Role of deferiprone in chelation therapy for transfusional iron overload.

Before 1987, iron chelation therapy for patients with thalassemia major and other refractory anemias requiring regular transfusions depended almost entirely on one drug, deferoxamine. The drug has dramatically increased survival in patients with thalassemia major in countries where it is readily available.1,2 Although many other compounds had been tried as iron-chelating agents in experiments with animals and humans, none had proved sufficiently effective and free of side effects to warrant further development and widespread clinical use. Throughout the world, however, most patients with thalassemia major still do not receive adequate chelation with deferoxamine because of its high cost and the lack of compliance with the arduous regime of self-administered subcutaneous infusions at least 5 days a week.3,4 In Malaysia, for instance, deferoxamine is available to only a few of the 5000 patients with thalassemia major.5 Toxic or allergic side effects also develop in a minority of patients. Death from iron overload, usually from cardiac failure, continues to occur in patients in poor countries, where deferoxamine is unaffordable, and in more developed countries, where failure of compliance in at least one third of the patients enables excessive iron accumulation.6,7 The orally active iron chelator deferiprone (1,2 dimethyl-3hydroxypyrid-4-1, also known as L1, CP20, Ferriprox, or Kelfer) has emerged from a long, extensive search for new therapies for iron overload. Deferiprone is a synthetic compound first designed in Professor R.C. Hider’s laboratories at the University of Essex.8 In 1987, 2 papers were published showing that deferiprone could achieve effective short-term iron chelation.9,10 Iron excretion levels in the urine, in response to deferiprone in patients with heavy iron overload and with myelodysplasia and thalassemia major, were found to be similar to those obtained with therapeutic doses of deferoxamine. In those studies and a subsequent study in India,11 iron excretion was found to be related to the dose of deferiprone within the range of 25 to 100 mg/kg body weight per day and to the iron load of the patient. Several groups subsequently confirmed in longer term studies that deferiprone was an orally active iron chelator,11-15 and substantial data concerning the efficacy and toxicity of deferiprone have accumulated over 15 years. The results of these trials and of animal and cell culture studies have been extensively reviewed.16-18 Studies have shown that treatment with deferiprone reduces serum ferritin levels and concentrations in some but not all patients,19-21 that it can be given safely for 4 years or more,22,23 and that it is effective in reducing the iron burden in patients with thalassemia intermedia.24 Data have also shown that urinary iron excretion can be increased and serum ferritin levels can be decreased by raising the dose of deferiprone above the widely used regimen of 75 mg/kg body weight per day and by combining deferiprone therapy with deferoxamine therapy.5,11,13,25 Formal long-term toxicity studies have not been performed, however, with higher doses or with combination therapy. Deferiprone has been licensed in India since 1994. The European Union granted marketing approval for deferiprone in 1999 under the “exceptional circumstances” policy that requires further studies. Deferiprone achieved full marketing authorization in Europe in April 2002 after the sponsor fulfilled its specific obligations for additional studies. Nevertheless, some workers consider that deferiprone, because of its variable efficacy and potential side effects, should not be widely used outside clinical trials, even as second-line therapy to deferoxamine.4,26