Elsevier

Transfusion Science

Volume 23, Issue 3, December 2000, Pages 211-223
Transfusion Science

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

https://doi.org/10.1016/S0955-3886(00)00089-8Get rights and content

Abstract

Iron is essential for all living organisms. Under normal conditions there is 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 transfusions in thalassaemia and other chronic refractory anaemias can result in excessive iron deposition in tissues and organs. This excess iron is toxic, resulting in tissue and organ damage and unless it is removed it can be fatal to those chronically transfused. Iron removal in transfusional iron overload is achieved using chelation therapy with the chelating drugs deferoxamine (DF) and deferiprone (L1). Effective chelation therapy in chronically transfused patients can only be achieved if iron chelators can remove sufficient amounts of iron, equivalent to those accumulated in the body from transfusions, maintaining body iron load at a non-toxic level. In order to maintain a negative iron balance, both chelating drugs have to be administered almost daily and at high doses. This form of administration also requires 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 days per week), is effective in iron removal and has low toxicity. However, less 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 cases toxicity. In the last 10 years we have witnessed the emergence of oral chelation therapy, which could potentially change the prognosis of all transfusional iron-loaded patients. The only clinically available oral iron chelator is L1, which has so far been taken by over 6000 patients worldwide, in some cases daily for over 10 years, with very promising results. L1 was able to bring patients to a negative iron balance at doses of 50–120 mg/kg/day. It increases urinary iron excretion, decreases serum ferritin levels and 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, controllable and manageable. These include agranulocytosis (0.6%), musculoskeletal and joint pains (15%), gastrointestinal complaints (6%) and zinc deficiency (1%). The incidence of these toxic side effects could in general be reduced by using lower doses of L1 or combination therapy with DF. Combination therapy could also benefit patients experiencing toxicity with DF and those not responding to either chelator alone. The overall efficacy and toxicity of L1 is comparable to that of DF in both animals and humans. Despite the steady progress in iron chelation therapy with DF and L1, further investigations are required for optimising their use in patients by selecting improved dose protocols, by minimising their toxicity and by identifying new applications in other diseases of iron imbalance.

Section snippets

Iron imbalance

Iron is an essential trace element found in many proteins, which play a key role in the metabolic pathways involved in the growth and development of humans and almost all other organisms. Under normal conditions total body iron in adults is about 4.5 g and is uniformly distributed as haemoglobin (2.6 g), myoglobin (0.4 g), non-haem storage iron in tissues (1.4 g), smaller amounts as enzymes and minute amounts in plasma. About 1–4 mg of dietary iron is absorbed daily mainly from the duodenum and

Transfusional iron overload in thalassaemia and other conditions

Transfusional iron overload is the most common metal-related toxicity condition with the highest mortality rate worldwide. The risk is higher in those belonging in the category of the most common inherited disorder namely the haemoglobinopathies. It is estimated that 270 million people are heterozygotes of a haemoglobinopathy and at least 200 000 babies are born each year, half with sickle cell disease and the other half with thalassaemia [1], [2], [3]. About 73% of those born with thalassaemia

Iron toxicity mechanisms

In all the conditions of iron overload, iron toxicity may arise mainly from the incapacity of cells to store iron in a safe storage form, resulting in lysosomal rupture and subsequent cellular and tissue damage. Potentially toxic forms of iron in iron overload are the low molecular weight labile iron pool and haemosiderin found intracellularly and the low molecular weight non-transferrin bound iron (NTBI) found extracellularly. Iron could catalyse the oxidative breakdown of most biomolecules

Methods for the assessment of iron overload

Estimation of the body iron status and the progress of iron chelation therapy in iron-loaded patients could be achieved by a variety of methods, all of which have limitations and none of which could precisely predict total body iron and extent of iron toxicity. This is mainly because of variability in body and organ iron distribution, iron detection methods, iron estimation and extrapolation to all other body iron pools and other factors such as the diet, infection, inflammation, erythropoietic

Chelating drugs and their mode of action

A chelator (χηλη, Greek claw of a crab) is a naturally occurring or chemically designed molecule which has high specificity and affinity for a metal ion, forming a complex with it. An ideal chelator designed for the decorporation of a particular metal from the body should be able to bind, carry and remove the metal out of the body without causing any toxicity. The chelator dose protocol should be selected for each patient and aimed to achieve maximum efficacy in iron removal and minimum

Deferoxamine

DF has been the mainstay of iron chelation therapy in transfusional iron loaded patients in the last forty years. It is a generic drug and could be produced chemically or isolated from the fungus streptomyces pilosus. The development of chelation therapy with DF involved different stages of various application techniques and experimentation protocols over the last 40-year period, including various methods of administration in order to improve its overall efficacy. The prolonged subcutaneous and

The α-ketohydroxypyridines

Hundreds of potentially orally active chelators have been tested in vitro and in animals and only 16 reached the stage of clinical evaluation, with mostly disappointing results because of either ineffectiveness or toxicity in humans [15], [16], [17]. The α-ketohydroxypyridines (KHP) is the most promising group of chelators [18]. They were designed to mimic the naturally occurring chelators mimosine, tropolone and maltol which were previously shown to be orally active and effective in binding

Deferiprone

L1 is the first oral iron chelating drug to be used in thalassaemia and other iron-loaded patients [28], [29]. Progress in its development has been very slow because it was mostly undertaken through research-orientated projects and supported by non-profit establishments. Pharmaceutical companies only showed an interest on L1 after it became clear that it would be a profitable financial venture.

It is estimated that more than 6000 patients in 40 countries have received L1 since the initiation of

Clinical use of L1

Many centres have reported the results of clinical trials since the first reports of the iron removal effects of L1 in transfusional iron loaded patients in 1987, all confirming the original findings that L1 is an effective, non-toxic, orally active chelator [28], [29], [43], [44], [45], [46], [47], [48], [49], [50], [51], [52], [53], [54], [55], [56]. Overall, L1 has so far been assessed in three different therapeutic areas of medicine, mainly for iron removal from iron-loaded patients,

Pharmacology of deferoxamine and deferiprone

DF is supplied in a vial as a freeze-dried solid of its mesylate salt, which is dissolved in water and administered with the aid of an electronic pump over an 8–12 h period. The rate of elimination of DF in blood is faster than L1 and depends on the route of administration. The half-life of elimination of i.v. DF is 5–10 min and im DF is 60 min. It is estimated that during the 8–12 h long s.c. DF administration, the elimination of DF is very fast and a plateau level in the plasma is achieved

Toxicity of deferiprone and deferoxamine

Most drugs have toxic side effects which may or may not be related to their pharmacological activity or toxicity findings in animals. A major aspect of toxicity in relation to iron chelation therapy is the removal or displacement of other essential metals. Two other iron chelating drugs namely DTPA and EDTA have been previously shown in iron-loaded patients to increase the excretion of Zn, Cu, Mn in addition to Fe resulting in toxic side effects. Increased excretion of Zn and Cu has also been

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