Immune Thrombocytopenic Purpura - the European Oncology ...

Immune Thrombocytopenic Purpura
New Treatment Options
By Dion Smyth, Birmingham City University, Birmingham, UK
Platelet count and symptoms
Introduction
24 - newsletter fall 2008
Immune (idiopathic) thrombocytopenic purpura (ITP) is a rare • > 50 x 10 9 /L Often asymptomatic
autoimmune disorder characterized by low numbers of circulating • 30-50 x 10 9 /L Easy bruising
platelets. Patients with ITP often have platelet counts of less than • 20 x 10 9 /L Petechiae and purpura
50 x 10 9 /L and, although otherwise well, they may feel fatigued
and have an increased tendency for bleeding, easy bruising, or
extravasation of blood from capillaries into skin and mucous
•

• patients planning to undergo medical or dental procedures likely to
provoke or bring about blood loss, such as the extraction of a tooth
• patients with lifestyles associated with an increased risk of
bleeding, such as those participating in hazardous or dangerous
activities such as full-on contact sports.
Current treatments for patients with ITP
Currently, four treatment options that focus on reducing
platelet destruction are commonly used: corticosteroids, anti-D
immunoglobulin, intravenous immunoglobulins (IVIGs), and
splenectomy. Corticosteroids, typically prednisone, are considered
the first line of therapy and are effective in 50-75% of patients.
(8) Unfortunately, the long-term use of corticosteroids can be
associated with various side effects, including hypertension, diabetes,
osteoporosis, glaucoma, and in extreme cases, Cushing’s syndrome
as well as an increased risk of infection associated with steroidinduced
immunosuppression.
Anti-D immunoglobulin is equally effective, but only in 70-75% of
Rhesus+ patients in the non-splenectomised setting (4). IVIGs
are recommended for patients unresponsive to corticosteroids, or
those with severe bleeding (7). Possible side effects associated with
immunoglobulins include fever, chills, headache, nausea, dyspnea,
and chest pain. In rare cases, patients may develop acute kidney
failure, aseptic meningitis, or haemolytic anaemia following the
administration of immunoglobulins.
Splenectomy is an option for patients with severe ITP refractory to
corticosteroids but the trend now is for more conservative medical
management of patients. Patients can have a lifelong increased risk
of infection following splenectomy, and 40-50% of splenectomised
patients later relapse (1).
Rituximab is not currently approved for the treatment of ITP but has
demonstrated efficacy. (9,10). Approximately 45-65% of patients have
a response to rituximab (11) but treatment can be complicated due
to unpredictable patterns of response. Some patients have an early
increase in platelet counts (after the first or second infusion) which
peak between weeks 6 and 10; others may have a late response
where increases in platelet count are first achieved 6 to 8 weeks after
treatment initiation and reached a peak count quickly.(12,13)
New treatment options for patients with ITP
New therapies developed to address sub-optimal platelet production
include growth factors that stimulate platelet production (4). The
first recombinant TPO—manufactured by adding the relevant DNA
into the existing genome of bacteria so that proteins are created
that stimulate the production of platelets—was similar to endogenous
TPO produced naturally in the body. The recombinant TPOs proved
to be immunogenic and the body’s immune system identified the
recombinant TPO as ‘foreign’ leading to the production of autoantibodies
and the destruction of endogenous TPO. The second
recombinant TPO receptor agonist, romiplostim and the small
molecule TPO receptor agonist, eltrombopag, currently in late phase
clinical development have no structural similarity to endogenous TPO
and do not stimulate an autoimmune response.
Romiplostim
Romiplostim is a thrombopoeisis-stimulating Fc-peptide fusion
protein (peptibody) which binds to the TPO receptor on the surface
of platelet-producing megakaryocytes (Figure 3). The binding of
romiplostim activates cell signalling pathways which lead to activation
of platelet production (4). Romiplostim is administered as a onceweekly,
subcutaneous injection and the dose of romiplostim is
individualised for each patient and their specific platelet level. The
efficacy and safety of romiplostim (1μg/kg weekly) was investigated
in two 24-week, parallel, placebo-controlled, double-blinded, phase
III trials, one in splenectomised patients (romiplostim N= 42; placebo
N = 21) and the other in non splenectomised patients (romiplostim
N=41; placebo N= 21) (14). Patients could receive concurrent ITP
therapy with corticosteroids, azathioprine, and danazol. The primary
endpoint of both studies was durable platelet response defined as
a weekly platelet count of ≥ 50 x 10 9 /L during at least 6 of the last
8 weeks of treatment, in the absence of rescue medication at any
time during the study. Transient response was defined as 4 or more
weekly platelet responses without a durable response from week
2-25. Platelet responses that occurred within 8 weeks of rescue
treatment were not included in any measures of platelet outcome.
Altogether 83% of the romiplostim-treated patients achieved an
overall platelet response (either durable or transient) compared
with 7% of patients receiving placebo (p

similar or worse compared with patients with diabetes or arthritis
(19). Patients report that the bruising and bleeding resulting from ITP
has a substantial negative effect on their quality of life, and fatigue
(possibly due to the anaemia caused by bleeding) hinders their
ability to perform their routine daily activities. (20). When presented
with a patient with ITP, the nurse therefore has to help the patient
adapt to the physical and psychosocial demands of the disease. The
changes to body image associated with corticosteroid treatment,
the implications of a potential splenectomy, rehabilitation, roles and
responsibilities, and the risk of sepsis are examples of some of the
fears and concerns that nurses should be assessing and addressing
when informing patients about, and explaining, different treatment
options to patients with ITP. Keeping up to date with the developing
and future therapeutic options enables the nurse to educate and
reassure the patient, thereby potentially alleviating fears of treatment
failure or that eventual splenectomy is unavoidable.
The long-term efficacy and safety of romiplostim are now being
confirmed in an ongoing, open-label, extension study (15). The
European Medicines Evaluation Agency is currently reviewing the
Marketing Authorisation Application for romiplostim. Romiplostim
was recently approved for the treatment of adults with chronic ITP in
the US and Australia.
Eltrombopag
Eltrombopag is a small molecule TPO receptor agonist that is
administered orally once-daily. It activates the TPO receptor by
binding to the transmembrane region. Although eltrombopag binds
to the receptor differently than endogenous TPO or romiplostim, the
final pathways seem to be identical (4). The results from a 6-week
treatment-period, placebo-controlled phase II trial where the primary
end point was a platelet count of ≥50 x 10 9 /L on day 43 of treatment
showed that 28%, 70%, and 81% of patients receiving, respectively,
30 mg, 50 mg or 75 mg of eltrombopag daily achieved this endpoint
(versus 11% in the placebo group). (16)
When considering the management of the patient, two important
Mild to moderate headache was the most commonly reported issues during the treatment of ITP arise: firstly, the need for treatment
adverse event followed by aspartate aminotransferase elevation, concordance and secondly, regular platelet count monitoring. A onceweekly
subcutaneous therapy such as romiplostim may facilitate
constipation, fatigue, and rash. Cataracts have been noted in both
preclinical and clinical studies of eltrombopag, and elevated alanine concordance; it also combines treatment with frequent platelet
transaminase in conjunction with raised bilirubin levels have been count monitoring and reinforces regular contact with medical staff
observed in some patients treated with eltrombopag (17). Phase III which may be reassuring for the patient. This approach facilitates
studies of eltrombopag are currently ongoing and the published data individually tailored and controlled dosing schedules and minimises
are awaited soon.
the risk of thrombosis that might occur if platelet counts increase
(e.g. due to irregular drug intake).
Discussion
With the development of the TPO receptor agonists, the treatment In adults, ITP is a chronic disease often associated with a remitting
options for patients with ITP have been widened. Current treatments – relapsing course. Many patients do not require treatment and the
can have many side effects and the treatment of ITP may result decision to introduce therapeutic interventions will be based upon
in increased morbidity from adverse effects and opportunistic the laboratory findings, clinical circumstances, and individual patient
infections, which often surpass the problems actually caused by ITP risk factors. The development of the upcoming TPO receptor agonists
(18). The phase III trials investigating romiplostim and the phase II provides patients with a new perspective to living with this chronic
trials on eltrombopag show that TPO receptor agonists appear to be medical condition.
well-tolerated and effective in patients with ITP (14, 16). As the TPO
receptor agonists are not immunosuppressive agents, the problems Acknowledgements
associated with immunosuppressive treatment can be avoided and This article was supported by Amgen Europe GmbH, Zug, Switzerland.
the overall health of the patient better maintained.
Author for Correspondence: 033 Bevan House, Birmingham City
Both the symptoms of ITP and its treatment affect the quality of life University, Edgbaston , Birmingham, B15 3TN, UK E-mail: dion.
of the patient; indeed the impact on quality of life is perceived as smyth@bcu.ac.uk
26 - newsletter fall 2008

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Feb 8;6:13, 2008
Update accreditation
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