Pediatric Hematology and Oncology

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Efficacy and safety of eltrombopag in the first-line

therapy of severe aplastic anemia in children

Ma Jie, Lingling Fu, Sidan Li, Yixuan He, Jiafeng Yao, Xiaoling Cheng, Liqiang
Zhang, Jie Zheng, Rui Zhang & Runhui Wu

To cite this article: Ma Jie, Lingling Fu, Sidan Li, Yixuan He, Jiafeng Yao, Xiaoling Cheng, Liqiang
Zhang, Jie Zheng, Rui Zhang & Runhui Wu (2021): Efficacy and safety of eltrombopag in the
first-line therapy of severe aplastic anemia in children, Pediatric Hematology and Oncology, DOI:
10.1080/08880018.2021.1900475

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PEDIATRIC HEMATOLOGY AND ONCOLOGY
https://doi.org/10.1080/08880018.2021.1900475

Efficacy and safety of eltrombopag in the first-line therapy

of severe aplastic anemia in children
Ma Jie, Lingling Fu, Sidan Li, Yixuan He, Jiafeng Yao, Xiaoling Cheng,
Liqiang Zhang, Jie Zheng, Rui Zhang, and Runhui Wu
Department of Pediatric Hematology and Oncology, Beijing Children Hospital, Beijing, China

ABSTRACT ARTICLE HISTORY

Eltrombopag is being investigated for the treatment of aplastic Received 8 June 2020
anemia (AA) by stimulating hematopoietic stem cell (HSC) prolifer- Revised 10 February 2021
ation. To evaluate the efficacy and safety of eltrombopag in the first- Accepted 1 March 2021
line therapy of pediatric AA. The present retrospective study
KEYWORDS
assessed pediatric patients with newly diagnosed AA administered Aplastic anemia; children;
immunosuppressive therapy (IST) (rabbit ATG combined with CSA) eltrombopag; first-
with eltrombopag at a single center from March to September 2017. line therapy
All patients were followed up for >2 years. A total of 14 patients (8
males), averagely aged 86 months, were enrolled in this study.
Eltrombopag was administered with a median time to initiation of
19.5 days after IST; the median course of treatment was 253 days.
Complete and overall response rates at 6 months were 64.3% (9/14
case) and 78.6% (11/14 cases), respectively. The survival rate was
100%, and no relapse occurred in responders. Eltrombopag was
well-tolerated; however, the most common adverse events included
indirect bilirubin elevation, jaundice, and transient liver-enzyme ele-
vation. By the end of follow-up, bone marrow chromosomes were
normal, and no abnormal myelodysplastic syndrome (MDS)-related
clones appeared. Addition of eltrombopag to IST is associated with
markedly increased complete response with respect to hematology
in pediatric patients with SAA compared with a historical cohort,
without intolerable side effects.

Aplastic anemia (AA) is a potentially life-threatening hematopoietic stem cell (HSC)

disorder resulting in cytopenia. Although its pathogenesis remains unclear, it is widely
admitted that the main cause of AA is the immunological attack of bone marrow hem-
atopoietic cells by dysfunctional T lymphocytes.1 The annual morbidity of AA was
reported to be 2–6 per million individuals in North America and Europe. In Asia,
including China, this value is tripled or even quadrupled.2 Curative treatment of severe
aplastic anemia (SAA) involves allogeneic hematopoietic stem cell transplantation
(HSCT). HSCT outcome improved significantly with time for both human leucocyte
antigen (HLA)-matched sibling donor (MSD) and alternative donor transplants, and
was better in children.3 Although HSCT is considered curative for the underlying bone
marrow aplasia, there remain significant associated risks, which include acute and

CONTACT Runhui Wu runhuiwu@hotmail.com Department of Pediatric Hematology & Oncology, Beijing Children
Hospital, No. 56 Nanlishi Road, Xicheng District, Beijing 100045, China.
ß 2021 Taylor & Francis Group, LLC
2 M. JIE ET AL.

chronic graft-versus-host disease, an increased risk of malignancy, and infertility related

to HSCT conditioning, although reduced intensity conditioning approaches may minim-
ize late morbidity.4 Immunosuppressive therapy (IST), combining antithymocyte globu-
lin (ATG) and cyclosporin A (CSA), could represent an alternative option and has been
widely used in patients lacking MSD or ineligible for HSCT because of age.5,6 While the
overall survival did not differ between patients treated with IST or HSCT, failure-free
survival was significantly inferior in patients receiving IST than in those undergoing
HSCT.3,5,6 The response rate to IST in children with AA is 50–80%. The long-term
overall survival rate of 90% and failure-free survival was 60%.3,7–13 Many studies report
outcomes with rATG due to the withdrawal of hATG from some European and Asian
markets in 2007. Studies mainly in adults, conducted by the NIH and EBMT, have
shown the superiority of hATG14,15; meanwhile, reports only assessing children in Asian
countries have shown that hATG and rATG have an equivalent efficacy.8 A potential
limit to the efficacy of immunosuppression is the stem-cell deficit. Therefore, agents
that engage HSCs and progenitor receptors might be beneficial. C-mpl is expressed on
HSCs and progenitor cells, and addition of recombinant thrombopoietin (TPO) ampli-
fies primitive HSCs in murine studies.16 Eltrombopag, an oral synthetic small-molecule,
is a noncompetitive TPO agonist. Because of good patient compliance and its potent
effects, eltrombopag is currently the only US Food and Drug Administration (FDA)-
approved thrombopoietin receptor agonist for the treatment of chronic immune
thrombocytopenia (ITP) in children.17 In recent years, eltrombopag has been demon-
strated to be effective for refractory and newly diagnosed AA in adults.18–21 However, a
recent study by the NIH showed that eltrombopag does not improve the overall
response rate (ORR) at 6 months in a pediatric cohort.22 There may be differences in
the efficacy of eltrombopag between children and adults. Herein, we reported the results
of a trial evaluating the combination of eltrombopag with IST in children with newly
diagnosed severe AA (SAA) to assess the efficacy and safety of eltrombopag in the first-
line treatment of Asian children with SAA.

Materials and methods

Patients
This investigator-initiated retrospective clinical study of eltrombopag in children with
newly diagnosed severe AA reviewed data in a single-center, Beijing Children’s Hospital
affiliated Capital Medical University, for a period of 6 months from March to
September 2017. The study was approved by the Ethics Committee of Beijing
Children’s Hospital.
Inclusion criteria were: <18-years of age; previously untreated SAA, defined by bone
marrow cellularity <30%, and at least 2 of the following criteria including absolute
neutrophil count (ANC) <0.5
109/L, pre-transfusion platelet count <20
109/L, and
pre-transfusion reticulocyte count <20
109/L.23 Those with congenital bone marrow
failure syndromes were excluded.
 PEDIATRIC HEMATOLOGY AND ONCOLOGY 3

Treatment regimen
1. Rabbit ATG (rATG) and CSA were administered as standard immunosuppression.
Before rATG administration, the patients received a subcutaneous test dose to check for
potential hypersensitivity: rATG at a dosage of 3.3–3.5 mg/kg/day intravenously for
5 days; methylprednisone at a dose of 2 mg/kg/day intravenously for 5 days (before each
dose of rATG), followed by oral prednisone that was tapered off over 14 days; subcuta-
neous granulocyte-colony stimulating factor (G-CSF) starting on day 1 to maintain the
ANC at 1.0
109/L; CsA at a dose of 5 mg/kg/day orally starting on day 1 to maintain
serum trough concentration at approximately 100–200 mg/dL. Serum CsA levels were
measured every 2–4 weeks while the patients were receiving the drug. CsA was adminis-
tered in full dose for at least 1.5 years and reduced by 1.5 years unless frequent dose
reductions or interruptions were required due to toxicity. The enrolled patients were
transfused with blood products as per the institutional policy.
2. Eltrombopag was administered orally on an empty stomach at a dose of 75 mg
daily in patients 6-years old, and at 2.5 mg/kg body weight/day in 2–5-year-old indi-
viduals. With platelet count >300
109/L or toxicity considered to be related to eltrom-
bopag, the drug was withheld until the count dropped to <100
109/L. For responders
not meeting the above criteria, eltrombopag was continued indefinitely or discontinued
at the discretion of the treating physician.

Observation indexes
1. Efficacy parameters: The primary indexes included complete response (CR) and par-
tial response (PR) rates at 3, 6, 12, and 24 months. Secondary indexes included the time
to response (TTR) and times of transfusion independence for G-CSF, RBC,
and platelets.
2. Safety parameters: Safety evaluation included the following parameters: tolerability
and toxicity of eltrombopag; paroxysmal nocturnal hemoglobinuria (PNH) clone (the
threshold PNH clone size was defined as 1% of red blood cells and/or granulocytes);
clonal evolution, defined as a new clonal cytogenetic abnormality or characteristic
changes in the bone marrow, consistent with the myelodysplastic syndrome (MDS) or
acute myeloid leukemia.

Data collection
Pretreatment baseline data included a complete medical history and physical examin-
ation, liver and kidney function tests, and complete blood count (CBC); bone marrow
aspiration and biopsy within 1 month of enrollment; and peripheral blood flow cytome-
try for PNH antigens (CD55 and CD59). In addition, cytogenetic and gene mutation
analyses were performed.
Follow-up data included CBC every 2–4 weeks and liver and kidney function assess-
ments every 1–2 months; a repeat bone marrow biopsy and/or aspiration for morph-
ology; and cytogenetics at 6, 12, and 24 months.
4 M. JIE ET AL.

Follow-up and response criteria

All patients were followed up by telephone by consulting the outpatient/inpatient med-
ical records. The references for response criteria were as follows.23 CR was defined as a
bone marrow sample showing <5% myeloblasts with normal maturation of all cell lines
and no dysplasia, peripheral blood ANC 1
109/L, hemoglobin 10 g/dL, and platelet
count 100
109/L. PR was reflected by transfusion independence and G-CSF with an
ANC 0.5
109/L, hemoglobin 8 g/dL, and platelet count 20
109/L. TTR was
defined as the interval between treatment initiation and the date of response. Time of
transfusion independence for RBC was defined as the interval between treatment initi-
ation and the date when the lowest hemoglobin level was more than 60 mg/L after the
last blood transfusion; time of transfusion independence for platelets was defined as the
interval between treatment initiation and the date when the lowest platelet count was
more than 10
109/L after the last platelet transfusion; time of transfusion independ-
ence for G-CSF was defined as the interval between treatment initiation and the date
when the lowest neutrophil count was more than 0.5
109/L after the last G-
CSF treatment.

Statistical analysis
Demographic and baseline clinical data were summarized by descriptive statistics with
Excel (Microsoft, Redmond, WA, USA). Normally distributed continuous variables were
presented as mean and standard deviation (SD), and non-normally distributed ones
were described as median and interquartile range (IQR). Discrete variables were
expressed as percentage. The Mann-Whitney U test was used to compare continuous
variables and Pearson v2 test was used for categorical variables. P < 0.05 indicated stat-
istical significance. All statistical analyses were performed with SPSS 21.0 for Windows
(IBM Co., Armonk, NY, USA).

Results
Patient characteristics
A total of 14 patients were enrolled in this study. The median age of the cohort at the
time of diagnosis was 86 (range, 24 to 186) months. The male-to-female ratio was
around 1.3:1 (8 males and 6 females). The median disease course before IST was 45
(30.25, 77.5) days. Small PNH clones were detected in 9/14 patients. The median rate of
PNH clones was 1.6 (1.25, 2.3) %. Baseline CBC data before treatment were: neutro-
phils, 0.215 (0.1525, 0.41)
109/L; lymphocytes, 1.105 (0.61, 1.595)
109/L; hemoglobin
(Hb), 67.5 (62.5, 78.75) g/L; platelets (PLT), 6.50 (4.75, 14)
109/L; reticulocytes, 23.2
(13.788, 35.725)
1012/L. Bone marrow biopsy showed <10% of nucleated cell prolifer-
ation in 3 cases, 10–20% in 6 cases, and 20–30% in 5 cases. All patients strictly followed
the medication regimen of eltrombopag, which was administered with a median time to
initiation of 19.5 (range, 4 to 113) days after IST. The median course of eltrombopag
treatment was 253 (range, 129 to 351) days (Table 1).
 PEDIATRIC HEMATOLOGY AND ONCOLOGY 5

Table 1. Patient characteristics.

Characteristic Value
Number of patients (no.) 14
Age in months, median (range) 86 (24-186)
Gender (male/female) 8/6
Course of disease before therapy (days), median (interquartile range) 45(30.25, 77.5)
PNH clones (no.) 9
Percentage of PNH clones (%), median (interquartile range) (interquartile range) 1.6（1.25, 2.3）
Baseline CBC before therapy, median (interquartile range)
Neutrophil count (
109/L） 0.215 (0.1525, 0.41)
Hemoglobin (g/L) 67.5 (62.5, 78.75)
Platelet count (
109/L) 6.50 ( 4.75, 14)
Reticulocyte count (
1012/L) 23.2 (13.788, 35.725)
Marrow cellularity
<10% of nucleated cells (no.) 3
10–20% of nucleated cells (no.) 6
20–30% of nucleated cells (no.) 5
Time to initiation of E-PAG (days after IST), median (range) 19.5 (4  113)
Course of treatment of E-PAG (days), median (range) 253 (129- 351)
Notes: PNH, paroxysmal nocturnal hemoglobinuria; CBC, complete blood count; E-PAG, Eltrombopag; IST, immunosup-
pressive therapy.

Hematological response
All 14 patients were evaluated for treatment response. The median follow-up time was
843.5 (range, 748 to 957) days until December 2019, which was more than 2 years. All
patients stopped the eltrombopag and the median time to stop eltrombopag for res-
ponders was 498 (range, 494 to 669) days at the end of follow-up. No patients stopped
CsA, but all patients began to reduce CsA at the end of follow-up.

Short-term efficacy (within 6 months of treatment)

1.1 At 3 months after therapy initiation, median neutrophil count was 1.425 (1.2175,
1.9575)
109/L, lymphocyte count was 0.845 (0.675, 1.33)
109/L, Hb was 103 (86.75,
113) g/L, PLT count was 64.50 (33.75, 120)
109/L, and reticulocyte count was 66.75
(47.675, 83.775)
1012/L. CR and PR rates were 7.1% (1/14) and 28.6% (4/14), respect-
ively, and 64.3% (9/14) of cases showed no response.
1.2 At 6 months after therapy, median neutrophil count was 1.605 (1.268, 2.31)
109/
L, lymphocyte count was 1.14 (0.74, 1.52)
109/L, Hb was 113.5 (85.25, 121.25) g/L,
PLT count was 130 (26.25, 172.5)
109/L, and reticulocyte count was 52(38.6, 65.25)

1012/L (Figure 1). CR and PR rates were 64.3% (9/14) and 14.2% (2/14), respectively.
HSC transplantation was performed in 3 cases with no response. In 11 patients with
treatment response, median time to response was 102 (75, 121) days, and median times
to transfusion independence were 43 (12, 53) and 37 (2, 53) days for platelets and red
blood cells, respectively. Eight children with bone marrow biopsy had >50% nucleated
cells (6 cases with CR and 2 with PR), 2 had 40–50% (both with CR), and 1 had
30–40% (CR). The primary efficacy end point (complete hematologic response rate at
6 months) exceeded the historical rate of 35.7% in the eltrombopag group (v2 ¼ 4.693,
P ¼ 0.03). The overall response rate (ORR) was also higher compared with the rate in
the historical cohort (v2 ¼ 0.131, P ¼ 0.717) (Table 2).24
6 M. JIE ET AL.

Figure 1. The change of complete blood cell count (CBC) within 24 months of treatment.

Table 2. Comparison between this study and our historical group without eltrombopag.
E-PAG group (14 cases) Historical cohort (28 cases)16 P value
3 months
CR (%) 7.1%（1/14） 10.7%（3/28）
ORR (%) 35.7%（5/14） 64.3%（18/28） 0.079
6 months
CR (%) 57.1%（8/14） 21.4%（6/28） 0.03
ORR (%) 78.5%（11/14） 67.8%（18/28） 0.717
TTR (days) 102（75, 121） 90（60, 90） 0.242
Time to transfusion independence (days) 43（13, 53） 33（20, 50） 0.593
Notes: CR, complete response; ORR, overall response rate; TTR, time to response.

Long-term outcomes
2.1 At 1 year after therapy initiation, all 11 responders were evaluated. One patient with
CR changed to PR, and 1 with PR converted to CR. In general, 9 cases (64.3%) showed
CR and 2 (14.3%) exhibited PR. Bone marrow biopsy from the patient with CR con-
verted to PR showed nucleated cells <20%, indicating a 20% reduction in cell number
compared with that obtained at 6 months.
2.2 Two years after therapy initiation, 9 cases still showed CR, and 2 had PR. No
change was observed in the patients’ response rate compared with 1 year after therapy
initiation. Bone marrow nucleated cell counts in 2 patients with PR were <50%
(20–40% and 40–50%, respectively). Furthermore, bone marrow nucleated cell count
was <10% in 1 patient with CR, who exhibited a 50% reduction than before. Although
the patient is currently in complete remission, the possibility of long-term relapse
 PEDIATRIC HEMATOLOGY AND ONCOLOGY 7

cannot be excluded. At a median follow-up of 2.3 (range: 2–2.6) years, CR and ORR
were 64.3% (9/14 cases) and 78.6% (11/14 cases), respectively, while the overall survival
rate was 100% and no relapses occurred in the responders. There was no rebound
thrombocytopenia upon stopping the eltrombopag. Only one patient’s platelet count
dropped from normal to below 100
109/L before stopping eltrombopag, and there was
no further drop after stopping eltrombopag.

Safety
1. Tolerability: Eltrombopag was not discontinued because of adverse events in any
patient. The most common adverse events were indirect bilirubin elevation and jaundice
(64.3%, 9 patients). Three patients (21.4%) showed transient elevations in liver enzyme
levels. The above abnormal laboratory indicators were self-resolved or disappeared after
eltrombopag withdrawal. None of the patients developed new cataracts or thrombo-
embolic events during the study, and no rashes or myelofibrosis were reported. Adverse
events not attributed to eltrombopag by the investigators included neutropenic infec-
tions and known toxic effects of ATG and CSA. One patient showed femoral head
necrosis at 1 year after IST, which improved after surgery.
2. Clone evolution: At 6 months after ATG therapy initiation, the responders’ PNH
clones were negative; at 12 months, tiny PNH clones appeared in 5 children. At
24 months after therapy 6 patients displayed tiny PNH clones (ratio of CD55 and CD59
defective cells <10%), and 1 had large PNH clones (47%). However, no PNH-related
clinical manifestations were detected. At 6, 12, and 24 months, bone marrow chromo-
somes were normal, and no abnormal MDS-related clones was found (Table 3).

Discussion
Aplastic anemia in childhood is usually acquired, caused by immune-mediated destruc-
tion of hematopoietic progenitor cells. For children not eligible for MSD-HSCT,
immunosuppressive therapy (IST) with horse anti-thymocyte globulin (hATG) plus
cyclosporine (CsA) is the treatment of choice, with an initial overall response rate of
70–80%. In patients treated with IST, 20–30% do not respond, while 10–30% of res-
ponders relapse. Non-responders receive either a second course of IST with suboptimal
results or proceed with HSCT from a matched unrelated donor (MUD).1,25 The
response rates were comparable between the horse and rabbit ATG groups for severe
aplastic anemia in children. However, the long term overall survival rates in the hATG
group were significantly better than those in the rATG group. Rabbit ATG caused more
profound immunosuppression, which might be responsible for the higher incidence of
severe infections.8 While G-CSF alone is not recommended for the treatment of AA,
addition of G-CSF to ATG and CSA in SAA and vSAA increases neutrophil counts and
reduces infections and hospitalization days in the first 3 months of treatment, but has
no effects on survival, response to treatment and relapse.26
Currently, the emerging eltrombopag, a thrombopoietin receptor agonist, seems to be
effective in adult patients with AA. Addition of eltrombopag to IST contributes to rapid
and robust recovery of blood cell counts and restoration of trilineage hematopoiesis,
 8
M. JIE ET AL.

Table 3. Demographic and clinical characteristics of 14 patients with severe aplastic anemia treated with immunosuppressive therapy and eltrombopag.
Baseline Effectiveness Safety
Disease
course Time to
before Time to G-CSF platelet Time to RBC Time to Response Response Response Elevated Elevated
Age therapy independence independence independence responses after Response after after liver indirect MDS-related
No. Gender (M/F) (months) (days) (days) (days) (days) (days) 3 months after 6 months 12 months 24 months enzymes bilirubin clone
P1 M 90.00 32 121.00 57.00 54.00 121.00 NR CR CR CR N N N
P2 M 74.00 46 428.00 NR NR N N N
P3 F 89.00 32 75.00 53.00 53.00 75.00 PR CR CR CR Y Y N
P4 F 186.00 44 141.00 51.00 57.00 141.00 NR CR CR CR N Y N
P5 M 91.00 25 376.00 NR NR N Y N
P6 F 51.00 50 118.00 51.00 43.00 118.00 NR PR PR PR N Y N
P7 M 53.00 71 153.00 .00 .00 153.00 NR CR CR CR N N N
P8 M 110.00 24 121.00 18.00 37.00 121.00 NR CR CR CR Y Y N
P9 F 83.00 32 332.00 NR NR N Y N
P10 F 90.00 102 82.00 43.00 17.00 82.00 CR CR CR CR Y Y N
P11 F 54.00 603 71.00 12.00 .00 71.00 PR CR PR PR N N N
P12 M 24.00 97 102.00 63.00 46.00 102.00 NR PR CR CR N Y N
P13 M 92.00 55 58.00 33.00 2.00 58.00 PR CR CR CR N N N
P14 M 43.00 17 94.00 4.00 13.00 94.00 PR CR CR CR N Y N
Total F/M (1.3:1) 86 (52.5, 91.25 ) 45 (30.25, 102 (75, 121) 43 (12, 53) 37 (2, 53) 102 (75, 121) 35.7% 78.5% 78.5% 78.5% 21.4% 64.3% 0
months 77.5) days days days days
months
Notes: G-CSF: granulocyte-colony stimulating factor; RBC: red blood cell; MDS: myelodysplastic syndromes; immune thrombocytopenia; N: No; Y: Yes; PR: partial response; NR: no
response; CR: complete response; M: male; F: female.
 PEDIATRIC HEMATOLOGY AND ONCOLOGY 9

Table 4. Comparison between different research groups.

1st pediatric 2nd pediatric
Our E-PAG study eltrombopag study eltrombopag study Previous IST studies
(14 cases) (39 cases)14 (11 cases)21 in children6,7,22,23,24
ORR (%) 78.6 72 81.8 46.2-82
CR (%) 64.3 – 72.7 11.6-64
OS (%) 100 – 90.9 73-92
EFS (%) 78.6 – 72.7 63-64
Relapse rate (%) 0 43% 9.1 1.9-33
Clonal evolution 0 8% 0 3.2-8.5
rate (%)
Note: ORR, overall response rate; CR, complete response; OS, overall survival rate; EFS, event free survival rate.

even after drug discontinuation. Eltrombopag has been recently approved for use as
first-line treatment for adult patients with SAA in combination with standard IST.20
Reports assessing the use of eltrombopag in pediatric SAA are rare and conflicting. In a
recent study of 39 pediatric patients with SAA, addition of eltrombopag to IST did not
improve the ORR at 6 months compared with a historical cohort of pediatric patients
administered IST.22 However, in the present case series, the CRR at 6 months after IST
was significantly higher compared with our historical cohort. In addition, the overall
long-term survival was 100%, while event-free survival was found in 78.6% cases. All
responders showed a persistent response after stopping the eltrombopag treatment,
which the median time to stop eltrombopag for responders was 498 (range, 494 to 669)
days at the end of follow-up. This may be because the follow-up time was relatively
short, and most of the children with CSA have been administered reduced drug
amounts, but have not stopped treatment. These results were consistent with another
pediatric eltrombopag study performed in Greece. The latter study showed ORR and
CR of 81.8% and 72.7%, respectively, and an overall long-term remission rate among
initial responders of 89% with a prolonged observation time, indicating a durable
response, at least comparable to the expected rates for pediatric patients treated with
IST.27 In the real-world data represented by the present patients, use of eltrombopag
alongside IST showed a trend of improved response in blood cell counts (Table
4).3,7–13,22,27 In the future, the improved response rate may affect whether a BMT
should be pursued.
In addition, AA might evolve to other hematological diseases, especially paroxysmal
nocturnal hemoglobinuria. About 15% of AA patients evolve to myelodysplastic syn-
drome, acute myeloid leukemia, or both after IST.28 Eltrombopag stimulates hematopoi-
etic stem cell proliferation; therefore, it is alarming that the drug exacerbates clone
evolution, although this remains unclear. All currently available studies of eltrombopag
for AA treatment have shown abnormal clonal evolution in 15% to 20% patients, in
accordance with the vast historical experience of IST regimens without eltrombopag in
SAA.18–21 However, cytogenetic abnormalities have been observed in the historical
cohort for up to 10 years; thus, longer follow-up of eltrombopag-treated patients would
be crucial in defining the risk of this approach. The present study carried out follow-up
for >2 years, and no cases of clonal evolution were observed to date.
The potential toxicity of eltrombopag includes thrombocytosis, thrombosis, reversible
bone marrow fibrosis, rebound thrombocytopenia, cataract formation, and reversible
hepatic dysfunction.17 Previous reports have demonstrated that eltrombopag is well-
10 M. JIE ET AL.

tolerated.18–21 In the current study, the side effects of eltrombopag mainly included ele-
vated liver enzymes and bilirubin. Liver enzymes should be monitored in all patients,
with the drug dosage adjusted according to the published protocols. Mild-to-moderate
indirect bilirubin increase is common and usually not detrimental to the patient.
Conclusions Addition of eltrombopag to immunosuppressive therapy is associated
with markedly increased hematological complete response rate in patients with severe
aplastic anemia compared with a historical cohort, without intolerable side effects.
However, sample size was relatively small in this study, resulting in poor representative-
ness. Since this was a retrospective study, the addition time of eltrombopag and treat-
ment course varied, necessitating further prospective studies.

References
1. Young NS. Aplastic anemia. N Engl J Med. 2018;379(17):1643–1656. doi:10.1056/
NEJMra1413485.
2. Montane E, Ibanez L, Vidal X, et al. Epidemiology of aplastic anemia: a prospective multi-
center study. Haematologica. 2008;93(4):518–523. doi:10.3324/haematol.12020.
3. Locasciulli A, Oneto R, Bacigalupo A, et al. Outcome of patients with acquired aplastic
anemia given first line bone marrow transplantation or immunosuppressive treatment in
the last decade: a report from the European Group for Blood and Marrow Transplantation
(EBMT). Haematologica. 2007;92(1):11–18. doi:10.3324/haematol.10075.
4. Ades L, Mary JY, Robin M, et al. Long-term outcome after bone marrow transplantation
for severe aplastic anemia. Blood. 2004;103(7):2490–2497. doi:10.1182/blood-2003-07-2546.
5. Dufour C, Pillon M, Socie G, et al. Outcome of aplastic anaemia in children. A study by the
severe aplastic anaemia and paediatric disease working parties of the European group blood
and bone marrow transplant. Br J Haematol. 2015;169(4):565–573. doi:10.1111/bjh.13297.
6. Yoshida N, Kobayashi R, Yabe H, et al. First-line treatment for severe aplastic anemia in
children: bone marrow transplantation from a matched family donor versus immunosup-
pressive therapy. Haematologica. 2014;99(12):1784–1791. doi:10.3324/haematol.2014.109355.
7. Scheinberg P, Wu CO, Nunez O, Young NS. Long-term outcome of pediatric patients with
severe aplastic anemia treated with antithymocyte globulin and cyclosporine. J Pediatr.
2008;153(6):814–819. doi:10.1016/j.jpeds.2008.06.004.
8. Jeong DC, Chung NG, Cho B, et al. Long-term outcome after immunosuppressive therapy
with horse or rabbit antithymocyte globulin and cyclosporine for severe aplastic anemia in
children. Haematologica. 2014;99(4):664–671. doi:10.3324/haematol.2013.089268.
9. Deyell RJ, Shereck EB, Milner RA, et. al. Immunosuppressive therapy without hematopoi-
etic growth factor exposure in pediatric acquired aplastic anemia. Pediatr Hematol Oncol.
2011;28(6):469–478. doi:10.3109/08880018.2011.568043.
10. Pongtanakul B, Kumar Das P, Charpentier K, et. al. Outcome of children with aplastic
anemia treated with immunosuppressive therapy. Pediatr Blood Cancer. 2008;50(1):52–57.
doi:10.1002/pbc.21377.
11. Rogers ZR, Nakano TA, Olson TS, et al. Immunosuppressive therapy for pediatric aplastic
anemia: a North American Pediatric Aplastic Anemia Consortium study. Haematologica.
2019;104(10):1974–1983. doi:10.3324/haematol.2018.206540.
12. Dufour C, Pillon M, Passweg J, et al. Outcome of aplastic anemia in adolescence: a survey
of the Severe Aplastic Anemia Working Party of the European Group for Blood and
Marrow Transplantation. Haematologica. 2014;99(10):1574–1581. doi:10.3324/haematol.
2014.106096.
13. Garanito MP, Carneiro JD, Odone Filho V, Scheinberg P. Outcome of children with severe
acquired aplastic anemia treated with rabbit antithymocyte globulin and cyclosporine A. J
Pediatr. 2014; 90(5):523–527. doi:10.1016/j.jped.2014.02.004.
 PEDIATRIC HEMATOLOGY AND ONCOLOGY 11

14. Scheinberg P, Nunez O, Weinstein B, et al. Horse versus rabbit antithymocyte globulin in
acquired aplastic anemia. N Engl J Med. 2011;365(5):430–438. doi:10.1056/NEJMoa1103975.
15. Marsh JC, Bacigalupo A, Schrezenmeier H, et al. Prospective study of rabbit antithymocyte
globulin and cyclosporine for aplastic anemia from the EBMT Severe Aplastic Anaemia
Working Party. Blood. 2012;119(23):5391–5396. doi:10.1182/blood-2012-02-407684.
16. Hitchcock IS, Kaushansky K. Thrombopoietin from beginning to end. Br J Haematol. 2014;
165(2):259–268. doi:10.1111/bjh.12772.
17. Kim TO, Despotovic J, Lambert MP. Eltrombopag for use in children with immune
thrombocytopenia. Blood Adv. 2018;2(4):454–461. doi:10.1182/bloodadvances.2017010660.
18. Olnes MJ, Scheinberg P, Calvo KR, et al. Eltrombopag and improved hematopoiesis in
refractory aplastic anemia. N Engl J Med. 2012;367(1):11–19. doi:10.1056/NEJMoa1200931.
19. Desmond R, Townsley DM, Dumitriu B, Olnes MJ, Scheinberg P, et al. Eltrombopag
restores trilineage hematopoiesis in refractory severe aplastic anemia that can be sustained
on discontinuation of drug. Blood. 2014;123(12):1818–1825. doi:10.1182/blood-2013-10-
534743.
20. Townsley DM, Scheinberg P, Winkler T, et al. Eltrombopag added to standard immuno-
suppression for aplastic anemia. N Engl J Med. 2017;376(16):1540–1550. doi:10.1056/
NEJMoa1613878.
21. Winkler T, Fan X, Cooper J, et al. Treatment optimization and genomic outcomes in
refractory severe aplastic anemia treated with eltrombopag. Blood. 2019;133(24):2575–2585.
doi:10.1182/blood.2019000478.
22. Groarke EM, Patel BA, Diamond C, et al. Outcomes in pediatric patients with severe aplas-
tic anemia treated with standard immunosuppression and eltrombopag. Blood. 2019;
134(Supplement_1):454–454. doi:10.1182/blood-2019-124811.
23. Subspecialty Group of Hematology, Society of Pediatrics, Chinese Medical Association The
Editorial Board, Chinese Journal of Pediatrics. Recommendations for diagnosis and treat-
ment of acquired aplastic anemia in children. Zhonghua Er Ke Za Zhi. 2014;52(2):103–106.
24. Qi P, Zheng J, Ma J, Su Y, Zhang L, et al. The impact of recombinant human thrombo-
poietin in the immunosuppressive therapy for children with severe aplastic anemia. J China
Pediatr Blood Cancer. 2018;23(4):184–188.
25. Hartung HD, Olson TS, Bessler M. Acquired aplastic anemia in children. Pediatr Clin
North Am. 2013;60(6):1311–1336. doi:10.1016/j.pcl.2013.08.011.
26. Tichelli A, Schrezenmeier H, Socie G, et al. A randomized controlled study in patients with
newly diagnosed severe aplastic anemia receiving antithymocyte globulin (ATG), cyclospor-
ine, with or without G-CSF: a study of the SAA Working Party of the European Group for
Blood and Marrow Transplantation. Blood. 2011;117(17):4434–4441. doi:10.1182/blood-
2010-08-304071.
27. Filippidou M, Avgerinou G, Tsipou H, et al. Longitudinal evaluation of eltrombopag in
paediatric acquired severe aplastic anaemia. Br J Haematol. 2020;190(3):e157–e173. doi:10.
1111/bjh.16766.
28. Ogawa S. Clonal hematopoiesis in acquired aplastic anemia. Blood. 2016;128(3):337–347.
doi:10.1182/blood-2016-01-636381.