What is iron chelation therapy for a patient with beta thalassemia major?

Iron Chelation Therapy in Beta Thalassemia Major

Iron chelation therapy is a life-saving treatment that uses medications to bind and remove excess iron accumulated from chronic blood transfusions in patients with beta thalassemia major, preventing fatal organ damage—particularly cardiac failure, which historically caused 70% of deaths in these patients. 1

Why Iron Chelation is Essential

• Patients with beta thalassemia major require regular blood transfusions to survive, but each transfusion introduces approximately 200-250 mg of iron that the body cannot naturally eliminate 1
• Without chelation therapy, iron accumulates in vital organs—especially the heart, liver, and endocrine glands—causing irreversible damage and death, typically by age 10 in unchelated patients 1
• The heart is particularly vulnerable to iron toxicity, and cardiac iron overload remains the leading cause of death even in the modern chelation era 1

The Three Available Iron Chelators

Deferoxamine (Parenteral Administration)

• Administered subcutaneously at 20-50 mg/kg/day via portable pump over 8-14 hours for 5-7 days per week, or as continuous intravenous infusion at 50 mg/kg/day when intensive chelation is needed 1, 2
• Has a very short plasma half-life of 30 minutes, requiring prolonged infusion for effectiveness 3
• Remains the gold standard for acute cardiac decompensation requiring immediate intensive chelation 1

Deferiprone (Oral Administration)

• Administered orally at 75-100 mg/kg/day divided into three daily doses due to its short half-life of 1.5-2.5 hours 2, 4
• Deferiprone is the preferred agent for patients with cardiac iron overload (T2 <20 ms) or established heart failure because it demonstrates superior cardiac iron clearance compared to other chelators* 1, 2
• FDA-approved for transfusional iron overload in thalassemia syndromes when current chelation therapy is inadequate 4

Deferasirox (Oral Administration)

• Administered orally at 20-40 mg/kg/day once daily as dispersible tablets dissolved in water or juice at least 30 minutes before meals 2
• Has a longer elimination half-life of 8-16 hours, allowing once-daily dosing 2
• Offers superior convenience for maintenance therapy in stable patients without cardiac involvement 2
• Should NOT be used in acute heart failure or patients with marginal renal perfusion 1, 2

When to Start Chelation Therapy

• Initiate chelation after approximately 20 red blood cell transfusions OR when serum ferritin reaches ≥1000 ng/mL 5, 3
• Earlier initiation should be considered for potential hematopoietic stem cell transplant candidates, as moderate iron overload before transplantation increases transplant-related mortality 5, 3
• Any patient with cardiac T2 <20 ms on MRI requires immediate intensification of iron chelation therapy regardless of other parameters* 2, 3

Treatment Selection Algorithm

For Acute Cardiac Decompensation or Heart Failure:

1. Immediately commence 24-hour continuous intravenous deferoxamine at 50 mg/kg/day 1
2. Introduce deferiprone as soon as possible at 75 mg/kg/day in three divided doses 1
3. After stabilization (which can occur within 14 days but may take months), transition to combination therapy with daily subcutaneous deferoxamine plus daily oral deferiprone 1, 2

For Cardiac Iron Overload Without Heart Failure (T2* <20 ms):

• Deferiprone monotherapy at 75-100 mg/kg/day is the drug of choice 2
• Alternatively, combination therapy with deferoxamine and deferiprone can be used for more aggressive iron removal 1, 2

For Maintenance Therapy in Stable Patients:

• Deferasirox 20-40 mg/kg/day once daily offers the best convenience and compliance 2, 6
• Deferoxamine subcutaneous infusion 5-7 nights per week remains effective for patients who tolerate it 2

For Severe Iron Overload Without Cardiac Involvement:

• Combination therapy with deferasirox and deferiprone achieves maximum iron removal, with mean iron excretion seven times higher than monotherapy 7

Critical Monitoring Requirements

• Serum ferritin every 3 months (monthly if possible), targeting levels <1000 ng/mL 2, 5
• Cardiac T2 MRI annually in all transfusion-dependent patients starting at age 10* 2, 5
• Liver iron concentration annually by MRI 2
• Annual electrocardiography and echocardiography 2
• Weekly absolute neutrophil count (ANC) monitoring with deferiprone due to agranulocytosis risk 2, 4
• Monthly renal function, hepatic function, and complete blood count 5

Understanding T2* MRI Values

• T2* <6 ms indicates severe cardiac iron loading with 47% risk of developing heart failure within 1 year (relative risk 270 compared to T2* >10 ms) 1, 5
• T2* <10 ms indicates severe cardiac iron overload requiring aggressive combination therapy 1, 2
• T2* 10-20 ms indicates mild to moderate cardiac iron loading requiring intensified chelation 1, 2
• T2* >20 ms is considered safe, though annual monitoring should continue 1, 2

Critical Clinical Pitfalls to Avoid

Delayed Cardiac Iron Clearance

• Cardiac iron removal is extremely slow even with intensive chelation, requiring several years of continuous treatment 1, 2
• Treatment must continue long-term with regular T2* monitoring to prevent premature discontinuation, as cardiac iron can persist even after clinical stabilization 1
• Compliance with iron chelation is essential for long-term survival after acute cardiac failure 1

Inappropriate Agent Selection

• Never use deferasirox in acute heart failure or renal impairment—it can worsen outcomes 1, 2, 5
• Failing to use deferiprone in cardiac iron overload misses the most effective cardiac-specific agent 2
• Deferoxamine intensification (continuous intravenous or subcutaneous) showed survival in 17 of 20 patients with heart failure, compared to historical mortality rates of 50% within 1 year 1

Monitoring Failures

• Not monitoring neutrophils weekly with deferiprone risks life-threatening agranulocytosis that can lead to serious infections and death 2, 4
• Serum ferritin and liver iron concentration may not correlate well with cardiac iron load—direct cardiac T2* measurement is essential 8
• Interrupt deferiprone immediately if neutropenia develops or if any infection occurs 4

Hemodynamic Management Errors

• Patients with thalassemia have baseline low blood pressure and high cardiac index due to chronic anemia—do not aggressively treat low blood pressure if cerebral and renal perfusion are maintained 1
• Avoid aggressive inotropic therapy, which can be detrimental in iron cardiomyopathy 1
• Overdiuresis can precipitate acute renal failure due to reduced preload, especially with concurrent liver disease and hypoalbuminemia 1

Long-Term Treatment Considerations

• Chelation therapy may need adjustment according to liver iron and serum ferritin levels to prevent chelator-mediated toxicity once iron burden decreases 1
• Long-term follow-up by a specialist center is essential to achieve optimal outcomes 1
• Combination therapy with deferoxamine and deferiprone has been used extensively for long-term management of patients with impaired left ventricular function without decompensated heart failure 1