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Maria Domenica Cappellini
Professor of Internal Medicine
Fondazione Ospedale Maggiore Policlinico
Regina Elena – IRCCS
University of Milan
Iron is a key physiological element essential for a wide range of processes, such as erythropoiesis, oxygen transport, oxidative energy production, mitochondrial respiration, the inactivation of harmful oxygen radicals and DNA synthesis. Most of the body’s iron is used by the bone marrow for the production of haemoglobin and is recycled via the phagocytosis of senescent red blood cells by reticuloendothelial macrophages in the liver. Normal iron homeostasis results in uptake and loss of small amounts of iron, 1–2mg per day, leading to a total body iron content of 3–4g.(1) Loss of iron occurs through sloughing of epithelial cells, desquamation and menstruation, and is replaced by dietary iron, thereby maintaining a delicate natural balance. Situations that introduce unusually high concentrations of iron into the system, however, present a significant clinical problem, as the body has no mechanism of actively excreting excess iron.
Iron overload can occur due to defects in genes encoding proteins that play a key role in iron homeostasis, such as HFE (haemochromatosis), haemojuvelin (type IIa juvenile haemochromatosis), hepcidin (type IIb juvenile haemochromatosis) and ferroportin (African iron overload), resulting in increased uptake of dietary iron and subsequent iron overload.(2–5) In contrast to this type of hereditary, or primary, iron overload, iron accumulation can occur as a result of the treatment of a disease, resulting in “secondary” iron overload. This arises principally due to regular blood transfusion therapy in patients with chronic anaemia, including thalassaemia major, sickle cell disease, myelodysplastic syndromes (MDS) and other rare congenital anaemias. As each unit of blood contains 200−250mg of iron, patients can become iron overloaded after only 10–20 transfusions.(1,6)
Cumulative iron toxicity
Under normal conditions only small amounts of iron are actually stored, but in patients with transfusional haemosiderosis iron begins to accumulate initially in the parenchymal cells of the liver and then, as the condition worsens, in the heart, spleen and endocrine glands. In these organs, iron catalyses the generation of highly toxic hydroxyl free radicals (HO–), leading to oxidative tissue damage and a number of serious clinical sequelae, which, if left untreated, result in ongoing organ damage and significant morbidity and mortality (see Figure 1).(7–9) Cardiac complications are particularly problematic and are a leading cause of death in patients with transfusional haemosiderosis.(10–16) As the liver is the primary storage site for excess iron, the standard method of measuring iron is through the assessment of liver biopsy material, thereby determining the liver iron concentration (LIC) as a surrogate marker of total body iron levels. Normal LIC is considered to be between 0.6 and 1.2mg/g dw (dosing weight), and levels of >7mg/g dw are associated with increased clinical risk.(17,18)
Iron chelation therapy
Chelators are compounds that can form metal complexes with iron and promote its excretion from the body. Iron chelation therapy became available in the 1960s, representing a major advance in the management of patients requiring lifesaving blood transfusion therapy. For the first time, patients were able to receive a transfusion regimen appropriate for their degree of anaemia, rather than a suboptimal schedule that was necessary to limit iron accumulation. Over 40 years of deferoxamine (Desferal(®), DFO) use has established this iron-chelating agent as the reference standard therapy, the use of which significantly reduces morbidity and mortality in regularly transfused patients.(7–9,19) However, DFO is a large molecule with low bioavailability, necessitating a regimen of subcutaneous infusions (8–12 hours a day, five to seven times each week). Treatment is, therefore, troublesome and time-consuming and can be painful due to infusion-site reactions. As optimal morbidity and mortality benefits are inextricably linked with good treatment compliance, many patients are believed to die prematurely due to poor adherence to this demanding regimen.(7,20,21) While compliance with DFO in controlled clinical studies appears to be relatively high (approximately 85%), in practice, compliance may be as low as 50%.(22)
As most patients will require lifelong transfusion therapy, and therefore long-term chelation therapy, suboptimal compliance with DFO regimens can present a significant challenge. Poor general compliance may go some way to explaining the fact that, despite the availability of effective therapy, cardiac disease remains the primary cause of death in many types of secondary iron overload, particularly in patients with β-thalassaemia major.(10)
It can be anticipated that the availability of an oral iron chelator would significantly improve therapeutic compliance by alleviating the practical aspects and limiting the emotional impact of a demanding chronic therapy. One agent that is available in a three-times-daily oral table formulation is deferiprone (Ferriprox(®)), which has been available for some time in many countries outside the USA and Canada (where it has not received approval). The use of this agent is, however, mainly limited to second-line use due to safety risks, such as drug-related agranulocytosis and arthropathy. (23)
Data on use of deferipone in paediatric patients >6 years of age are limited, and no data are available for patients <6 years old. In addition, it has a tablet formulation that makes it difficult to administer to children. While deferiprone has provided an alternative in some patients unable to receive DFO treatment, there is a real need for a convenient and effective therapy.
Oral iron chelation therapy with deferasirox: a new approach
Deferasirox (Exjade(®), ICL670) is a novel once-daily, oral iron chelator (dispersible tablet formulation) that has recently received approval from the US (FDA) and Swiss (Swissmedic) authorities as first-line treatment of chronic iron overload due to transfusional haemosiderosis in adult and paediatric patients (aged 2 years and over). The efficacy and safety of deferasirox have been established in a comprehensive programme of clinical studies involving patients of varying ages (>2 years old) and with a wide range of transfusion-dependent anaemias.(24–26) Deferasirox therefore represents the first significant advance in this therapeutic area since the introduction of DFO several decades ago. Having demonstrated similar efficacy to DFO when used at comparable therapeutic doses, deferasirox offers the potential to optimise patient outcomes by facilitating adherence to long-term therapy. In recent years, the importance of transfusion therapy has been recognised in many additional indications, such as for the prevention of stroke in very young sickle cell patients.(27) The availability of deferasirox complements such changes in clinical practice, and it also extends the availability of transfusion therapy to patients, such as those with MDS, for whom treatment with DFO may have been considered impractical. Consequently, deferasirox has the potential to expand the number of patients that can be considered for beneficial transfusion therapy, in the knowledge that the resultant iron accumulation can be conveniently and effectively controlled.