What is chelation therapy, including its administration methods, approved indications, and contraindications?

What is Chelation Therapy?

Chelation therapy is a medical treatment that uses chemical agents to bind and remove excess metals from the body, primarily indicated for transfusional iron overload in conditions like thalassemia and myelodysplastic syndromes, as well as acute heavy metal poisoning from lead, arsenic, and mercury. 1

Mechanism and Procedures

Chelation works through chemical binding where a ligand molecule with lone pairs of electrons forms ring-like complex structures with metal ions, allowing excretion from intracellular and extracellular spaces. 2, 3 The effectiveness depends on the chelator's denticity—the number of coordination sites it occupies on the metal ion. 1

Available Chelating Agents and Administration Methods

Three main iron chelators are FDA-approved:

• Deferoxamine (Desferal): A hexadentate ligand binding iron in 1:1 molar ratio, administered subcutaneously via portable pump over 8-14 hours for 5-7 days/week at 20-50 mg/kg/day, or by continuous IV infusion when intensive chelation is needed. 1

• Deferiprone: A bidentate ligand binding iron in 3:1 molar ratio, given orally three times daily at 75-100 mg/kg/day due to its short 1.5-2.5 hour half-life. 1, 4

• Deferasirox: Administered orally once daily at 20-40 mg/kg/day with approximately 90% fecal excretion. 1

For acute heavy metal poisoning, agents like 2,3-dimercaptosuccinic acid (DMSA) and dimercaptopropionic sulfonate (DMPS) are used, though hydrophilic chelators access intracellular metal deposits inefficiently. 2, 5

Approved Indications

Iron Overload Conditions

Chelation therapy is indicated for:

• Transfusion-dependent patients requiring ≥2 units/month for >1 year 1
• Ferritin levels >1,000 ng/mL 1
• Low-risk myelodysplastic syndrome (IPSS low or intermediate-1, WHO classifications RA, RARS, 5q-) 1
• β-thalassemia major with transfusional iron overload 1
• Patients with life expectancy ≥1 year without comorbidities limiting prognosis 1
• Allograft candidates to reduce transplant-related morbidity and mortality 1
• Patients requiring organ function preservation 1

Heavy Metal Poisoning

Chelation is the preferred treatment for reducing toxic effects of lead, arsenic, and mercury intoxications. 2, 3

Duration of Therapy

Chelation should continue as long as the patient requires transfusion therapy and iron overload remains clinically relevant, discontinuing when ferritin declines to <1,000 ng/mL without additional transfusions needed. 1

Contraindications and Important Limitations

Absolute Contraindications

• Hypersensitivity to deferiprone or formulation excipients 4
• **Life expectancy <1 year** (unless organ preservation is immediately warranted, as iron complications take >1 year to manifest) 1

Specific Contraindications by Condition

Chelation therapy is NOT recommended for:

• Atherosclerotic cardiovascular disease: The ACC/AHA provides a Class III: No Benefit recommendation for claudication in peripheral artery disease and uncertain benefit for stable ischemic heart disease, with significant risks including hypocalcemia, renal failure, and death. 6

• Chronic cadmium exposure: Chelation is ineffective due to cadmium's 10-30 year biological half-life. 7

• Chronic heavy metal toxicity with prolonged chelation: The American College of Cardiology recommends immediate discontinuation as prolonged chelation causes severe zinc and essential mineral depletion. 7

Relative Contraindications and Cautions

Avoid co-administration with:

• Drugs associated with neutropenia or agranulocytosis (if unavoidable, closely monitor ANC) 4
• UGT1A6 inhibitors 4
• Polyvalent cations (iron, aluminum, zinc)—maintain ≥4-hour interval 4

Critical Safety Monitoring

Mandatory Monitoring for Deferiprone

Due to risk of agranulocytosis (0.6-4% of patients) that can lead to serious infections and death:

• Measure absolute neutrophil count (ANC) before starting therapy 4
• Monitor ANC regularly throughout treatment 4
• Interrupt therapy if neutropenia develops 4
• Interrupt if infection develops and increase ANC monitoring frequency 4
• Patients must report any infection symptoms immediately 4

Monitoring for All Iron Chelators

• Serum ferritin and transferrin saturation for iron overload monitoring 1
• Serum ferritin every 3 months in transfusion-dependent patients 1
• Liver enzymes monthly—discontinue for persistent elevations 1
• Zinc levels—supplement if deficiency develops 1, 7
• Ophthalmologic and audiological testing for deferoxamine (risk of sensorineural deafness and visual disturbances) 1
• Growth monitoring in pediatric patients 1
• Renal function (creatinine monitoring for deferasirox) 1

Deferoxamine-Specific Risks

Serious adverse events occur particularly at higher doses relative to iron burden, including local infusion-site reactions, Yersinia and Klebsiella infections, renal toxicity, and acute respiratory distress syndrome with excessively high IV doses. 1

Common Pitfalls to Avoid

Never use excessive deferoxamine dosages (mean daily dose should not exceed 40 mg/kg) to prevent growth retardation, sensorineural ototoxicity, ocular toxicity, and bone deformities. 8

Do not use chelation for cardiovascular disease—the FDA has only approved EDTA for iron overload and lead poisoning, not for ASCVD, where proven therapies like beta-blockers, ACE inhibitors, and statins should be used instead. 6

Avoid NSAIDs in cadmium toxicity as they exacerbate cadmium-related renal dysfunction. 7

Monitor for essential metal depletion—metal selectivity is crucial to prevent depletion of essential metals during long-term chelation. 5