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Published on 1 July 2006

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Latest progress in iron overload treatment


Ersi Voskaridou
Head of Department
Thalassaemia Centre
Laikon General Hospital

Survival and complication-free survival of patients with thalassaemia major (TM) have significantly improved in recent years as a consequence of better management. Chelation therapy with deferoxamine (DFO) has been associated with marked reduction in mortality and morbidity in patients with TM.(1) This agent proved to be highly efficient, with very few side-effects; however, the fact that it cannot be absorbed when given orally, and therefore has to be administered subcutaneously, prompted several investigators to seek and evaluate other iron-binding agents in an attempt to identify the “ideal” oral iron chelator. The ultimate goal of an iron chelator is to prevent iron-induced toxicity (ie, to prevent organ damage and, hence, premature death). This can be accomplished by various agents that bind free iron, ­wherever this is available, and are excreted in the urine or through the bile in the stools. This free iron can be found intracellularly, at the cellular surface or in the serum; this means that an ideal iron chelator should have a high specificity and affinity for iron but not for other metals and should be able to move easily in and out of tissues and cells. Moreover, the ideal chelator should be absorbable by mouth, display a slow rate of metabolism, be excreted easily when bound to iron, be free of acute or chronic toxicity and not promote bacterial growth.

The number of iron chelators that have been devised and evaluated over the last 20 years is important and is ever increasing, which implies that the goal has not yet been reached. Currently available chelators display large differences in molecular weight and solubility, varying concentrations in plasma and half-lives, ­varying access to tissues and chelating properties and different toxicities (see Table 1). Of the chelating agents that have been proposed so far, the following three have been adequately evaluated and widely applied in clinical practice.


Although DFO is very effective in ­preventing iron overload, compliance is a major issue and can ­significantly limit the efficacy of this agent. Therefore, deferiprone, an orally active chelator, has been approved in parts of Europe as second-line treatment for adult TM patients who are either unable to receive deferoxamine or for whom response to ­deferoxamine treatment is unsatisfactory.(2) Deferiprone has a relatively short half-life, necessitating three-times-daily dosing.

Deferasirox is the first oral iron chelator that can be given once daily due to its long plasma half-life. Deferasirox binds iron in a 2:1 ratio (a “­tridentate” chelator), is readily absorbed orally, reaches a peak value at two hours and remains in the plasma for several hours before being excreted in the stools (more than 90%). Total exposure to the drug is proportional to dose. The drug has a high specificity for iron and does not seem to bind zinc and copper. Extensive preclinical testing in several iron-loaded animal species(3) was soon followed by reports of the pharmacokinetic properties, tolerability, efficacy and safety of the drug, which demonstrated that:

  • Deferasirox given at the well-tolerated dosages of 10–30mg/kg once daily may achieve negative iron balance in patients with transfusion-dependent thalassaemia.
  • The long plasma half-life of the drug creates an artificial unsaturated iron-binding capacity, thus allowing neutralisation of the noxious effects of the circulating non-transferrin-bound iron (NTBI).
  • The side-effects of the drug are rather insignificant.(4,5)

Preclinical studies have demonstrated that ­deferasirox enters cellular compartments, chelates iron and diminishes intracellular oxidative stress. It is phagocytised by hepatocytes, and it removes iron from cardiac cells and subcellular compartments such as the cytosol, lysosomes and mitochondria.(6) In vivo, it mobilises iron from the reticuloendothelial system and removes it from hepatocytes and cardiac cells.(7) An important subentity of NTBI is the labile plasma iron (LPI), which is characterised by its important redox activity.(8) It is essential for an iron chelator to keep concentrations of LPI at low levels at all times to prevent uptake of LPI into cells, where it can cause oxidative stress and ensuing organ damage. The long plasma half-life of deferasirox is well suited to provide 24-hour protection from NTBI species. Data from clinical trials show that LPI is suppressed for 24 hours by deferasirox when using daily doses of 20 or 30mg/kg.(9) To date, deferasirox has been evaluated in multinational studies involving more than 1,000 patients (nearly half of them children) in 12 countries. Two large randomised prospective clinical studies have investigated the efficacy and safety of ­deferasirox in removing excess body iron, compared with the standard therapy, DFO. Study 107 involved 586 patients with β-thalassaemia, and study 109 involved 195 patients with sickle cell disease.(10,11) These studies showed that deferasirox induces a dose-­dependent removal of iron, comparable to that achieved with DFO. Study 107 (biopsy data) showed that iron deposits were reduced in all functional areas of the liver, including patients with or without advanced fibrosis or cirrhosis.(12) Another small clinical study (22 patients) evaluated the effect of deferasirox on heart iron and demonstrated that deferasirox removes iron from the heart, as evidenced by a statistical significant increase in T2(*).(13)

The most common adverse events in these studies are mild to moderate and transient. Gastrointestinal disturbances occurred in 26% of patients, skin rashes in 7% of patients and increased serum creatinine levels (mild, nonprogressive, dose-dependent) in 34% of patients.(10,11)

In conclusion, deferasirox is orally active, well absorbed and has a long plasma half-life. It shows the potential of protecting cells from intracellular oxidative stress and removing iron from the heart. However, additional studies are needed to demonstrate efficacy in ­reducing heart and liver iron in patients with thalassaemia and other transfusion-dependent patients.


  1. Borgna-Pignatti C, et al. Haematologica 2004;89:1187-93.
  2. Cohen AR, et al. Br J Haematol 2000;108:305-12.
  3. Hershko C, et al. Blood 2001;97:1115-22.
  4. Galanello R, et al. J Clin Pharmacol 2003;43:565-72.
  5. Nisbet-Brown E, et al. Lancet 2003;361:1597-602.
  6. Cabantchik ZI, et al. Blood 2005;106:11, Abstract 824.
  7. Wood J. Blood 2005:106:11, Abstract 2695.
  8. Esposito B, et al. Blood 2003;102:2670-7.
  9. Daar S, et al. Blood 2005;106:11, Abstract 2697.
  10. Kattamis A, et al. Blood 2005;106:11, Abstract 2692.
  11. Vichinsky E, et al. Blood 2005;106:11, Abstract 2334.
  12. Angelucci E, et al. Blood 2005;106:11, Abstract 2696.
  13. Porter JB, et al. Blood 2005;106:11, Abstract 2690.

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