What is the dose and caution for Eltrombopag (thrombopoietin receptor agonist) in treating aplastic anemia?

Eltrombopag in Aplastic Anemia: Indication, Caution, and Dose

For patients with severe aplastic anemia refractory to immunosuppressive therapy, eltrombopag should be initiated at 150 mg orally once daily (or 75 mg daily for patients of East/Southeast Asian ancestry or those with hepatic impairment), with dose adjustments based on response and tolerability. 1, 2

Indication

Primary Indication:

• Eltrombopag is indicated for severe aplastic anemia patients who have had an insufficient response to prior immunosuppressive therapy 3
• The American Society of Hematology suggests adding eltrombopag to supportive care for patients with aplastic anemia refractory to initial immunosuppressive therapy 1
• Emerging evidence supports use in treatment-naïve elderly patients ineligible for antithymocyte globulin (ATG) therapy 4

Patient Selection:

• Patients with relapsed/refractory disease after ATG and cyclosporine 4, 5
• Patients ineligible for bone marrow transplantation 3
• Elderly patients unfit for standard immunosuppressive therapy may benefit as first-line treatment 4

Dosing

Standard Dosing:

• Initial dose: 150 mg orally once daily for most patients 2, 3
• Treatment duration: Minimum 12 weeks to assess response, with continuation for responders 5, 3
• Median daily dose in real-world use: 150 mg 4

Dose Modifications:

For East/Southeast Asian Ancestry:

• Reduce initial dose to 75 mg daily 2

For Hepatic Impairment (Child-Pugh Class A, B, or C):

• Reduce initial dose (specific reduction required per FDA labeling) 2
• Patients with baseline ALT or AST >5× ULN were ineligible in clinical trials 2

Dose Adjustments:

• Can be increased as needed up to maximum 150 mg daily based on response 5
• In robust responders, stable hematological counts may be maintained after discontinuation 3

Expected Response

Efficacy Rates:

• Overall hematologic response rate: 47% (95% CI 38-56%) for refractory patients treated with eltrombopag alone 6
• Response in at least one lineage: 64% in treatment-naïve patients, 74% in relapsed/refractory patients 4
• Trilineage improvement: 27% in treatment-naïve, 34% in relapsed/refractory patients 4

Timeline to Response:

• Transfusion independence rates: 7% at 1 month, 33% at 3 months, 46% at 6 months 4
• Responses develop more slowly in ATG treatment-naïve patients 4
• Primary endpoint assessment at 12 weeks 5

Magnitude of Response:

• Median hemoglobin increase: 3 g/dL (IQR 1.4-4.5) in responders 4
• Median platelet count increase: 42×10⁹/L (IQR 11-100) 4
• Median neutrophil count increase: 1,350 per cubic millimeter 5

Cautions and Monitoring

Critical Safety Concerns:

Clonal Evolution:

• Karyotype abnormalities occur in 10% overall (95% CI 7-14%) 6
• Higher rate of 17% (95% CI 10-24%) in refractory patients treated with eltrombopag alone 6
• Lower rate of 8% (95% CI 3-13%) when combined with immunosuppressive therapy without prior ATG 6
• Cytogenetic abnormalities observed in 19% of patients in some studies 3
• Dysplasia reported in 5% of patients 3

Hepatotoxicity:

• Increased liver transaminases are the only dose-limiting toxicity 3
• Liver function abnormalities reported in 13% of patients 7
• Monitor liver function tests regularly 2

Thrombotic Risk:

• Thrombosis is a treatment-related serious adverse event 7
• Monitor for signs of thromboembolism 2

Bone Marrow Changes:

• Increased bone marrow reticulin reported 7
• Serial bone marrow biopsies showed normalization of trilineage hematopoiesis in responders without increased fibrosis 5

Rebound Thrombocytopenia:

• Worsening thrombocytopenia may occur upon discontinuation 7

Monitoring Requirements:

• Complete blood counts regularly to assess response 1
• Bone marrow evaluations to monitor for clonal evolution and dysplasia 6, 3
• Liver function tests for hepatotoxicity 2, 3
• Cytogenetic monitoring for chromosomal abnormalities 6

Important Clinical Pitfalls

Drug Interactions:

• Do not administer with polyvalent cations (calcium, aluminum, magnesium) as they chelate eltrombopag and limit absorption 2
• Separate administration from metal cation-containing preparations 2

Combination Therapy Concerns:

• In myelodysplastic syndrome, combination with azacitidine showed increased progression to AML (12% vs 6% with placebo) 7
• This concern is specific to MDS, not aplastic anemia, but warrants awareness 7

Special Populations:

• Pediatric patients must be able to swallow tablets whole 2
• Safety and effectiveness not established in pediatric patients with aplastic anemia 2
• No dosage adjustment needed in geriatric patients, though 18% of aplastic anemia patients in trials were ≥65 years 2

Pregnancy and Lactation:

• Can cause fetal harm; effective contraception required during treatment and for 7 days after stopping 2
• Breastfeeding not recommended during treatment 2