Management of Aplastic Anemia Patients on Eltrombopag
For patients with aplastic anemia taking eltrombopag, continue treatment with careful monitoring for hepatotoxicity and cytogenetic abnormalities, aiming for multilineage hematologic response over 3-6 months, with consideration for discontinuation only after achieving robust near-normalization of blood counts sustained for at least 6-9 months. 1, 2
Initial Treatment Strategy
Dosing and Escalation
- Start eltrombopag at 25 mg once daily for patients of East/Southeast Asian ancestry, or 50 mg once daily for other populations 3, 4
- Escalate dose every 2 weeks based on platelet response: 25 mg → 50 mg → 75 mg → maximum 100 mg daily 4
- For patients with hepatic impairment (Child-Pugh Class A, B, or C), reduce the initial dose 3
- Patients with baseline ALT or AST >5× upper limit of normal should not receive eltrombopag 3
Expected Response Timeline
- Initial hematologic response typically occurs within 3-4 months of treatment 2
- 40-48% of patients with refractory severe aplastic anemia achieve hematologic response in at least one lineage by 3-6 months 4, 5, 2
- Multilineage (bi- or trilineage) responses develop with continued treatment, often requiring extended therapy beyond 6 months 4, 2
- When combined with first-line immunosuppressive therapy (horse ATG plus cyclosporine), overall response rates reach 80-94% at 6 months 6
Critical Monitoring Requirements
Hepatotoxicity Surveillance
- Monitor liver function tests regularly - hepatotoxicity with increased transaminases occurs in 13% of patients and represents the only dose-limiting toxicity 1, 5
- Increased ALT/AST is the primary safety concern requiring dose adjustment or discontinuation 1
- Check liver enzymes at baseline, every 2 weeks during dose escalation, then monthly once stable 3
Cytogenetic Monitoring
- Perform bone marrow evaluation with cytogenetic analysis at baseline and every 6 months during treatment 7, 2
- Cytogenetic abnormalities develop in 8-19% of patients, with higher rates (17%) in refractory disease treated with eltrombopag alone versus 8% when combined with immunosuppressive therapy 8, 5
- Chromosome 7 abnormalities (loss or partial deletion) are particularly concerning and occurred in 5 patients in one cohort 2
- Despite cytogenetic changes, progression to myelodysplastic syndrome or acute myeloid leukemia remains uncommon in short-term follow-up 4, 5, 2
Hematologic Monitoring
- Check complete blood counts every 2-3 weeks initially to assess response 7
- Monitor for excessive platelet elevation that could increase thrombotic risk 1, 3
- Assess transfusion requirements and reduction in transfusion dependency 7
Discontinuation Strategy
Criteria for Attempting Discontinuation
- Achieve robust near-normalization of blood counts maintained for at least 6-9 months on stable eltrombopag dose 2
- Specifically, patients should demonstrate trilineage recovery with counts approaching normal ranges 2
- Five patients in the landmark study discontinued eltrombopag after a median of 28.5 months (range 9-37 months) and maintained stable counts off drug 2
Discontinuation Protocol
- Unlike ITP where gradual tapering is recommended 9, the aplastic anemia literature describes abrupt discontinuation in robust responders 2
- Monitor blood counts weekly for the first month after discontinuation, then every 2-4 weeks for 3-6 months 7
- Watch for rebound cytopenias upon discontinuation 1
Post-Discontinuation Outcomes
- Patients with robust responses maintained stable hematopoiesis for a median of 13 months (range 1-15 months) off eltrombopag 2
- This suggests eltrombopag can restore sustainable hematopoiesis in a subset of patients 2
Special Clinical Scenarios
Refractory Disease (Failed Prior Immunosuppression)
- The American Society of Hematology suggests adding eltrombopag to supportive care for patients refractory to initial immunosuppressive therapy 1
- Response rates are lower (40-48%) compared to first-line combination therapy 4, 5, 2
- Higher risk of cytogenetic abnormalities (17%) in this population 8
First-Line Combination Therapy
- For treatment-naïve severe aplastic anemia, combine eltrombopag with horse ATG plus cyclosporine starting from day 1 and continuing for 6 months 6
- This approach yields complete response rates of 58% and overall response rates of 94% at 6 months 6
- Markedly superior to historical immunosuppression alone (10% complete response, 66% overall response) 6
Non-Severe Aplastic Anemia
- Eltrombopag demonstrates efficacy in non-severe disease, with 15 of 21 Japanese patients having non-severe AA in one study 4
- Treatment approach and monitoring remain similar to severe disease 4
Common Adverse Events and Management
Frequent but Mild Toxicities
- Nasopharyngitis and abnormal hepatic function are most common, typically grade 1-2 4
- Severe rashes occurred in 2 patients requiring early discontinuation 6
- Fatigue, bradycardia, and gastrointestinal symptoms may occur 3
Serious Adverse Events
- Thrombosis is a treatment-related serious adverse event requiring vigilance 1
- Monitor for signs of thromboembolism, particularly if platelet counts exceed normal ranges 1, 3
- In overdose situations, platelet counts can rise excessively (one case reached 929 × 10⁹/L) 3
Critical Pitfalls to Avoid
- Do not delay treatment while awaiting complete diagnostic workup in severe disease 7
- Do not continue eltrombopag indefinitely without attempting discontinuation in robust responders - sustainable hematopoiesis off drug is achievable 2
- Do not ignore cytogenetic surveillance - chromosome 7 abnormalities warrant heightened monitoring even without immediate progression to malignancy 2
- Do not use eltrombopag in patients with baseline ALT/AST >5× ULN 3
- Do not combine with azacitidine - this combination in myelodysplastic syndrome showed increased progression to AML 1
- Do not transfuse non-irradiated blood products - all blood products must be irradiated and filtered 1, 7