Discussion
Eltrombopag interacts selectively with the thrombopoietin receptor without competing with thrombopoietin; it interacts with the transmembrane domain of human thrombopoietin receptor, initiates a signaling cascade and induces the proliferation and differentiation of bone marrow progenitor cells, and leads to increased proliferation and differentiation of human bone marrow progenitor cells into megakaryocytes and elevated platelet production[18].
The National Institutes of Health (NIH) conducted an adult SAA study, which enrolled 92 consecutive patients in a prospective phase 1–2 study of IST plus eltrombopag as the first line therapy. The CR and OR rates were 39.1% and 87.0% at 6 months, respectively, and the response rate of the eltrombopag group was higher than that of the control group, suggesting that addition of eltrombopag to IST is associated with markedly higher rate of hematologic response among SAA patients[11]. Based on this study, the FDA approved eltrombopag for the first-line treatment of SAA. Meanwhile, the NIH published a prospective study of eltrombopag in children in 2021, with eltrombopag as the first-line therapy for IST of AA, which showed that in the eltrombopag and control groups, the OR rates were 70% and 72%, respectively, at 6 months (P=0.78). CR totaled 30% in the eltrombopag group versus 23% in the control group at 6 months, without statistical significance (P=0.42). This pointed out that addition of eltrombopag to standard IST did not improve outcomes in children with SAA, and eltrombopag in the pediatric population should not automatically be considered the standard of care [14]. On the other hand, a study performed in Greece showed OR and CR rates of 81.8% and 72.7% at 3 months, respectively, indicating addition of eltrombopag to IST is associated with increased hematological response[19]. St. Jude Children’s Research Hospital reported in 2021 that addition of eltrombopag to standard IST was well tolerated and resulted in satisfactory hematological response at 6 and 12 months [15]. Olga Goronkova firstly published a multicenter randomized study assessing eltrombopag in combination with standard IST in children with SAA for efficacy and safety in 2022. They concluded that adding eltrombopag to standard IST was well tolerated and increased the CR rate in children [20]. Previous studies assessing children have shown conflicting results. We conducted this study, analyzed SAA cases in children in our center retrospectively, and compared the eltrombopag + IST group with the standard IST group, with comparable baseline features in the two groups. This study showed a faster response in blood count because of the shorter time from G-CSF, red blood cell transfusion and platelet transfusion; meanwhile, eltrombopag reduced the response time. Furthermore, the CR rates were higher in the eltrombopag group compared with the control group at 3 months and 6 months after IST, suggesting that eltrombopag shows a better and earlier hematological response. However, the CR rate at 12 months and the OR rates at 3, 6 and 12 months after IST all showed no significant differences between the two groups. Therefore, in this study eltrombopag combined with IST showed no advantages in OR and long-term CR rates. Whether our findings were affected by loss to follow-up and different follow-up times is unknown.
In a study by the NIH on pediatric SAA, 43% cases relapsed (n=12) in the eltrombopag group versus 27% in the control group, with a trend towards higher relapse rate compared with IST alone. EFS at 1432.5 days (median follow-up time in the eltrombopag group) in 6-month responders was significantly lower in the eltrombopag group (57%) compared with the IST group (69%) [14]. However, other pediatric studies showed no significant differences in relapse rate and EFS between the eltrombopag and control groups[15-16]. In this study, the OS rates were 97.0% in the eltrombopag group and 96.0% in the control group. There was no significant difference in relapse rate between the two groups. Clonal evolution, progression to myelodysplastic syndrome and acute myeloid leukemia were also assessed in this study. Until the end of follow-up, no cases of clonal evolution were found in the eltrombopag group, while one case in the control group progressed to myelodysplastic syndrome. There were few cases of clonal evolution, which may be related to insufficient follow-up time. Long-term EFS rates in this study were 66.6% in the eltrombopag group and 57.1% in the control group, with no significant difference.
The potential toxicity of eltrombopag includes thrombocytosis, thrombosis, reversible bone marrow fibrosis, rebound thrombocytopenia, cataract formation, and reversible hepatic dysfunction[20]. Many studies have reported that eltrombopag shows satisfactory safety in children [4] [11] [14-16]. Eltrombopag was not discontinued because of adverse events in any patient in this study, showing that eltrombopag is well tolerated in children with SAA.
Based on these results, eltrombopag added to IST confers faster hematological response and higher early hematological response rate. Eltrombopag is well tolerated in pediatric aplastic anemia patients. However, it has no impact on long-term response rate and prognosis in this study. A prospective study is required, and long-term survival needs further investigation.