Date Published: 
Friday, 3 January, 2014

Updates in iron therapy

Across multiple therapy areas, iron deficiency and its consequences have featured throughout publications and global congresses over the course of the last year. Provided below is an overview of the key updates in iron deficiency from throughout 2013. This summary highlights the trends in content related specifically to iron therapy and deficiency from three major congresses. Most recently, the American Society of Hematology (ASH; 5–10 December, LA, USA) congress reported on several key issues in iron deficiency, including its relation to prognosis in elderly patients with aggressive lymphoma receiving first line immunochemotherapy. BioIron 2013 (14–18 April, London, UK) covered several topical subjects within the field, including the relationship of tumour growth and metastasis with iron status in cancer patients, its effect on patients with heart failure, the role of hepcidin in iron regulation, optimal routes of iron therapy and the effect of iron status on infection. Similarly, the European Hematology Association congress (EHA; 13–16 June, Stockholm, Sweden) featured the effects of iron status on cancer progression, and included several reports on the efficacy of iron therapy formulations. Below is an overview of the key updates in iron from BioIron, EHA and ASH, as well as highlights from associated meetings from 2013.

Iron in cancer

A key focus of this year’s congresses was the importance of iron for improving outcomes in patients with cancer. At BioIron 2013, Dr Ganz discussed recent advances in understanding of the pathogenesis of anaemia caused by inflammation, in diseases that include cancer1. Although multiple types of anaemia can develop in patients with cancer, the most common are mediated by the effects of inflammatory cytokines on iron metabolism, erythrocyte survival and the differentiation of erythrocyte precursors in the marrow. Dr Ganz presented the mechanisms of anaemia of inflammation in cancer and then applied these to a model of anaemia elicited in mice by microbial components1.

During EHA, Dr Tantawy and colleagues also reported that functional iron deficiency represents an appreciable cause of anaemia in childhood patients with cancer. Serum ferritin level alone was found to be an unreliable marker for assessment of iron status in children with cancer. Transferrin saturation and assessment of the reticulocyte haemoglobin content were found to be accurate indicators of true and functional iron deficiency in cancer patients2.

Following on from this research into anaemia in paediatric cancer patients, Dr Delarue and colleagues (during ASH) looked at iron parameters in relation to prognosis in elderly patients with aggressive lymphoma receiving first line immunochemotherapy, in an analysis of the LYSA LNH 03-6B study3. The authors demonstrated that elderly patients with untreated aggressive lymphoma and iron deficiency show similar characteristics compared with the whole population. The authors suggested that the high frequency of iron deficiency at diagnosis indicates that intravenous iron may be considered as a frontline treatment for chemotherapy-associated anaemia. A Phase III trial is planned, to investigate efficacy of intravenous iron therapy alone compared to placebo, in reducing requirements for blood transfusions and erythropoiesis-stimulating agents (ESAs)3.

During EHA, Dr Hedenus and colleagues also presented results from a study investigating intravenous iron therapy as sole anaemia therapy in patients with lymphoid malignancies, chemotherapy-induced anaemia and functional iron deficiency2. The prospective, randomised Phase II study evaluated ferric carboxymaltose without additional ESA for correction of anaemia and functional iron deficiency in patients with lymphoid malignancies receiving antineoplastic therapy. Patients treated with ferric carboxymaltose were found to have a significant haemoglobin increase versus baseline at any treatment week compared with the control group. No blood transfusion or ESA treatment was given in either group, and no treatment-related adverse events were recorded during the study. The study authors suggested that ferric carboxymaltose without additional ESA may increase and correct haemoglobin levels and is well tolerated in patients with lymphoid malignancies, chemotherapy induced anaemia and functional iron deficiency2.

The potential role of iron in tumour growth was also explored at BioIron. Dr Torti discussed how the iron-responsive element-binding protein-2 (IRP2) dysregulation may foster iron acquisition and tumour growth in breast cancer cells1. Since iron is tightly bound to transferrin, cells throughout the body have receptors for transferrin–iron complexes on their surfaces, such as IRP2. This receptor engulfs and internalises both the protein and the iron attached to it. Once inside, the cell transfers the iron to ferritin, for storage; regulation of this process is thought to foster iron acquisition. Dr Torti explained how IRP2 knockdown was reported to reduce the labile iron pool and induce apoptosis in breast cancer cells in a dose-dependent manner1. IRP2 blockade was shown to slow tumour growth and prolong survival of tumour-bearing mice. Furthermore, Dr Torti highlighted that IRP2 increases with tumour grade and is associated with human breast cancer molecular subtypes with a poor prognosis. Building on this evidence, Dr Huang and colleagues demonstrated that mice fed an iron-deficient diet had significantly higher tumour volumes and lung metastases compared to those fed normal iron diets, suggesting that host iron deficiency could be a contributor to poor prognosis in young breast cancer patients1.

For further information on iron in cancer, please see the oncology ‘essentials’ section of this website and check out the latest news on iron in cancer by clicking here.

Iron in cardiology

The significant role of iron in patients with chronic heart failure also featured across congresses. Dr Amaral and colleagues investigated whether iron deficiency is the most prognostically adverse cause of anaemia in patients undergoing coronary artery bypass surgery and presented results at BioIron 20131. The authors hypothesized that iron deficiency, even in the absence of anaemia, would be detrimental to hospital outcomes in this patient group. They found that patients with iron deficiency anaemia were more likely to be diabetic, with poorer left ventricular ejection fractions, more congestive symptoms, and higher Canadian Cardiovascular Society class, EuroSCORE and post-operative renal and neurological complications. Iron deficiency anaemia was associated with increased inpatient mortality independently of all covariates including the EuroSCORE. Iron deficiency also predicted an escalated risk of death independently of anaemia1.

Dr Barakat and colleagues presented their findings from a study which investigated anaemia in relation to chronic heart failure severity and improved iron status in relation to prognostic benefit to patients1. The authors aimed to establish whether the causes of anaemia vary with disease severity or whether improved iron status over time confers a survival advantage. Results demonstrated increasing levels of transferrin saturation over time are related to better survival independently of New York Heart Association class, left ventricular ejection fraction and baseline transferrin saturations. The authors concluded that anaemia of chronic disease increases whilst non-iron deficiency anaemia decreases in prevalence with increased chronic heart failure severity1.

Several studies related to the use of intravenous iron to improve outcomes in patients with chronic heart failure were also presented at the European Society of Cardiology congress 2013 (31 August – 4 September, Amsterdam, The Netherlands). A detailed report on this congress, including iron-related content, can be found by clicking here.

For further information on iron in heart disease please see the cardiology ‘essentials’ section.

Hepcidin and iron regulation

The role and uses of the iron regulatory hormone hepcidin continues to prove a popular area of focus. At BioIron 2013, Dr Goodnough and colleagues provided evidence that non-responsiveness to oral iron in patients with iron deficiency anaemia can be predicted from patients' baseline hepcidin levels, which have superior positive predictive values compared to transferrin saturation or ferritin levels1.

Professor Campostrini and colleagues measured serum hepcidin isoforms in patients with inflammatory bowel disease versus control subjects. The authors suggested that, in inflammatory bowel disease patients, serum hepcidin-25 is influenced by iron stores, inflammation and iron requirement for erythropoiesis. Thus hepcidin-25 determination may be useful in the differential diagnosis of anaemias in this patient group1.

The relationship between hepcidin, iron and infection was discussed in a number of presentations and abstracts at BioIron this year. In particular, Dr Drakesmith’s lecture highlighted the importance of iron for growth and development, and discussed that approximately 25% of the world’s children have iron deficiency anaemia1. However, he pointed out that iron is also of importance to infectious agents, which also need the element to develop. Dr Drakesmith discussed the Pemba trial, which showed an increase in malaria in children given iron and folic acid, and underlined the difficulty for policy makers in deciding whether to recommend prescribing iron in children at risk of the disease. He later went on to explain how hepcidin levels may be useful in establishing whether a patient will benefit from iron therapy without risk of contracting malaria. Dr Drakesmith concluded by describing hepcidin as superior to ferritin as a predictor of response to iron therapy and indicated that it should be considered in future recommendations for the treatment of iron deficiency anaemia1.

For further information on the relationship between iron and infection please click here for an article discussing the topic. For video footage of Professor Gunter Weiss discussing iron and infection at BioIron 2013, please click here.

Iron therapy treatment options

Several new iron therapy formulations became available this year as discussed by Professor Iain Macdougall at BioIron 2013 in his lecture “Selecting optimal modes of iron supplementation”. Professor Macdougall discussed the use of iron as a therapeutic agent for the treatment of patients with anaemia and iron deficiency1. Most importantly, he explained factors which can help to determine the optimal mode of iron therapy administration such as the demand for iron, the quantity and speed of iron delivery desired, and the degree of underlying inflammation and hepcidin activity. He suggested that advantages of various routes of iron administration must be weighed against possible risk before a clinical decision is made to treat1.

During EHA, Professor Vadhan-Raj presented data on the safety and efficacy of ferumoxytol for the episodic treatment of iron deficiency anaemia in patients with a history of unsatisfactory oral iron therapy – these were the results of a Phase III open-label, six month extension study2. The authors reported that ferumoxytol increased haemoglobin levels compared with placebo in these patients. They stated that a consistent treatment effect was observed, and durability of the effect was demonstrated by the majority of patients not requiring further iron treatment following the initial course during this six month study2.

Several notable studies on the importance of iron therapy treatment in nephrology were also presented in 2013. Topical studies included research presented on intravenous iron therapy use in chronic kidney disease, the use of iron status in predicting outcomes for patients with chronic kidney disease, ability of iron therapy to reduce blood transfusions and use of ESAs, and the effect of iron status on patients’ undergoing dialysis treatment.

For example, Professor MacDougall presented results at the American Society of Nephrology congress (ASN) from the FIND-CKD trial of 626 anaemic patients with non-dialysis dependent chronic kidney disease and iron deficiency not receiving an ESA. The results showed that intravenous ferric carboxymaltose targeting a ferritin range of 400–600 μg/L significantly delayed the requirement for ESA therapy or other anaemia therapy compared to oral iron in anaemic patients with non-dialysis dependent chronic kidney disease and iron deficiency. High target ferric carboxymaltose led to a greater haemoglobin increase compared with oral iron, maintained haemoglobin, and was well tolerated4.

Dr Dekker and colleagues presented results at ASN from a study investigating intravenous ferric carboxymaltose for reducing the need for ESA in chronic haemodialysis4. The authors found that using ferric carboxymaltose instead of low molecular weight iron dextran significantly reduced the need for the ESA without compromising haemoglobin levels4.

In another presentation at ASN, Dr Vivian H Lin discussed the use of soluble ferric pyrophosphate (SFP) administered via dialysate for reducing ESA and intravenous iron requirements while maintaining haemoglobin in haemodialysis-dependent patients with chronic kidney disease. The authors found that SFP, delivered via dialysate, required 35% less ESA and 48% less intravenous iron compared to placebo, while maintaining haemoglobin concentrations4.

For further information on the types of iron therapy please see the ‘Dosing and treatment’ section of our website or check out the latest news relating to treatments in iron deficiency by clicking here.