Iron is involved in many critical steps of cellular metabolism such as cellular respiration, heme synthesis, production of oxygen radicals, antioxidation, and DNA synthesis and repair, as well as in cellular proliferation and inflammation. Normal body iron stores are 3-4 g; an excess of iron of 20 g or more can lead to organ damage (6). Most additional iron can be stored within the reticuloendothelial system (RES). However, if the iron level exceeds the capacity of the RES to retain it, the excess iron will be released into the plasma. Normally, transferrin binds this released iron but, if the plasma iron concentration continues to rise, transferrin saturation may result. This scenario may occur with sequential transfusions: when the RES cannot retain all of the iron, it then diffuses into the plasma in amounts that exceed the capacity of transferrin to bind it. As a result, non-transferrin-bound iron, which seems to be the major mediator of extrahepatic tissue damage in transfusional iron overload, appears in the plasma (7). The harmful effects of excess iron may result from deposition into tissues and organs, but also from oxidative stress. Non-transferrin-bound plasma iron is deposited specifically in tissues with high level of transferrin receptors (eg, liver, heart, anterior pituitary, and pancreas). As the human body has no mechanism for excreting excess iron, and each unit of transfused RBCs contains 200-250 mg of iron, iron overload can readily occur in patients given multiple transfusions, typically after 10 to 20 transfusions (6). In the absence of treatment to reduce iron overload, progressive cardiomyopathy, cirrhosis, endocrinopathy and diabetes can have a serious impact on morbidity and mortality. Iron chelation therapy in patients given multiple transfusions aims to prevent or reverse some of these consequences and has been associated with a reduced morbidity and mortality (8, 9).

Serum ferritin is the most common indirect parameter used to assess body iron stores in the clinical setting. Measurement of serum ferritin is easy and inexpensive but individual values may be affected by infection, inflammation, liver disease, vitamin C deficiency, and hemolysis (10). Although ferritin is not the most accurate marker of iron overload, ferritin levels do correlate with transfusion burden (11) and liver iron concentration (LIC) (10), and trends in ferritin levels are useful for following iron load.

Liver biopsy is considered the gold standard for direct measurement of total body iron, but the use of this invasive technique is excluded in many patients because of thrombocytopenia and neutropenia, which may predispose to bleeding and infectious complications (12).

Non-invasive measurement techniques are being developed, including T2^* MRI and magnetic susceptometry using a superconducting quantum interference device (SQUID). These techniques have been shown in some studies to provide results that correlate well with liver biopsy-determined iron concentrations (13-15), but they are not widely available worldwide.

The data reported in a recent study indicate that serial measurements of serum ferritin are useful for monitoring chelation therapy with DFX so that doses may be adjusted according to the ongoing iron load due to transfusion (5). The DFX prescribing information recommends monitoring serum ferritin monthly to assess the patient's response to therapy and adjusting the DFX dose, if necessary, every 3 to 6 months (16).

Deferoxamine (DFO) has been in widespread clinical use since the late 1970s and has provided unequivocal evidence that effective chelation therapy can arrest the progression of, and prevent early death from, iron overload (17). DFO is a trihydroxamic acid sideraphore secreted by Streptomyces pilosus, a fungus. DFO is a hexadentate chelator with a very high and selective affinity for iron. One molecule of DFO binds one atom of iron. DFO is administered as long parenteral infusions because the plasma half-life is short (min) and it is not active orally. It is usually given as an overnight subcutaneous infusion 5 to 7 nights per week. It is mainly distributed extracellularly and the protein binding in plasma is low (<10%). After complexing with iron it is excreted rapidly as ferrioxamine, mainly through the kidney and one-third into bile through the feces. Thus, its efficacy is also dependent upon adequate urine output and may be facilitated by dialysis in the case of kidney dysfunction. This requirement is extremely demanding and can result in poor adherence, thereby compromising efficacy and outcomes (18).

Deferiprone (L1; CP20; 1,2-dimethyl-3-hydroxypyrid-4-one) is an orally active hydroxypyridineone first used in humans in 1987. Deferiprone is a bidentate chelator. Three molecules of deferiprone are needed to bind one atom of iron. An advantage of this compound is that the iron chelate of deferiprone carries no net charge and, therefore, can penetrate membranes easily, allowing removal of potentially toxic iron from tissues (19). Other major advantages include oral administration and rapid absorption through the gastrointestinal tract. Deferiprone is mainly metabolized as glucuronide conjugates and is excreted via the renal route. It has a half-life of 2-3 hr. The typical dosage of deferiprone is 75 mg/kg/day in 3 divided doses, up to 100 mg/kg daily (20, 21). Deferiprone is rapidly absorbed mainly from the stomach and reaches the circulation quickly. However, there may possibly be food-drug interactions or other gastric factors that delay the appearance of the drug in the blood following oral administration. Wide variations in the metabolism and clearance of deferiprone among patients have been observed, mainly depending on the iron overload and availability of chelatable iron (22). This agent is approved in some Asian and European countries for second-line treatment of iron overload, but not in the USA and Canada due to its narrow therapeutic index and safety concerns including a risk of agranulocytosis (23, 24).

DFX (ICL670) is a new oral tridentate iron (Fe³⁺) chelator developed specifically for the treatment of chronic iron overload. It is an N-substituted bis-hydroxyphenyl-triazole selected from more than 700 compounds screened as part of a national drug development program (25). Two molecules of DFX are needed to bind one atom of iron. With a plasma half-life of 8 to 16 hr, once-daily dosing permits circulating drug to continuously scavenge non-transferrin-bound "labile plasma iron," which is the chemical species responsible for generating toxic oxygen intermediaries that can cause tissue damage in iron-overloaded subjects (26). Hepatocytes readily take up DFX, which chelates hepatocellular iron. The DFX-iron complex is then excreted in the bile (27). Within cells, DFX chelates cytosolic iron, leading to ferritin degradation by the proteasome (28).

Transfusion-dependent patients (MDS, AA, pure red cell aplasia, myelofibrosis, etc.) need iron chelation therapy. Transfusion-dependent patients are defined as those receiving>8 RBC units with a serum ferritin level>1,000 ng/mL in at least two successive tests. Patients should have a life expectancy of more than 1 yr.

Oral DFX and deferoxamine are available in Korea. However, due to short half life and poor compliance, deferoxamine is not recommended as a standard treatment for iron overload. Oral DFX is a recommended treatment in Korean patients with iron overload. The recommended initial daily dose of DFX is 20 mg/kg body weight, taken on an empty stomach at least 30 min before food. Tablets are available in dosages of 125, 250, or 500 mg and should be dispersed in water or orange or apple juice.

After initiating iron chelation therapy, serum ferritin levels and organ functions including cardiac, hepatic and renal functions should be checked monthly during the first 3 months and then at least once every 3 months. It is recommended that serum ferritin levels be maintained below 1,000 ng/mL and that, when ferritin levels are <500 ng/mL at two successive tests, iron chelation should be discontinued. If ferritin levels continue to increase after initiating therapy, increase the DFX dose up to 30 mg/kg/day. After discontinuing iron chelation, if serum ferritin levels increase above 1,000 ng/mL, restart DFX at the same dose. This guideline is summarized in Table 1.

Safety data for DFX have been reported in many studies for patients with various anemias (53-56). In the EPIC study, DFX was well tolerated with a clinically manageable side effect profile (5). According to previous studies, the most common drug-related adverse events (AE) were gastrointestinal (GI) disturbances such as abdominal pain (6%), nausea (22%), vomiting (8%), and diarrhea (15%). These events were seen to be generally mild-to-moderate in severity and dose dependent, tended to occur early in the course of treatment and usually lasted less than 1 week, and in general, resolved spontaneously without the need for dose adjustment or discontinuation of treatment (5).

Some mild increases in serum creatinine levels have been observed and these appear to be dose dependent. In patients with β-thalassemia, 3% overall had serum creatinine values that increased more than 33% above baseline but were still within the normal range (57). In patients with AA, 25% experienced an increase in serum creatinine to more than 33% above baseline and higher than the upper limit of normal (ULN) on two consecutive visits, but there were no progressive increases. The only factor identified as having a significant impact on serum creatinine was concomitant use of the immunosuppressive agent cyclosporine, a drug with a well-recognized potential to impair renal function. Careful monitoring of renal function is necessary in patients with AA who are receiving concomitant cyclosporine and DFX (4).

In the 1-yr trials, up to 2% of patients developed elevations in serum transaminases. These elevations were not related to dose (5). In previous studies, up to 11% of patients developed dose-dependent skin eruptions and most symptoms were mild to moderate (5).

Although the increases in adverse events described above have been reported as dose dependent, recent data showed that the safety profile of DFX in patients who received more than 30 mg/kg/day was consistent with that of patients who received less than 30 mg/kg/day (59). Interestingly, this study also demonstrated that no adverse events were observed following escalation to over 30 mg/kg/day that were not present at lower doses.

There was a higher incidence of drug-related AEs and higher treatment discontinuation rates in patients with MDS than in patients with other chronic anemias (5). This may be related to the risk of disease progression, preexisting co-morbidities, use of concomitant medication, and the advanced ages of patients with MDS.

Most AEs resolved spontaneously and no patients with renal or hepatic failure or drug-related cytopenia have been reported in any of the studies to date. The only contraindication to DFX is prior hypersensitivity to the drug.

DFX has not been investigated in pregnant or breast feeding women, or in pediatric patients younger than 2 yr. Iron chelation should be ceased as soon as pregnancy is confirmed. Caution should be considered in patients older than 65 yr due to a greater frequency of preexisting suppressed hepatic, renal, or cardiac function.