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TAH0010.1177/2040620718798798Therapeutic Advances in HematologyD Gómez-Almaguer
Introduction
Immune thrombocytopenia (ITP) is a bleeding antiplatelet antibodies are detected and the Correspondence to:
David Gómez-Almaguer
disorder affecting 3 to 4 per 100,000 adults/ immune attack may be carried out directly by Hematology Service,
year.1,2 Apart from the risk of severe bleeding, cytotoxic T-cells.8 Facultad de Medicina y
Hospital Universitario Dr
patients with ITP may also have poor quality of José Eleuterio González,
life, comparable to that of patients with diabetes.3 Under normal circumstances, a decrease in plate- Francisco I. Madero and
José E. González, 64460
ITP is caused by a decrease in platelet count let count leads to increased plasma thrombopoi- Monterrey, Mexico
below 100 × 109/l as a result of increased destruc- etin level, which induces a compensatory boost in dgomezalmaguer@gmail.
com
tion and insufficient production of platelets, platelet production in bone marrow.9 Through
caused by an autoimmune reaction.1,4 Multiple this mechanism, platelet production may increase
immunologic abnormalities are likely to be more than 20-fold.10 However, patients with ITP
involved in the immune reaction to platelets, and appear to have defects in this physiological mech-
impaired regulatory T-lymphocyte (Treg) activity anism. The level of thrombopoietin in serum is
is considered to play a significant role.5–8 In not elevated in response to thrombocytopenia in
most patients with ITP, the immune attack is such patients and, accordingly, a compensatory
mediated by antiplatelet antibodies secreted by boost in platelet production is absent.9,11
plasma cells.8 These autoreactive antibodies
cause opsonization of platelets by macrophages Conventionally, the goal of first-line therapy for
and may interfere with platelet production by ITP is to quickly increase platelet count in patients
impairing megakaryocyte function.8 Importantly, with high risk of bleeding or active bleeding, while
in approximately 40% of patients with ITP, no durability of response and long-term safety and
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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 treatment option for ITP that can address
Therefore, most patients with ITP relapse and insufficient platelet production, thrombopoietin
consequently receive multiple lines of monother- receptor agonists (TPO-RAs), including eltrom-
apy, including repeated courses of first-line treat- bopag, play a central role in combination treat-
ments until a treatment providing a durable ment approaches for ITP (Figure 1).15
platelet response is found. During this ‘trial and
error’ period, which may last months or even
years, these patients may experience significant Conventional treatment of immune
disease burden associated with the risk of bleed- thrombocytopenia
ing events and adverse effects of treatment.3,13 In
addition, there is a small but significant group of Treatment-naïve patients
multirefractory patients who do not achieve a sta- First-line management options for ITP usually
ble response with any available monotherapy.14 include corticosteroids (dexamethasone, pred-
Both of these patient groups could benefit from nisone) and immunoglobulins [intravenous immu-
the potential synergistic efficacy of combination noglobulin (IVIG), Rho(D) immune globulin
treatments that simultaneously address multiple (anti-D)], which produce fast but transient
disease mechanisms. Being the only available responses.4 Corticosteroids show an initial response
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D Gómez-Almaguer
in 60–70% of patients within 2–14 days, but the mycophenolate mofetil, and vincristine, have
response often lasts <6 months.4,16 IVIG will pro- been used to treat refractory ITP. While most of
duce a response in 1–3 days in 90% of patients, but these agents have limited efficacy as monother-
the response typically lasts only 2–4 weeks4,16 apy, they are sometimes preferred due to their
low cost.4,12,25
The rapid effects of first-line treatments are pri-
marily mediated through inhibition of platelet
opsonization, which is the final step of platelet Eltrombopag for treatment of immune
destruction (Figure 1).8,17 However, these rea- thrombocytopenia
gents have other direct and indirect effects on TPO-RAs are the only therapeutic option for ITP
the immune system, including decreasing that increases platelet production (Figure 1).15 In
autoantibody production and rescuing Treg addition to promoting platelet production from
function, which may play a role in their clinical existing megakaryocytes, TPO-RAs may also
activity.8,15 enhance proliferation of megakaryocytes in bone
marrow, as suggested by in vitro studies and clini-
cal trials in patients with aplastic anemia.26–28
Refractory patients Importantly, TPO-RAs may reduce platelet
For patients refractory to first-line treatments, destruction by restoring Treg and regulatory
common therapeutic options include TPO-RAs, B-cell activity, thereby attenuating the autoim-
the anti-CD20 antibody rituximab, splenectomy, mune response to platelets.8,29 In patients treated
and immunosuppressive agents.4,12 Rituximab, with TPO-RAs for >3 months, Treg activity was
which is licensed for use in certain hematologic significantly improved compared with the pre-
malignancies and autoimmune disorders, depletes treatment group (p = 0.001) and was similar to
the B-cell pool involved in the production of the Treg activity in healthy subjects (p = 0.9).8,29
autoreactive antibodies and may also restore Treg Moreover, preliminary evidence suggests that
activity.5,18 Although this drug is often used in autoantibody levels in patients with ITP may pro-
patients with refractory ITP, it has a variable gressively decrease with TPO-RA treatment,
response rate and limited duration of response.19,20 which may contribute to restoration of immune
In uncontrolled studies, 63% of patients showed tolerance to platelets.30
an immediate response to a single course of ritux-
imab, and the 2-year response rate was 40%.19,21 Eltrombopag is an oral TPO-RA approved for use
In the only placebo-controlled trial of rituximab, in more than 80 countries, including the United
no significant benefits beyond 1.5 years were States and European Union countries.22 In rand-
reported.20 omized, controlled trials, eltrombopag has been
shown to safely and durably increase platelet
Splenectomy is the oldest option for long-term count in both adults and children with refractory
management of ITP and is still being used due to ITP.31–33 Clinical evidence from patients who
its high durable response rate (60–70%).6,22 received eltrombopag for up to 8.8 years supports
Nevertheless, this invasive option is associated that eltrombopag retains its safety and efficacy
with both risk of surgical complications and life- with long-term continuous use,34 even though it
long risks caused by the loss of splenic function, would be necessary to evaluate further related
including infection, thromboembolism, and even events associated with eltrombopag for a longer
malignancy.22,23 Therefore, once effective phar- term.
maceutical management options became availa-
ble, the use of splenectomy has declined; however, Although many patients require continuous treat-
it must still be considered according to patients’ ment with eltrombopag to maintain a response, in
comorbidity risk and preference, and it is a very approximately 30% of patients, eltrombopag induces
effective therapeutic option. To date, no long- disease remission and can be discontinued.30,35–37
term outcomes have been compared between However, it is important to note, that these stud-
patients undergoing splenectomy and those ies defined remission rate using different criteria,
treated with medical therapies.24 besides, some of these patients could achieve
spontaneous remission. On the other hand, some
Many other agents with immunosuppressive patients achieving remission with eltrombopag
properties, including azathioprine, cyclosporine had ITP that was highly refractory (seven lines of
A (CSA), cyclophosphamide, danazol, dapsone, prior therapy, including splenectomy) and had
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Therapeutic Advances in Hematology 9(10)
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
been diagnosed as long as 40 years before receiving Eltrombopag and high-dose dexamethasone
eltrombopag, suggesting that eltrombopag- as first-line treatment for newly diagnosed
induced remission may be feasible in any patient immune thrombocytopenia
with ITP achieving an initial response with In our open-label, single-arm study [ClinicalTrials.
eltrombopag.37 It was proposed that restoration gov identifier: NCT01652599], we studied the
of immune tolerance by reduction of autoanti- potential ability of eltrombopag in combination
body levels and increase in Treg function may with corticosteroids to increase the response rate
play a role in TPO-RA-induced remission.30,37 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)
Eltrombopag combinations for in combination with a limited course of eltrom-
newly diagnosed/persistent immune bopag (50 mg, days 5–32).38 All patients had a
thrombocytopenia response (platelet count ⩾ 30 × 109/l) at the end
Improving the efficacy and durability of first-line of treatment (day 33), and the proportion of
treatments would reduce the number of patients patients with platelet count ⩾ 50 × 109/l at
who fail therapy and, therefore, help spare them 6 months was 75% with the addition of eltrom-
from the burdensome ‘trial and error’ period. We bopag versus 37% reported with dexamethasone
and others investigated whether the outcomes of alone in a similar study cited as a historical con-
first-line treatments could be improved by the trol.38 The combination was well tolerated, with
addition of eltrombopag in several clinical studies no reports of adverse events, myelofibrosis, or
(Table 1). thrombosis.38
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Therapeutic Advances in Hematology 9(10)
ITP are scarce, several studies reported the results decreased the relapse rate at 3 months (29.4%
on combinations of rituximab plus recombinant versus 87.5% with rhTPO only; p < 0.01).48
thrombopoietin (rhTPO).
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D Gómez-Almaguer
therapy may benefit from eltrombopag as a bridge ITP attain their treatment goals. Future studies
therapy. are needed to confirm the preliminary evidence,
develop potential diagnostic methods to identify
Finally, eltrombopag in combination with IST treatment approaches based on pathogenic mech-
may be a viable option in patients who are refrac- anisms, and elucidate optimal ISTs for eltrom-
tory to eltrombopag as a single agent, which is bopag combinations.
becoming more relevant, as it is increasingly used
in earlier disease stages, as illustrated by a recent Funding
claims database analysis in the United States.50 ClinicalThinking, Inc., NJ, USA provided medi-
Many ISTs were permitted in clinical trials of cal writing and editorial support for the prepara-
eltrombopag, and no serious adverse events tion of this manuscript, which was funded by
attributed to concomitant use of these therapies Novartis Pharmaceuticals Corporation, East
with eltrombopag have been reported.51,52 Hanover, NJ, USA. Novartis did not influence
However, these trials included only a small num- the content of the manuscript nor did the author
ber of patients receiving each combination. It also receive financial compensation for authoring the
should be noted that danazol, azathioprine, and manuscript.
6-mercaptopurine are associated with liver toxic-
ity12 and should be used with caution in patients Conflict of interest statement
receiving eltrombopag. The author declares no conflicts of interest in
preparing this article. The author has received
Importantly, no dose reduction appears to be honoraria for speaker roles by Novartis, Amgen,
required when eltrombopag is used in combina- Celgene, Bristol, Janssen and Tecnofarma, none
tion with other ITP therapies. For adult patients related to products discussed in this publication.
with ITP, the recommended starting dose for
eltrombopag is 50 mg/day, which can be increased
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