Background
Phase 2 single-arm prospective study. 153 treatment-naïve severe aplastic anemia (SAA) patients without a matched sibling donor, enrolled in sequential cohorts to optimize eltrombopag timing: cohort 1 (n=31, eltrombopag day 14); cohort 2 (n=31, day 1 without escalation); cohort 3 (n=91, day 1 with dose escalation). All received standard horse ATG (hATG) + cyclosporine. Eltrombopag is a thrombopoietin receptor agonist that stimulates hematopoietic stem cell proliferation. Designed to improve on the historical ~66% response rate with hATG + cyclosporine alone.
Interventions and follow up
Regimen: Horse ATG (hATG) + cyclosporine + eltrombopag in three sequential cohorts varying start time/dose — cohort 1 (day 14, 150 mg, n=31); cohort 2 (day 1, 150 mg no escalation, n=31); cohort 3 (day 1 with escalation, n=91)
Primary endpoint: Hematologic response at 6 months (robust = CR or partial response by NIH criteria)
Median follow up: 24 months
Primary endpoint: Hematologic response at 6 months (robust = CR or partial response by NIH criteria)
Median follow up: 24 months
Results
Overall response at 6 months (cohorts 2+3): 94% (vs ~66% historical IST alone)
Complete response at 6 months (cohorts 2+3): 58% (vs ~11% historical)
Cohort 3 at 6 months: 94% overall response, 58% CR
2-year overall survival: 97%
Complete response at 6 months (cohorts 2+3): 58% (vs ~11% historical)
Cohort 3 at 6 months: 94% overall response, 58% CR
2-year overall survival: 97%
Adverse events
Hepatic: eltrombopag-related liver transaminase elevation grade ≥3 in ~15% (required dose reduction/discontinuation in some)
Clonal evolution: cytogenetic evolution in 8% (5/62 evaluable), including monosomy 7
Other: serum sickness from hATG 7%; opportunistic infections from immunosuppression common; no thromboembolic events attributed to eltrombopag
Clonal evolution: cytogenetic evolution in 8% (5/62 evaluable), including monosomy 7
Other: serum sickness from hATG 7%; opportunistic infections from immunosuppression common; no thromboembolic events attributed to eltrombopag
Conclusions
Adding eltrombopag to standard hATG + cyclosporine substantially improved hematologic response rates in treatment-naïve SAA (94% vs ~66% historical), with a notably high complete response rate (58%), establishing this triplet as a new treatment standard.
Key Limitations
Design: single-arm with historical comparison rather than a randomized control
Population: single-center NIH cohort; may not generalize to community practice
Safety: clonal cytogenetic evolution (8%, including monosomy 7) raises concern over long-term clonal/MDS risk requiring extended surveillance
Population: single-center NIH cohort; may not generalize to community practice
Safety: clonal cytogenetic evolution (8%, including monosomy 7) raises concern over long-term clonal/MDS risk requiring extended surveillance
Clinical Context
Established horse ATG + cyclosporine + eltrombopag as front-line immunosuppressive therapy for SAA in patients who are not transplant candidates; eltrombopag was FDA approved for first-line SAA (with IST) in November 2018. The subsequent randomized RACE trial (Peffault de Latour, NEJM 2022) confirmed superior response and faster recovery with added eltrombopag. Allogeneic HSCT from a matched sibling donor remains preferred for younger patients with a suitable donor. ESMO guidelines incorporate the triplet for non-transplant candidates.