What is the treatment for pediatric patients with transfusional iron overload, specifically those with beta-thalassemia major?

Pediatric Diseases Requiring Iron Chelation

Primary Indications

Iron chelation therapy is required in pediatric patients with transfusion-dependent β-thalassemia major, sickle cell disease requiring chronic transfusions, and other transfusion-dependent anemias when serum ferritin reaches ≥1000 ng/mL or after receiving ≥20 red blood cell transfusions. 1

β-Thalassemia Major

• This is the most common pediatric indication for iron chelation, as patients require lifelong regular transfusions from early childhood to maintain hemoglobin levels and prevent complications of chronic anemia. 2
• Transfusion therapy is initiated to maintain pre-transfusion hemoglobin 9-10 g/dL and post-transfusion 13-14 g/dL, which suppresses ineffective erythropoiesis but inevitably leads to iron accumulation. 1
• Each unit of packed red blood cells contains 200-250 mg of elemental iron, and the body has no physiological mechanism to excrete this excess iron. 3
• Cardiac iron loading is the leading cause of death in these patients, accounting for approximately 70% of mortality. 3
• Before chelation therapy became available, patients with transfused but unchelated β-thalassemia typically died by age 10 from cardiac complications. 3

Sickle Cell Disease

• Children with sickle cell disease require iron chelation after 12 to 20 transfusions when they are on chronic transfusion programs. 4
• Chronic transfusion therapy is most commonly prescribed for primary or secondary stroke prophylaxis in high-risk children. 4
• Transfusions are also used for select children with recurrent vaso-occlusive complications who do not respond to other disease-modifying therapies like hydroxyurea. 4

Other Transfusion-Dependent Anemias

• Myelodysplastic syndromes (MDS) in pediatric patients with low or intermediate-1 risk disease and ongoing transfusion requirements. 1
• Rare congenital anemias including Diamond-Blackfan anemia and other bone marrow failure syndromes requiring regular transfusions. 5

Initiation Criteria

Start iron chelation when any of the following thresholds are met:

• Serum ferritin ≥1000 ng/mL (some guidelines suggest 1000-2500 ng/mL range). 1
• After receiving ≥20 red blood cell transfusions. 1
• Cardiac T2* MRI shows significant reduction indicating cardiac iron loading (T2* <20 ms suggests cardiac iron accumulation). 4, 1

Age Considerations

• Deferasirox is approved for pediatric patients ≥2 years of age with transfusional iron overload. 1, 6
• Evidence on efficacy and safety of iron chelation for children ≥2 years is widely available, though emerging data explores earlier initiation in younger patients. 7
• Cardiac iron loading typically does not occur before 10 years of age in children receiving both transfusions and chelation, though occasional cases as young as 7 years have been recorded when chelation access is limited. 4

Available Chelation Agents

Deferoxamine (DFO)

• This is the reference-standard chelator for patients with severe cardiac iron overload or cardiac failure. 4, 1
• Requires subcutaneous or intravenous administration over 8-10 hours, typically 4-5 nights per week at 40 mg/kg/day. 8
• The prolonged infusion regimen results in poor adherence, which is a major limitation. 5
• For acute cardiac failure, continuous intravenous infusion at 75 mg/kg/day (divided into 3 doses) is recommended. 4

Deferasirox

• This is the preferred first-line oral chelator for most pediatric patients ≥2 years of age due to once-daily dosing and superior patient satisfaction. 1, 5
• The long half-life (16-18 hours) provides sustained 24-hour iron chelation coverage. 5
• In a 5-year prospective study, deferasirox effectively reduced liver iron concentration by 7.8 mg Fe/g dry weight and median serum ferritin by 706 ng/mL in β-thalassemia patients. 2
• Common adverse effects include abdominal pain (21-28%), diarrhea (12-47%), nausea (11-26%), and increased creatinine (7-14%). 6
• Severe cutaneous adverse reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported and require immediate discontinuation. 6
• Should be avoided in patients with marginal renal perfusion or acute heart failure. 4

Deferiprone

• Oral chelator administered three times daily at 75 mg/kg/day. 8
• Preliminary evidence suggests deferiprone may be more effective than deferoxamine in chelating cardiac iron. 5
• Major adverse effects include agranulocytosis (requiring weekly white blood cell monitoring), neutropenia, gastrointestinal symptoms, liver dysfunction, and arthropathy. 8, 5

Combination Therapy

• Combined therapy with deferoxamine and deferiprone is highly effective for patients with significant iron overload or cardiac involvement. 4, 8
• In a prospective study of 55 β-thalassemia patients, combination therapy reduced mean serum ferritin from 3,088 ng/mL to 2,051 ng/mL (p<0.001) over 22 months. 8
• Significant improvement in myocardial function (ejection fraction and fractional shortening) was demonstrated after minimum 1 year of combination therapy. 8
• This approach is used extensively for long-term management of patients with impaired left ventricular function without decompensated heart failure. 4

Monitoring Requirements

Establish a comprehensive monitoring protocol:

• Serum ferritin every 3 months (monthly if possible) in all transfusion-dependent patients receiving chelation. 1
• Renal function, hepatic function, and complete blood count monthly. 1
• Cardiac T2* MRI to assess cardiac iron loading, with treatment intensification when T2* <10 ms and maximal therapy when T2* <6 ms. 4
• Auditory and ophthalmic testing (including slit lamp examinations and dilated fundoscopy) before starting treatment and every 12 months thereafter. 6
• Weekly white blood cell counts when using deferiprone due to agranulocytosis risk. 5

Treatment Goals

• Maintain serum ferritin <1000 ng/mL to prevent organ dysfunction, particularly cardiac and hepatic complications. 1
• Cardiac iron removal is very slow, requiring several years of intensive chelation even after resolution of acute cardiac failure. 4
• The prospective risk of developing heart failure within 1 year is 47% if cardiac T2* is <6 ms, with relative risk of 270 compared to patients with T2* >10 ms. 4

Critical Pitfalls

• Poor adherence to chelation therapy is the primary cause of preventable morbidity and mortality in transfusion-dependent thalassemia. 9
• Dose-related adverse effects (gastrointestinal symptoms, increased creatinine, skin rash) may lead to discontinuation if not properly managed. 6
• Patients with cardiac T2* between 6-10 ms require intensified chelation, while those with T2* <6 ms should be treated similarly to overt heart failure. 4
• Deferasirox doses >25 mg/kg/day (equivalent to 17.5 mg/kg/day deferasirox tablets) when serum ferritin <1000 mcg/L increase auditory adverse events in pediatric patients. 6