A subgroup of individuals required long-term treatment with eltrombopag (EPAG) to treat aplastic anemia and immune thrombocytopenia. Due to polyvalent cation chelation, prolonged therapy results in iron depletion that was previously overlooked. Researchers compared patients treated at the NIH for aplastic anemia, myelodysplastic syndrome, and unilinear cytopenias with immunosuppression without EPAG and those treated with EPAG. They analyzed iron measurements, length of therapy, response evaluation, relapse rates, and standard demographic characteristics. They included 521 individuals treated with (n=315) or without EPAG (n=206) in 11 studies with multi-year follow-up (3.6 vs. 8.5 years, respectively). Duration of EPAG exposure was linked with ferritin reduction (p = 4 × 10−14), regardless of response, maximum dose, or degree of initial iron overload, as measured by ferritin concentration. Clearance followed first-order kinetics with a quicker clearance (half-life 15.3 months) than previous responders (half-life 47.5 months, p = 8 × 10−10). The risk of iron depletion depended on ferritin levels at baseline and the length of treatment. Ferritin levels at baseline did not correspond with the response of bone marrow failure to EPAG or relapse risk, nor did iron clearance correlate with disease response. In conclusion, EPAG chelates total body iron as effectively as commercially available chelators. Prolonged use could deplete iron, leading to iron-deficiency anemia that mimicked relapse and was amenable to iron supplementation.