Iron Overload

Iron overload occurs when excess iron accumulates in the body. Those receiving iron therapy are vulnerable to iron overload as we lack major mechanisms for iron excretion (minor ones are cell desquamation and occult blood loss). Excess iron is deposited in body organs - pancreas, liver, pituitary and heart in particular- causing fibrosis and eventual organ failure.
Untransfused thalassaemics increase their dietary iron absorption by 2-5 g per year and with regular transfusions this increases to an excess of over 10 g of iron per year.¹

Iron overload occurs with:

• Hereditary haemochromatosis - this is a genetic condition where individuals show increased iron absorption and organ deposition. Untreated homozygotes tend to show signs and symptoms of significant iron overload by middle-age. Complications include diabetes mellitus, cirrhosis, cardiomyopathy and pituitary failure. Preferred treatment is with repeated venesection although some patients do require chelation therapy.
• Repeated red blood cell transfusions - from as little as 10 transfusions. It is a common problem in transfusion-dependent patients, for example, those with thalassaemia major, sickle cell disease and myelodysplastic syndromes.²

In those with refractory anaemias where repeated venesection is not an option, iron chelation can be used. Chelating agents form chelator-iron complexes which are then safely excreted in urine or via the stools. Desferrioxamine removes iron bound to ferritin and haemosiderin but not that bound to transferrin, haemoglobin, myoglobin or cytochromes.

Iron chelators currently in use:

Desferrioxamine mesilate³

• Important first-line treatment for chronic iron overload over the last 30 years. It is usually given subcutaneously over 8-12 hours, 3-7 times a week, often with a pump at night-time. It can also be given intramuscularly but this is painful or intravenously when a patient is receiving a blood transfusion, for example. It has led to significant life expectancy gains for those with conditions such as thalassaemia major.¹
• It is also used for the emergency treatment of iron poisoning in an overdose (see box below) and for the treatment of aluminium overload in dialysis patients.

Poor compliance with the demanding regimen associated with desferrioxamine and cardiac disease (from myocardial iron deposition) continuing to be the leading cause of death in young adults with thalassaemia major has lead to a drive to improve chelation therapies.⁴

Deferasirox (or ICL670)⁵

Is given orally. It has recently been licensed for the treatment of chronic iron overload in:

• Adults and children over 6 years with thalassaemia major who receive >7 ml/kg/month packed red cells.
• Adults and children over 2 years with thalassaemia major who receive infrequent transfusions but in whom desferrioxamine is contraindicated or inadequate.
• Adults and children with other anaemias in whom desferrioxamine is contraindicated or inadequate.

Deferipone⁶

Is also given orally.

• It has been available in Europe (although not the US) over the last decade and is licensed for treatment of iron overload in patients with thalassaemia major in whom desferrioxamine is contra-indicated or not tolerated.
• It has been used second-line due to its side-effect profile. Of particular concern has been its risk of agranulocytosis (0.5 cases per 100 patient years of treatment) and neutropenia (2.5 cases per 100 patient years) and risk of neurological disorders in children due to chronic overdosing.⁷
• It achieves a total iron excretion less than with desferrioxamine but appears to offer better cardioprotection - retrospective epidemiological data show reduced cardiac events and mortality rate in those receiving deferipone compared to desferrioxamine.⁸

New strategies have emerged involving combination therapy. Using desferrioxamine and deferipone together has advantages above monotherapy. Studies have shown progressive falls in serum ferritin, decreased myocardial iron and an improved ejection fraction in thalassaemia major patient with mild to moderate cardiac iron loading on combination therapy with improvements seen after as little as six months' treatment.^9,10

• Pregnancy - deferiprone is a significant teratogenic risk and contraception is advised for all women of child-bearing age receiving treatment. Desferrioxamine and deferasirox both show risks of teratogenicity in animal studies and should only be used in pregnancy where benefit of treatment outweighs risk.
• Breastfeeding - manufacturers advise avoiding deferiprone and deferasirox when breast feeding and only use desferrioxamine where potential benefit outweighs risk.
• Severe liver impairment - avoid defasirox.
• Renal impairment - avoid defasirox if baseline creatinine clearance is less than 60 ml/min.

• Monitor BP whilst giving desferrioxamine mesilate, slow infusion if hypotension develops.
• If giving desferrioxamine intravenously at the same time as a blood transfusion, do not add to the blood bag or use the same line.
• Iron excretion with desferrioxamine can be enhanced by co-administration, starting after one month's treatment with desferrioxamine, of ascorbic acid (200 mg od adults, 100 mg od infants). Give separately from food and avoid in those with cardiac impairment.
• Warn patients of red-brown urine discoloration associated with deferiprone.
• Adjust deferasirox dose according to creatinine clearance.

For desferrioxamine mesilate

• Eye and ear checks 3-monthly (risk of hearing and visual disturbance including lens opacity and retinopathy)
• Body-weight and height 3-monthly in children (risk of growth retardation especially in high dose)
• Liver function

For deferasirox

• Eye and ear checks 12-monthly
• Body-weight, height and sexual development 12-monthly in children
• Renal function weekly during the first month of treatment and monthly afterwards
• Liver function monthly
• Proteinuria tests monthly

For deferiprone

• Weekly neutrophil count
• Plasma zinc concentration
• Liver and renal function

With desferrioxamine mesilate¹²

• Iron overload patients are susceptible to infection and their use of desferrioxamine may increase the risk of certain infections, for example Yersinia enterocolitica. Stop therapy if symptoms of fever, pharyngitis, diffuse abdominal pain or enterocolitis. Resume after antibiotic treatment and clinical improvement.
• Stop drug if hearing or visual disturbance. Restart following recovery, depending on risk/benefit ratio with close monitoring.

With deferasirox⁵

• Stop if serum creatinine levels are more than a third higher than baseline levels on two consecutive tests. Reduce dose but stop permanently if raised creatinine persists after a dose reduction.

With deferiprone⁶

• Neutropenia and agranulocytosis are serious complication associated with deferiprone. Patients must be aware of potential signs and to see their doctor immediately if they develop sore throat or fever. If neutropenia is found (neutrophils<1.5/10⁹/L, treatment should be discontinued. Rechallenege is not recommended.⁷
• If GI disturbance develops, try reducing dose and then reincreasing slowly to improve tolerance.
• Stop if treatment causes a persistent rise in transaminase levels.
• Particular care with dosage in children receiving long term therapy is needed. Neurological disturbances have been reported in children who have received chronic overdose. These resolved when deferiprone was stopped.⁷