Chelation Therapy for Iron Overload

Chelation therapy removes excess iron after repeated transfusion or in non-transfusion-dependent states, preventing cardiac, hepatic and endocrine damage. It is started when the body iron burden reaches a threshold (about 10 to 20 transfusions, serum ferritin over 1000 micrograms/L, or liver iron concentration over 7 mg/g dry weight). Drugs are deferoxamine, deferiprone and deferasirox.

Mechanism. Chelators bind free and labile iron, forming a complex excreted in urine (deferoxamine, deferiprone) or bile (deferasirox). Combination therapy gives additive removal and clears cardiac iron.

Pharmacokinetics. Deferoxamine has a half-life of 20 minutes and needs prolonged infusion. Deferiprone half-life 2 to 3 hours. Deferasirox half-life 8 to 16 hours, allowing once-daily oral dosing.

Titration. Adjust every 3 to 6 months in line with the ferritin trend (aim for ferritin under 1000 micrograms/L and falling), liver iron and cardiac T2* by magnetic resonance imaging. Reduce the dose when ferritin falls under 500 micrograms/L to avoid overchelation.

Intensive chelation. Cardiac iron or heart failure: continuous deferoxamine 50 to 60 mg/kg over 24 hours by central line, with or without deferiprone, in a specialist centre.

Acute iron poisoning. Deferoxamine 15 mg/kg/h intravenously for severe poisoning (shock, coma, acidosis); stop when the patient is well and urine colour returns to normal.

• First-line. Deferasirox for adults and children over 2 years (oral, once daily); deferoxamine for children under 2 years and when oral drugs are unavailable or not tolerated.
• Alternative. Deferiprone for thalassaemia major when other chelators are inadequate (cardiac iron benefit).
• Specialist. Combination deferoxamine and deferiprone for severe cardiac siderosis; non-transfusion-dependent thalassaemia (deferasirox at lower dose); myelodysplastic syndrome.
• Emergency. Acute iron poisoning; cardiac failure from iron overload.

Selection. Choose by age, adherence, organ iron burden and access. Deferasirox is easiest for adherence; deferiprone best for cardiac iron; deferoxamine remains the choice when others are unavailable.

Contraindications. Deferiprone: neutropenia or agranulocytosis history, pregnancy. Deferasirox: creatinine clearance under 40 mL/min, severe liver impairment, high-risk myelodysplasia with low platelets, advanced malignancy. Deferoxamine: hypersensitivity, anuria.

Serious adverse effects.

• Deferoxamine: injection-site reactions, high-frequency hearing loss, retinal and visual toxicity, growth retardation in young children at high doses, Yersinia infection (stop during fever and diarrhoea).
• Deferiprone: agranulocytosis (about 1%) and neutropenia, joint pain, gastrointestinal upset.
• Deferasirox: renal impairment, proteinuria, Fanconi-like syndrome, liver injury, gastrointestinal haemorrhage, rash.

Major interactions. Deferasirox with NSAIDs, bisphosphonates and other nephrotoxins (renal and gastrointestinal harm); aluminium antacids; deferiprone with other drugs causing neutropenia; vitamin C over 200 mg daily with deferoxamine in iron-overloaded patients with cardiac disease.

Common prescribing errors.

• Starting deferiprone without a baseline count and weekly monitoring.
• Not adjusting deferasirox for falling creatinine clearance.
• Overchelation in patients with low iron burden.
• Missing nightly deferoxamine because of pump burden.
• Continuing deferoxamine during febrile illness.

Special groups.

• Pregnancy: stop deferiprone and deferasirox; deferoxamine can be used in late pregnancy if needed.
• Breastfeeding: avoid.
• Children: deferasirox from 2 years; deferoxamine under 2 years; growth and hearing monitoring.
• Older adults: reduce deferasirox dose; monitor renal function.
• Kidney: avoid deferasirox under 40 mL/min; adjust deferoxamine.
• Liver: reduce or avoid deferasirox in moderate or severe impairment.
• East Africa: thalassaemia is less frequent than sickle cell disease, but repeated transfusion in sickle cell disease, malaria-related anaemia and marrow failure can cause overload; ferritin may be raised by infection and inflammation, so interpret with care.

Monitoring. Ferritin every 3 months; liver iron and cardiac T2* yearly; full blood count weekly with deferiprone; serum creatinine and urine protein monthly (deferasirox); liver enzymes monthly; audiology and eye examination yearly.

Referral and escalation. Cardiac siderosis or heart failure; neutrophils under 1.5 x 10^9/L; creatinine rise over 33% from baseline; hearing or visual loss; failure to reduce ferritin.

Comparison with alternative classes. Chelation removes iron without further blood loss, unlike venesection, which suits non-anaemic overload such as haemochromatosis. Deferasirox improves adherence, while deferoxamine has the longest safety record.