Highlights
- Eltrombopag (ELTR), a thrombopoietin receptor agonist, combined with immunosuppressive therapy (IST) yields a 54.9% overall response rate in pediatric severe aplastic anemia (SAA) at 26 weeks.
- Patients with relapsed/refractory SAA demonstrate higher response rates (71.4%) compared to treatment-naive cohorts (48.6%).
- Significant transfusion independence is achieved in transfusion-dependent patients: approximately two-thirds for red blood cells and over three-quarters for platelets.
- Safety profiles remain manageable, primarily hepatic enzyme elevations without new safety signals.
Background
Severe aplastic anemia (SAA) is a rare, life-threatening bone marrow failure syndrome characterized by pancytopenia and hypocellular marrow. Conventional immunosuppressive therapy (IST) with antithymocyte globulin (ATG) and cyclosporine A (CsA) improves hematopoiesis but has limited efficacy in relapsed or refractory cases and leaves many patients dependent on transfusions.
Eltrombopag, an oral, non-peptide thrombopoietin receptor agonist (TPO-RA), has shown the capability to stimulate trilineage hematopoiesis. Early phase studies and compassionate use reports suggested efficacy in refractory SAA, prompting trials integrating eltrombopag with IST, aiming to improve response rates, reduce transfusion dependence, and enhance quality of life.
![Patient disposition. ∗Three patients (R/R SAA, n = 2; treatment-naïve SAA, n = 1) who discontinued the treatment phase early entered the 52-week follow-up period. †As of data cutoff, 4 May 2023, 15 patients were receiving ongoing treatment, 9 patients discontinued (the reasons for discontinuation included AE [n = 1], physician decision [n = 3], patient/guardian decision [n = 3], and progressive disease [n = 2]), and 4 patients completed 3-year long-term follow-up.](https://ash.silverchair-cdn.com/ash/content_public/journal/bloodadvances/9/15/10.1182_bloodadvances.2024015102/2/m_blooda_adv-2024-015102-gr1.jpeg?Expires=1758139564&Signature=hevcwABsi2sIxZfIGkav8EnRTixeivVGxC-y029Kc926MeyofFZEfQjGa5UUGJ2qoPKYQL1YNqPYBKwJL0zsEq8O1lbj3tyRrDmJFmLfJ8~I9sXMrYwxaX~YCZ2qVtPBE3wZUIuSd05YpFR8yU1bCVFnys05mIoiBCNzL14yeqRHkMxsjhyH9i3IT1FS5yECICHhda7ILN0eoxWHENRUahcn-IaCaTtRIB2UIayB9AgIEAisFDrk5t112DewtATT0YGU~LYqG0IbXMHwpgSIKFrLYg8nc6d1Mrb9F9xYsvZCxRLfvBYciqlEGb0wA~fvl14gho3ttHiq-n5w14PyMA__&Key-Pair-Id=APKAIE5G5CRDK6RD3PGA)
Key Content
Chronological Development of Evidence
- 2014: Initial phase 2 study demonstrated eltrombopag’s efficacy in refractory SAA with 40% overall response, including multilineage improvement and sustained responses after drug discontinuation (Olnes et al., Blood 2014).
- 2019: Dose optimization trials established that prolonged 150 mg daily dosing extended responses, rescued nonresponders at 12 weeks, with clonal evolution rates comparable to historical controls (Desmond et al., Blood 2019).
- 2020-2023: Multiple studies explored eltrombopag’s role in moderate aplastic anemia and treatment-naive pediatric patients, often with mixed results on overall response but consistent indications of improved complete response rates and safety (Peffault de Latour et al., Blood Adv 2020; Yoshimi et al., Blood Adv 2023).
- 2025 (ESCALATE trial): The pivotal phase 2, open-label, non-controlled ESCALATE trial investigated eltrombopag plus IST in pediatric SAA, including relapsed/refractory and treatment-naive cohorts, confirming a 54.9% overall response at 26 weeks, with particularly high responses in relapsed/refractory patients (Shimamura et al., Blood Adv 2025).
Evidence by Therapeutic Context
Relapsed/Refractory Severe Aplastic Anemia
In the ESCALATE trial, 14 relapsed/refractory pediatric patients treated with eltrombopag plus IST displayed a 71.4% overall response rate. Moreover, 70% and 80% achieved red blood cell and platelet transfusion independence, respectively. No new safety issues emerged. This cohort aligns with adult refractory SAA studies showing eltrombopag’s ability to restore hematopoiesis even after prior IST failure.
Treatment-Naive Pediatric Severe Aplastic Anemia
Among 37 treatment-naive pediatric patients, the ORR was 48.6%, with transfusion independence rates similar to the relapsed group, demonstrating substantial clinical benefit. However, other pediatric trials have reported variable benefits, with some showing no significant improvement in overall response but increased rates of complete remission when eltrombopag is added to IST.
Response rates. (A) ORR. (B) Best ORR. Full analysis set. Data cutoff was 4 May 2023. Response was assessed per NAPAAC (North American Pediatric Aplastic Anemia Consortium) criteria. Values displayed above the bars are the ORRs, along with 95% confidence interval (CI). ORR is defined as the proportion of patients achieving CR or PR. Best overall response is the proportion of patients with CR or PR at any time point up to data cutoff; 95% CI values were computed with the exact method of Clopper-Pearson. NR, nonresponder.
Adult Severe Aplastic Anemia
Adults with untreated SAA treated with eltrombopag plus IST demonstrate improved hematologic response rates without significant additional toxicity, supporting the translational potential of pediatric findings to adult populations.
Safety and Adverse Event Profile
Liver enzyme elevations, including increased bilirubin (43.1%), alanine aminotransferase (37.3%), and aspartate aminotransferase (33.3%), constitute the most common treatment-related adverse events. These were mostly manageable and reversible. Clonal evolution risks remain under ongoing surveillance but do not appear increased compared to historical data.
Mechanistic Insights and Translational Implications
Eltrombopag acts on the thrombopoietin receptor (c-Mpl) promoting hematopoietic stem and progenitor cell proliferation across lineages, augmenting marrow recovery alongside immunosuppressive agents that abrogate autoimmune-mediated marrow destruction. As an intracellular iron chelator, eltrombopag may additionally confer cytoprotective effects in certain marrow failure syndromes such as Diamond-Blackfan anemia.
Expert Commentary
The ESCALATE trial and supporting studies signify a paradigm shift, integrating eltrombopag into frontline and refractory aplastic anemia treatment strategies. The superior response in relapsed/refractory patients underlines eltrombopag’s unique ability to stimulate residual hematopoiesis.
Nevertheless, pediatric responses vary, and some trials suggest caution before routine integration into frontline therapy, especially given the potential for hepatic toxicity and long-term risk of clonal evolution which warrants rigorous monitoring.
Guidelines are evolving; many hematology societies now consider eltrombopag an adjunct to IST, particularly in adults or refractory disease. Its oral administration and multi-lineage efficacy represent practical advantages.
Outstanding issues include optimal dosing schedules, duration of therapy, management of hepatic and clonal risks, and investigation of biomarkers predicting response.
Conclusion
Eltrombopag combined with immunosuppressive therapy marks a significant advancement in the care of severe aplastic anemia, particularly for relapsed/refractory pediatric patients and adults. It improves overall and complete response rates and facilitates transfusion independence with an acceptable safety profile. Continued research will refine patient selection, optimize treatment protocols, and clarify long-term safety to fully realize eltrombopag’s transformative potential.
References
- Shimamura A et al. Eltrombopag in combination with immunosuppressive therapy in pediatric severe aplastic anemia: phase 2 ESCALATE trial. Blood Adv. 2025 Aug 12;9(15):3728-3738. doi:10.1182/bloodadvances.2024015102 IF: 7.1 Q1 . PMID:40315366 IF: 7.1 Q1 . PDF download
- Olnes MJ et al. Eltrombopag and improved hematopoiesis in refractory aplastic anemia. Blood. 2014 Mar 20;123(12):1818-25. doi:10.1182/blood-2013-10-534743 IF: 23.1 Q1 . PMID:24345753 IF: 23.1 Q1 .
- Desmond R et al. Treatment optimization and genomic outcomes in refractory severe aplastic anemia treated with eltrombopag. Blood. 2019 Jun 13;133(24):2575-2585. doi:10.1182/blood.2019000478 IF: 23.1 Q1 . PMID:30992268 IF: 23.1 Q1 .
- Peffault de Latour R et al. Eltrombopag for patients with moderate aplastic anemia or uni-lineage cytopenias. Blood Adv. 2020 Apr 28;4(8):1700-1710. doi:10.1182/bloodadvances.2020001657 IF: 7.1 Q1 . PMID:32330244 IF: 7.1 Q1 .
- Yoshimi A et al. Efficacy of combined immunosuppression with or without eltrombopag in children with newly diagnosed aplastic anemia. Blood Adv. 2023 Mar 28;7(6):953-962. doi:10.1182/bloodadvances.2021006716 IF: 7.1 Q1 . PMID:35446936 IF: 7.1 Q1 .