Long-term eltrombopag for bone marrow failure depletes iron

Area of Science:

• Hematology
• Pharmacology
• Internal Medicine

Background:

• Eltrombopag (EPAG) is approved for aplastic anemia and immune thrombocytopenia, often requiring long-term treatment.
• Prolonged EPAG use can lead to significant iron depletion due to its polyvalent cation chelation properties.
• This iron depletion has been an underappreciated consequence of long-term eltrombopag therapy.

Purpose of the Study:

• To investigate the impact of long-term eltrombopag therapy on iron parameters in patients with bone marrow failure syndromes.
• To compare iron depletion and related outcomes in patients treated with EPAG versus historical controls receiving immunosuppression without EPAG.
• To assess the relationship between EPAG duration, iron levels, and clinical response or relapse.

Main Methods:

• Retrospective review of 521 patients treated at the NIH for aplastic anemia, myelodysplastic syndrome, and unilineage cytopenias.
• Comparison of patients treated with EPAG (n=315) to a historical cohort treated with immunosuppression (n=206).
• Analysis of iron parameters, duration of therapy, response, relapse rates, and demographic data over multiyear follow-up (3.6 years for EPAG, 8.5 years for historical cohort).

Main Results:

• Duration of EPAG exposure significantly correlated with ferritin reduction (p < 10^-14), irrespective of response or initial iron status.
• Iron clearance followed first-order kinetics with a faster half-life (15.3 months) on EPAG compared to historical responders (47.5 months, p < 10^-10).
• Risk of iron depletion depended on baseline ferritin and therapy duration; it did not correlate with EPAG response or relapse risk.

Conclusions:

• Eltrombopag effectively chelates total body iron, comparable to established iron chelators.
• Prolonged EPAG use can lead to iron depletion, potentially causing iron-deficiency anemia that mimics disease relapse.
• Iron deficiency induced by EPAG is responsive to iron supplementation, necessitating monitoring during long-term treatment.