Iron-chelating therapy and the treatment of thalassemia

The UK Thalassaemia Register records births, deaths and selected clinical data of patients with thalassaemia who are resident in the UK. A study of survival and causes of death was undertaken which aimed to include the possible impact of T2* cardiovascular magnetic resonance (CMR). The Register was updated to the end of 2003, copies of death certificates were obtained, and causes of death in beta thalassaemia major were extracted. In addition, patients who had T2* CMR assessment of cardiac iron load and/or received the oral iron chelator deferiprone were identified from clinical records. The main causes of death were anaemia (before 1980), infections, complications of bone marrow transplantation and cardiac disease due to iron overload. From 1980 to 1999 there were 12.7 deaths from all causes per 1,000 patient years. Forty per cent of patients born before 1980 had T2* cardiovascular magnetic resonance between 2000 and 2003, and 36% of these patients were prescribed deferiprone before end of 2003. In 2000–2003, the death rate from all causes fell significantly to 4.3 per 1,000 patient years (-62%, p < 0.05). This was mainly driven by the reduction in the rate of deaths from iron overload which fell from 7.9 to 2.3 deaths per 1,000 patient years (-71%, p < 0.05). Since 1999, there has been a marked improvement in survival in thalassaemia major in the UK, which has been mainly driven by a reduction in deaths due to cardiac iron overload. The most likely causes for this include the introduction of T2* CMR to identify myocardial siderosis and appropriate intensification of iron chelation treatment, alongside other improvements in clinical care.

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Improved survival of thalassaemia major in the UK and relation to T2* cardiovascular magnetic resonance

Protection against tissue damage in vivo by desferrioxamine: what is its mechanism of action?

The practical management of iron overload requires reliable estimation of body iron content and distribution as well as an understanding of how iron overload translates into clinical consequences. In this article, it will be seen that our ability to estimate the distribution of excess tissue iron, to predict its consequences and therefore to tailor treatment accordingly is surprisingly imprecise. Our understanding of how iron chelators best prevent these consequences is also limited. It will be seen that the safest and most effective ways of removing excess iron vary depending on the degree and rate of iron loading as well as the underlying condition being treated. Evidence of benefit in survival with chelation treatment takes many years to emerge and currently only exists for thalassaemia major patients treated with desferrioxamine. Long-term survival benefits have not been demonstrated in other iron-overloaded conditions or with other chelation regimens. In such circumstances, practical treatment protocols are necessarily based on inference rather than direct evidence.

https://onlinelibrary.wiley.com/doi/pdf/10.1046/j.1365-2141.2001.03195.x

Practical management of iron overload

Iron is the most abundant transition metal within the brain, and is vital for a number of cellular processes including neurotransmitter synthesis, myelination of neurons, and mitochondrial function. Redox cycling between ferrous and ferric iron is utilized in biology for various electron transfer reactions essential to life, yet this same chemistry mediates deleterious reactions with oxygen that induce oxidative stress. Consequently, there is a precise and tightly controlled mechanism to regulate iron in the brain. When iron is dysregulated, both conditions of iron overload and iron deficiencies are harmful to the brain. This review focuses on how iron metabolism is maintained in the brain, and how an alteration to iron and iron metabolism adversely affects neurological function.

/pdf/a-delicate-balance-iron-metabolism-and-diseases-of-the-brain-1jetrk8702.pdf

A delicate balance: Iron metabolism and diseases of the brain

The main iron chelator used for transfusional iron overload is desferrioxamine, which is expensive, has toxic side effects, and has to be given subcutaneously. An orally active iron chelator is therefore required. The effects of oral 1,2-dimethyl-3-hydroxypyrid-4-one on urinary iron excretion were studied in eight patients who had received multiple transfusions: four had myelodysplasia and four beta thalassaemia major. Different daily doses of the drug up to 100 mg/kg/day, alone or in combination with ascorbic acid, were used. In three patients with thalassaemia the effect of the drug was compared with that of subcutaneous desferrioxamine at the same daily dose. In all eight patients a single dose of oral 1,2-dimethyl-3-hydroxypyrid-4-one resulted in substantial urinary iron excretion, mainly in the first 12 hours. Urinary iron excretion increased with the dose and with the degree of iron loading of the patient. Giving two or three divided doses over 24 hours resulted in higher urinary iron excretion than a single dose of the same amount over the same time. In most patients coadministration of oral ascorbic acid further increased urinary iron excretion. 1,2-Dimethyl-3-hydroxypyrid-4-one caused similar iron excretion to that achieved with subcutaneous desferrioxamine at a comparable dose. In some cases the iron excretion was sufficiently high (maximum 99 mg/day) to suggest that a negative iron balance could be easily achieved with these protocols in patients receiving regular transfusions. No evidence of toxicity was observed on thorough clinical examination or haematological and biochemical testing in any of the patients. None of the patients had any symptoms that could be ascribed to the drug. These results suggest that the oral chelator 1,2-dimethyl-3-hydroxypyrid-4-one is as effective as subcutaneous desferrioxamine in increasing urinary iron excretion in patients loaded with iron. Its cheap synthesis, oral activity, and lack of obvious toxicity at effective doses suggest that it should be developed quickly and thoroughly tested for the management of transfusional iron overload.

T Kourouclaris

Papers

Effective chelation of iron in beta thalassaemia with the oral chelator 1,2-dimethyl-3-hydroxypyrid-4-one.