A risk-benefit assessment of iron-chelation therapy

Iron overload caused by lifelong transfusion-dependent anaemias, such as beta-thalassaemia major, usually results in lethal cardiac toxicity in the second decade of life if not treated by iron chelation. There is no physiological mechanism for excreting the excess iron accumulated from blood transfusions and, unlike hereditary haemochromatosis, venesection is not an option. Therefore, chelation therapy is the only way to remove excess iron. This must be removed while not depriving cells of the essential iron needed for normal metabolism. Additionally, the iron chelator must prevent iron from participating in the generation of harmful free radicals. Parenteral chelation therapy with deferoxamine (desferrioxamine) is well established as promoting negative iron balance, reversing cardiac toxicity, and prolonging life expectancy well into the fourth decade of life and, most likely, beyond. Unfortunately, poor compliance with the rigours of parenteral treatment in a minority of patients limits its regular use, resulting in reduced life expectancy in these patients. Use of deferoxamine in excessive dosages may result in growth retardation, sensorineural ototoxicity and ocular toxicity, as well as bone deformities. These effects can be largely avoided if the dosage is adjusted to take account of the degree of iron overload (using the therapeutic index) and if the mean daily dose does not exceed 40 mg/kg. Nevertheless, it is recommended that patients be regularly monitored for such adverse effects. Deferiprone (L1; CP20) is an orally absorbed bidentate hydroxypyridinone iron chelator that can induce urinary iron excretion, promote negative iron balance and reduce hepatic iron levels in some transfusion-dependent patients, particularly in those who are markedly iron overloaded and have not received regular deferoxamine therapy. The long term efficacy and toxicity of deferiprone are the subjects of some controversy, and the published results of randomised controlled trials are awaited. Preliminary results suggest that when currently recommended dosages of deferiprone (75 mg/kg/day) are used, hepatic iron settles at levels that still put most patients at an increased risk from iron overload. A number of adverse effects may occur, and require cessation of therapy in up to 30% of patients. These effects include arthritis, nausea and (most seriously) agranulocytosis in 0.6 to 4% of patients. The risk of the latter complication means that frequent white blood cell counts are mandatory for patients taking this drug. There remains an urgent need to identify an orally active chelator regimen that is as effective as deferoxamine and has an acceptable degree of tolerability.