<div>Abstract</div><div>Background: This study compared the efficacy and safety of CsA
monotherapy with eltrombopag (E-PAG) + CsA combined treatment in
children with severe aplastic anemia (SAA).</div><div>Method: The study including 30 children had SAA. Ten were a
retrospective cohort treated with CsA monotherapy. The other 20 were
prospective cohort received E-PAG + CsA . All patients were evaluated
for partial (PR) and complete (CR) hematological response at 3, 6, and
12 months. overall response (OR), overall survival rates (OS) and
treatment safety.</div><div>Results: OR for the E-PAG patients was 40% after three months of
therapy. At six months, this had increased to 75 % with significantly
higher CR rate (40%) than in the CsA group (p = 0.0001). After a year
of treatment, the CR for the E-PAG regimen had increased to 50% and the
OR to 85%, compared to 20% in the CsA group (p = 0.0001). The OS at 12
months was 100% in the E-PAG group compared to 80% in the CsA cohort.
At 24 months, the OS in the E-PAG group was 90%.</div><div>Conclusion: CsA + E-PAG was found to be a safe and effective alternative
treatment for children with SAA particularly in countries with limited
resources.</div><div>Introduction</div><div>Aplastic anemia (AA) is a life-threatening condition characterized by
pancytopenia and hypocellular bone marrow but without major dysplastic
symptoms or marrow fibrosis1,2. The incidence of acquired AA is about
two children per million each year in Europe and North America but this
number is 2–3 times higher in East Asia2,3. AA affects both genders
equally and can occur at any age. However, it is slightly more common
during childhood, and 50% of cases occur in the first three decades of
life4,5. The pathogenesis of AA is multifactorial and may involve an
abnormal hematopoietic microenvironment, hematopoietic stem
cell/progenitor cell deficiencies, immunity disorders, or mutation of
the genes responsible for haematopoiesis. Any of these factors can cause
damage or primary defects of the stem cells or marrow microenvironment6.</div><div>Aplastic anemia presents clinically as anemia and the associated
neutropenia and thrombocytopenia that can lead to potentially
life-threatening infections or bleeding, respectively. The condition
usually necessitates frequent red blood cell transfusions. It can be
difficult to differentiate between the acquired and inherited forms of
this disease. Inherited causes are responsible for about 25–30% of
pediatric cases of AA5. Acquired aplastic anemia may be idiopathic
(&gt;80%), post-infection (15% [particularly after
hepatitis, Epstein-Barr virus, human immune deficiency virus,
parvovirus, and mycobacteria]), or toxin/ drug-induced (4%)7,8.</div><div>All patients should be screened in differential diagnosis to rule out
hypoplastic myelodysplasia/leukemia, congenital marrow failure,
infections, and paroxysmal nocturnal haemoglobinuria. Hematopoietic stem
cell transplantation (HSCT) from a human leukocyte antigen (HLA)-matched
sibling donor is the definitive curative therapy for AA9 and produces
excellent results10. The major drawback of HSCT is that only 30% of
patients have a suitably matched donor. Also, there is a risk of
graft-versus-host disease (GVHD), which can cause mortality or
morbidities with long-term effects on quality of life11. Less common
complications of HSCT include malignancies and infertility.
Unfortunately, allogeneic transplantation is not possible in most
developing countries. The alternative treatment for AA in about
two-thirds of cases is immunosuppressive therapy (IST) consisting of
anti-thymocyte globulin (ATG) (horse or rabbit) and cyclosporine
(CsA)12,13. IST carries a satisfactory long-term response but 30% –
40% of patients do not respond and pancytopenia9 or thrombocytopenia
can continue after therapy, even in cases with improvements in
life-threatening neutropenia14. HSCT and IST regimens can control the
manifestation of AA effectively but both have limitations. HSCT is very
expensive and requires a suitable donor. Many patients do not meet the
requirements for HSCT. Yet, IST can leave a significant number of
patients with persistent cytopenia. The treatment of these latter
patients is regular transfusions, which is expensive, inconvenient, and
carries the risk of serious side effects related to iron overload.</div><div>CsA is sometimes used alone as a monotherapy in countries with poor
resources15.16. It is an effective immunosuppressant, inexpensive,
accessible, can be administered to outpatients and is less toxic than
combined treatment with ATG. The response rate to CsA monotherapy is
between 30% and 50%17,18. Thrombopoietin (TPO) is a glycoprotein class
1 hematopoietic cytokine, primarily manufactured in the liver19. It is
an important regulator of haematopoiesis20. It acts through c-Mpl TPO
receptors expressed in hematopoietic stem cells and progenitor cells.
TPO causes signal transduction events that prevent apoptosis, improve
cell viability, promote growth and possibly increase differentiation21.
Eltrombopag (E-PAG) is an oral thrombopoietin mimetic that selectively
binds to c-Mpl at the transmembranes and juxtamembranes of TPO
receptors. It can circumvent the inhibitory effect of interferon-γ on
HSCs and signal the c-MPL to yield a stimulatory effect. Noteworthy,
interferon-γ found to have an inhibitory effect on the endogenous TPO by
forming a heterodimer-hindering signalling through c-MPL and
consequently inhibits HSCs activation22.</div><div>There is no competition for binding sites as E-PAG binds to different
sites than TPO19. E-PAG promotes thrombopoiesis, the release of
platelets from mature megakaryocytes23, and other forms of hematopoietic
stem cell differentiation20,21,23,24. E-PAG was approved by the Drug
Administration (FDA) in 2008 as the first oral platelet growth factor
treatment for adults with chronic immune thrombocytopenic purpura (ITP).
In 2015, this approval was extended to include children aged 1 to 17
with chronic ITP. It has recently demonstrated excellent results as a
treatment for AA, with trilineage responses in some patients and
transfusion independence in many25,26. It was licensed by the European
Medicines Agency for AA in 2015. In 2017, the National Institutes of
Health made E-PAG a standard of care in AA27.</div><div>To the best of our knowledge, no previous research has compared the
efficacy and safety of E-PAG + CsA with that of CsA alone in pediatric
patients with SAA. We designed this study to explore the effectiveness
and safety of eltrombopag added to CsA in pediatric severe aplastic
anemia (SAA)</div><div>Methods</div><div>Design</div><div>This was a prospective, single centre clinical trial conducted at Assiut
University Children’s Hospital in Egypt. The study enrolled 30 SAA
patients between 1 and 18 years old. Our sample comprised two groups. 10
patients (CsA group) were a historical cohort who received cyclosporine
(CsA) monotherapy from August 2016 to February 2018; because ATG was
unavailable for financial reasons and E-PAG had not yet been approved by
health insurers when these patients were treated. This cohort was our
comparison group. Twenty patients fulfilled the eligibility criteria28
were recruited prospectively in the study from October 20 19 to August
2021 and treated with E-PAG + CsA (E-PAG group). All patients were
evaluated for their hematological response to treatment, and to
determine complete response (CR), partial response (PR), and Overall
response (OR) rates and treatment safety after 3, 6, and 12 months of
treatment. Pre-treatment evaluations included a complete medical history
and physical examination, complete blood count (CBC) with differential,
serum chemistry, bone marrow aspiration and biopsy, viral serology,
immunological tests, flow cytometric tests, a diepoxybutane clastogenic
stress assay, and inherited bone marrow failure panel and HLA typing.
Patient follow-ups were performed every 2–4 weeks and included a CBC
and monitoring of kidney and liver function.</div><div>Eligibility criteria</div><div>Children with newly-diagnosed and previously untreated SAA and adequate
hepatic and renal functions who met the modified Camitta criteria for
SAA were eligible for inclusion in this study29. According to these
criteria, a diagnosis of SAA may be made if bone marrow cellularity is
&lt;25% and/or at least two of the following criteria are met:
(i) the absolute neutrophil count is below 0.5 × 109/L, (ii) the
platelet count is below 20 × 109/L, (iii) the reticulocyte count is
below 20 × 109/L.</div><div>The exclusion criteria were inherited bone marrow failure,
myelodysplasia, AA secondary to infection or organ failure,
underproduction anaemias secondary to B12, folate or iron deficiency, or
with other reversible causes. Patients with documented hypersensitivity
to any of the component medications were also excluded. The study was
approved by Assiut University’s Ethical Committee for Clinical Research
and informed consents were obtained from the guardians of trial
participants before the study.</div><div>Treatment plan</div><div>Patients aged 1–5 years received an initial oral dose of E-PAG of 25 mg
once daily. Those aged &gt;5 years received an initial daily
dose of 50 mg /day30. Dose was escalated by 25 mg every two weeks in all
patients, and then maintained at the maximum dose when it was reached.
In patients aged 1–5, the maximum dose was 75 mg ; in patients over
five, it was 150 mg. Adjustments and reductions of the E-PAG dose were
made where necessary based on the pharmacokinetic data for ITP31.
Patients experienced distinct adverse events in response to treatment
were excluded from the study.</div><div>Oral CsA treatment in both groups was initiated at 5–10 mg/kg/day and
the dose adjusted to maintain trough levels of 170–270 ng/ml. CsA was
continued for at least 12 months as tolerated and, in those who
responded, continued at a fixed daily dose for at least an additional
six months before weaning. Serum CsA levels were measured every two to
four weeks while patients were receiving the drug30.</div><div>Supportive therapy</div><div>Supportive therapy was allowed for both cohorts throughout the study
when required. This included granulocyte colony-stimulating factor
(G-CSF), iron chelation, or platelet transfusion (if the count was
&lt;10,000/μL with an apparent bleeding tendency or
&lt;20,000/μL with fever) and red blood cell (RBC) transfusion
(if hemoglobin was &lt;7 g/dL or in the presence of significant
symptoms, such as exertional dyspnea or anemic heart failure).</div><div>Primary outcome measures</div><div>The primary outcomes were safety, hematological response either CR or
PR, and OR rates of combined E-PAG + CsA treatment after 3, 6, and 12
months, using the standard guidelines for the diagnosis and treatment of
pediatric AA28.</div><div>Response criteria</div><div>A hematological response was defined as a platelet count increase of at
least 20 000/μL and/or platelet transfusion independence for a minimum
of eight weeks, a hemoglobin level increase of at least 1.5 g/L or a
reduction in the number of PRBCs units transfused by at least four for
eight consecutive weeks (compared with transfusion requirements during
the eight weeks preceding study treatment onset) and an increase of
absolute neutrophil count (ANC) of &gt;500/μL in patients with
a pre-treatment count &lt;500/μl. A PR was defined as a blood
count no longer meeting the Camitta criteria for SAA and no transfusion
dependence for platelets or red blood cells . A CR was defined as Hb
levels of ≥100 g/l, a platelet count ≥100 × 109/L, ANC of ≥1 × 109/L and
transfusion and growth factor independence. OR rates included all PR and
CR within each group.</div><div>Secondary outcome measures</div><div>Secondary outcomes were the tolerability and toxicity of the E-PAG + CsA
combination.</div><div>Statistical analysis</div><div>Data analyses were carried out using SPSS version 20. Descriptive
statistics were expressed as frequencies and percentages for categorical
data. Continuous variables were expressed as medians and interquartile
ranges (IQR Q1 to Q3) as the sample size was small. Categorical data
were compared using z score tests when the expected frequencies were
less than five. The Mann-Whitney U test was used to determine
differences in continuous variables between groups. A p-value of
&lt;0.05 was deemed statistically significant.</div><div>Results</div><div>Patient characteristics</div><div>A total of 30 patients were enrolled in this study. Ten of these
received CsA alone (CsA group) and the other 20 received E-PAG + CsA
(E-PAG group). The demographic and clinical characteristics and baseline
CBC of the groups are shown in Table 1. Age and sex were matched between
groups.</div><div>There was no significant difference between the groups in the baseline
CBC. Bone marrow biopsies showed &lt;10% nucleated cell
proliferation in eight patients, 10%–20% in fourteen patients, and
20%–30% in eight patients.</div><div>Hematological response</div><div>Summaries of the hematological responses of both groups before treatment
and after 3, 6, and 12 months of treatment are provided in Tables 2 and
3. All 30 patients were dependent on platelet and RBC transfusions
before the treatment regimen began.</div><div>Hematological response after three months of treatment</div><div>At the three months evaluation, two patients in the E-PAG group (10 % )
fulfilled the hematological criteria for CR and no longer required
transfusion of packed red blood cells (PRBCs) or platelets. Six more
patients (30%) in this group achieved PR. All six were still PRBC
transfusion-dependent but no longer required platelet transfusion. The
remaining twelve (60%) E-PAG patients did not meet any of the response
criteria and were still transfusion-dependent. In contrast, none of the
10 patients in the CsA group fulfilled the criteria for hematological
response and all (100%) continued to require regular PRBC and platelet
transfusions. Additionally, ANC, Hg and platelets (Table 4) were
significantly higher in the E-PAG group than the CsA group (p = 0.04, p
= 0.01, p = 0.009, respectively).</div><div>Hematological response after six months of treatment</div><div>At the six-month assessment a CR was found in seven (35%) of the E-PAG
patients and PR in another eight patients (40%), all but three (who
required transfusion of blood components) of whom were
transfusion-independent. The remaining five E-PAG patients (25%) showed
no response to the combination therapy. In the CsA group, only two
patients (20%) met the PR criteria and seven showed no response to
treatment (Table 3). One patient died of a severe infection in the
fourth month of CsA. All of the remaining nine were still PRBC and
platelet transfusion-dependent. The highest response rate in the E-PAG
group was associated with a significant increase in ANC, Hb and platelet
counts (Table 4) compared to that in the CsA group (p = 0.01, 0.01 and
0.004, respectively).</div><div>Hematological response after 12 months of treatment</div><div>At 12 months, the number of patients in the E-PAG group who fulfilled
the CR criteria had increased to ten (50%) and PR to seven (35%).
Fourteen patients no longer required PRBC transfusion and seventeen had
become independent of platelet transfusion.</div><div>Three patient (15%) in the E-PAG group had not responded to the therapy
and was still dependent on transfusion support and waiting for a bone
marrow transplant (BMT) (Table 2). In the CsA group, another patient
died of a massive intracranial haemorrhage (Table 3). Two of the eight
patients who had previously attained PR after six months of treatment
achieved CR (25%) and were no longer transfusion-dependent. Another two
patients displayed PR (25%), with one still dependent on PRBC and
platelet transfusions every eight weeks and the other requiring only
platelet transfusion. Lastly, four patients in this group did not fulfil
any of the hematological response criteria and were still
transfusion-dependent. Furthermore, ANC, Hb and platelet were
significantly higher in the E-PAG group than the CsA group (p = 0.04, p
= 0.047 and p = 0.01, respectively) (Table 4).</div><div>Overall response and survival rates</div><div>At three months, the OR rate in the E-PAG group was 40% (10% CR and
30% PR) which differed significantly from 0% in the CsA group (p =
0.006). At six months, CRs in the E-PAG had risen significantly to 35%
(p = 0.0001), with an 75% OR rate. The OR rate in the CsA group had
increased to 20% (Table 5) .</div><div>Lastly, at the one year evaluation, the OR was 85% (50% CR and 35%
PR) in the E-PAG group compared to 50% (25% CR and 25% PR) in the CsA
group (p = 0.001). The overall survival rate at one year was 100% in
the E-PAG group and 80% in the CsA group.</div><div>Side effects and clonal evolution</div><div>Overall, both treatment arms had acceptable toxicities. None of the
patients had to withdraw from the study due to adverse events. The most
common adverse event in the E-PAG group was indirect bilirubin elevation
(n = 3, 15%). Two patient (10%) showed transient elevation of their
liver enzyme levels and two patient experienced headaches. The abnormal
levels of bilirubin and liver enzymes self-resolved or disappeared after
transient E-PAG dose adjustment. Hirsutism , a known CsA side effect,
occurred in two E-PAG patient. Asymptomatic gum hypertrophy was noted in
one patient but did not require a decrease in drug dosage (Table 2). In
the CsA group, mild renal dysfunction was seen in one patient but this
subsided after decreasing the CsA dose to 5mg/kg for two weeks.
Hirsutism occurred in two patients (Table 3).</div><div>Long-term outcomes (at 24 months) of the E-PAG group</div><div>At the two-year evaluation of the E-PAG group, eight ( 40%) of the
patients who had responded completely still fulfilled the CR criteria
without the need for transfusion support, while one patient (5%) had
clinical signs of clonal evolution and one had relapse (5%). One of the
seven PR patients now met the CR criteria while four patients (20%) had
undergone BMT since the previous follow-up. The other two PR patients,
their parents refused the BMT. The two E-PAG patient (10%) who had not
responded to therapy had died of severe infection before reaching the
top of the BMT waiting list while one had undergone BMT. There was no
two-year follow-up of the CsA group due to the retrospective data
collection for that group.</div><div>Discussion</div><div>CsA has been used to treat AA patients lacking a donor, the financial
means, or medical eligibility for HSCT since the 1980s. CsA is a potent
immunosuppressant. It is inexpensive, easily available, and
non-myelotoxic. CsA exerts its effects by suppressing early T cell
activation, inhibiting lymphokine production32,33. Several studies have
demonstrated the effectiveness of CsA in the treatment of SAA43,35. It
has a 50% response rate in SAA refractory to treatment with ATG or
anti-lymphocyte globulin (ALG)36,37.</div><div>In the present study, we evaluated CsA monotherapy in 10 children with
SAA. The response rates were 20% and 50% after 6 and 12 months,
respectively, in eight of the 10 patients (due to a mortality rate of
20%). These figures support those found in a previous retrospective
evaluation of CsA monotherapy in 66 children with AA, which found a 47%
response rate in SAA cases over a period ranging from 2 to 34 weeks38.
Another study of 44 children evaluated combined CsA + corticosteroid
treatment of AA. They reported a mortality rate of 44.9% (18 patients).
42.3% of the surviving patients showed a CR but most had non-SAA. After
18 months, the response rate was 34.6%39.</div><div>Our results differ from those found in studies of CsA treatment for
adults with SAA. Shetty et al. recorded a 56.2% response rate to CsA in
20 adult patients with SAA after three months39, while Ghazaly et al.
found a 50% response in adults with SAA at six months15.</div><div>E-PAG is a thrombopoietin receptor agonist that has proven effective in
adults with AA. When combined with IST, E-PAG is well-tolerated, and
produces improved response rates, recovery of blood cell counts, and
restoration of trilineage haematopoiesis, even after drug
discontinuation. E-PAG has recently been approved for use as a
first-line treatment for adult patients with SAA in combination with
standard IST28.</div><div>Studies to evaluate the efficacy of E-PAG in pediatric SAA are rare and
most assess its use of E-PAG with standard IST of ATG + CsA (Table 6
)30,40,41,42.</div><div>To the best of our knowledge, this is the first prospective study to
evaluate the efficacy and safety of E-PAG in combination with CsA alone
in children with SAA.</div><div>In the present study, the OR rate of E-PAG patients was 40% after three
months of therapy, with two patient achieving CR and six, PR . At six
months, the OR was 75% with a CR of 35% and most of these patients
were independent of transfusion support. In contrast, the CsA group
experienced 20% PR at six months. After a year of regular treatment,
the rate of complete responses to the E-PAG regimen had increased to ten
patients (50%), with an OR rate of 85%. The survival rate at 12 months
was 100% compared to 80% in the CsA cohort. Additionally, the E-PAG
group experienced a 90% survival rate at 24-month follow-up, although
one of the survivors underwent a hematological relapse. Elevated
transaminase levels or indirect elevation of bilirubin levels occurred
in five of the patients treated with E-PAG. Renal insufficiency occurred
in one CsA patient. The elevations and renal insufficiency were
corrected with dose adjustments. Hirsutism, a known side effect of CsA,
was observed in both cohorts.</div><div>Lesmana et al.30 conducted a retrospective comparison of children with
SAA treated with IST and E-PAG and those treated with standard IST. The
CR rate in the IST and E-PAG group was 29% at 6 months and 58% at 12
months, while the OR rate was 77.7 % at six and 100% 12 months.
However, they recorded a significantly higher rate of renal
insufficiency and elevated transaminase in the E-PAG cohort. These
results were somewhat similar to our own, which may suggest that E-PAG
and CsA exert similar effects to E-PAG and IST.</div><div>Another recent study of the efficacy and safety of E-PAG as a first-line
treatment of pediatric AA found CR and OR rates at six months of 64.3%
(9/14 case) and 78.6% (11/14 cases), respectively, with a 100%
survival rate at 24 months and no relapse or intolerable side effects.
They found a significantly higher rate of CR rate in SAA children
treated with E-PAG + IST than that seen in the historical cohort41. This
data shows a notable convergence between the results of the different
treatment regimens used in that study and this one.</div><div>Fang et al.,40 found IST + E-PAG to be more effective than IST alone in
children with SAA. The CR and OR were significantly higher in their IST
+ E-PAG group than their IST group after six months (CR: 17.9% vs.
50%; p &lt; 0.05, OR: 69.2% vs. 94.4%, p &lt; 0.05).
The present study found roughly equivalent, significantly higher CRs and
ORs, in children treated CsA + E-PAG to the outcomes obtained with
children treated with IST + E-PAG.</div><div>In a study of Scheinberg et al.,42 54 treatment-naïve adults with SAA
treated with E-PAG + CsA for six months, the goal OR rate was met by
46.3% of patients with 5.4% achieving CR. The OR rate at three months
was 40.7%. Townsley et al.27conducted a prospective study of a cohort
of 92 patients, 19 of whom were children, treated with IST + E-PAG. This
study divided patients into three cohorts according to the day of E-PAG
treatment initiation. The third cohort in whom E-PAG treatment was
initiated on day one reported an OR rate of 80% and 87% after three
and six months, respectively, while the CR was 30% at three and six
months. They found the beneficial effects of E-PAG to be directly
proportionate to the length of exposure to the drug. In addition to the
hematologic response, bone marrow was found to be highly enriched with
hematopoietic stem cells and multipotent progenitors after three and six
months of therapy.</div><div>Moreover, Hwang et al43, investigated E-PAG in AA patients on a
non-trial all-comer basis over a 4.5-year period. They concluded that,
E-APG in AA patients was feasible, safe, and associated with very goo
responses.</div><div>IST in the form of ATG and CsA is well-established as an alternative
treatment for patients with SAA when an HLA-matched familial donor is
not available 10, 12, 13,44. However, in healthcare systems with
inadequate resources, few patients can afford such an expensive
combination. E-PAG + CsA is an available, safe, easily monitored
treatment option for pediatric SAA in developing nations where economic
considerations are paramount. Combined cyclosporine + eltrombopag was
found to be an effective and safe alternative treatment for pediatric
SAA, particularly in countries with limited resources. This study was
limited by its small sample size and the lack of similar studies in
pediatric groups. A larger prospective study with longer follow-up is
essential to evaluate response stability</div><div>Declarations</div><div>Ethical Statement</div><div>This study was conducted in accordance with the tenets of the
Declaration of Helsinki 1964. The study was approved by Assiut
University’s Ethical Committee for Clinical Research. Signed statements
of informed content to participation and publication were obtained from
the guardians of trial participants before the study. The consent
requirement was waived for retrospective participants by the above-named
ethics committee. .</div><div>Conflict of interest</div><div>None of the authors have any potential conflict of interest to declare</div><div>Source of funding: No</div><div>This work was supported by Assiut university, faculty of medicine The
funders had no role in study design, data collection, and analysis,
decision to publish, or preparation of the manuscript..</div><div>Consent for publication: N/A</div><div>Code avalibility: N/A</div><div>Data Availability : All data generated or analysed during this study are
included in this published article.</div><div>Authors’ contributions: Mervat A M Youssef, coordinated the research,
conducted literature searches and wrote the manuscript. Mai A
Abdelfattah designed, collected date and reviewed and revised the
manuscript, Mohammed H ghazaly reviewed and revised the manuscript. and
contributed with the data collection.</div><div>Ethical Statement</div><div>The study was approved by Assiut University’s Ethical Committee for
Clinical Research. Signed statements of informed content to
participation and publication were obtained from the guardians of trial
participants before the study. The consent requirement was waived for
retrospective participants by the above-named ethics committee.</div><div>Conflict of interest</div><div>None of the authors have any potential conflict of interest to declare</div><div>Source of funding:</div><div>This work was supported by Assiut university, faculty of medicine The
funders had no role in study design, data collection, and analysis,
decision to publish, or preparation of the manuscript..</div><div>Authors’ contributions:</div><div>Mervat A M Youssef, coordinated the research, conducted literature
searches performed statistical analyses and wrote the manuscript.</div><div>Mai A Abdelfattah designed, collected date and reviewed and revised the
manuscript.</div><div>Mohammed H ghazaly reviewed and revised the manuscript. and contributed
with the data collection.</div><div>References</div><div>1. Guinan EC. Acquired aplastic anemia in childhood. Hematol Oncol Clin
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