What is the next step in management for a patient with Myelodysplastic Syndrome (MDS) who has received 15 units of Packed Red Blood Cell (PRBC) transfusions and has a serum ferritin level indicative of iron overload?

Iron Chelation Therapy for MDS with Transfusional Iron Overload

Initiate iron chelation therapy immediately with deferasirox, as this patient has met multiple criteria: serum ferritin >2000 ng/mL (well above the 1000 ng/mL threshold) and 15 units of PRBC transfusions indicating significant iron burden. 1

Rationale for Immediate Chelation

Your patient has clearly exceeded the established thresholds for iron chelation therapy:

• Ferritin threshold exceeded: Serum ferritin >1000 ng/mL significantly worsens survival in MDS patients with secondary iron overload, and your patient's ferritin of >2000 ng/mL is double this critical threshold 1

• Transfusion burden threshold met: With 15 units of PRBC transfusions, this patient has surpassed the threshold where liver iron accumulation begins (>24 units leads to increased liver iron, and cardiac abnormalities develop after >100 units) 1

• Survival impact: Transfusion dependency with secondary iron overload (ferritin >1000 ng/mL) is associated with a 30% increase in hazard for every 500 ng/mL increase in serum ferritin above this threshold 1

Specific Chelation Protocol

Starting Dose

• Initiate deferasirox at 14 mg/kg/day (tablet formulation) taken once daily on an empty stomach or with a light meal 2
• If using the older oral suspension formulation, start at 20 mg/kg/day 1

Pre-Treatment Assessment Required

Before initiating chelation, obtain:

• Baseline renal function: Ensure eGFR ≥40 mL/min/1.73 m² (chelation is contraindicated below this level) 2
• Baseline liver function tests: Reduce starting dose by 50% if Child-Pugh B hepatic impairment is present 2
• Complete blood count: Ensure platelet count >50 × 10⁹/L (contraindicated below this threshold) 2
• Auditory and ophthalmic testing: Baseline slit lamp examination and dilated fundoscopy 2

Monitoring Schedule During Chelation

Monthly monitoring:

• Serum ferritin to assess response and prevent overchelation 2
• Complete blood count to detect cytopenias 2

Every 3 months minimum (monthly preferred):

• Serum creatinine and eGFR 1
• Liver function tests (ALT, AST, bilirubin) 2

Every 12 months:

• Auditory testing (audiometry) 2
• Ophthalmic examination (slit lamp and fundoscopy) 2

Consider MRI assessment:

• Liver iron concentration (LIC) by MRI every 1-2 years using validated R2, T2*, or R2* methods 3
• Cardiac T2* MRI if high iron burden or evidence of cardiac dysfunction 3

Dose Adjustments Based on Response

If ferritin decreases appropriately:

• Continue current dose if ferritin remains >1000 ng/mL 2
• Reduce dose by 3.5-7 mg/kg if ferritin falls below 1000 ng/mL at 2 consecutive visits, especially if dose is >17.5 mg/kg/day 2
• Interrupt therapy if ferritin falls below 500 ng/mL and continue monthly monitoring 2

If ferritin remains elevated or increases:

• Increase dose by 3.5-7 mg/kg increments (maximum 28 mg/kg/day for tablets) 2
• Reassess transfusion burden and consider combining with erythropoiesis-stimulating agents if appropriate 4

Critical Safety Considerations

Renal Function Monitoring

• If serum creatinine increases by ≥33% above baseline: Repeat within 1 week, and if still elevated, reduce dose by 7 mg/kg 2
• Discontinue immediately if eGFR falls below 40 mL/min/1.73 m² 2
• Interrupt during volume depletion (vomiting, diarrhea, decreased oral intake) and resume only when volume status normalized 2

Hepatotoxicity Monitoring

• Monitor ALT monthly; interrupt if ALT rises significantly or if signs of hepatic failure develop 2
• Avoid in severe (Child-Pugh C) hepatic impairment 2

Hematologic Toxicity

• Interrupt immediately if cytopenias develop until cause determined 2
• Monitor CBC monthly as neutropenia, agranulocytosis, worsening anemia, and thrombocytopenia can occur 2

Severe Adverse Reactions Requiring Discontinuation

• Severe skin reactions (Stevens-Johnson syndrome, TEN, DRESS): Discontinue permanently 2
• Hypersensitivity reactions (anaphylaxis, angioedema): Discontinue permanently 2

Additional Management Considerations

Assess MDS Risk Status

• Chelation is most beneficial in low-risk and intermediate-1 risk MDS (IPSS classification) where life expectancy exceeds 1 year 1
• Patients with RA, RARS, RCMD, RCMD-RS, and del(5q) benefit most due to longer survival 1

Consider Stem Cell Transplant Candidacy

• If patient is a potential allogeneic stem cell transplant candidate, chelation is particularly important as ferritin >1000 ng/mL at transplant is associated with higher mortality and increased hepatic complications 1, 3
• Chelation prior to transplant decreases procedure-related hepatic complications 1

Organ Function Preservation

• Initiate chelation when there is need to preserve cardiac, hepatic, or endocrine function regardless of other factors 1
• Cardiac abnormalities and liver iron accumulation are documented concerns with this transfusion burden 1

Common Pitfalls to Avoid

• Do not delay chelation waiting for higher ferritin levels; your patient already exceeds the threshold by 2-fold 1
• Do not continue chelation at high doses (14-28 mg/kg/day) when ferritin approaches normal range, as this can result in life-threatening adverse events 2
• Do not ignore volume depletion: Interrupt chelation during acute illnesses causing dehydration 2
• Do not use with aluminum-containing antacids due to drug interactions 2
• Do not use concomitantly with strong UGT inducers (rifampicin, phenytoin, phenobarbital) or bile acid sequestrants without dose adjustment 2