Eltrombopag received FDA approval for the treatment of refractory severe aplastic anemia (rSAA) based on treatment of 43 patients with doses escalating from 50-150mg daily for 12 weeks. Response kinetics suggested that more prolonged administration of EPAG at a dose of 150 mg could speed and improve response rates. We enrolled 40 rSAA patients in a study of EPAG 150mg daily, with a primary endpoint of response at 24 weeks. Twenty of 40(50%) responded at 24 weeks, 5/20(25%) would have been deemed non-responders at 12 weeks, the endpoint of the prior study. 15/19 responding patients continuing on EPAG had drug discontinued for robust response with 5/15 requiring EPAG re-initiation for relapse in 5/15, with all recovering response. To analyze risk of clonal progression, we combined long-term data from the 83 rSAA patients enrolled in both studies. Evolution to an abnormal karyotype occurred in 16(19%), most within 6 months of EPAG initiation. Targeted deep sequencing/whole exome sequencing was performed pre-EPAG and at primary response endpoint, and/or time of clonal evolution or longest follow-up. Cytogenetic evolution did not correlate with mutational status, and overall mutated allele fractions of myeloid cancer genes did not increase on EPAG. In summary, extended administration of EPAG at a dose of 150mg for 24 weeks rescued responses in some patients with rSAA not responding at 12 weeks. The temporal relationship between clonal evolution and drug exposure suggests that EPAG may promote expansion of dormant pre-existing clones with an aberrant karyotype.