798798

research-article2018
TAH0010.1177/2040620718798798Therapeutic Advances in HematologyD Gómez-Almaguer

Therapeutic Advances in Hematology Review

Eltrombopag-based combination treatment

Ther Adv Hematol

2018, Vol. 9(10) 309­–317

for immune thrombocytopenia DOI: 10.1177/

2040620718798798

© The Author(s), 2018.

Article reuse guidelines:
David Gómez-Almaguer sagepub.com/journals-
permissions

Abstract:  Immune thrombocytopenia (ITP) is a bleeding disorder caused by a decrease in

platelet count resulting from increased destruction and insufficient production of platelets.
Although impaired regulatory T-lymphocyte activity plays a critical role in platelet destruction,
many other immunologic abnormalities are also likely to be involved. Importantly, patients
with ITP appear to have defects in a thrombopoietin-mediated physiological mechanism
that compensates for a decrease in platelet count by increasing platelet production. Thus,
simultaneous treatment of multiple pathogenic pathways involved in ITP could potentially
result in synergistic efficacy. While conventional treatments for ITP suppress or modulate
the immune system to reduce platelet destruction, a unique class of ITP therapy, namely
thrombopoietin receptor agonists (TPO-RAs), improves platelet production by activating the
thrombopoietin pathway. As hypothesized, preliminary studies show that combinations of
eltrombopag, an oral TPO-RA, with conventional treatments improve outcomes in both newly
diagnosed and refractory patients. In this review, the clinical experience with eltrombopag-
based combinations in patients with ITP is summarized and the implications of the available
data are discussed.

Keywords:  immune thrombocytopenia, drug combinations, drug synergism, immunosuppressive

agents, eltrombopag, romiplostim, rituximab

Received: 31 May 2018; revised manuscript accepted: 14 August 2018.

Introduction
Immune thrombocytopenia (ITP) is a bleeding
disorder affecting 3 to 4 per 100,000 adults/
year.1,2 Apart from the risk of severe bleeding,
patients with ITP may also have poor quality of
life, comparable to that of patients with diabetes.3
ITP is caused by a decrease in platelet count
below 100 × 109/l as a result of increased destruc-
tion and insufficient production of platelets,
caused by an autoimmune reaction.1,4 Multiple
immunologic abnormalities are likely to be
involved in the immune reaction to platelets, and
impaired regulatory T-lymphocyte (Treg) activity
is considered to play a significant role.5–8 In
most patients with ITP, the immune attack is
mediated by antiplatelet antibodies secreted by
plasma cells.8 These autoreactive antibodies
cause opsonization of platelets by macrophages
and may interfere with platelet production by
impairing megakaryocyte function.8 Importantly,
in approximately 40% of patients with ITP, no
antiplatelet antibodies are detected and the Correspondence to:
David Gómez-Almaguer
immune attack may be carried out directly by Hematology Service,
cytotoxic T-cells.8 Facultad de Medicina y
Hospital Universitario Dr
José Eleuterio González,
Under normal circumstances, a decrease in plate- Francisco I. Madero and
José E. González, 64460
let count leads to increased plasma thrombopoi- Monterrey, Mexico
etin level, which induces a compensatory boost in dgomezalmaguer@gmail.
com
platelet production in bone marrow.9 Through
this mechanism, platelet production may increase
more than 20-fold.10 However, patients with ITP
appear to have defects in this physiological mech-
anism. The level of thrombopoietin in serum is
not elevated in response to thrombocytopenia in
such patients and, accordingly, a compensatory
boost in platelet production is absent.9,11
Conventionally, the goal of first-line therapy for
ITP is to quickly increase platelet count in patients
with high risk of bleeding or active bleeding, while
durability of response and long-term safety and

journals.sagepub.com/home/tah 309
Therapeutic Advances in Hematology 9(10)

Figure 1.  Pathogenesis of immune thrombocytopenia and therapeutic mechanisms of current treatments.
Reduction of Treg/Breg activity may result in deregulation of B cells and production of autoantibodies. These autoantibodies
bind platelets, resulting in their opsonization by APCs (primarily megakaryocytes) and antigen presentation, leading to
maintained autoimmune response. Antiplatelet antibodies may also bind megakaryocytes, thereby interfering with platelet
production.
Reduced Treg activity may also result in increased cytotoxic T-cell activity, which induces destruction of platelets and
megakaryocytes through apoptosis.
In patients with ITP, the thrombopoietin-mediated mechanism through which reductions in platelet counts are compensated
does not appear to be activated. TPO-RAs (eltrombopag and romiplostim) may significantly increase platelet production and
may be able to counterbalance increased destruction. Moreover, TPO-RAs may restore the activity of both Tregs and Bregs,
which may help re-establish the immune tolerance to platelets. The anti-CD20 antibody rituximab specifically eliminates
antibody-producing B cells and may inhibit targeting of platelets for opsonization. Other immunosuppressive treatments
for ITP, including corticosteroids and IVIG, reduce the capacity of the immune system to remove antibody-coated platelets.
These treatments often have other direct and indirect effects on the immune system, which may play a role in their clinical
activity.
APC, antigen presenting cell; Breg, regulatory B cell; ITP, immune thrombocytopenia; IVIG, intravenous immunoglobulin;
TPO-RA, thrombopoietin receptor agonist; Treg, regulatory T cell.

tolerability are considered less of a priority.12
Therefore, most patients with ITP relapse and
consequently receive multiple lines of monother-
apy, including repeated courses of first-line treat-
ments until a treatment providing a durable
platelet response is found. During this ‘trial and
error’ period, which may last months or even
years, these patients may experience significant
disease burden associated with the risk of bleed-
ing events and adverse effects of treatment.3,13 In
addition, there is a small but significant group of
multirefractory patients who do not achieve a sta-
ble response with any available monotherapy.14
Both of these patient groups could benefit from
the potential synergistic efficacy of combination
treatments that simultaneously address multiple
disease mechanisms. Being the only available
treatment option for ITP that can address
insufficient platelet production, thrombopoietin
receptor agonists (TPO-RAs), including eltrom-
bopag, play a central role in combination treat-
ment approaches for ITP (Figure 1).15
Conventional treatment of immune
thrombocytopenia
Treatment-naïve patients
First-line management options for ITP usually
include corticosteroids (dexamethasone, pred-
nisone) and immunoglobulins [intravenous immu-
noglobulin (IVIG), Rho(D) immune globulin
(anti-D)], which produce fast but transient
responses.4 Corticosteroids show an initial response

310 journals.sagepub.com/home/tah

in 60–70% of patients within 2–14 days, but the
response often lasts <6 months.4,16 IVIG will pro-
duce a response in 1–3 days in 90% of patients, but
the response typically lasts only 2–4 weeks4,16
The rapid effects of first-line treatments are pri-
marily mediated through inhibition of platelet
opsonization, which is the final step of platelet
destruction (Figure 1).8,17 However, these rea-
gents have other direct and indirect effects on
the immune system, including decreasing
autoantibody production and rescuing Treg
function, which may play a role in their clinical
activity.8,15
Refractory patients
For patients refractory to first-line treatments,
common therapeutic options include TPO-RAs,
the anti-CD20 antibody rituximab, splenectomy,
and immunosuppressive agents.4,12 Rituximab,
which is licensed for use in certain hematologic
malignancies and autoimmune disorders, depletes
the B-cell pool involved in the production of
autoreactive antibodies and may also restore Treg
activity.5,18 Although this drug is often used in
patients with refractory ITP, it has a variable
response rate and limited duration of response.19,20
In uncontrolled studies, 63% of patients showed
an immediate response to a single course of ritux-
imab, and the 2-year response rate was 40%.19,21
In the only placebo-controlled trial of rituximab,
no significant benefits beyond 1.5 years were
reported.20
Splenectomy is the oldest option for long-term
management of ITP and is still being used due to
its high durable response rate (60–70%).6,22
Nevertheless, this invasive option is associated
with both risk of surgical complications and life-
long risks caused by the loss of splenic function,
including infection, thromboembolism, and even
malignancy.22,23 Therefore, once effective phar-
maceutical management options became availa-
ble, the use of splenectomy has declined; however,
it must still be considered according to patients’
comorbidity risk and preference, and it is a very
effective therapeutic option. To date, no long-
term outcomes have been compared between
patients undergoing splenectomy and those
treated with medical therapies.24
Many other agents with immunosuppressive
properties, including azathioprine, cyclosporine
A (CSA), cyclophosphamide, danazol, dapsone,
journals.sagepub.com/home/tah 311
D Gómez-Almaguer
mycophenolate mofetil, and vincristine, have
been used to treat refractory ITP. While most of
these agents have limited efficacy as monother-
apy, they are sometimes preferred due to their
low cost.4,12,25
Eltrombopag for treatment of immune
thrombocytopenia
TPO-RAs are the only therapeutic option for ITP
that increases platelet production (Figure 1).15 In
addition to promoting platelet production from
existing megakaryocytes, TPO-RAs may also
enhance proliferation of megakaryocytes in bone
marrow, as suggested by in vitro studies and clini-
cal trials in patients with aplastic anemia.26–28
Importantly, TPO-RAs may reduce platelet
destruction by restoring Treg and regulatory
B-cell activity, thereby attenuating the autoim-
mune response to platelets.8,29 In patients treated
with TPO-RAs for >3 months, Treg activity was
significantly improved compared with the pre-
treatment group (p = 0.001) and was similar to
the Treg activity in healthy subjects (p = 0.9).8,29
Moreover, preliminary evidence suggests that
autoantibody levels in patients with ITP may pro-
gressively decrease with TPO-RA treatment,
which may contribute to restoration of immune
tolerance to platelets.30
Eltrombopag is an oral TPO-RA approved for use
in more than 80 countries, including the United
States and European Union countries.22 In rand-
omized, controlled trials, eltrombopag has been
shown to safely and durably increase platelet
count in both adults and children with refractory
ITP.31–33 Clinical evidence from patients who
received eltrombopag for up to 8.8  years supports
that eltrombopag retains its safety and efficacy
with long-term continuous use,34 even though it
would be necessary to evaluate further related
events associated with eltrombopag for a longer
term.
Although many patients require continuous treat-
ment with eltrombopag to maintain a response, in
approximately 30% of patients, eltrombopag induces
disease remission and can be discontinued.30,35–37
However, it is important to note, that these stud-
ies defined remission rate using different criteria,
besides, some of these patients could achieve
spontaneous remission. On the other hand, some
patients achieving remission with eltrombopag
had ITP that was highly refractory (seven lines of
prior therapy, including splenectomy) and had
Therapeutic Advances in Hematology 9(10)

Table 1.  Studies of eltrombopag combinations for immune thrombocytopenia.

Title Population N EPAG dose Concomitant Response Response Reference

(duration) therapy (dose, at end of at 6
duration) treatment months

Eltrombopag Newly 12 50 mg (days Dexamethasone 100% 75% Gómez-

and high-dose diagnosed 5–32) (40 mg, days 1–4) Almaguer
dexamethasone as adult ITP et al.38
frontline treatment of
newly diagnosed ITP in
adults [ClinicalTrials.
gov identifier:
NCT01652599]

Eltrombopag, low- Newly 13 50 mg Dexamethasone 100% 100% Gómez-

dose rituximab, and diagnosed (days 1–28) (40 mg, days Almaguer
dexamethasone adult ITP 1–4), Rituximab et al.39
combination as (100 mg/week, 4
frontline treatment of doses)
newly diagnosed ITP

Eltrombopag plus Adult ITP 39 50–150 mg Prednisone 64% 54% Tran et al.40
steroid in patients diagnosed (12 weeks) (⩾10 mg/kg) or
with severe persistent within IVIG (weaned over
ITP within 6 months of 6 months 6 weeks)
diagnosis
High-dose Chronic ITP 11 50–75 mg Dexamethasone 100% 100% Magro
dexamethasone (days 1–28) (40 mg, days 1–4) et al.41
and eltrombopag in
chronic ITP: a single-
institution experience

EPAG, eltrombopag; ITP, immune thrombocytopenia; IVIG, intravenous immunoglobulin.

been diagnosed as long as 40 years before receiving
eltrombopag, suggesting that eltrombopag-
induced remission may be feasible in any patient
with ITP achieving an initial response with
eltrombopag.37 It was proposed that restoration
of immune tolerance by reduction of autoanti-
body levels and increase in Treg function may
play a role in TPO-RA-induced remission.30,37
Eltrombopag combinations for
newly diagnosed/persistent immune
thrombocytopenia
Improving the efficacy and durability of first-line
treatments would reduce the number of patients
who fail therapy and, therefore, help spare them
from the burdensome ‘trial and error’ period. We
and others investigated whether the outcomes of
first-line treatments could be improved by the
addition of eltrombopag in several clinical studies
(Table 1).
Eltrombopag and high-dose dexamethasone
as first-line treatment for newly diagnosed
immune thrombocytopenia
In our open-label, single-arm study [ClinicalTrials.
gov identifier: NCT01652599], we studied the
potential ability of eltrombopag in combination
with corticosteroids to increase the response rate
in the first-line treatment of ITP.38 During the
study, 12 adult patients with newly diagnosed
ITP received dexamethasone (40 mg, days 1–4)
in combination with a limited course of eltrom-
bopag (50 mg, days 5–32).38 All patients had a
response (platelet count ⩾ 30 × 109/l) at the end
of treatment (day 33), and the proportion of
patients with platelet count ⩾ 50 × 109/l at
6 months was 75% with the addition of eltrom-
bopag versus 37% reported with dexamethasone
alone in a similar study cited as a historical con-
trol.38 The combination was well tolerated, with
no reports of adverse events, myelofibrosis, or
thrombosis.38

312 journals.sagepub.com/home/tah

Eltrombopag, high-dose dexamethasone,
and low-dose rituximab for newly diagnosed
immune thrombocytopenia
The combination of rituximab with high-dose
dexamethasone was shown to be more effective
than either therapy alone and induced durable
remission in the majority of adult women with
refractory ITP who had been diagnosed for
<1 year.42,43 Similarly, we showed that the com-
bination of rituximab plus high-dose dexametha-
sone may be a more effective first-line therapy
than dexamethasone alone. In adult patients who
received this first-line combination therapy, the
complete sustained response rate at 6 months
and relapse rate were 76.2% and 15.8%, respec-
tively, compared with 30% and 62.5% for a his-
torical group who received standard first-line
treatment with prednisone.44 Nevertheless, >20%
of these patients and >80% of patients in other
populations (e.g. adult men, disease duration >
1 year) will relapse.43
We hypothesized that the addition of eltrom-
bopag to this combination could address the
pathological defects in patients who were refrac-
tory to the combination of steroid plus rituximab,
thereby resulting in responses in virtually all
patients and a reduced relapse rate with triple
therapy. We performed an open-label, single-arm
study including 13 patients (aged ⩾ 16 years)
with newly diagnosed ITP who received eltrom-
bopag (50 mg/day, days 1–28) in combination
with low-dose weekly rituximab (100 mg/week,
four doses) and high-dose dexamethasone
(40 mg/day, days 1–4).39 All patients had a
response at a median of 4  days (range 3–10  days),
and all but one achieved a complete response in
9 days (range 7–22 days). Two patients relapsed
at 5 and 12 months after diagnosis, respectively,
with a probability of relapse-free survival of 79%
at 2 years.39 The treatment combination was
generally well tolerated. Adverse events were mild
and included thrombocytosis (platelet count
> 400 × 109/l; n = 2), insomnia (n = 2), and
myalgia (n = 1).39
Eltrombopag plus steroid in patients with
severe persistent immune thrombocytopenia
within 6 months of diagnosis
This multicenter, single-arm, open-label study
included 39 patients with platelet count <30 ×
109/l despite a daily dose of prednisone of 1 mg/kg
for >2 weeks from diagnosis or required pred-
nisone ⩾ 10 mg/day or recurrent IVIG to
journals.sagepub.com/home/tah 313
D Gómez-Almaguer
maintain platelet count ⩾ 30 × 109/l within
6 months of diagnosis.40 In combination with each
patient’s ongoing steroid therapy, the investiga-
tors administered eltrombopag at 50–150 mg/day
based on platelet count.40 Steroids were weaned
over 6 weeks, if weaning was considered clinically
possible. Of 39 patients enrolled, 35 (90%) com-
pleted 12 weeks of treatment. Discontinuations
prior to week 12 occurred in four patients: three
required new ITP therapy and one developed
thrombocytosis.40 At week 12, the response rate
was 64%, with a complete response seen in 41%
of patients and a median platelet count among
responders of 168 × 109/l. At week 26, the
response rate was 54%, with 28% of patients
achieving a complete response.40 Two patients
had serious adverse events (venous thromboem-
bolism), but there were no other adverse events or
deaths.40
Eltrombopag combinations for refractory
immune thrombocytopenia
Patients with multirefractory ITP who do not
respond to any available monotherapy have a high
risk of morbidity and even death,14 and, there-
fore, urgently require additional therapeutic
options. Simultaneous activation of platelet pro-
duction and inhibition of autoimmune response
to platelets through the use of eltrombopag, in
combination with immunosuppressant therapy,
may be an effective option in these patients.14
Eltrombopag and high-dose dexamethasone for
chronic immune thrombocytopenia
In an unselected series of 11 patients with chronic
ITP treated at a single institution from May 2014
to December 2015, patients received dexametha-
sone (40 mg/day) for 4 days every 28 days and
eltrombopag (50–75 mg/day) daily. All patients
achieved a response (platelet count ⩾ 30 × 109/l),
with a complete response (platelet count ⩾ 100 ×
109/l) seen in 10 of 11 patients.41 The median
time to maximum response was 12 weeks (range
3–39 weeks). Responses were maintained in all
patients after a median follow up of 29 weeks
(range 8–89 weeks) but complete response was
lost in five patients.41
Thrombopoietin in combination with rituximab
for refractory immune thrombocytopenia
While clinical trial data on eltrombopag/rituximab
combination therapy in patients with refractory
Therapeutic Advances in Hematology 9(10)
ITP are scarce, several studies reported the results
on combinations of rituximab plus recombinant
thrombopoietin (rhTPO).
A multicenter, randomized, open-label study of
rituximab [ClinicalTrials.gov identifier:
NCT01525836] (100 mg/week, 4 weeks) plus
rhTPO (300 U/kg/day, 14 days) compared with
rituximab alone in 115 patients with corticoster-
oid-resistant or relapsed ITP45 demonstrated an
increased complete response rate and decreased
time to response with rituximab plus rhTPO
compared with rituximab alone (45% versus 24%,
7 days versus 28 days, respectively). The rates of
long-term responses (6, 12, and 24 months) were
numerically greater in patients who received com-
bination therapy, but the difference did not reach
statistical significance (p = 0.12)
A single-arm study of 14 patients with refractory
ITP who received low-dose rituximab in combi-
nation with rhTPO46 reported a response rate of
93%, with 50% complete response. Relapses were
observed in two patients at 6 and 16 months after
complete response, respectively. Severe pulmo-
nary complications, potentially related to rituxi-
mab, caused death in two elderly patients with
concurrent diabetes. Furthermore, it is important
to note that a small patient series of romiplostim
in combination with rituximab is available with
similar documented success.47
Eltrombopag in combination with
immunosuppressive therapy for refractory
immune thrombocytopenia
Several immunosuppressive therapies (ISTs; e.g.
CSA, cyclophosphamide, as well as the antime-
tabolites azathioprine, 6-mercaptopurine and
mycophenolate mofetil) have been used in
patients with ITP with varying success.4,12
However, because combinations of these agents
with eltrombopag have not been formally investi-
gated in patients with ITP, direct evidence sup-
porting the safety and efficacy of these
combinations is limited.14,48,49
Although eltrombopag plus CSA is commonly
studied in patients with aplastic anemia, no clini-
cal study has directly investigated this combina-
tion in patients with ITP. Indirect evidence comes
from a randomized, controlled study in 36 patients
with steroid-resistant ITP, which showed that
CSA (1.5–2.0 mg/kg, twice daily for 3 months)
plus rhTPO (1  µg/kg, 14  days) significantly
314 journals.sagepub.com/home/tah
decreased the relapse rate at 3 months (29.4%
versus 87.5% with rhTPO only; p < 0.01).48
Eltrombopag combinations for immune
thrombocytopenia with other medications
Before the availability of rituximab and TPO-
RAs, other agents, including danazol, dapsone,
and vinca alkaloids, were used as alternative treat-
ments for ITP. While these therapies are not rec-
ommended as monotherapy under current ITP
treatment guidelines due to the lack of sufficient
clinical trial data supporting their efficacy in ITP,4
their low cost may allow their inclusion in combi-
nation therapies in patients who are refractory to
other options.
Discussion
Two major obstacles in the treatment of ITP are
the high rate of relapse with first-line treatments
and the significant minority of patients who are
refractory to multiple lines of treatment. It may
be possible to surmount these challenges by mod-
ifying the current therapeutic approach, which
relies on monotherapies targeting only one aspect
of the disease mechanism.
Preliminary clinical evidence suggests that
improvement of platelet production with eltrom-
bopag may enhance the outcomes of concomitant
ITP therapies. First, eltrombopag added to stand-
ard first-line therapy increased the durability of
response and decreased the relapse rate. Thus, in
patients with newly diagnosed ITP, when used as
frontline therapy, eltrombopag may help reduce
the need for additional courses of steroid or IVIG.
A relatively short duration of eltrombopag treat-
ment early in the disease may increase Treg activ-
ity, thereby potentially altering the natural course
of the disease without the need for continued
administration.
Second, eltrombopag in combination with
immune modulation may be effective in patients
who are refractory to single-agent ITP treatments.
By inhibiting the autoimmune response to plate-
lets and reducing antiplatelet antibodies, which
may interfere with megakaryocyte function,8 ster-
oids may induce an immunologic environment
more permissive to a response to eltrombopag.
While available clinical data do not suggest a
major long-term benefit with TPO pathway acti-
vation in combination with rituximab,45 it is pos-
sible that patients who are receiving rituximab

therapy may benefit from eltrombopag as a bridge
therapy.
Finally, eltrombopag in combination with IST
may be a viable option in patients who are refrac-
tory to eltrombopag as a single agent, which is
becoming more relevant, as it is increasingly used
in earlier disease stages, as illustrated by a recent
claims database analysis in the United States.50
Many ISTs were permitted in clinical trials of
eltrombopag, and no serious adverse events
attributed to concomitant use of these therapies
with eltrombopag have been reported.51,52
However, these trials included only a small num-
ber of patients receiving each combination. It also
should be noted that danazol, azathioprine, and
6-mercaptopurine are associated with liver toxic-
ity12 and should be used with caution in patients
receiving eltrombopag.
Importantly, no dose reduction appears to be
required when eltrombopag is used in combina-
tion with other ITP therapies. For adult patients
with ITP, the recommended starting dose for
eltrombopag is 50  mg/day, which can be increased
to 75 mg/day if a sufficient platelet count is not
reached.31 Higher doses (75–150 mg/day) are
approved in patients with severe aplastic anemia
and have been tested in a limited number of
patients with ITP.14,31,43,53 Preliminary results
suggest increased efficacy in some patients, but
more evidence is needed.53
Because increased platelet destruction in ITP
may result from diverse immunologic abnormali-
ties, combinations of ISTs with distinct mecha-
nisms of actions may further increase response
rates. A pilot study of eltrombopag, rituximab,
and dexamethasone as first-line ITP therapy
showed a remarkable 100% initial response, with
a 2-year relapse-free survival rate of 79%.39
Conclusions
With improved understanding of the pathogene-
sis of ITP, the therapeutic potential of combina-
tion treatments that address multiple disease
mechanisms has become clear. As the only drug
class that may improve platelet production in
ITP, TPO-RAs, including eltrombopag, are
essential components of combination therapies
for ITP. Albeit limited, current evidence is con-
sistent with expectations and suggests that combi-
nation therapy with eltrombopag may help
patients with newly diagnosed or highly refractory
journals.sagepub.com/home/tah 315
D Gómez-Almaguer
ITP attain their treatment goals. Future studies
are needed to confirm the preliminary evidence,
develop potential diagnostic methods to identify
treatment approaches based on pathogenic mech-
anisms, and elucidate optimal ISTs for eltrom-
bopag combinations.
Funding
ClinicalThinking, Inc., NJ, USA provided medi-
cal writing and editorial support for the prepara-
tion of this manuscript, which was funded by
Novartis Pharmaceuticals Corporation, East
Hanover, NJ, USA. Novartis did not influence
the content of the manuscript nor did the author
receive financial compensation for authoring the
manuscript.
Conflict of interest statement
The author declares no conflicts of interest in
preparing this article. The author has received
honoraria for speaker roles by Novartis, Amgen,
Celgene, Bristol, Janssen and Tecnofarma, none
related to products discussed in this publication.
References
1. Rodeghiero F, Stasi R, Gernsheimer T, et al.
Standardization of terminology, definitions and
outcome criteria in immune thrombocytopenic
purpura of adults and children: report from an
international working group. Blood 2009; 113:
2386–2393.
2. Terrell DR, Beebe LA, Vesely SK, et al. The
incidence of immune thrombocytopenic purpura in
children and adults: A critical review of published
reports. Am J Hematol 2010; 85: 174–180.
3. McMillan R, Bussel JB, George JN, et al. Self-
reported health-related quality of life in adults
with chronic immune thrombocytopenic purpura.
Am J Hematol 2008; 83: 150–154.
4. Neunert C, Lim W, Crowther M, et al.
The American Society of Hematology 2011
evidence-based practice guideline for immune
thrombocytopenia. Blood 2011; 117: 4190–4207.
5. Stasi R, Cooper N, Del Poeta G, et al. Analysis
of regulatory T-cell changes in patients with
idiopathic thrombocytopenic purpura receiving B
cell-depleting therapy with rituximab. Blood 2008;
112: 1147–1150.
6. Stasi R and Newland AC. ITP: a historical
perspective. Br J Haematol 2011; 153: 437–450.
7. Cines DB, Bussel JB, Liebman HA, et al. The
ITP syndrome: pathogenic and clinical diversity.
Blood 2009; 113: 6511–6521.
Therapeutic Advances in Hematology 9(10)
8. Zufferey A, Kapur R and Semple JW.
Pathogenesis and therapeutic mechanisms in
immune thrombocytopenia (ITP). J Clin Med;
6. Epub ahead of print 9 February 2017. DOI:
10.3390/jcm6020016.
9. Nichol JL. Endogenous TPO (eTPO) levels in
health and disease: possible clues for therapeutic
intervention. Stem Cells Dayt Ohio 1998;
16(Suppl. 2): 165–175.
10. Kaushansky K. Historical review:
megakaryopoiesis and thrombopoiesis. Blood
2008; 111: 981–986.
11. Bromberg ME. Immune thrombocytopenic
purpura — the changing therapeutic landscape. N
Engl J Med 2006; 355: 1643–1645.
12. Cuker A and Neunert CE. How I treat refractory
immune thrombocytopenia. Blood. Epub ahead
of print 6 April 2016. DOI: 10.1182/blood-2016-
03-603365.
13. Brown TM, Horblyuk RV, Grotzinger KM, et al.
Patient-reported treatment burden of chronic
immune thrombocytopenia therapies. BMC Blood
Disord 2012; 12: 2.
14. Mahévas M, Gerfaud-Valentin M, Moulis G,
et al. Characteristics, outcome, and response
to therapy of multirefractory chronic immune
thrombocytopenia. Blood 2016; 128: 1625–1630.
15. Raj AB. Immune Thrombocytopenia:
pathogenesis and treatment approaches. J
Hematol Transfus 2017; 5: 1056.
16. Arnold DM. Positioning new treatments in the
management of immune thrombocytopenia.
Pediatr Blood Cancer 2013; 60(Suppl. 1): S19–
S22.
17. Mizutani H, Furubayashi T, Imai Y, et al.
Mechanisms of corticosteroid action in immune
thrombocytopenic purpura (ITP): experimental
studies using ITP-prone mice, (NZW x BXSB)
F1. Blood 1992; 79: 942–947.
18. Rituxan [prescribing information]. Genentech
Inc. San Fransisco, CA.
19. Arnold DM, Dentali F, Crowther MA,
et al. Systematic review: efficacy and safety
of rituximab for adults with idiopathic
thrombocytopenic purpura. Ann Intern Med 2007;
146: 25–33.
20. Ghanima W, Khelif A, Waage A, et al. Rituximab
as second-line treatment for adult immune
thrombocytopenia (the RITP trial): a multicentre,
randomised, double-blind, placebo-controlled
trial. Lancet Lond Engl 2015; 385: 1653–1661.
21. Godeau B, Porcher R, Fain O, et al.
Rituximab efficacy and safety in adult
316 journals.sagepub.com/home/tah
splenectomy candidates with chronic immune
thrombocytopenic purpura: results of a
prospective multicenter phase 2 study. Blood
2008; 112: 999–1004.
22. Ghanima W, Godeau B, Cines DB, et al. How
I treat immune thrombocytopenia: the choice
between splenectomy or a medical therapy
as a second-line treatment. Blood 2012; 120:
960–969.
23. Kristinsson SY, Gridley G, Hoover RN, et al.
Long-term risks after splenectomy among 8,149
cancer-free American veterans: a cohort study
with up to 27 years follow-up. Haematologica
2014; 99: 392–398.
24. Chaturvedi S, Arnold DM and McCrae KR.
Splenectomy for immune thrombocytopenia:
down but not out. Blood. 2018; 131: 1172–1182.
25. Audia S, Godeau B and Bonnotte B. Is there still
a place for ‘old therapies’ in the management
of immune thrombocytopenia? Rev Med Interne
Fondee Par Soc Natl Francaise Med Interne 2016;
37: 43–49.
26. Di Buduo CA, Currao M, Pecci A, et al.
Revealing eltrombopag’s promotion of human
megakaryopoiesis through AKT/ERK-dependent
pathway activation. Haematologica 2016; 101:
1479–1488.
27. Olnes MJ, Scheinberg P, Calvo KR, et al.
Eltrombopag and improved hematopoiesis in
refractory aplastic anemia. N Engl J Med 2012;
367: 11–19.
28. Townsley DM, Scheinberg P, Winkler
T, et al. Eltrombopag added to standard
immunosuppression for aplastic anemia. N Engl J
Med 2017; 376: 1540–1550.
29. Bao W, Heck S, Karpoff M, et al. Improved
regulatory T cell activity in patients with chronic
immune thrombocytopenia purpura treated with
thrombopoietic agents. Blood 2009; 114: 684.
30. Ghadaki B, Nazi I, Kelton JG, et al. Sustained
remissions of immune thrombocytopenia
associated with the use of thrombopoietin
receptor agonists. Transfusion (Paris) 2013; 53:
2807–2812.
31. Novartis. Promacta [package insert]. Novartis
Pharmaceuticals Corporation, East Hanover, NJ.
32. Bussel JB, Cheng G, Saleh MN, et al.
Eltrombopag for the treatment of chronic
idiopathic thrombocytopenic purpura. N Engl J
Med 2007; 357: 2237–2247.
33. Grainger JD, Locatelli F, Chotsampancharoen
T, et al. Eltrombopag for children with chronic
immune thrombocytopenia (PETIT2): a

randomised, multicentre, placebo-controlled trial.
Lancet Lond Engl 2015; 2: e315–e325.
34. Wong RSM, Saleh MN, Khelif A, et al. Safety
and efficacy of long-term treatment of chronic/
persistent ITP with eltrombopag: final results of
the EXTEND study. Blood. Epub ahead of print
17 October 2017. DOI: 10.1182/blood-2017-04-
748707.
35. Bussel J, Shah KM, Brigstocke S, et al. Tapering
eltrombopag in patients with chronic ITP: how
successful is this and in whom does it work?
Blood. 2015; 126: 1054.
36. Leven E, Miller A, Boulad N, et al. Successful
discontinuation of eltrombopag treatment in
patients with chronic ITP. Blood 2015; 120: 1085.
37. Gonzalez-Lopez TJ, Sanchez-Gonzalez B, Pascual
C, et al. Sustained response after discontinuation
of short-and medium-term treatment with
eltrombopag in patients with immune
thrombocytopenia. Platelets 2015; 26: 83–86.
38. Gómez-Almaguer D, Herrera-Rojas MA, Jaime-
Pérez JC, et al. Eltrombopag and high-dose
dexamethasone as frontline treatment of newly
diagnosed immune thrombocytopenia in adults.
Blood 2014; 123: 3906–3908.
39. Gomez-Almaguer D, Cantu-Rodriguez O,
Gutierrez-Aguirre CH, et al. Eltrombopag, low-
dose rituximab, and high-dose dexamethasone
combination for patients with newly diagnosed
immune thrombocytopenia: a pilot ‘total therapy’
study. Blood 2016; 128: 1369–1369.
40. Tran H, Bird R and Chunilal S. A multicentre,
single arm, open label study evaluating the efficacy
and safety of eltrombopag in patients with severe
persistent immune thrombocytopenic purpura
(ITP) within six months of diagnosis. Poster
presented at EHA 2017, https://learningcenter.
ehaweb.org/eha/2017/22nd/181207/huyen.
tran.a.multicentre.single.arm.open.label.study.
evaluating.the.efficacy.html?f=m2t1574 (accessed
26 October 2017).
41. Magro D, Levato L, Eugenio P, et al. High-
dose dexamethasone and eltrombopag in
chronic immune thrombocytopenia: a single
institution experience. Haematologica 2017;
102: 1–217.
42. Bussel JB, Lee CS, Seery C, et al. Rituximab and
three dexamethasone cycles provide responses
similar to splenectomy in women and those with
immune thrombocytopenia of less than two years
duration. Haematologica 2014; 99: 1264.
43. Chapin J, Lee CS, Zhang H, et al. Gender and
duration of disease differentiate responses to
journals.sagepub.com/home/tah 317
D Gómez-Almaguer
rituximab-dexamethasone therapy in adults with
immune thrombocytopenia. Am J Hematol 2016;
91: 907–911.
44. Gomez-Almaguer D, Tarin-Arzaga L, Moreno-
Jaime B, et al. High response rate to low-dose
rituximab plus high-dose dexamethasone as
frontline therapy in adult patients with primary
immune thrombocytopenia. Eur J Haematol 2013;
90: 494–500.
45. Zhou H, Xu M, Qin P, et al. A multicenter
randomized open-label study of rituximab plus
rhTPO vs rituximab in corticosteroid-resistant or
relapsed ITP. Blood 2015; 125: 1541–1547.
46. Li Y, Wang YY, Fei HR, et al. Efficacy of
low-dose rituximab in combination with
recombinant human thrombopoietin in
treating ITP. Eur Rev Med Pharmacol Sci
2015;19(9):1583–1588.
47. Pohlen M, Sargin B, Zicholl S, et al. Combination
of romiplostim and rituximab: effective therapy of
severe immune thrombocytopenia. Eur J Haematol
2010; 84: 362–364.
48. Cui Z-G, Liu X-G, Qin P, et al. Recombinant
human thrombopoietin in combination with
cyclosporin A as a novel therapy in corticosteroid-
resistant primary immune thrombocytopenia.
Chin Med J (Engl) 2013; 126: 4145–4148.
49. Anwer F, Yun S, Nair A, et al. Severe refractory
immune thrombocytopenia successfully treated
with high-dose pulse cyclophosphamide and
eltrombopag. Case Rep Hematol 2015; 2015:
583451.
50. Stafkey-Mailey D, Roy A and Tasneem L.
Evaluation of treatment patterns among patients
with newly diagnosed, persistent, and chronic
immune thrombocytopenia (ITP) treated with
eltrombopag in real world setting in the US
Blood. 2017; 130: 2078.
51. Bussel JB, Provan D, Shamsi T, et al. Effect of
eltrombopag on platelet counts and bleeding
during treatment of chronic idiopathic
thrombocytopenic purpura: a randomised,
double-blind, placebo-controlled trial. Lancet
2009; 373: 641–648.
52. Cheng G, Saleh MN, Marcher C, et al.
Eltrombopag for management of chronic
immune thrombocytopenia (RAISE): a 6-month,
randomised, phase 3 study. Lancet 2011; 377:
393–402.
53. Keefe PJ, Morrissey MC, McGuinn CE, et al. Visit SAGE journals online
journals.sagepub.com/
Randomized double-blind study of increasing
home/tah
doses of eltrombopag in patients with chronic
ITP. Blood 2015; 126: 1057. SAGE journals