What is the recommended oral iron chelation therapy for a patient with iron overload?

Oral Iron Chelation Therapy

For patients with transfusional iron overload, deferasirox is the recommended oral iron chelator at 20-40 mg/kg/day once daily, taken on an empty stomach or with a light meal, with dose adjustments based on serum ferritin levels (target <1000 ng/mL) and body iron burden. 1, 2

Available Oral Iron Chelating Agents

Deferasirox (First-Line Oral Agent)

• Administered orally at 20-40 mg/kg/day once daily as dispersible tablets dissolved in water or juice at least 30 minutes before meals, or swallowed whole with water on an empty stomach or with a light meal 3, 2
• Provides 24-hour chelation coverage with once-daily dosing, offering superior convenience and compliance compared to parenteral options 4
• Elimination half-life of 8-16 hours allows sustained iron suppression without rebound between doses 3, 5
• Most appropriate for long-term maintenance therapy in stable patients with transfusional iron overload 3, 6

Deferiprone (Cardiac-Specific Agent)

• Administered orally at 75-100 mg/kg/day divided into three daily doses due to short plasma half-life of 1.5-2.5 hours 3, 6
• Preferred agent for patients with cardiac iron overload (T2 <20 ms) or established heart failure*, demonstrating superior cardiac iron clearance compared to other chelators 3, 7, 6
• Available in the USA only through FDA treatment use program 7
• Licensed in Europe for β-thalassemia when deferoxamine is inadequate or contraindicated 1

Clinical Indications and Patient Selection

Myelodysplastic Syndromes (MDS)

• Consider chelation in patients with low or INT-1 risk MDS who have received or are anticipated to receive >20 RBC transfusions, with ongoing transfusion needs anticipated and serum ferritin >2500 ng/mL 1
• Target serum ferritin reduction to <1000 ng/mL 1
• Retrospective evidence suggests transfusional iron overload contributes to increased mortality and morbidity in early-stage MDS 1

Thalassemia and Other Transfusion-Dependent Anemias

• Initiate deferasirox at 20 mg/kg/day for patients with established iron overload from chronic transfusions 2, 8
• Dose escalation to 30-40 mg/kg/day may be required based on serum ferritin trends and liver iron concentration 2, 8
• For cardiac iron overload in thalassemia, deferiprone is the preferred oral agent at 75-100 mg/kg/day in three divided doses 3, 6

Alternative to Phlebotomy

• Iron chelation is indicated when phlebotomy is contraindicated due to significant anemia, hemodynamic instability, or malignancy 7
• Particularly relevant in hemochromatosis patients who cannot tolerate blood removal 7

Dosing Algorithm and Adjustments

Initial Dosing Strategy

• Start deferasirox at 20 mg/kg/day for most patients with transfusional iron overload 2, 8
• For MDS patients, dosing may begin at 14 mg/kg/day based on baseline liver iron concentration 2
• Adjust dose every 3-6 months based on serum ferritin trends and safety parameters 2

Dose Modification for Iron Burden

• If serum ferritin falls below 1000 mcg/L at 2 consecutive visits, consider dose reduction, especially if deferasirox dose exceeds 17.5 mg/kg/day 2
• If serum ferritin falls below 500 mcg/L, interrupt therapy and continue monthly monitoring 2
• Risk of overchelation is particularly high in pediatric patients receiving 14-28 mg/kg/day deferasirox when iron burden approaches normal range 2

Combination Therapy Considerations

• Combination therapy with deferasirox plus deferoxamine or deferiprone plus deferoxamine shows enhanced efficacy for severe iron overload, particularly cardiac iron 6, 9
• Meta-analysis demonstrates significantly improved left ventricular ejection fraction with combination deferiprone and deferoxamine versus deferoxamine monotherapy 9
• For acute cardiac decompensation, initiate deferiprone 75 mg/kg/day immediately and consider adding continuous IV deferoxamine 50-60 mg/kg/day 3, 6

Monitoring Requirements

Baseline Assessment

• Measure serum ferritin, liver iron concentration (by MRI preferred), and assess cardiac function with T2* MRI in transfusion-dependent patients 1
• Obtain baseline serum creatinine/creatinine clearance and liver function tests before initiating deferasirox 1, 2

Ongoing Monitoring

• Monitor serum ferritin every 3 months with target <1000 ng/mL 1, 3, 6
• Measure serum creatinine and liver function tests monthly during deferasirox therapy 1, 2
• Perform cardiac T2 MRI annually in transfusion-dependent patients starting at age 10* 3, 6
• Monitor liver iron concentration annually by MRI 3, 6
• Weekly neutrophil monitoring is mandatory with deferiprone due to agranulocytosis risk 3, 6, 9

Critical Safety Considerations and Black Box Warnings

Deferasirox-Specific Warnings

• FDA black box warning for acute renal failure and hepatic failure, some with fatal outcomes, particularly in patients with multiple comorbidities and advanced hematologic disorders 1, 2
• Postmarketing reports of cytopenias (agranulocytosis, neutropenia, thrombocytopenia) and gastrointestinal bleeding, with some fatal events 1, 2
• Contraindicated in patients with platelet counts <50 x 10⁹/L 2
• Risk of gastrointestinal ulceration and hemorrhage, particularly when combined with NSAIDs, corticosteroids, oral bisphosphonates, or anticoagulants 2

Age-Related Toxicity Risks

• Elderly patients require more frequent monitoring due to increased risk of serious and fatal adverse reactions in postmarketing surveillance 2
• Pediatric patients are at risk when volume-depleted or when receiving 14-28 mg/kg/day deferasirox as iron burden approaches normal range 2
• Interrupt deferasirox in volume-depleted patients and resume only when renal function and fluid volume normalize 2

Deferiprone-Specific Warnings

• Risk of agranulocytosis and neutropenia requires weekly complete blood count monitoring 3, 7, 6, 9
• Contraindicated in pregnancy, as are all iron chelation drugs 7
• Joint pain (arthropathy) and gastrointestinal disturbances are common adverse events 9, 4

Comparative Adverse Event Profile

• Adverse events occur less frequently with deferasirox monotherapy compared to deferiprone (RR 0.45,95% CI 0.24-0.84) 9
• Adverse events are significantly increased with combination deferasirox plus deferiprone versus deferasirox alone (RR 0.33,95% CI 0.13-0.84) 9
• Deferasirox causes more adverse events than deferoxamine in head-to-head trials 9

Common Clinical Pitfalls

Overchelation

• Continued administration of deferasirox at 14-28 mg/kg/day when body iron burden approaches normal range can result in life-threatening adverse events 2
• Failure to reduce dose when serum ferritin falls below 1000 mcg/L risks renal and hepatic toxicity 2
• Pediatric patients are particularly vulnerable to overchelation complications when doses exceed 17.5 mg/kg/day with ferritin <1000 mcg/L 2

Inappropriate Agent Selection

• Using deferasirox in acute heart failure or renal impairment worsens outcomes due to nephrotoxicity risk 3, 2
• Failing to use deferiprone for cardiac iron overload misses the most effective cardiac-specific agent 3, 6
• Not recognizing that cardiac iron removal requires several years even with intensive chelation, leading to premature discontinuation 3, 6

Monitoring Failures

• Not monitoring neutrophils weekly with deferiprone risks life-threatening agranulocytosis 3, 6
• Inadequate renal and hepatic function monitoring with deferasirox increases risk of acute organ failure 1, 2
• Relying solely on serum ferritin without MRI assessment of liver and cardiac iron may miss organ-specific iron deposition 1

Drug Interactions

• Coadministration with NSAIDs, anticoagulants, or corticosteroids increases gastrointestinal bleeding risk 2
• Dose adjustment required with strong UGT inducers or bile acid sequestrants 5
• Monitor patients closely when combining with CYP3A4/5, CYP2C8, or CYP1A2 substrates 5