What is the approach to iron chelation therapy in pediatric patients with iron overload?

Iron Chelation in Pediatric Patients

When to Initiate Iron Chelation Therapy

Iron chelation should be initiated in pediatric patients when serum ferritin reaches ≥1000 ng/mL or after receiving ≥20 red blood cell transfusions, particularly in those with transfusion-dependent anemias such as β-thalassemia major, sickle cell disease, or myelodysplastic syndromes. 1

Specific Initiation Criteria

• Start chelation when:
  • Serum ferritin ≥1000-2500 ng/mL 1
  • Patient has received ≥20 RBC transfusions 1
  • Transfusion requirement is ≥2 units/month sustained for >1 year 1
  • Cardiac T2* MRI shows significant reduction (indicating cardiac iron loading) 1
  • Patient is a future candidate for allogeneic stem cell transplant (chelate early, as even moderate iron overload increases transplant-related mortality) 1

Patient Selection

• Prioritize patients with:
  • Relatively favorable prognosis (low or intermediate-1 risk disease in MDS) 1
  • Anticipated ongoing transfusion requirements 1
  • Need to preserve organ function and quality of life 1

Available Iron Chelators for Pediatric Use

Deferasirox (Oral)

Deferasirox is FDA-approved for pediatric patients ≥2 years of age with transfusional iron overload and represents the most convenient first-line option due to once-daily oral dosing. 2

Dosing Protocol

• Starting dose: 14-20 mg/kg/day orally once daily 2
• Dose adjustments: Can be increased by 3.5-7 mg/kg/day every 3-6 months based on serum ferritin trends and tolerability 2
• Maximum dose: Generally 28 mg/kg/day, though higher doses (up to 40 mg/kg/day equivalent of dispersible tablet formulation) have been studied 3
• Available formulations: Dispersible tablets and granules (both demonstrate comparable compliance and efficacy) 4

Critical Safety Monitoring for Deferasirox

• Renal function: Estimate GFR using age-appropriate eGFR equations before initiation and monthly thereafter 2
• Hepatic function: Monitor ALT, AST, and bilirubin monthly 2
• Serum ferritin: Check monthly to assess response and avoid overchelation 2
• Blood counts: Monitor for cytopenias (neutropenia, thrombocytopenia, worsening anemia) 2

FDA Black Box Warnings - Critical Pitfalls

• Acute renal failure and hepatic failure have been reported, some with fatal outcomes, particularly in patients with comorbidities 1, 2
• Contraindicated if:
  • eGFR <40 mL/min/1.73 m² 2
  • Platelet count <50 × 10⁹/L 2
• Interrupt deferasirox immediately for:
  • Volume depletion (vomiting, diarrhea, decreased oral intake) 2
  • Acute illness causing dehydration 2
  • Elevated transaminases 2

Overchelation Risk in Pediatric Patients

• Higher risk of renal adverse events when deferasirox doses exceed 17.5 mg/kg/day (equivalent to 25 mg/kg/day of dispersible tablets) while serum ferritin is <1000 mcg/L 2
• Reduce dose or interrupt therapy if serum ferritin falls below 1000 mcg/L at two consecutive visits, especially if dose >17.5 mg/kg/day 2
• Interrupt therapy if serum ferritin falls below 500 mcg/L 2
• Continued administration when body iron burden approaches normal range can result in life-threatening adverse events 2

Deferoxamine (Parenteral)

Deferoxamine remains the gold standard for patients with severe cardiac iron overload or cardiac failure, requiring subcutaneous or intravenous administration. 1, 5

Dosing Protocol

• Standard subcutaneous therapy: 20-60 mg/kg/day via slow infusion over 8-12 hours, 5-7 days per week 1, 5
• Severe cardiac iron overload/cardiac failure: Continuous intravenous infusion at 50-60 mg/kg/day for rapid cardiac iron removal 1, 5
• Portable infusion pumps are typically used for overnight subcutaneous administration 5

Efficacy and Outcomes

• Long-term subcutaneous deferoxamine increases survival and decreases cardiac complications in transfusion-dependent thalassemia patients 1
• Intravenous deferoxamine for 12 months significantly improves cardiac T2* MRI values (5.1±1.9 ms to 8.1±2.8 ms), left ventricular ejection fraction (52±7.1% to 63±6.3%), and reduces LV volume and mass 1
• Clinical stabilization in cardiac failure may occur within 14 days but complete cardiac iron removal can take months to years 5

Limitations

• Poor compliance due to need for frequent parenteral administration 1
• High maintenance cost 1
• Poor oral bioavailability 1

Deferiprone (Oral)

Deferiprone is available in Europe but only through FDA treatment use program in the United States; it shows particular efficacy for cardiac iron removal. 1

Key Characteristics

• Dosing: 75-100 mg/kg/day in divided doses 1, 5
• Cardiac efficacy: Superior cardiac iron removal compared to deferoxamine monotherapy 1
• Limitations: Long-term efficacy and safety not fully established; clinical efficacy less consistent than deferoxamine 1

Combination Therapy

Combination of deferoxamine plus deferiprone demonstrates superior efficacy for cardiac iron removal compared to monotherapy, particularly in patients with moderate to severe cardiac iron loading. 1, 5

• Randomized controlled trial showed combination therapy (subcutaneous deferoxamine + oral deferiprone 75 mg/kg/day) reduced myocardial iron, improved ejection fraction, and improved endothelial function better than deferoxamine alone in thalassemia major patients 1
• Combination of deferasirox (30 mg/kg/day) plus deferoxamine (2500 mg/day for 4 days/week) successfully reduced severe iron overload in refractory cases, improving both liver and cardiac MRI T2* values 6

Monitoring Protocol

Frequency and Parameters

Monitor serum ferritin every 3 months (monthly if possible) in all transfusion-dependent pediatric patients receiving chelation therapy. 1, 5

Essential Monitoring Components

• Serum ferritin: Every 3 months minimum, monthly preferred; target <1000 ng/mL 1, 5
• Renal function: Monthly eGFR using pediatric-appropriate equations; evaluate renal tubular function 2
• Hepatic function: Monthly ALT, AST, bilirubin 2
• Complete blood count: Monitor for cytopenias 2
• Cardiac assessment:
  • Cardiac T2* MRI annually starting at age 10 years in transfusion-dependent patients 5
  • Electrocardiography and echocardiography annually 5
• Liver iron concentration: Annual MRI assessment 5

Intensified Monitoring Situations

• Increase monitoring frequency during:
  • Volume depletion episodes 2
  • Fever or acute illness 2
  • When deferasirox dose is 14-28 mg/kg/day and iron burden approaching normal range 2
  • Presence of other nephrotoxic risk factors 2

Special Considerations in Pediatric Populations

Age-Specific Risks

Pediatric patients face higher risks of renal toxicity, particularly when volume depleted or when continued on standard doses as iron burden normalizes. 2

• Acute kidney injury and acute liver injury/failure have occurred in pediatric patients in postmarketing surveillance 2
• Higher deferasirox exposures create greater probability of renal toxicity, leading to decreased renal function, increased drug exposure, and progressive kidney injury 2
• Juvenile animal studies showed increased renal toxicity in young rats compared to adults at equivalent doses 2

Critical Pitfalls to Avoid

Never continue standard chelation doses during acute illnesses causing volume depletion—this is a leading cause of serious adverse events in pediatric patients. 2

• Interrupt deferasirox for:
  • Vomiting, diarrhea, or prolonged decreased oral intake 2
  • Any acute illness causing volume depletion 2
• Resume only when: Oral intake and volume status normalized, and renal function reassessed 2
• Avoid concomitant nephrotoxic drugs (NSAIDs, aminoglycosides) 2

Contraindications Specific to Pediatric Iron Overload

Iron supplementation is absolutely contraindicated in pediatric patients with thalassemia or other transfusion-dependent anemias—the anemia is due to ineffective erythropoiesis, not iron deficiency. 7

• Transfusion-dependent patients accumulate ~200 mg iron per unit transfused, combined with increased GI absorption from hepcidin suppression 7
• Never supplement iron based on low hemoglobin alone in these patients 7
• Avoid vitamin C supplementation in iron-overloaded patients, as it mobilizes iron from stores and can accelerate cardiac deterioration 7

Disease-Specific Approaches

β-Thalassemia Major

• Most extensively studied population for iron chelation 3, 8, 4
• Deferasirox well-tolerated in children as young as 2 years with β-thalassemia 3
• Maintain pre-transfusion hemoglobin 9-10 g/dL and post-transfusion 13-14 g/dL to suppress ineffective erythropoiesis while minimizing iron loading 7
• Lifelong chelation typically required 5

Sickle Cell Disease

• 81% of pediatric patients on deferasirox in one large center had sickle cell disease 9
• Adherence to oral therapy documented in 76% of patients 9
• Serum ferritin decreased in 44% of compliant patients vs. 11% of poorly compliant patients after 12 months 9
• Mild changes in creatinine and liver function tests did not result in long-term discontinuation 9

Myelodysplastic Syndromes (Rare in Pediatrics)

• Chelation recommended for low or intermediate-1 risk MDS with transfusion dependence 1
• Retrospective data suggest adequate chelation may improve survival in highly transfused patients 1
• Heart MRI studies show cardiac iron overload (T2* <20 ms) associated with decreased LV ejection fraction and heart failure risk after 70-80 RBC concentrates 1

Treatment Goals and Duration

Target Endpoints

The primary goal is to maintain serum ferritin <1000 ng/mL while preventing organ dysfunction, particularly cardiac and hepatic complications. 1

• Cardiac T2 target:* >20 ms (values <20 ms associated with cardiac dysfunction) 1
• Liver iron concentration: Monitor annually and adjust therapy accordingly 5
• Use minimum effective dose to maintain low iron burden and avoid overchelation 2

Duration of Therapy

• Transfusion-dependent patients: Lifelong chelation typically required 5
• Post-cardiac failure: Continue for several years to completely remove cardiac iron 5
• Evaluate need for ongoing chelation in patients whose conditions no longer require regular transfusions 2

Practical Implementation

Starting Chelation in Clinical Practice

1. Assess baseline status:

   • Serum ferritin, complete metabolic panel, CBC, eGFR 1, 2
   • Consider baseline cardiac T2* MRI if heavily transfused 5
   • Document transfusion history (number of units, frequency) 1

2. Select appropriate chelator:

   • First-line: Deferasirox 14-20 mg/kg/day for most pediatric patients ≥2 years 2
   • Severe cardiac iron overload: Deferoxamine IV or combination therapy 1, 5
   • Refractory cases: Consider combination deferasirox + deferoxamine 6

3. Educate patient/family:

   • Importance of compliance (adherence rates ~76% with oral therapy) 9
   • Signs of volume depletion requiring treatment interruption 2
   • Need for regular monitoring 2
   • Use non-hormonal contraception (deferasirox renders hormonal contraceptives ineffective) 2

4. Implement monitoring schedule:

   • Monthly: Serum ferritin, renal function, hepatic function, CBC 2
   • Every 3-6 months: Assess for dose adjustment based on ferritin trends 2
   • Annually: Cardiac T2* MRI, liver iron concentration MRI, ECG, echocardiogram 5

Dose Adjustment Algorithm

• If ferritin decreasing appropriately: Continue current dose 2
• If ferritin stable or increasing despite adequate dose: Increase by 3.5-7 mg/kg/day every 3-6 months (max 28 mg/kg/day) 2
• If ferritin <1000 mcg/L at 2 consecutive visits and dose >17.5 mg/kg/day: Reduce dose 2
• If ferritin <500 mcg/L: Interrupt therapy and monitor monthly 2