Iron chelation therapy

Abstract

Patients with refractory anaemias such as thalassaemia major requiring regular blood transfusions accumulate iron at a rate of approximately 0.5 mg/kg body weight per day. Unless this iron is removed, death will occur in about 70% of these patients due to cardiac arrhythmia or failure. Desferrioxamine (DFX) is the only widely available, effective and safe drug for chelating iron. It is usually given by daily subcutaneous (SC) infusions, 40 mg/kg, over 8-12 hours. In heavily iron loaded patients, toxic, free non-transferrin bound iron (NTBI) will accumulate in plasma between DFX infusions. Continuous intravenous or SC DFX is, therefore, needed in patients with iron induced cardiomyopathy. Compliance and cost in poor countries remain major problems with DFX therapy. Deferiprone (DFP), (1-2 dimethyI-3-hydroxypyrid-4-one, L1) is an effective iron chelator when given orally, forming 3:1 (DFP:iron) complexes and producing iron loss in urine equivalent in many patients to that caused by equivalent doses of DFX. DFP is now licensed in India, but still under clinical trial elsewhere. In the long term, it can maintain a proportion of transfusion dependent patients in iron balance at a 'safe' body iron mass (liver iron 2500 ug/L, NTBI present in plasma, liver iron >15 mg/kg dry weight). Liver fibrosis has also been suggested but not proven to be a long term complication of DFP therapy. Our recent studies show that both chelators can be given safely on the same day for a year or more and achieve additive urine iron excretion. Faecal iron excretion induced by DFX, as shown by Grady and colleagues, is unaffected. Combination therapy allows effective chelation protocols in which DFP is given daily and DFX on 1 or 2 days each week, without the necessity to give high, potentially toxic doses of either drug. Combined therapy may also overcome problems of compliance and expense with daily DFX infusions.