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Eltrombopag in combination with immunosuppressive therapy in pediatric severe aplastic anemia: phase 2 ESCALATE trial
Akiko Shimamura1, Alexey Maschan2, Caroyln Bennett3
1Division of Hematology/Oncology, Boston Children's Hospital, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Harvard Medical School, Boston, MA.
Insights
Eltrombopag combined with immunosuppressive therapy (IST) demonstrated a 54.9% overall response rate in pediatric severe aplastic anemia (SAA) patients. This combination therapy showed promise, particularly in relapsed/refractory SAA cases, with manageable safety.
Area of Science:
- Hematology
- Pediatric Oncology
- Pharmacology
Background:
- Severe aplastic anemia (SAA) is a rare, life-threatening condition characterized by pancytopenia and bone marrow failure.
- Pediatric SAA presents unique challenges, necessitating evaluation of novel therapeutic strategies.
- Eltrombopag, a thrombopoietin receptor agonist, has shown efficacy in adult SAA.
Purpose of the Study:
- To evaluate the efficacy and safety of eltrombopag in combination with immunosuppressive therapy (IST) in pediatric patients with severe aplastic anemia (SAA).
- To assess response rates and transfusion independence in both treatment-naïve and relapsed/refractory pediatric SAA populations.
- To identify treatment-related adverse events associated with this combination therapy in children.
Main Methods:
- The ESCALATE study enrolled 51 pediatric patients (1 to <18 years) with SAA, categorized into treatment-naïve (n=37) and relapsed/refractory (r/r, n=14) cohorts.
- Patients received eltrombopag (starting dose 25-50 mg/day, max 150 mg/day) with cyclosporine A, with or without horse anti-thymocyte globulin, for 26 weeks.
- Overall response rate (ORR) and transfusion independence were assessed using North American Pediatric Aplastic Anemia Consortium criteria.
Main Results:
- The overall response rate (ORR) at 26 weeks was 54.9% across both cohorts.
- The r/r SAA cohort showed a higher ORR (71.4%) compared to the treatment-naïve cohort (48.6%).
- Among transfusion-dependent patients, significant rates of red blood cell (66.7%) and platelet (76.7%) transfusion independence were achieved, with sustained responses observed post-treatment.
Conclusions:
- Eltrombopag in combination with IST is effective in treating pediatric severe aplastic anemia, showing a favorable overall response rate.
- The combination therapy demonstrated a trend towards a higher ORR in the relapsed/refractory SAA cohort.
- The safety profile was consistent with known risks, with liver function test abnormalities being the most common adverse events, and no new safety signals were identified.
Abstract:
Severe aplastic anemia (SAA) is a rare, life-threatening disease with acquired pancytopenia and hypocellular bone marrow. ESCALATE evaluated eltrombopag in combination with immunosuppressive therapy (IST) in pediatric patients (aged 1 to <18 years) with relapsed/refractory (R/R) or treatment-naïve SAA. The eltrombopag starting dose was 25 mg/d for patients aged 1 to <6 years and 50 mg/d for patients aged 6 to <18 years; dose modifications (maximum dose, 150 mg/d) were allowed to achieve a target platelet count of 50 × 109/L to 200 × 109/L. Eltrombopag was administered with cyclosporine A, with or without horse antithymocyte globulin, for 26 weeks and could be extended if clinically beneficial. Fifty-one patients were treated (R/R SAA, n = 14; treatment-naïve SAA, n = 37). Data were analyzed overall and as 2 cohorts: R/R and treatment-naïve cohorts. The overall response rate (ORR; per North American Pediatric Aplastic Anemia Consortium criteria) at 26 weeks was 54.9% in both cohorts combined and 71.4% and 48.6% in the R/R and treatment-naïve cohorts, respectively; most responders had sustained responses after discontinuing eltrombopag. Among baseline transfusion-dependent patients, 66.7% and 76.7% achieved red blood cell and platelet transfusion independence, respectively, with rates of 70% and 80% for the R/R cohort and 65.6% and 75.8% for the treatment-naïve cohort, respectively. The most common treatment-related adverse events were abnormalities in liver function tests, including increased bilirubin (43.1%), alanine aminotransferase (37.3%), and aspartate aminotransferase (33.3%). Eltrombopag with IST showed a trend toward a favorable ORR in the R/R cohort, with no new safety signals. This trial was registered at www.clinicaltrials.gov as #NCT03025698.
