442525

2012

TAH332040620712442525G ChengTherapeutic Advances in Hematology

Therapeutic Advances in Hematology

Review

Eltrombopag, a thrombopoietinreceptor agonist in the treatment of

adult chronic immune thrombocytopenia:
a review of the efficacy and safety profile

Ther Adv Hematol

(2012) 3(3) 155164
DOI: 10.1177/
2040620712442525
The Author(s), 2012.
Reprints and permissions:
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Gregory Cheng

Abstract: Chronic immune thrombocytopenia (ITP) is an autoimmune disorder characterized

by a low platelet count that has persisted for more than 12 months. Patients may be
asymptomatic but those with severe disease may have significant morbidity and require
treatment. Corticosteroids and intravenous immunoglobulin are recommended as
first-line treatments. Recently, two thrombopoietin-receptor agonists, romiplostim and
eltrombopag have been licensed for the treatment of chronic ITP. The current indications
for thrombopoietin-receptor agonists are for splenectomized adult patients with chronic
ITP who are refractory to other treatments and adult nonsplenectomized patients in whom
splenectomy is contraindicated. This article reviews data on the pharmacology, clinical
efficacy and safety profile of eltrombopag in the treatment of ITP.
Keywords: eltrombopag, immune thrombocytopenia, thrombopoietin-receptor agonist

Introduction
Immune thrombocytopenia (ITP) is an immunemediated disease characterized by transient or
persistent decrease of the platelet count to less
than 100 109/liter. The term newly diagnosed
ITP is used to describe all cases at diagnosis.
Persistent ITP is defined as ITP lasting between
3 and 12 months from diagnosis while chronic
ITP is defined as the presence of ITP for more
than 12 months. Secondary ITP includes all
forms of immune-mediated thrombocytopenia
except primary ITP [Rodeghiero et al. 2008].
The major therapeutic goal for ITP is to use minimal treatment to maintain platelet counts that are
sufficient to reduce bleeding symptoms with the
least amount of side effects. Since most fatal
bleeding in adult ITP occurs with platelet counts
lower than 30 109/liter [Cohen et al. 2000;
Portielje et al. 2001], current guidelines suggest
that treatment should only be considered in
symptomatic patients with counts less than 30
109/liter [Rodeghiero et al. 2008; Provan et al.
2010]. Corticosteroids are the standard initial
treatment [Cines and Blanchette, 2002; Provan

et al. 2010]. Prednisolone 0.52 mg/kg/day is the

common starting dose for patients with ITP. After
the platelet count increases to more than 50
109/liter, prednisolone should be tapered off to
the minimal effective dose required to maintain a
platelet count over 3050 109/liter. If no significant increase in platelet count is observed after
4 weeks of treatment with high-dose prednisolone,
the drug should be tapered off quickly [Pizzuto
and Ambriz, 1984; Ben-Yehuda et al. 1994].

Correspondence to:
Gregory Cheng, MD, PhD
Dr Stanley Ho Medical
Development Foundation,
9/F ICBC Tower, Macau
Landmark, 555 Avenida da
Amizade, Macau
gcheng@cuhk.edu.hk

One to four cycles of dexamethasone 40 mg/day

for 4 days is the preferred corticosteroid regimen
in some centers, with response rates of 5080% in
newly diagnosed adult patients with ITP [Cheng
et al. 2003; Mazzucconi et al. 2007]. Some patients
had prolonged response after treatment with
high-dose dexamethasone. However, a recent
study suggested that dexamethasone was not
more effective than conventional doses of prednisolone [Bae et al. 2011]. According to the
International Consensus Report [Provan et al.
2010] on investigation and management of ITP,
prednisolone, dexamethasone, or methyprednisolone are all acceptable first-line treatments.

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Therapeutic Advances in Hematology 3 (3)

Intravenous immunoglobulin (IVIG) and anti-D
are effective in raising the platelet counts but the
effects are usually transient. They are recommended as first-line treatments, especially in
emergency situations [Scaradavou et al. 1997;
George et al. 2003; Spahr and Rodgers, 2008].
For patients with chronic ITP whose condition
failed to respond to corticosteroids or who have
severe adverse effects from corticosteroids,
splenectomy is the second-line therapy in many
centers. However, about 1520% of patients do
not respond to splenectomy and another 1520%
of responders relapse weeks, months, or years
later [Schwartz et al. 2003; Kojouri et al. 2004].
In addition, many patients with chronic ITP are
reluctant to have splenectomy because of fear of
complications such as bleeding, infection, thrombosis, and the reported mortality rates of 0.2
1.0% [Kojouri et al. 2004].
In patients who were refractory to or relapsing
after splenectomy or when splenectomy was contraindicated, a variety of immunosuppressive or
cytotoxic drugs such as vincristine, cyclophosphamide, aziathioprine, dapsone, cyclosporine
A, mycophenolate mofetil and rituximab were
used with a response rate of 2080% [Hernndez
et al. 1995; Reiner et al. 1995; Kappers-Klunne
and vant Veer, 2001; Maloisel et al. 2004; Kotb
et al. 2005; Boruchov et al. 2007; Godeau et al.
2008]. However, most of the studies with immunosuppressive agents were not randomized clinical trials and patients may have serious infection
complications from prolonged use.
In a prospective phase II trial patients with ITP
were given rituximab at doses of 375 mg/m2
weekly for 4 weeks [Godeau et al. 2008]. Onethird of the patients had a platelet count of 50
109/liter or higher without any additional treatment after 2 years of observation. Most patients
with a durable (> 1 year) complete response will
respond to repeat treatment if they relapse. A
combination of rituximab with high-dose dexamethasone as initial therapy may result in an
even higher response rate [Zaja et al. 2010].
However, after 3 years of follow up, around 25%
of the patients with ITP had platelet counts over
50 109/liter.
Rituximab is currently not registered for the treatment of chronic ITP and can cause fulminant
hepatitis in hepatitis B carriers [Fianchi et al.
2007]. Therefore, rituximab is contraindicated in

patients with active hepatitis B infection and

prophylaxis with lamuvidine is required in patients
who carry hepatitis B without active infection.
Also, more than 50 cases of progressive multifocal
leukoencephalopathy associated with rituximab
treatment have been reported in patients with
lymphoma and systemic lupus erythematosus
[Carson et al. 2009]. Additional long-term safety
data are required before rituximab can be recommended as a frontline therapy.
Recently, impaired platelet production was
observed in many patients with ITP [Hoffman
et al. 1985; Chang et al. 2003; Houwerzijl et al.
2004; McMillan et al. 2004]. Therefore, stimulation of megakaryopoiesis by thrombopoietin
or thrombopoietin-mimetic agents may be useful in the treatment of ITP. Recombinant thrombopoietin had been shown to increased platelet
counts in patients with ITP [Nomura et al.
2002; Zhao et al. 2004] but was associated with
production of autoantibodies that crossreact
with and neutralize endogenous thrombopoietin, leading to severe thrombocytopenia [Li et al.
2001; Basser et al. 2002]. Recently, two thrombopoietin-receptor (TPO-R) agonists, romiplostim (AMG-531, Nplate; Amgen, Thousand
Oaks, CA, USA) and eltrombopag (Revolade,
Promacta; GlaxoSmithKline, Brentford, UK)
have been licensed for the treatment of chronic
ITP [Wang et al. 2004; Erickson-Miller et al.
2005]. They have no sequence homology with
native thrombopoietin and should not stimulate
production of antithrombopoietin antibodies.
The current indications of TPO-R agonists are
for relapsed splenectomized adult patients with
chronic ITP who are refractory to other treatments or adult nonsplenectomized patients in
whom splenectomy is contraindicated [Provan
et al. 2010].
This article reviews data on the pharmacology,
clinical efficacy, and safety profile of eltrombopag
in the treatment of ITP.
Mechanism of action and pharmacokinetics
Eltrombopag is a low molecular weight, synthetic nonpeptide TPO-R agonist [EricksonMiller et al. 2005]. It has excellent oral
bioavailabilty with a peak concentration occurring 26 h after oral administration and a half
life of 2132 h [GlaxoSmithKline, 2011]. It is
highly bound to human plasma proteins (>99%).
Unlike native thrombopoietin which binds to

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G Cheng
the extracellular domain of the thrombopoietin
receptor, eltrombopag selectively binds to the
trans-membrane domain of the receptor. It
stimulates megakaryocytopoiesis through the
Janus kinase/signal transducer and activator of
transcription (JAK/STAT) signaling pathway.
Eltrombopag did not affect agonist-induced
platelet aggregation or activation in in vitro and
ex vivo studies using platelet samples from
healthy volunteers and patients with chronic
ITP [Erhardt et al. 2004].
Each film-coated tablet contains 25 or 50 mg of
eltrombopag olamine. Administration of eltrombopag concomitantly with polyvalent cations was
found to significantly reduce eltrombopag absorption by up to 60% [GlaxoSmithKline, 2011],
therefore eltrombopag should be taken at least
4 h before or after antacids, dairy products, other
food products, or mineral supplements containing polyvalent cations. Eltrombopag is metabolized in the liver with cytochrome P450 isoenzymes
CYP1A, CYP2C8, and uridine diphosphate glucuronosyltransferase (UGT 1A1 and UGT1A3)
as major pathways. Eltrombopag did not inhibit
or induce cytochrome P450 enzymes. However,
clinical drug interactions between eltrombopag
and cytochrome P450 substrates, inducers, or
inhibitors have not been extensively investigated.
Eltrombopag is not a substrate for P-glycoprotein
or organic anion transporting polypeptide
(OATP) 1B1. However, it is an inhibitor of OATP
1B1and coadministration of eltrombopag with
rosuvastatin (an OATP1B1 substrate) was accompanied by a twofold increase in plasma rosuvastatin. Therefore, in patients with ITP taking
eltrombopag, the dose of concomitant statins
(rosuvastatin, pravastatin, simvastatin, and lovastatin) should be reduced and statin side effects
should be monitored carefully. In total, 59% of a
dose of eltrombopag is excreted in feces (20% as
unchanged drug) and 31% in urine (0% as
unchanged drug). [GlaxoSmithKline, 2011].
Systemic exposure to the drug is increased in people of East Asian descent (based on estimates from
a population-based pharmacokinetic model). As a
consequence, an initial dose decrease to 25 mg/
day is recommended in these patients.
Clinical efficacy studies
The clinical efficacy of eltrombopag in chronic
ITP has been examined in a 6-week dose-finding

trial [Bussel et al. 2007], a 6-week phase III trial

[Bussel et al. 2009], a 6-month phase III trial
[Cheng et al. 2011b], an extension study [Saleh
et al. 2011] and one intermittent therapy trial
[Bussel et al. 2008].
Dose response study (TRA100773A)
The objective of the TRA100773A dose-finding
study was to determine the optimal dose of
eltrombopag. A total of 118 patients with chronic
ITP were randomized in a 1:1:1:1 ratio into four
groups receiving 30, 50, 75 mg of eltrombopag,
or placebo daily for 6 weeks [Bussel et al. 2007].
The study patients must have had chronic ITP
for at least 6 months and a platelet count less
than 30 109/liter at baseline. These patients had
not responded to at least one prior therapy,
including splenectomy, or had relapsed within
3 months of previous therapy. Within each treatment arm, patients were also stratified according
to use of concomitant ITP therapy, platelet count
less than 15109/liter or more than 15 109/liter,
and splenectomy status. The primary endpoint
was a platelet count greater than 50 109/liter or
more at the day 43 visit. If a patients platelet
counts were greater than 200 109/liter, treatment was discontinued, but the patient would
continue to be followed up over the full trial duration and counted as a responder. The incidence
and severity of bleeding events were assessed
using the World Health Organization (WHO)
Bleeding Scale. Significantly far more patients in
the eltrombopag 50 mg group (n = 30) and
75 mg group (n = 28) had platelet counts greater
than 50 109/liter compared with patients (n =
29) receiving placebo (70% and 81% respectively
versus 11%, p values < 0.001 for both groups).
The response rate of recipients of eltrombopag
30 mg daily (n = 30) did not significantly differ
from that of subjects receiving placebo (28%
versus 11%). The median day 43 platelet counts
in subjects on eltrombopag 50 or 75 mg/day were
128 109/liter and 183 109/liter respectively
compared with only 16 109/liter in the placebo
group [Bussel et al. 2007].
This improvement in platelet counts was accompanied by a significant reduction in bleeding symptoms in patients in the eltrombopag 50 or 75 mg/
day groups. Thrombopoietin levels were within the
normal range at baseline in all four groups (54-57
ng/ liter) and were unaffected by the response to
eltrombopag therapy [Bussel et al. 2007].

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Therapeutic Advances in Hematology 3 (3)

Phase III study (TRA100773B)
Based on the results of the dose-finding
TRA100773A study, another 114 patients were
randomized in a 2:1 ratio to receive eltrombopag
50 mg/day or placebo [Bussel et al. 2009].
Inclusion criteria and primary response were similar to the phase II dose-finding TRA100773A
study [Bussel et al. 2007]. In this trial, if the platelet
count was still less than 50 109/liter after 3 weeks
of treatment with eltrombopag 50 mg/day, the
dosage would be increased to 75 mg/day for the
remaining 3 weeks. Again, within each treatment
arm, patients were stratified according to use of
concomitant ITP therapy, platelet count less than
15 109/liter or more than 15 109/liter and
splenectomy status. Subjects on concomitant ITP
medications (corticosteroids, azathioprine, danazol, cyclosporine A or mycophenolate mofetil)
could be enrolled provided that the dose had been
stable for at least 1 month prior to enrollment.
These subjects were allowed to continue their
concomitant ITP medication during the study.
Significantly more subjects on eltrombopag (n =
73) demonstrated a response with platelet counts
greater than 50 109/liter on day 43 compared
with the placebo group (n = 37) (59% versus 16%;
p < 0.0001). In 34 patients receiving eltrombopag,
the dosage was increased to 75 mg/day on or after
day 22 of the study because of no response to a 50
mg/day dosage. Of these, 10 patients (29%)
achieved a platelet count greater than 50 109/
liter on day 43. Patients receiving eltrombopag
had lower risks of bleeding compared with those
on placebo [odds ratio (OR) 0.27; 95% confidence interval (CI) 0.090.88; p = 0.029] [Bussel
et al. 2009]. Severe bleeding events during the 6
weeks occurred only in patients who did not
respond to eltrombopag, or in those receiving placebo. No clinically significant bleeding (WHO
grade 24) occurred while patients had platelet
counts greater than 50 109/liter.
In both the phase II TRA 100773A and phase III
100773B studies, similar response rates to eltrombopag were observed irrespective of the splenectomy status, whether the patients were on
concomitant ITP medications and whether the
baseline counts were less than 15 109/liter. In
patients responding to treatment, the platelet
counts started to increase after 1 week of treatment, peaked around the second week and were
maintained throughout the remaining weeks. For
most patients, the platelet count returned to baseline levels within 2 weeks of stopping eltrombopag

therapy. Transient decreases in platelet counts to

less than 10 109/liter and at least 10 109/liter
below baseline (rebound thrombocytopenia) were
observed in 11% and 13% of patients receiving
eltrombopag and placebo respectively following
treatment discontinuation in this phase III trial
[Bussel et al. 2009]. In the 6-week post-treatment
period of the phase III 100773B trial, the eltrombopag and placebo groups had similar incidences
of bleeding. Therefore, increased incidence of
rebound thrombocytopenia with worsening of
bleeding symptoms following withdrawal of
eltrombopag was not observed.
Study TRA102537 (RAISE)
RAISE (Randomized Placebo-controlled ITP
Study with Eltrombopag) [Cheng et al. 2011b]
was a double-blind phase III study addressing the
safety and efficacy of prolonged 6-month treatment of patients with ITP with eltrombopag.
Adult patients with ITP of more than 6 months
duration, whose condition had previously
responded to at least one ITP treatment and had
platelet counts less than 30 109/liter at the time
of enrollment were eligible for the study.
Concomitant ITP medications could be continued if the dosage had been stable for at least
1 month. Again, within each treatment arm,
patients were stratified according to use of concomitant ITP therapy, baseline platelet counts
less than 15 109/liter or greater than 15 109/
liter and splenectomy status. A total of 197
patients were randomized in a 2:1 ratio to treatment with eltrombopag (n = 135) or placebo (n =
62). Study patients were started with 50 mg/day
of eltrombopag or matching placebo. At the end
of 3 weeks of treatment, if the platelet counts were
less than 50 109/liter, the dose could be increased
to 75 mg/day. However, if subjects platelet counts
were greater than 200 109/liter, the study medication would be reduced to 25mg per day. After
6 weeks of therapy, if the platelet counts were
more than 100 109/liter on two successive visits,
concomitant ITP medications could be reduced
or discontinued. The primary endpoint was the
odds of responding with platelet counts between
50 and 400 109/liter at least once during the
6-month study period. Bleeding symptoms were
prospectively evaluated using the WHO Bleeding
Scale. Other secondary endpoints included
median platelet counts, reduction of baseline ITP
medication, use of rescue medication, healthrelated quality of life (HRQOL), and safety.

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G Cheng
The median age was 52 years in the placebo arm
and 47 years in the eltrombopag group. There was
a higher proportion of female patients (69%) in
both groups and 70% of patients were white.
Approximately half of the patients in the placebo
and eltrombopag groups (50% and 47% respectively) were receiving ITP medication at randomization or had baseline platelet counts of less than
15 109/liter (48% and 50% respectively). About
one-third of the patients in each arm had been
splenectomized. About 80% of the placebo and
eltrombopag-treated patients had received at least
two prior therapies, and more than 50% in each
group had three or more prior therapies.
In the primary efficacy analysis, patients receiving
eltrombopag were eight times more likely to
achieve the primary endpoint of a platelet count
between 50 and 400109/liter (OR 8.20, 95% CI
3.5918.73, p < 0.001) compared with those in
the placebo group. Baseline median platelet
counts were around 16 109/liter in both groups.
In the placebo group, the counts never exceeded
30 109/liter. In contrast, the median platelet
counts rose to 36 109/liter in the eltrombopag
group after 1 week of treatment and stayed around
5291 109/liter for the remainder of the study.
Similar responses were observed irrespective of
splenectomy status, baseline platelet count, or
baseline ITP medication use.
Like the observation in the two 6-week trials, the
platelet counts started to increase by the end of
the first week of treatment, peaked at the second
week, and were maintained throughout the
6-month study period. After stopping eltrombopag, the platelet counts usually returned to
baseline levels in 2 weeks.
Bleeding symptoms were similar in both groups at
baseline. From day 15 onwards, patients in the
eltrombopag group had less bleeding symptoms
compared with those in the placebo group (79%
versus 93% for grade 14 bleeding and 33% versus
53% for grade 24 bleeding). Three eltrombopagtreated patients (2%) had grade 3 or higher
adverse bleeding events compared with four
patients (7%) in the placebo group (p = 0.03).
The eltrombopag and placebo groups had similar
incidence of rebound thrombocytopenia (7%
each). No increased incidence of serious bleeding
episodes was observed in the eltrombopag group
in the post-treatment period (4%; n = 6) compared with placebo (10%; n = 6).

A total of 59% (37/63) of patients receiving

eltrombopag were able to reduce or discontinue
concomitant ITP medications compared with
32% (10/31) in the placebo group (p = 0.02).
Rescue medications were required in 18%
(24/135) of patients receiving eltrombopag compared with 40% (25/62) in the placebo group
(p = 0.001). Five out of eight HRQOL domains
(physical function, physical role, emotional function, vitality, and social function) showed significant improvements from baseline in patients
receiving eltrombopag [Cheng et al. 2011b].
EXTEND study
EXTEND is an ongoing, multicenter, open-label
extension study [Saleh et al. 2011]. Patients with
ITP who had not experienced any eltrombopagrelated serious adverse event or drug intolerance
and had completed treatment and follow up with
either eltrombopag or placebo in a prior eltrombopag clinical study are eligible. They must have a
washout period of at least 4 weeks. Eltrombopag
treatment is initiated at 50 mg once daily. The
dose of eltrombopag will be adjusted to the minimal effective dose (between 75 mg once daily to
25 mg once daily, or less) necessary to maintain
platelet counts of at least 50 109/liter in conjunction with the minimal dose of concomitant
ITP medication. Patients will be followed until
withdrawal or eltrombopag becomes commercially available. The primary objective is to assess
the long-term safety and tolerability of eltrombopag as measured by clinical laboratory tests,
and frequency of adverse events. Secondary endpoints include the proportion of patients who
achieve platelet counts of at least 50 109/liter at
least once during treatment.
A total of 301 patients were enrolled in the ongoing EXTEND study. Median duration of follow
up was 121 weeks. More than half (58%) of
the patients had been followed for more than
104 weeks, 28% (84/301) for more than 3 years,
and 8% (23/301) for over 4 years. A total of 79%
of the patients were white and 15% (45/301) were
Asians. About one-third of the patients had splenectomy (38%, n = 115), or were on concomitant
ITP medications (34%, n = 101). Overall, 88%
(264/301) of patients achieved platelet counts of
at least 50 109/liter at any time during the study.
Median platelet counts increased to at least 50
109/liter by week 2, and remained consistently at
50 109/liter or higher throughout observation.
At baseline, 56% of patients reported bleeding

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Therapeutic Advances in Hematology 3 (3)

symptoms (WHO grades 14) compared with
16%, 19%, and 9% of patients at 52, 104, and
156 weeks respectively. At 52, 104, and 156
weeks, the proportion of patients with clinically
significant bleeding (WHO grades 24) was
reduced from 16% at baseline to 3%, 5%, and 0%
respectively. At baseline, 101/301 patients
reported the use of concomitant ITP medications. Of these 101 patients, 69% attempted to
reduce or discontinue concomitant ITP medication and 43% had a sustained reduction or permanently stopped at least one concomitant
medication. Late resistance to eltrombopag was
not observed. In some patients, the platelet counts
dropped following reduction or discontinuation
of concomitant medications, and required rescue
therapy. It is difficult to ascertain whether this
was due to resistance to eltrombopag or reduction
of concomitant ITP medications
REPEAT trial
The REPEAT (Repeat Exposure to Eltrombopag
in Adults with Idiopathic Thrombocytopenic
Purpura) trial was a phase II, noncomparative
study of the intermittent treatment of ITP with
eltrombopag. Patients with previously treated
chronic ITP and baseline platelet counts of 2050
109/liter (n = 66) were eligible. Patients received
eltrombopag 50 mg/day for up to a maximum of
6 weeks for three cycles. Each cycle of treatment
was followed by an off-therapy period of 4 weeks.
A response to treatment was defined as a platelet
count of more than 50 109/liter and at least twice
the baseline count at day 43 of the treatment
cycle. If the platelet count was more than 200
109/liter at day 43 of the treatment cycle, eltrombopag treatment was discontinued but the patient
was still followed up and counted as a responder.
Patients who did not respond in cycle 1 did not
continue in the study. The primary endpoint of
REPEAT was consistency between cycles
whether a similar proportion of patients who
showed a response in cycle 1 also responded in
cycles 2 or 3 [Bussel et al. 2008]. A total of 80% of
patients responded in cycle 1 and were thus permitted to continue in the study. A total of 87% of
cycle 1 responders also responded in cycle 2 or 3.
Median platelet counts remained above 70 109/
liter after day 8 in all three cycles.
Safety issues
The safety concerns of eltrombopag are based on
toxicity studies in rats, mice, rabbits, and dogs

[European Medicine Agency, 2009] and those

reported from clinical trials [Bussel et al. 2007,
2008, 2009; Cheng et al. 2011b; Saleh et al. 2011].
Hepatocyte degeneration, often accompanied
by increased serum liver enzymes, was observed
in mice, rats, and dogs at doses that were associated with morbidity and mortality [European
Medicine Agency, 2009]. Approximately 10%
of the patients receiving eltrombopag in the
6-week TRA100773A and TRA100773B studies [Bussel et al. 2007, 2009], in the RAISE study
[Cheng et al. 2011b], and in the EXTEND study
[Saleh et al. 2011] had elevations of alanine aminotransferase (ALT) at least three times the
upper limit of normal compared with around 3%
in the placebo group (p > 0.05). In these patients,
the elevated ALT returned to normal levels
while the patients continued on eltrombopag or
promptly after treatment discontinuation. In the
EXTEND study, all bilirubin elevations were
indirect bilirubin, which is not indicative of serious liver injury. Moreover, the Hepatobilary
Laboratory Abnomalities (HBLAs) observed
during the EXTEND study were not always the
same HBLA experienced by the patient during
the previous eltrombopag study. Some patients
who had experienced HBLAs during the RAISE
study did not have recurrence of the HBLAs
when retreated with eltrombopag in the EXTEND
study. So far there is no clinical evidence that
eltrombopag, at the recommended dose, would
result in serious irreversible liver damage.
However, liver function tests should be monitored
regularly, and if there is progressive increase in
serum aminotransferases, the drug should be
stopped. For patients with underlying liver failure, the drug should be used with caution and a
lower starting dose of 25 mg is recommended.
In the RAISE study [Cheng et al. 2011b], three
patients (2%) receiving eltrombopag reported ontherapy thromboembolic events (two with pulmonary embolism, one had deep vein thrombosis)
compared with none in the placebo group. All
three patients had risk factors for venous thrombosis and the platelet counts were less than
50,000/l around the time of the thrombotic
events. In the EXTEND study [Saleh et al. 2011],
18 patients (6%) experienced 25 confirmed or
suspected thromboembolic events with an incidence rate of 3.02/100 patient years. Deep vein
thrombosis (n =10) and cerebral vascular events
(n = 7) were the most common thromboembolic
events. The majority of these patients (15/18)

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experienced thromboembolic events at a platelet
count within the normal range and lower than
the maximum platelet count achieved during
eltrombopag treatment. All 18 patients had at
least one thromboembolic risk factor such as
hypertension, smoking, or obesity. The frequency
of thromboembolic events in patients treated
with eltrombopag in the EXTEND study is similar
to that reported for the ITP patient population
[Sarpatwari et al. 2010]. The data so far do not
suggest an increased risk of thromboembolism
with eltrombopag treatment. However, in patients
with underlying risk factors of thrombosis, eltrombopag should be used with caution, perhaps starting at a lower dose, monitoring the platelet counts
very carefully, and aiming at the minimal platelet
counts adequate to reduce bleeding symptoms.
TPO-R agonists may increase the risk for developing or progressing reticulin fiber deposition in
bone marrow [Douglas et al. 2002]. Over 180 ontreatment bone marrow biopsies were performed
on more than 100 patients in the EXTEND study
[Saleh et al. 2011]. These patients had received
eltrombopag for 14 years and 39 patients had
two or more bone marrow biopsies. No significant
increase in fibrosis was observed. None of the
patients had an abnormal karyotype of bone marrow cells, increased bone marrow blast count
greater than 3%, or any clinically relevant bone
marrow abnormality other than those compatible
with ITP. For patients on eltrombopag, peripheral
blood smears should be examined for morphological abnormalities such as teardrop, nucleated
red blood cells, leucoerythroblastic pictures, dysplastic changes, or cytopenia. If such abnormalities develop or are worsening, a bone marrow
biopsy should be performed. A loss of response
or failure to maintain a platelet response with
eltrombopag treatment within the recommended
dosing range should also prompt a search for
causative factors such as myelofibrosis.
One concern about treatment with TPO-R agonists is the possibility of rebound thrombocytopenia upon withdrawal of the drug. For patients
treated with eltrombopag , thrombopoietin levels
were within the normal range at baseline and were
unaffected by eltrombopag therapy. Transient
decreases in platelet counts to less than 10 109/
liter and at least 10 109/liter below baseline
(rebound thrombocytopenia) were observed in
11% and 13% of eltrombopag and placebo recipients following treatment discontinuation in the
controlled clinical trials [Bussel et al. 2009].

Post-therapy bleeding events were reported by a

lower proportion of patients receiving eltrombopag (4%) compared with placebo (10%) in the
RAISE study [Cheng et al. 2011b]. Nonetheless,
platelet counts and bleeding symptoms should be
monitored closely following discontinuation of
eltrombopag.
Treatment-related cataracts were observed in
rodents and were dose and time dependent. The
clinical relevance of these findings is unknown. In
the RAISE Study [Cheng et al. 2011b], similar
incidences of worsening cataracts were observed in
the eltrombopag and placebo group (8% and 10%
respectively). However, for patients on eltrombopag, routine monitoring for cataracts is recommended. Renal tubular toxicity was observed in
studies of up to 14 days duration in mice and rats
at doses that were generally associated with morbidity and mortality. In humans, fecal elimination
of eltrombopag is the dominant route and only
31% of the metabolized drug is excreted in urine
[GlaxoSmithKline, 2011]. Currently, no dose
adjustment is needed in patients with renal impairment, but eltrombopag should be used with caution in these patients with close monitoring of
serum creatinine urine analysis.
Eltrombopag was not carcinogenic in mice at
doses up to 75 mg/kg/day or in rats at doses up to
40 mg/kg/day (exposures up to four times the
human clinical exposure based on area under the
curve). In the pre- and postnatal development
study in rats, there were no undesirable effects on
pregnancy [European Medicine Agency, 2009],
parturition, or lactation of female rats at maternally nontoxic doses (10 and 20 mg/kg/day) and
no effects on the growth, development, neurobehavioral, or reproductive function of the offspring.
However, at a maternally toxic dose of 60 mg/kg/
day (six times the human clinical exposure based
on AUC) in rats, eltrombopag treatment was
associated with embryo lethality and reduced
fetal body weight [European Medicine Agency,
2009]. Eltrombopag is not recommended during
pregnancy and in women of childbearing potential not using contraception.
Eltrombopag was detected in the plasma of all rat
pups for the entire sampling period following
administration of medicinal product to the mothers, suggesting that rat pup exposure to eltrombopag was likely via lactation [European Medicine
Agency, 2009]. Therefore, eltrombopag should be
used with caution in lactating mothers.

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Therapeutic Advances in Hematology 3 (3)

Conclusions
Eltrombopag is an orally administered smallmolecule nonpeptide TPO-R agonist. It has been
shown to effectively increase platelet counts and
reduce bleeding symptoms in patients with
chronic ITP with overall response rate of 60
80%. Eltrombopag is well tolerated and has a
good safety profile. It is recommended for splenectomized patients with ITP who are refractory
to other treatments (e.g. corticosteroids, immunoglobulins). It may also be considered as second-line treatment for adult nonsplenectomized
patients who refused surgery or in whom surgery
is contraindicated.
The recommended starting dose of eltrombopag
is 50 mg once daily. For patients of East Asian
ancestry, eltrombopag should be initiated at a
reduced dose of 25 mg once daily. After initiating
eltrombopag, if no significant increase in platelet
counts is observed after 23 weeks of treatment,
could the dose may be increased. After achieving
a stable platelet count on a specific dose, the dose
should be further adjusted to the lowest dose sufficient to maintain a platelet count of around
50 109/liter with minimal bleeding symptoms.
In the EXTEND study, 13 of 301 patients (4.5%)
had prolonged remission (median 50 weeks)
without ITP therapy following discontinuation of
eltrombopag [Cheng et al. 2001a]. The median
time from diagnosis of ITP was 24 months (range
673 months) and the median duration of eltrombopag therapy was 237 days (range 141014
days). Therefore, in some patients with chronic
ITP, it may be possible to gradually taper and
eventually discontinue eltrombopag. If the disease relapses, eltrombopag can be restarted at the
previous effective dose. According to data from
the REPEAT study, such patients will still be
responsive to eltrombopag.
In most responding patients, platelet counts start
to increase after the first week of therapy and peak
at the second week. Therefore, eltrombopag may
be used in the preparation of patients with chronic
ITP for elective surgery. Patients can start taking
eltrombopag at home 2 weeks before the scheduled surgery, thus avoiding presurgical admission
for IVIG infusion, which is common practice.
Eltrombopag should be taken at least 4 h before
or after any products such as antacids, dairy products (or other calcium-containing food products),
or mineral supplements containing polyvalent

cations (e.g. iron, calcium, magnesium, aluminum,

selenium, and zinc).
Eltrombopag is not recommended for use in children and adolescents below the age of 18 years
due to insufficient data on safety and efficacy.
Even though no increased incidence of thromboembolic events, myelofibrosis, or irreversible
hepatic damage was reported in follow up over
4 years, patients on eltrombopag should still be
monitored closely for such adverse events.
Acknowledgements
This research received no specific grant from any
funding agency in the public, commercial, or notfor-profit sectors.
Conflict of interest statement
The authors declare no conflicts of interest in
preparing this article.

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