Latest advances in iron chelation therapy

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A Victor Hoffbrand
DM FRCP FRCPath Dsc
Emeritus Professor of Haematology
Royal Free Hospital
and University Collefe Medical School
London
UK
E:[email protected]

Patients with refractory anaemias who require regular blood transfusions become iron overloaded. Each unit of blood contains 200�250mg of iron for which the body has no mechanism of excretion. When over 50-100 units have been transfused, excess iron damages the liver, the endocrine organs and, most importantly, the heart. Death from cardiac failure or arrhythmia is likely. Chelation therapy aims at reducing this iron burden by promoting iron excretion in the urine or faeces, or both. The most common condition worldwide requiring iron chelation therapy is beta-thalassaemia major, but a proportion of patients with other inherited anaemias (eg, sickle cell anaemia) or with acquired transfusion-dependent anaemias (eg, myelodysplasia, myelofibrosis or aplastic anaemia) also require iron chelation therapy. Three iron-chelating drugs, deferoxamine, deferiprone and deferasirox, are now available within the European Union (see Table 1). These are discussed in the order of their historical introduction into clinical practice.

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Deferoxamine
Deferoxamine (DFO) is inactive by mouth, but it has been the mainstay of iron-chelating treatment since regular subcutaneous infusion therapy with DFO was introduced in 1976.(1,2) DFO is the only drug licensed for all indications. It is usually given by slow daily subcutaneous infusion over 8-12 hours on at least five nights each week. It has increased substantially the life expectancy for thalassaemia major patients who comply with this demanding schedule. It may also be given by continuous intravenous infusion to try and reverse cardiac failure when previous chelation has failed. There are, however, a number of drawbacks with its use. Many patients do not comply with the regimen of self-administered daily infusions and so develop clinical problems due to iron overload, usually dying of cardiac failure. Even in those who do comply, cardiac and endocrine abnormalities such as diabetes mellitus, growth failure, delayed puberty, hypothyroidism or hypoparathyroidism may occur. The cost of the drug and of the infusion pump, tubing and needles needed for its administration preclude its use in many poor countries. Disposable prefilled infusions designed to give 24 or 48 hours continuous therapy increase compliance but also costs. Side-effects may occur, and these are particularly marked in those with a low iron burden and may require discontinuation of the drug (see Table 1).

Deferiprone
Deferiprone was introduced into clinical practice in 1987.(3-5) It was the first iron chelator to be effective when given by mouth. It is now licensed for patients for whom DFO for whatever reason is unsatisfactory. Three molecules are needed to bind one atom of iron. It is metabolised to a glucuronide derivative that is incapable of binding iron. Individual variation in the speed of glucuronidisation partly accounts for the wide range of response. The standard total dose is 75mg/kg body weight each day, divided into three approximately equal subdoses taken at 6-8 hourly intervals. Doses up to 100mg/kg have been less well studied but seem equally safe and usually more effective. Deferiprone has a low molecular weight and so penetrates into cells, including cardiac cells, more efficiently than DFO. Data obtained by magnetic resonance imaging (MRI) using the T(2)(*) technique to measure cardiac iron show that the drug is superior to DFO at removing iron from the heart.(6) This beneficial effect on the heart is also shown by improved cardiac function (eg, left ventricular ejection fraction in patients receiving the drug for one year or more). In Italy,(7) the UK and Cyprus,(8) its use has been associated with a substantial reduction in iron-induced cardiac damage and mortality.

Combined therapy in which deferiprone is given daily and DFO on a few days each week has been found to be effective in patients for whom either drug alone, for whatever reason, is inadequate.(9) Patients will often comply well with only one or two days each week of DFO infusions.(6-8) The drugs may be given on the same day with at least an additive effect on iron excretion. No data suggest any increase in toxicity of either drug when they are given together.(10,11) The most important side-effect of deferiprone is agranulo cytosis, which occurs in about 1% of thalassaemia major patients, with milder degrees of neutropenia in a further few patients. Weekly complete blood count is required. The falls in neutrophil counts recover spontaneously once the drug is discontinued. Females are more frequently affected. Whether the incidence of agranulocytosis is the same in patients with myelodysplasia and other causes of refractory anaemia, such as in thalassaemia major, is unknown. Arthropathy is another side-effect, the incidence being higher in Indian compared with European patients.

Deferasirox
Deferasirox (ICL 670, Exjade(R)), an iron chelator, causes iron excretion solely by the faecal route.(12) It has a long plasma half-life, so a once-daily dose is used. A recent phase III pivotal study in 290 patients showed that, at doses of 20-30mg/kg weight daily, the drug is effective at reducing serum ferritin and liver iron concentration in thalassaemia major patients receiving regular blood transfusions.(12) It is generally well tolerated, with minor skin rashes, transient rises in liver enzymes and gastrointestinal symptoms being the most frequent side-effects. A mild, nonprogressive rise in serum creatinine occurred in 34-36% of the studied patients. This rise in creatinine is transient despite continuation of the drug at the same dose.(12) Only preliminary data are available concerning the effects of deferasirox on cardiac iron. In-vitro data suggest that it is capable of removal of iron from myocytes, and preliminary clinical data are consistent with this.

References

1. Mourad FH, Hoffbrand AV,Sheikh-Taha M, et al. Comparison between desferrioxamine and combined therapy with desferrioxamine and deferiprone in iron overloaded thalassemia patients.Br J Haematol 2003 121;187-9.
2. Piga A, Gaglioti C, Fogliacco E,Tricta F. Comparative effects of deferiprone and desferrioxamine on survival and cardiac disease in patients with thalassemia major: a retrospective analysis. Haematologica 2003:88;489-96.
3. Anderson LJ, Wonke B, Prescott E,et al. Comparative effects of oral deferiprone and subcutaneous desferrioxamine on myocardial iron concentrations and ventricular function in beta-thalassaemia.Lancet 2002 360;516-20.
4. Hoffbrand AV. Deferiprone therapy for transfusional iron overload.Clin Haematol 2005;18;299-318.
5. Taher A, Sheikh-Taha M, Sharara A,et al. Safety and effectiveness of 100mg/kg/day deferiprone in patients with thalassemia major: a two-year study.Acta Haematol 2005;114;146-9.
6. Pennell DJ, Berdoukas V, Karagiorga M, et al. Randomized controlled trial of deferiprone or deferoxamine in beta-thalassemia major patients with asymptomatic myocardial siderosis.Blood 2006;107:3738-44.
7. Borgna-Pignatti C, Cappellini MD,De Stefano P, et al. Cardiac morbidity and mortality in deferoxamine or deferiprone treated patients with thalassemia major. Blood 2006;107:3733-7.
8. Telfer P, Coen PG, Christou S, et al. Survival in medically treated thalassemia patients in Cyprus. Trends and risk factors over the period 1980-2004. Haematologica 2006;91:1187-92.
9. Wonke B, Wright C, Hoffbrand AV. Combined therapy with deferiprone and desferrioxamine. Br J Haematol 1998;103:361-4.
10. Kattamis A, Ladis V, Berdousi H, et al. Iron chelation treatment with combined therapy with deferiprone and deferioxamine: a 12-month trial.Blood Cells Mold Dis 2006;36:21-5.
11. Galanello R, Kattamis A, Piga A,et al. A prospective randomized controlled trial on the safety and efficacy of alternating deferoxamine and deferiprone in the treatment of iron overload in patients with thalassemia. Haematologica 2006;91:1241-3.
12. Cappellini MD, Cohen A, Piga A, et al. A phase III study of deferasirox (ICL 670), a once-daily oral iron
    chelator, in patients with β-thalassemia. Blood 2006;107:3455-62.