Transfusional iron overload and chelation therapy with deferoxamine and deferiprone (L1)

Iron is essential for all living organisms. Under normal conditions there i s no regulatory and rapid iron excretion in humans and body iron levels are mainly regulated from the absorption of iron from the gut. Regular blood t ransfusions in thalassaemia and other chronic refractory anaemias can resul t in excessive iron deposition in tissues and organs. This excess iron is t oxic, resulting in tissue and organ damage and unless it is removed it can be fatal to those chronically transfused. Iron removal in transfusional iro n overload is achieved using chelation therapy with the chelating drugs def eroxamine (DF) and deferiprone (L1). Effective chelation therapy in chronic ally transfused patients can only be achieved if iron chelators can remove sufficient amounts of iron, equivalent to those accumulated in the body fro m transfusions, maintaining body iron load at a non-toxic level. In order t o maintain a negative iron balance, both chelating drugs have to be adminis tered almost daily and at high doses. This form of administration also requ ires that a chelator has low toxicity, good compliance and low cost. DF has been a life-saving drug for thousands of patients in the last 40 years. It is mostly administered by subcutaneous infusion (40-60 mg/kg, 8-12 h, 5 da ys per week), is effective in iron removal and has low toxicity. However, l ess than 10% of the patients requiring iron chelation therapy worldwide are able to receive DF because of its high cost, low compliance and in some ca ses toxicity. In the last 10 years we have witnessed the emergence of oral chelation therapy, which could potentially change the prognosis of all tran sfusional iron-loaded patients. The only clinically available oral iron che lator is L1, which has so far been taken by over 6000 patients worldwide, i n some cases daily for over 10 years, with very promising results. L1 was a ble to bring patients to a negative iron balance at doses of 50-120 mg/kg/d ay. It increases urinary iron excretion, decreases serum ferritin levels an d reduces liver iron in the majority of chronically transfused iron-loaded patients. Despite earlier concerns of possible increased risk of toxicity, all the toxic side effects of L1 are currently considered reversible, contr ollable and man ageable. These include agranulocytosis (0.6%), musculoskele tal and joint pains (15%), gastrointestinal complaints (6%) and zinc defici ency (1%). The incidence of these toxic side effects could in general be re duced by using lower doses of L1 or combination therapy with DF. Combinatio n therapy could also benefit patients experiencing toxicity with DF and tho se not responding to either chelator alone. The overall efficacy and toxici ty of L1 is comparable to that of DF in both animals and humans. Despite th e steady progress in iron chelation therapy with DF and L1, further investi gations are required for optimising their use in patients by selecting impr oved dose protocols, by minimising their toxicity and by identifying new ap plications in other diseases of iron imbalance. (C) 2000 Elsevier Science L td. All rights reserved.