Children with refractory/relapsed (R/R) or previously untreated severe aplastic anemia (SAA) who received eltrombopag (ETB) had a positive overall response rate (ORR), according to study results presented at the 2022 ASH Annual Meeting.

The multi-institutional, phase 2, dose-escalation ESCALATE study (ClincialTrials.gov Identifier: NCT03025698) assessed the pharmacokinetics (PK), safety, efficacy, and acceptability of the thrombopoietin receptor agonist ETB in pediatric patients (age 1 to <18 years) with R/R SAA after immunosuppressive therapy (IST; cohort A) or those who had previously untreated SAA (cohort B).

The participants received ETB as tablets or powder for oral suspension. Those in cohort A received ETB with IST (horse antithymocyte globulin [hATG] + cyclosporin A [CsA]) or ETB + CsA, by investigator choice. Participants in cohort B received ETB + hATG + CsA. The initial ETB dose was 50 mg/day (25 mg/day in patients aged <6 years) and was adjusted to achieve a target platelet count of 50 to 200 × 109/L. The maximum allowed daily dose was 150 mg. The data cutoff for the current analysis was 78 weeks. ETB was administered for 26 weeks and initiated with CsA (for ≥104 weeks) with or without hATG (days 1-4). The follow-up included 52 additional weeks when ETB could be continued.


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The primary endpoint was ETB PK. Secondary endpoints included safety/tolerability, ORR, bone marrow cellularity, morphology, cytogenetics, paroxysmal nocturnal hemoglobinuria (PNH) clonal evolution, and acceptability/palatability. The ORR included participants who had a complete or partial response.

A total of 51 patients (14 in cohort A, 37 in cohort B) were included. At week 26, the ORRs were 71.5% for cohort A and 45.9% for cohort B. At week 52, the ORRs were 50.9% and 45.9% in the 2 groups, respectively.

The most common adverse events (AEs) among all patients were increased bilirubin (43%), alanine aminotransferase (41%), creatinine (39%), and aspartate aminotransferase (33%), hypertension (31%), hypomagnesemia (26%), and increased blood urea (24%).

A patient with R/R SAA had PNH on day 329, with no sustained response. Additionally, 2 patients had bone marrow chromosomal abnormalities, and 1 patient with treatment-naïve SAA progressed to acute myeloid leukemia on day 1261.

Among the 48 patients who had bone marrow assessment at baseline, 29 had no bone marrow fibrosis progression (25 with no change in grade and 4 with a reduction in grade). The other patients had mild and transient changes, with 7 patients who had grade 0 bone marrow at baseline progressing to grade 1.

A majority of participants (37/51) achieved the maximum ETB daily dose of 150 mg/day. The median duration of ETB exposure at the maximum dose was 140 days (range, 19-884), and the median daily dose intensity was 105.4 mg/day (range, 8.1-142.8). The tablet and powder for oral suspension formulations of ETB were similar regarding acceptability and palatability.

The area under the curve during the dosing interval at steady state (AUCtau,ss) in μg∙h/mL was 1230 (43) among participants aged 1 to <6 years vs 733 (63) in those aged 6 to <18 years, per geometric mean (coefficient of variation percentage). The dose-adjusted AUCtau,ss in μg∙h/mL was 447 (54) in those aged 1 to <6 years vs 321 (58) in those aged 6 to <18 years. The dose-adjusted maximum plasma concentration at steady state in μg/mL was 25.8 (46) in those aged 1 to <6 years vs 16.6 (52) in those aged 6 to <18 years.

“ETB is a well-tolerated treatment option for pediatric patients with R/R or treatment-naïve SAA,” the investigators commented in their presentation. “The pharmacokinetics of ETB in pediatric patients with SAA showed relatively higher exposure in younger (1 to <6 years) vs older (6 to <18 years) patients.”

Disclosure: Some of the study authors declared affiliations with biotech, pharmaceutical, or device companies. Please see the original reference for a full list of authors’ disclosures.

Reference
Shimamura A, Maschan A, Bennett C, et al. Eltrombopag in pediatric patients with previously untreated or refractory/relapsed severe aplastic anemia: the phase II escalate trial. Presented at ASH 2022. December 10-13, 2022. Abstract 289.