Eltrombopag in combination with immunosuppressive therapy in pediatric severe aplastic anemia: phase 2 ESCALATE trial

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.

Graphical abstract

Figure 1.

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.

Figure 2.

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.

Figure 3.

Eltrombopag exposure and response duration. Swimmer plot for duration of response (NAPAAC criteria) and exposure to eltrombopag in the R/R cohort (A) and treatment-naïve SAA cohort (B). Full analysis set. Swimmer plots with each lane representing an individual patient’s treatment duration, timing of CR/PR, response duration, and if applicable, drug interruption. The purple line represents time on eltrombopag, the green line represents duration of response without interruption of NR, and the gray bar represents time off treatment. NR, nonresponder.