Background
Phase 2 single-arm prospective study. 25 patients with refractory severe aplastic anemia (SAA) who had failed ≥1 immunosuppressive course (hATG + cyclosporine) and were not candidates for or declined allogeneic HSCT. Eltrombopag (Promacta/Revolade) is a small-molecule thrombopoietin receptor (c-Mpl) agonist hypothesized to stimulate primitive hematopoietic stem cell proliferation. This was the first study to demonstrate hematologic responses with a TPO-RA in refractory aplastic anemia.
Interventions and follow up
Regimen: Eltrombopag 50 mg PO daily, escalated to 75 mg then 150 mg over 2-week intervals based on platelet response; continued in responders
Primary endpoint: Hematologic response at 16 weeks (any lineage: platelet ≥20×10⁹/L increase, ANC ≥0.5×10⁹/L increase, or Hgb ≥1.5 g/dL increase)
Median follow up: 16 weeks (primary); extension follow-up
Primary endpoint: Hematologic response at 16 weeks (any lineage: platelet ≥20×10⁹/L increase, ANC ≥0.5×10⁹/L increase, or Hgb ≥1.5 g/dL increase)
Median follow up: 16 weeks (primary); extension follow-up
Results
Hematologic response at 16 weeks: 11/25 (44%)
Tri-lineage response (CR): 7/25 (28%)
Clonal cytogenetic abnormalities: 6/24 evaluable (25%) — including monosomy 7, trisomy 8, del(13q)
Median Hgb increase (responders): +4.5 g/dL
Tri-lineage response (CR): 7/25 (28%)
Clonal cytogenetic abnormalities: 6/24 evaluable (25%) — including monosomy 7, trisomy 8, del(13q)
Median Hgb increase (responders): +4.5 g/dL
Adverse events
Hepatic: ALT/AST elevation grade ≥3 in 4 patients (led to dose reduction)
Clonal evolution: cytogenetic evolution in 6/24 evaluable (25%), a concerning signal including acquired monosomy 7 (some abnormalities spontaneously regressed)
Other: nausea, fatigue, headache grade 1–2 common; no thromboembolic events; no deaths attributed to eltrombopag
Clonal evolution: cytogenetic evolution in 6/24 evaluable (25%), a concerning signal including acquired monosomy 7 (some abnormalities spontaneously regressed)
Other: nausea, fatigue, headache grade 1–2 common; no thromboembolic events; no deaths attributed to eltrombopag
Conclusions
Eltrombopag produced hematologic responses in 44% of patients with refractory SAA who had failed prior immunosuppression, establishing TPO receptor agonism as a novel approach to drive hematopoietic stem cell recovery in aplastic anemia.
Key Limitations
Design: small single-arm study (N=25) without a randomized control
Population: highly selected single-center NIH refractory cohort
Safety: 25% rate of clonal cytogenetic abnormalities (including monosomy 7) raises clonal-evolution/MDS concern and mandates close cytogenetic monitoring
Population: highly selected single-center NIH refractory cohort
Safety: 25% rate of clonal cytogenetic abnormalities (including monosomy 7) raises clonal-evolution/MDS concern and mandates close cytogenetic monitoring
Clinical Context
This proof-of-concept trial led to FDA approval of eltrombopag (Promacta) for refractory SAA in August 2014. It established TPO-receptor agonism as a salvage strategy in IST-refractory SAA and set the stage for moving eltrombopag into the first-line setting (Townsley 2017; RACE trial). Allogeneic HSCT remains an option for eligible refractory patients with a suitable donor. Ongoing cytogenetic surveillance is recommended given the clonal-evolution signal.