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Coagulation Disorders Platelet Disorders
Romiplostim – A Thrombopoiesis-stimulating Peptibody for the Management of
Chronic Immune Thrombocytopenic Purpura in Adults
a report by
Adrian Newland
Professor of Haematology, Barts and the London NHS Trust
Idiopathic or immune thrombocytopenic purpura (ITP) is an autoimmune The role of splenectomy in the treatment algorithm varies because the
condition characterised by an abnormally low number of platelets in the decision to perform splenectomy is often patient-specific. Approximately
circulating blood. Initially, ITP was thought to be caused by antibody- one-third of patients do not respond to splenectomy,
6,7
and in a recent
mediated platelet destruction,
1
but better understanding of the meta-analysis a five-year relapse rate of 32% after splenectomy was
pathogenesis of the condition has indicated that insufficient or reported in this patient population.
8
In addition, the risks and benefits of
inadequate platelet production also plays a role.
2
ITP can be acute or this surgical procedure to the patient must be carefully weighed.
chronic. Acute ITP is normally seen in children between three and five Increasingly, patients are opting out of surgery as they become more aware
years of age, often occurs after a viral infection and has a seasonal of the risk–benefit ratio and the alternative treatments available to them.
9
incidence. It usually presents, as the name suggests, with sudden onset
of bruising and bleeding.
3
In contrast, chronic ITP is typically seen in It was recognised that platelet production is suboptimal in a substantial
adults, is usually more serious and has no seasonal variation. A proportion proportion of patients with ITP,
10,11
which prompted a search for
of patients with ITP may be diagnosed incidentally, but frequently there treatments that enhance platelet production. Thrombopoietin (TPO;
is a slow, insidious onset of symptoms. In contrast to acute ITP, where megapoietin; megakaryocyte growth and development factor; c-mpl
remission is seen in the majority of patients, fewer than 10% of patients ligand), the key regulator of megakaryopoiesis and platelet production,
with chronic ITP experience spontaneous remission and therefore these was identified in 1994.
12,13
The first studies with recombinant
patients need long-term management. thrombopoietins (pegylated recombinant human megakaryocyte growth
and development factor [PEG-rHuMGDF] and recombinant human TPO
Corticosteroids are typically used as initial treatment, but if platelet levels [rhTPO]) were discontinued because of problems with the development
fall precipitously or the clinical situation is serious and there is a need to of cross-reacting antibodies, leading to severe, persistent
rapidly raise the count, intravenous immune globulins (including anti-D) thrombocytopenia.
14
Nevertheless, this research paved the way for the
may be administered. A variety of agents have been used when first-line development of the next generation of thrombopoiesis-stimulating
treatments fail, but few of these are specifically licensed for use in ITP. therapies, which produced romiplostim. Other products in development
These agents include steroids (dexamethasone), azathioprine and other include the small-molecule TPO receptor agonists eltrombopag
15
and
cytotoxic agents such as cyclophosphamide, as well as immune-suppressive AKR-501.
16
These newer agents and their place in treatment strategies
agents such as rituximab, cyclosporine and mycophenolate mofetil, which have recently been reviewed.
17
act primarily by interfering with autoantibody production or by blocking
platelet destruction. These treatments may be associated with significant Romiplostim
side effects, and the increased incidence of infection due to immune Romiplostim (AMG 531, Amgen, Thousand Oaks, CA, US) is a novel
suppression is associated with up to 50% of the mortality seen in ITP.
4,5
recombinant thrombopoiesis-stimulating Fc-peptide fusion protein
(‘peptibody’) that was developed for the treatment of ITP. Romiplostim
was recently approved for the treatment of adults with chronic ITP in the
Adrian Newland is a Professor of Haematology at Barts
and the London NHS Trust, where he developed the
US and Australia. In addition, the European Committee for Medicinal
leukaemia and bone marrow transplant unit in the Products for Human Use has issued a positive opinion recommending
early 1980s. He now has a particular interest in
marketing authorisation for romiplostim in the EU. The molecule has two
immunohaematology and is studying the molecular basis
of autoimmune disease, in particular thrombocytopenia,
domains: a peptide domain that binds to the TPO receptor and activates
and piloting the clinical use of novel treatments. He is also
intracellular pathways, stimulating megakaryopoiesis, and a carrier
Centre Lead for Haematology in the Medical School,
Director of Pathology for the Trust and Clinical Director of
antibody crystallisable (Fc) fragment that undergoes endothelial
the North East Thames Cancer Network. As a haematologist, Professor Newland has been recirculation, thereby extending its circulating half-life. Romiplostim has
particularly involved in workforce training and curriculum development, and until recently
no sequence homology with endogenous human TPO.
18
chaired the national Intercollegiate Committee on Haematology. He was President of the
British Society for Haematology (BSH) in 1998–1999 and is the UK representative on the
European Union of Medical Specialities (EUMS) and Chairman of the Science and Education
In vitro studies in human and murine megakaryocytes indicated that
Committee of the International Society for Haematology. He was elected to the Council of
romiplostim binds the TPO receptor in a similar manner to endogenous
the Royal College of Pathologists from 1993 to 1996 and was re-elected in 1999. He was
Vice President from 2002 to 2005 and became President in November 2005. Professor TPO. This stimulates megakaryopoiesis via tyrosine phosphorylation and
Newland has been closely involved with the review of pathology services and has worked
triggering of Janus kinase (JAK)-2 and signal transducers and activators of
with the Department of Health on Modernising Scientific Careers.
transcription (STAT)-5.
19
In healthy volunteers, single intravenous or
E: a.c.newland@qmul.ac.uk
subcutaneous doses of romiplostim ranging from 0.3 to 10.0µg/kg and
from 0.1 to 2.0µg/kg, respectively, were well tolerated and induced dose-
48 © TOUCH BRIEFINGS 2008
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