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Immune Thrombocytopenia


The Emergence of Thrombopoietin Receptor Agonists as a Novel Treatment for Immune Thrombocytopenia


Roberto Stasi, Elizabeth Rhodes, Reuben Benjamin, Hubertus Buyck, Fenella Willis, Muriel S Shannon and Edward C Gordon-Smith


Department of Haematology, St George’s, University of London


Abstract


Two thrombopoietin receptor agonists, romiplostim and eltrombopag, have completed phase III trials in patients with chronic immune thrombocytopenia and were shown to successfully improve platelet counts. Due to their proven efficacy and favourable side-effect profile, they have been granted marketing authorisation for use in this condition in the US, the EU and other countries. This article focuses on these two agents, their pre-clinical development and clinical trial results.


Keywords Immune thrombocytopenic purpura (ITP), thrombopoietin receptor (TPO-R) agonists, romiplostim, eltrombopag, platelet response


Disclosure: Roberto Stasi has received honoraria for participation on advisory boards and as a speaker at medical education events supported by GlaxoSmithKline and Amgen. The remaining authors have no conflicts of interest to declare. Acknowledgement: Editorial assistance was provided by Touch Briefings. Received: 15 April 2009 Accepted: 20 February 2010 Citation: European Oncology & Haematology, 2011;7(1):63–70 Correspondence: Roberto Stasi, Department of Haematology, St George’s Hospital, Blackshaw Road, London, SW17 0QT, UK. E: roberto.stasi@stgeorges.nhs.uk


Support: The publication of this article was funded by GlaxoSmithKline. The views and opinions expressed are those of the authors and not necessarily those of GlaxoSmithKline.


Primary immune thrombocytopenia (ITP), until recently referred to as idiopathic thrombocytopenic purpura (ITP), is an acquired autoimmune disorder defined by isolated thrombocytopenia (platelet count <100x 109/l) and the exclusion of other causes of thrombocytopenia.1


Quite recently a new class of drugs, the thrombopoietin receptor (TPO-R) agonists, have shown remarkable efficacy. Recently published guidelines based on the highest level of evidence recommend the use of these agents for the treatment of patients with chronic ITP.10


Two of The clinical manifestations of ITP are highly


variable and range from the completely asymptomatic patient to frank haemorrhage from any site, the most serious of which is intracranial.2 Several matters in terms of the optimal treatment of adult patients with chronic ITP remain unresolved. There is limited evidence based on randomised trials to guide management decisions and for some patients morbidity from the side effects of therapy may exceed any problems caused by the ITP.2,3


Currently, treatment is considered appropriate for symptomatic patients and for those at risk of bleeding.4–8


Once the decision to treat


a patient with ITP has been made, provided the patient’s situation is not life-threatening, corticosteroids are the standard initial treatment.4 Intravenous immunoglobulins are generally recommended for patients with critical bleeding and for those unresponsive to corticosteroids.4


The platelet count also can be supported by anti-D immunoglobulin, which is active in 70–75% of Rh-positive patients only in the pre-splenectomy setting.9


Splenectomy is traditionally


considered to be the second-line treatment in adults with ITP in whom achieving a safe platelet count with initial prednisone therapy has failed. For those who are refractory or relapse after splenectomy, there is a long list of available approaches,5 modest response rates.


most of which have © TOUCH BRIEFINGS 2011


these drugs, romiplostim and eltrombopag, have been approved for use in chronic refractory ITP in the US, the EU and in many other countries. This article discusses the rationale for megakaryocyte stimulation in ITP and presents the results of clinical trials with these new agents.


Pathophysiology of Immune Thrombocytopenia For many years the prevailing view was that ITP resulted solely from excessive platelet clearance and destruction, mediated by autoreactive antibodies directed against platelet glycoproteins.11 Kinetic studies conducted in the early 1970s using chromium-51 (51Cr)-labelled allogeneic platelets demonstrated shortened platelet survival and increased platelet turnover in ITP patients,12,13 consistent with this hypothesis. Interestingly, platelet survival was found to be inversely related to the quantity of bound antiplatelet antibodies.14


However, when autologous indium-111 (111In)-labelled autologous platelets were studied in the 1980s it became evident that there was considerable heterogeneity in platelet turnover between patients.15–19 Although the platelet lifespan is often markedly decreased, in some patients the lifespan is only mildly reduced; furthermore, platelet turnover (a measure of platelet production) is frequently suboptimal.


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