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.