At what ferritin level should iron chelation therapy be initiated in Sickle Cell Anemia and what are the doses of iron chelators?

Iron Chelation Therapy in Sickle Cell Anemia

Ferritin Threshold for Initiation

Iron chelation therapy should be initiated when serum ferritin reaches ≥1,000 ng/mL in patients with sickle cell disease receiving chronic transfusions. 1, 2

Primary Initiation Criteria

• Start chelation when ferritin ≥1,000 ng/mL with ongoing transfusion requirements, as this threshold is associated with significantly worsened survival and increased mortality when exceeded 1, 3

• Alternatively, initiate when transfusion burden is ≥2 units per month sustained for more than one year, regardless of ferritin level, as cardiac abnormalities develop after >100 units and liver iron accumulation occurs after >24 units 1

• The FDA-approved deferasirox label specifies that therapy should only be considered when patients have received at least 100 mL/kg of packed red blood cells (approximately 20 units for a 40 kg person) AND serum ferritin is consistently >1,000 mcg/L 2

Important Caveats About Ferritin in Sickle Cell Disease

Serum ferritin is a poor marker for accurately assessing iron overload in sickle cell disease patients and should not be used alone to direct long-term chelation therapy. 4

• Studies show only weak correlation (R=0.350) between serum ferritin and quantitative liver iron in SCD patients, with 18.4% of patients having abnormal liver iron despite ferritin <1,000 mcg/L 5, 4

• Up to 47.4% of patients with significant hepatic iron overload had ferritin <2,000 mcg/L, and 30.4% with severe overload (LIC ≥7 mg/g) had ferritin <2,000 mcg/L 5

• MRI assessment of liver iron concentration (LIC) should be performed every 1-2 years in chronically transfused SCD patients to accurately assess iron burden, as ferritin alone is insufficient 6, 5

Dosing of Iron Chelators

Deferasirox (Oral - First Line)

Starting dose: 14 mg/kg/day orally once daily for patients ≥2 years old with eGFR >60 mL/min/1.73 m² 2

• Calculate doses to the nearest whole tablet and adjust for weight changes in pediatric patients 2

• Take on an empty stomach or with a light meal (<7% fat content, ~250 calories) 2

• Dose adjustments: Make changes in steps of 3.5 or 7 mg/kg every 3-6 months based on serum ferritin trends 2

• Maximum dose: 28 mg/kg/day - doses above this are not recommended 2

• For inadequate control (ferritin persistently >2,500 mcg/L), may increase up to 28 mg/kg/day 2

Dose Modifications Based on Response

• If ferritin falls below 1,000 mcg/L on two consecutive visits: Consider dose reduction, especially if dose >17.5 mg/kg/day 2

• If ferritin falls below 500 mcg/L: Interrupt therapy and continue monthly monitoring 2

• For patients with moderate hepatic impairment (Child-Pugh B): Reduce starting dose by 50% 2

• Avoid deferasirox in severe hepatic impairment (Child-Pugh C) 2

Special Clinical Scenarios Requiring Early Initiation

Pre-Transplant Patients

• Initiate chelation in stem cell transplant candidates even with moderate iron overload, as ferritin >1,000 ng/mL at transplant is associated with higher mortality and increased hepatic complications 1, 3

• Iron chelation prior to transplant decreases procedure-related hepatic complications 1

Organ Preservation

• Initiate chelation when there is evidence of organ dysfunction from iron overload, regardless of ferritin level or life expectancy 1, 3

• This applies even in patients with life expectancy <1 year if they already show signs of iron-related organ complications 1

• Cardiac T2* <20 milliseconds by MRI indicates significant heart iron overload and warrants immediate chelation 1

Monitoring Requirements

Before Starting Therapy

• Obtain baseline serum creatinine in duplicate and calculate eGFR 2

• Perform urinalysis and serum electrolytes to evaluate renal tubular function 2

• Check serum transaminases and bilirubin 2

• Obtain baseline auditory and ophthalmic examinations 2

During Therapy

• Monitor serum ferritin monthly and adjust dose every 3-6 months based on trends 2

• Check blood counts, liver function, and renal function monthly 2

• Perform MRI for liver iron content every 1-2 years using validated R2, T2*, or R2* methods 6

• Consider cardiac T2* MRI screening for patients with high iron burden (LIC >15 mg/g for ≥2 years), evidence of end-organ damage, or cardiac dysfunction 6

Interruption of Therapy

• Interrupt deferasirox for acute illnesses causing volume depletion (vomiting, diarrhea, prolonged decreased oral intake) and monitor renal function more frequently 2

• Resume therapy when oral intake and volume status normalize 2

Patient Selection Algorithm

Initiate chelation if ANY of the following criteria are met:

1. Serum ferritin ≥1,000 ng/mL with ongoing transfusions 1, 3
2. Transfusion burden ≥2 units/month for >1 year 1
3. Candidate for allogeneic transplant with elevated iron stores 1, 3
4. Evidence of organ dysfunction from iron overload 1, 3
5. Life expectancy ≥1 year (unless existing organ damage present) 1

Do NOT initiate if:

• Life expectancy <1 year without existing organ damage 1
• Patient is post-transplant and receiving ongoing immunosuppressive therapy (due to overlapping renal toxicity) 1

Common Pitfalls to Avoid

• Do not rely solely on ferritin levels - obtain MRI liver iron concentration for accurate assessment in SCD patients 5, 4

• Do not delay chelation until ferritin is extremely elevated - studies show chelation was initiated after a mean of 2.6 years of transfusions, often too late 7

• Do not continue chelation if ferritin falls below 500 mcg/L - interrupt therapy to avoid iron deficiency 2

• Do not use aluminum-containing antacids concurrently with deferasirox 2

• Do not start chelation prematurely (ferritin <1,000 ng/mL) unless specific indications exist (transplant candidate, organ dysfunction) 3