavioural abnormality in a child up to 10 years after iron repletion. There are approximately three billion people worldwide with iron deficiency (both with and without anaemia), but the condition is rarely at the forefront of healthcare services. An additional point is that approximately 40% of patients with iron deficiency report restless leg syndrome. Four years ago, colleagues and I decided to investigate this area and have already published two papers on the topic with further studies on their way1,2.

What are the main symptoms that you see troubling patients?

Iron deficient patients who are otherwise healthy may experience decreased exercise performance, fatigue, dizziness, pagophagia, sleeplessness and restless leg syndrome. In patients with other conditions, such as cancer, chronic kidney disease and cardiovascular disease, the effect of iron deficiency can be more severe and lead to worse patient outcomes and well-being. In perioperative patients, iron therapy markedly reduces transfusion risk which, in turn, reduces infection and improves patient outcomes for surgery. Iron therapy really does seem to improve patient well-being.

Which patients are most likely to develop iron deficiency?

Menstruating and pregnant women are often iron deficient. Men may also have iron deficiency, but in this patient group it is important to check for colon cancer as part of the treatment paradigm. In men, colon cancer is often the underlying cause of the iron deficiency and simply treating the deficiency may only prolong the time to diagnosis of cancer.

Most patients who experience iron deficiency are parous females or any patient with bleeding, such as patients with colon cancer, inflammatory bowel disease, and those who undergo gastric bypass. Iron deficiency is also common in patients with bleeding disorders where the blood loss is greater than the ability to replace it. 

How well is the importance of iron deficiency, as opposed to anaemia, known in the haematology community?

On a scale of one to ten, the importance of iron deficiency is somewhere between three and four. In 2010, some colleagues and I conducted the first ever education session on the administration of intravenous iron – it was poorly attended. I recently conducted another education session at the American Society of Clinical Oncology (ASCO) Annual Congress (30 May–03 June, 2014, Chicago, USA) and out of 40,000 people at the meeting, only 100 people attended this education session. The priority of treating iron deficiency is very low.

Why do you think this is?

The early intravenous iron preparations were dangerous. Early formulations of iron dextran gave rise to serious adverse events, such as shock and anaphylaxis, which is sometimes fatal. When physicians took into consideration the potentially fatal consequences of treatment, compared to the main symptom in an otherwise healthy iron deficient individual – fatigue – enthusiasm for its use was low.

However, in one of the first papers published on the administration of intravenous iron, Marchasin and colleagues found that all patients responded3. Several later studies also found that all patients responded with no fatal adverse events. Despite these studies, intravenous iron was still largely reserved for scenarios in which oral iron could not be used.

When recombinant erythropoietin (rEPO) became available for patients with chronic kidney disease, research indicated that intravenous iron increased the efficacy of rEPO by up to 40%. As a result, intravenous iron rapidly became a standard in dialysis. Several therapies were developed which were much safer than the original formulations but these were associated with infrequent minor infusion reactions. Since physicians were taught to expect anaphylaxis, a minor infusion reaction was often managed as anaphylactic shock, and premedicating patients with diphenhydramine became common. When administered with iron, many physicians mistake the side effects caused by diphenhydramine to be associated with iron therapy.

Guidelines now recommend that physicians do not prescribe diphenhydramine and should be aware that patients are much more likely to experience minor infusion reactions rather than anaphylaxis. The foundation for Kidney Disease Improving Global Outcome (KDIGO) are currently revising their guidelines in line with this.

Are there still unmet needs in iron deficiency and its treatment?

Yes, there are huge unmet needs. I always prescribe intravenous iron over oral and I have never seen a serious adverse event with the newer formulations (ferric carboxymaltose, ferumoxytol, low molecular weight iron dextran and others). My colleagues and I give approximately 30–35 infusions of intravenous iron per week. The unmet need is educating physicians on how to interpret the frequency and the nature of minor infusion reactions with intravenous iron and how to correctly use these therapies.

What treatment options are currently used and are these effective?

Other than oral iron, there are currently six intravenous iron formulations used in the USA, four of which are extremely convenient to administer. Ferric carboxymaltose, ferumoxytol, low molecular weight iron dextran and iron isomaltoside allow complete iron replacement, via total-dose infusion, within 15-60 minutes. 1000 mg of low molecular weight iron dextran requires 1 hour. It takes four or five visits with iron sucrose or ferric gluconate to do what the other therapies can do in 15-60 minutes. Despite this, iron sucrose is currently the most commonly used formulation in the USA. It is not as convenient for patients and physicians as some of the other formulations, and is of similar efficacy and safety. There are a lot of options but increased awareness of the different therapeutic agents available is needed.

How do the outcomes for patients with iron deficiency improve with treatment?

The outcomes are seen immediately. It is one of the few areas in medicine where you see instantaneous effects. Energy levels are often higher the next day. Pagophagia is often relieved within minutes of the infusion, restless leg syndrome is frequently relieved on the same day. The outcomes are dramatic.

What are you currently focusing on in your research and why is this area of particular interest?

Our current study is investigating 60 gravida patients, who are intolerant to oral iron, being treated with intravenous iron. We have received IND approval from the US FDA for this investigation. We are also conducting a double-blind study in patients with restless leg syndrome, another prospective study comparing iron isomaltoside with iron sucrose in a variety of iron deficient conditions. Lastly, we hope to shortly be conducting a study with ferric carboxymaltose as sole erythropoietic therapy in anaemic patients undergoing chemotherapy.

Are there any areas of iron deficiency or therapy that you would like to investigate in the future?

I would like to continue the investigation in pregnant women with iron deficiency and collect longitudinal follow-up data on the children of iron deficient women. In addition, sometimes iron deficient patients have an iron deficit of >3000 mg. I never administer more than 1000 mg as we do not really know where all of the iron goes. We do know that some of it saturates transferrin and that some of the circulating macrophages ingest the iron resulting in an iron reservoir. But we do not know how much and there is no in vitro data to support this. I would like to investigate treating iron deficient patients with an iron deficit of ≥2000 mg. I would give them 750, 1000, 1500 and 2000 mg intravenous iron therapy and look at whether there is a difference in the way they respond. If there is no difference in response then we may have to rethink the size of the doses that we are currently giving patients.