What is the role of iron binding cap (iron chelation therapy) in treating iron overload?

Iron Chelation Therapy for Iron Overload

Iron chelation therapy is the definitive treatment for secondary iron overload when phlebotomy is not feasible, particularly in patients with transfusion-dependent anemias, dyserythropoietic syndromes, or chronic hemolytic anemia. 1

Primary Indication: When Phlebotomy Cannot Be Used

Phlebotomy remains the first-line treatment for hereditary hemochromatosis (HH) and should be used whenever possible. 1 Iron chelation is reserved for specific scenarios where phlebotomy is contraindicated or impossible:

Absolute Indications for Chelation Therapy

• Transfusion-dependent anemias with ineffective erythropoiesis (β-thalassemia major, myelodysplastic syndromes, sickle cell disease on chronic transfusion programs) where phlebotomy would worsen anemia 1
• Dyserythropoietic syndromes or chronic hemolytic anemia with documented iron overload 1
• Patients being considered for allogeneic stem cell transplantation with elevated iron stores, as chelation reduces transplant-related hepatic complications and mortality 1

Initiation Criteria

Start chelation therapy when patients meet all of the following:

• ≥20 red blood cell transfusions received (approximately 25 units) 1, 2, 3
• Serum ferritin ≥1,000-2,500 ng/mL 1, 2, 3
• Ongoing transfusion requirements anticipated 1, 2
• Life expectancy ≥1 year (iron-related organ damage takes >1 year to manifest) 1
• Low or intermediate-1 risk disease (for MDS patients, as they have median survival >100 months and are prone to long-term iron toxicity) 1, 3

Available Iron Chelating Agents

Deferoxamine (Parenteral - First Generation)

• Administered via continuous subcutaneous infusion at 40 mg/kg/day for 8-12 hours nightly, 5-7 nights weekly 1
• Maximum dose approximately 2 g per 24 hours achieves maximal urinary iron excretion 1
• Preferred agent for severe cardiac iron overload or acute cardiac decompensation: use continuous IV at 50-60 mg/kg/day 2, 4
• Major limitations: parenteral route, discomfort, inconvenience, cost, and potential neurotoxicity 1
• Proven efficacy: numerous studies document prevention of iron overload complications in β-thalassemia 1

Deferasirox (Oral - FDA Approved)

• Initial dose: 20-40 mg/kg/day once daily (calculated to nearest whole tablet) for patients with eGFR >60 mL/min/1.73 m² 2, 5
• Provides 24-hour chelation coverage, most appropriate for long-term maintenance therapy in stable patients 2
• FDA Black Box Warnings: acute renal failure, hepatic failure, and gastrointestinal hemorrhage 2, 5
• Contraindications: eGFR <40 mL/min/1.73 m², poor performance status, high-risk MDS, advanced malignancies, platelet count <50 × 10⁹/L 5
• Common adverse events: diarrhea, vomiting, nausea, abdominal pain, skin rashes, increased serum creatinine 5

Deferiprone (Oral - FDA Approved)

• Dose: 75-100 mg/kg/day divided into three daily doses 2, 4, 6
• Preferred agent for cardiac iron overload or established heart failure, demonstrating superior cardiac iron clearance compared to other chelators 2, 3, 4
• FDA Black Box Warning: agranulocytosis and neutropenia (0.6-4% of patients) 6, 7
• Mandatory weekly neutrophil monitoring due to agranulocytosis risk 2, 4, 6
• Other adverse effects: arthritis (requiring cessation in up to 30% of patients), nausea 7

Treatment Algorithm by Clinical Scenario

For Stable Transfusion-Dependent Patients

Start with deferasirox 20-40 mg/kg/day once daily for long-term maintenance 2, 5

For Cardiac Iron Overload (T2* <20 ms)

Initiate deferiprone 75-100 mg/kg/day in three divided doses 2, 4

For Acute Cardiac Decompensation

Start continuous IV deferoxamine 50-60 mg/kg/day immediately, consider adding deferiprone 75 mg/kg/day 2, 4

For Severe Iron Overload or Inadequate Response

Combination therapy with deferasirox plus deferoxamine OR deferiprone plus deferoxamine shows enhanced efficacy 2, 4

Monitoring Requirements

Before Initiating Therapy

• Measure serum creatinine in duplicate (baseline renal function) 2, 5
• Obtain baseline liver function tests 2, 5
• Assess cardiac function with T2 MRI* in transfusion-dependent patients 2
• Measure liver iron concentration by MRI 2

During Therapy

• Serum ferritin every 3 months (monthly if possible), target <1,000 ng/mL 1, 2, 4
• Serum creatinine and liver function tests monthly (for deferasirox) 2, 5
• Weekly complete blood count with absolute neutrophil count (for deferiprone) 2, 4, 6
• Cardiac T2 MRI annually* starting at age 10 in transfusion-dependent patients 2, 4
• Liver iron concentration by MRI annually 2

Treatment Goals

• Target serum ferritin: 50-100 μg/L for HH (if chelation used) 1
• Target serum ferritin: <1,000 ng/mL for secondary iron overload 1, 2, 4
• Reduce hepatic iron concentration to <15,000 μg/g dry weight to significantly reduce risk of clinical disease 1

Critical Pitfalls and Safety Considerations

Deferasirox-Specific Warnings

• Avoid in patients with marginal renal perfusion or acute heart failure 3
• Risk particularly high in patients with multiple comorbidities and advanced hematologic disorders 2, 5
• Monitor for gastrointestinal hemorrhage, especially when combined with drugs having ulcerogenic or hemorrhagic potential 2, 5

Deferiprone-Specific Warnings

• Contraindicated in pregnancy 2, 6
• Interrupt therapy immediately if infection develops and monitor ANC more frequently 6
• Avoid co-administration with drugs associated with neutropenia or agranulocytosis 6
• Allow at least 4-hour interval between deferiprone and polyvalent cations (iron, aluminum, zinc supplements) 6

Deferoxamine-Specific Warnings

• Excessive dosages (>40 mg/kg mean daily dose) may cause: growth retardation, sensorineural ototoxicity, ocular toxicity, bone deformities 7
• Adjust dosage based on degree of iron overload using therapeutic index 7

Duration of Therapy

• Continue chelation as long as patient requires transfusion therapy and iron overload remains clinically relevant 1
• Withhold when ferritin declines to <1,000 ng/mL and no additional transfusions needed 1
• Cardiac iron removal requires several years of intensive chelation even after resolution of acute cardiac failure 3, 4

When NOT to Use Chelation

• Hereditary hemochromatosis: phlebotomy is first-line treatment 1
• Mild secondary iron overload in chronic hepatitis C (HIC <2,500 μg/g dry weight): phlebotomy not recommended, chelation not indicated 1
• Alcoholic liver disease: no published evidence of benefit from phlebotomy or chelation 1
• Life expectancy <1 year (unless already showing iron-related organ complications requiring preservation) 1