What is the recommended regimen for iron chelation therapy?

Iron Chelation Therapy Regimen

For acute heart failure in β-thalassemia major, immediately initiate continuous 24-hour intravenous deferoxamine at 50 mg/kg/day combined with oral deferiprone 75 mg/kg/day in three divided doses; for chronic transfusional iron overload without cardiac complications, start chelation when serum ferritin reaches ≥1000 ng/mL or after 20 red blood cell transfusions, using deferasirox 20-30 mg/kg/day as first-line oral therapy or deferoxamine 40-50 mg/kg/day subcutaneously 5-7 nights weekly. 1, 2

Clinical Context Determines Regimen Selection

Acute Cardiac Iron Overload with Heart Failure

Emergency management requires dual chelation therapy started immediately upon presentation. 1

• Deferoxamine: 50 mg/kg/day as continuous 24-hour intravenous infusion (uninterrupted) 1
• Deferiprone: Add 75 mg/kg/day orally in 3 divided doses as soon as possible after starting deferoxamine 1
• Duration: Continue for several years until cardiac T2* normalizes and left ventricular function recovers, even after clinical stabilization 1
• Monitoring: Continuous electrocardiographic and hemodynamic monitoring required; clinical stabilization may occur within 14 days but can take months 1

Critical caveat: Deferasirox should NOT be used in acute heart failure or marginal renal perfusion 1, 2. The prospective risk of developing heart failure is 47% within 1 year if cardiac T2* is <6 ms, with a relative risk 270 times higher than patients with T2* >10 ms 1, 2.

Chronic Transfusional Iron Overload (Non-Cardiac)

Initiation criteria (start when ANY of these thresholds are met):

• Serum ferritin ≥1000 ng/mL 1, 2
• After receiving ≥20 red blood cell transfusions 1, 2
• Transfusion requirement ≥2 units/month sustained for >1 year 1
• Cardiac T2* <20 ms on MRI (indicating cardiac iron accumulation) 1, 2

First-line oral chelation options:

Deferasirox (preferred for most patients):

• Starting dose: 20 mg/kg/day for patients receiving 2-4 packed red blood cell units/month 3
• Dose adjustment: 10 mg/kg/day if receiving <2 units/month; 30 mg/kg/day if receiving >4 units/month 3
• Titration: Adjust every 3 months based on serum ferritin trends and safety markers 4, 3
• Maximum dose: 40 mg/kg/day 5, 6
• Administration: Once daily as dispersible tablets; can be taken with or without food 4

Deferoxamine (parenteral alternative):

• Subcutaneous route: 40-50 mg/kg/day over 8-12 hours, 5-7 nights weekly using battery-operated pump 1, 5, 7
• Intravenous route: 40-50 mg/kg/day over 8-12 hours at rate up to 15 mg/kg/hour, 5-7 days weekly 5
• Maximum dose: 60 mg/kg/day in adults; 40 mg/kg/day in pediatric patients 5
• Intramuscular route: 500-1000 mg/day (maximum 1000 mg/day) - less commonly used 5

Deferiprone (oral alternative):

• Dose: 75-100 mg/kg/day in 3 divided doses 8, 6
• Timing: Morning, midday, and evening doses; taking with meals may reduce nausea 8
• Pediatric use: Demonstrated non-inferiority to deferasirox in children aged 1 month to 18 years 6

Combination Therapy for Severe Iron Overload

For patients with cardiac T2 between 6-10 ms or impaired left ventricular function without decompensated heart failure:*

• Daily subcutaneous deferoxamine (40-50 mg/kg/day) PLUS daily oral deferiprone (75 mg/kg/day) - both drugs taken together every day 1, 2
• This combination has been used extensively for long-term management and provides additive iron excretion 1, 7

Special Population Considerations

Pre-transplant patients:

• Start chelation early regardless of ferritin level, as even moderate iron overload increases transplant-related mortality 1, 2
• Iron overload before allogeneic stem cell transplant significantly worsens outcomes 1

Myelodysplastic syndromes (lower-risk):

• Initiate chelation when serum ferritin ≥1000 ng/mL in patients with low or intermediate-1 risk disease 1
• Strongly recommended for transplant candidates and those with cardiac T2* reduction 1
• More controversial in non-transplant candidates without major organ iron loading 1

Hemochromatosis:

• Phlebotomy is preferred over chelation when feasible 1
• Deferoxamine 40 mg/kg/day subcutaneously if phlebotomy contraindicated 1

Monitoring Protocol

Frequency of assessments:

• Serum ferritin: Every 3 months minimum (monthly if possible) in all transfusion-dependent patients 1, 2
• Cardiac MRI T2:* Regular intervals to monitor cardiac iron; improves over months with treatment 1, 2
• Left ventricular ejection fraction: Can improve substantially within weeks of intensive chelation 1
• Liver iron concentration: Monitor to prevent chelator-mediated toxicity 1

Safety monitoring specific to each chelator:

• Deferasirox: Monthly renal function, hepatic function, and complete blood count 1, 2
• Deferiprone: Weekly absolute neutrophil count due to agranulocytosis risk 8, 6
• Deferoxamine: Audiological and ophthalmological review prior to starting and annually thereafter 9

Treatment Goals

Target endpoints:

• Maintain serum ferritin <1000 ng/mL 1, 2
• Achieve cardiac T2* >20 ms (ideally >10 ms to minimize heart failure risk) 1, 2
• Reduce liver iron concentration to <7 mg Fe/g dry weight (ideally <15 mg Fe/g dry weight to prevent tissue damage) 1, 7
• Prevent or reverse organ dysfunction, particularly cardiac and hepatic complications 1, 2

Duration of therapy:

• Lifelong in transfusion-dependent conditions 6
• Several years minimum after cardiac iron overload, even with clinical improvement 1
• Cardiac iron removal is extremely slow; treatment continuation for years is essential even after acute heart failure resolution 1, 2

Adjunctive Vitamin C Supplementation

Vitamin C enhances iron availability for chelation but should be used cautiously:

• Start only after initial month of regular deferoxamine treatment 5
• Adult dose: Up to 200 mg daily in divided doses 5
• Pediatric dose: 50 mg daily for children <10 years; 100 mg daily for older children 5
• Larger doses do not increase iron excretion 5

Common Pitfalls to Avoid

Do not use deferasirox in:

• Acute heart failure or decompensated cardiac status 1, 2
• Marginal renal perfusion or renal failure 1

Do not delay chelation:

• Compliance with iron chelation is essential for long-term survival after acute cardiac failure 1
• Without escalation in therapy, cardiac T2* <6 ms carries 47% risk of heart failure within 1 year 1, 2

Avoid aggressive inotropic therapy:

• In thalassemia major patients with heart failure, aggressive inotropes can be detrimental 1
• Focus on maintaining cerebral and renal perfusion 1

Monitor for drug-specific toxicities:

• Deferiprone: agranulocytosis (2% incidence), arthropathy, gastrointestinal symptoms 7, 6
• Deferasirox: gastrointestinal disturbances (28%), skin rash (10%), renal dysfunction 10, 4
• Deferoxamine: neurotoxicity, local injection site reactions 1, 7