Background
Prospective, open-label, multicenter, investigator-led phase III RCT comparing horse ATG plus cyclosporine with or without eltrombopag in previously untreated patients with severe aplastic anemia (SAA).
Interventions and follow up
Arm A: immunosuppressive therapy (IST) alone – horse ATG + cyclosporine
Arm B: IST + eltrombopag (96 patients)
Primary endpoint: hematologic complete response (CR) at 3mo
mFollow up: 24mo
Arm B: IST + eltrombopag (96 patients)
Primary endpoint: hematologic complete response (CR) at 3mo
mFollow up: 24mo
Results
CR at 3mo: 10% (Arm A) vs 22% (Arm B); OR 3.2, 95% CI 1.3–7.8, P=.01
ORR at 6mo: 41% vs 68%
Median time to first response: 8.8mo vs 3.0mo
Event-free survival: 34% vs 46%
Karyotypic abnormality classified as MDS: 1 vs 2 patients
Somatic mutations detected at baseline: 29% vs 31%; at 6mo 66% vs 55%, without affecting hematologic response or 2-year outcome
ORR at 6mo: 41% vs 68%
Median time to first response: 8.8mo vs 3.0mo
Event-free survival: 34% vs 46%
Karyotypic abnormality classified as MDS: 1 vs 2 patients
Somatic mutations detected at baseline: 29% vs 31%; at 6mo 66% vs 55%, without affecting hematologic response or 2-year outcome
Adverse events
Overall: rate of severe adverse events was similar between the two groups; adding eltrombopag was generally well tolerated
Common events: elevated liver enzymes, gastrointestinal symptoms, and skin discoloration; clonal evolution rates similar to historical IST cohorts
Common events: elevated liver enzymes, gastrointestinal symptoms, and skin discoloration; clonal evolution rates similar to historical IST cohorts
Conclusions
Adding eltrombopag to standard IST improved the rate, rapidity, and strength of hematologic response vs IST alone in previously untreated SAA, without added toxicity.
Key Limitations
Open-label design; no OS benefit demonstrated at this follow-up. European trial used a different eltrombopag schedule than the prior NIH study, and longer follow-up is needed to assess late clonal evolution.
Clinical Context
Confirms, in a randomized European setting, the prior NIH single-arm experience supporting eltrombopag added to horse ATG plus cyclosporine as first-line therapy for SAA in patients not proceeding to upfront transplant. ESMO and ASH guidance endorse adding eltrombopag to IST.