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George J Kontoghiorghes
Postgraduate Research Institute of Science, Technology, Environment and Medicine
In the body, iron concentration is mainly regulated through metabolic pathways of iron absorption, utilisation and conservation. Most of the iron is utilised for the production of haemoglobin in the red blood cells. There is no physiological mechanism for the rapid excretion of excess iron from the body.
Iron overload is the most common metal toxicity condition, with the highest mortality rate worldwide. Increased iron absorption, repeated red blood cell transfusions or combination of these two processes are the main pathways causing excess body iron concentration and damage to various organs.(1) The most common conditions of iron overload are idiopathic (genetic) haemochromatosis, which affects one in about 300 people of mainly Caucasian descent, and Î²-thalassaemia, an inherited haemoglobinopathy with an annual birth rate of 100,000 which is mainly found in countries of the Mediterranean area, South East Asia and the Middle East. In the former condition, iron overload is caused by increased gastrointestinal iron absorption and can easily be treated using venesections. The treatment of Î²-thalassaemia patients involves the regular transfusion of red blood cells and iron chelation therapy, which is used for the removal of excess toxic iron accumulating in the body from transfusions.(2) In addition to Î²-thalassaemia, there are many conditions, such as myelodysplasia, sickle cell anaemia, cancer and renal dialysis, where iron overload is developed from regular transfusions.(1,3)
The rate of red blood cell transfusions in Î²-thalassaemia and other refractory anaemia conditions is aimed at maintaining haemoglobin levels at about 110ï¿½120g/l, which is causing a net iron deposition in the body of about 15-20mg/day. Excess iron is mainly stored in the liver and spleen, but also in the heart and other organs, causing toxic side-effects. Î²-Thalassaemia patients who do not receive effective chelation therapy usually die from congestive cardiac failure caused by iron overload toxicity before the age of 20 years. The early introduction of effective chelation therapy can prevent organ damage and increase their life span, in some cases to more than 50 years.
Regular clinical and laboratory follow-up, including assessment of excess body and organ iron load, is important for the overall prognosis, as well as the efficacy of the iron removal therapy in iron-loaded patients. The most common methods for the diagnosis of excess body iron load are serum ferritin levels and transferrin iron saturation, both of which increase in cases of iron overload. New, nonâ€‘invasive methods have also been developed, including magnetic resonance imaging T2 and T2(*) techniques, which can assess iron deposition in organs such as the liver and the heart. These diagnosis methods are critical for the prognosis of iron-loaded patients.(1,4)
Treatment of iron overload
Deferoxamine (DF) has been the mainstay of iron chelation therapy in the past 40 years. It has extended the lives of thousands of transfusional iron-loaded patients who have complied with its standard treatment (which usually involves the 8-12-hour subcutaneous [SC] administration of 40ï¿½60mg/kg/day, at least five days per week).(2,3) However, low compliance with the cumbersome SC DF treatment and insufficient use due to its high cost (4,250-8,500 Euros per patient per year) leads to excess iron deposition in the heart and cardiomyopathy, which are the main causes of death in thalassaemia patients.(3,5) These and other drawbacks in the use of DF, such as auditory and ocular toxicity, have led to investigations for new chelating drugs.
A new era in chelation therapy began with the design and development of the oral iron-chelating drug deferiprone (L1).(6) Clinical trials in transfusional iron-loaded patients using doses of 75-110mg/kg/day have indicated that L1 can increase iron excretion and cause negative iron balance in most patients. L1 was first approved in India in 1994 and in Europe in 1999. It is estimated that more than 15,000 patients in more than 50 countries worldwide have used L1. L1 is more effective than DF in the removal of excess iron from the heart and is also less expensive than DF in developing countries.(1,4) The toxic side-effects of L1 are reversible and manageable and include joint/ musculoskeletal pains, gastric intolerance, neutropenia, zinc deficiency and agranulocytosis (0.6%).(3,6) The dropout of patients using L1 is about 5%.(3)
Combination therapy with L1 and DF has been introduced in many patients not responding, not complying or for whom either DF or L1 has toxic side-effects.(7,8) The administration of L1 (80-110mg/kg/day) during the day and of DF (40-60 mg/kg/day) at least three nights per week, as suggested by the International Committee on Oral Chelators, appears to be universally effective for removing excess iron and maintaining negative iron balance in transfusional iron-loaded patients.(1)
At least three other promising oral iron chelators have recently reached the stage of clinical testing. The L1 derivative L1NAll has reached phase I clinical development with promising results.(1,9) Two other orally active chelators, namely deferasirox (ICL670, Exjade) and deferitrin (GT56-252), have reached phase III and phase II clinical development, respectively.(1,10,11) The iron-chelating drug market, which is currently estimated at 0.85bn Euros per year, is attracting a lot of interest from pharmaceutical companies.
ICL670, which has been developed by the pharmaceutical company Novartis, has received conditional FDA approval in November 2005. It has a very long plasma half-life and can only be administered once daily at 20-30mg/kg/day. It is generally ineffective in causing negative iron balance or depletion of excess iron from the heart but is effective in reducing liver iron.(1,10,12) Toxic side-effects mainly include gastric intolerance, skin rashes and increase in serum creatinine in 33% of the patients. The dropout rate in about 1,000 patients participating in clinical trials with ICL670 was 3-10%.
GT56-252 has been developed by the pharmaceutical company Genzyme, and preliminary results indicate that it can increase iron excretion both in iron-loaded animals and patients.(11)
So far, preclinical and clinical trial results for experimental iron-chelating drugs do not appear to be significantly better than established therapies with L1, DF or their combination regarding efficacy and toxicity. However, the introduction of new iron- chelating drugs will increase the prospect of more effective and less toxic chelation therapies. For many patients, future chelation strategies will involve combination therapies, especially since it is unlikely that the existing or the new chelating drugs will be effective for all patients as monotherapies.