Eltrombopag: an update on the novel, non-peptide thrombopoietin receptor agonist for the treatment of immune thrombocytopenia

Abstract

Immune thrombocytopenia (ITP) is characterised by a transient or persistent decrease in platelets accompanied by an increased risk of bleeding, which can have a significant negative impact on patients' health-related quality of life. The condition has long been associated with an increased rate of immune-mediated platelet destruction, and traditional treatments have targeted the reduction in platelet destruction; however, some interventional drugs are limited by transient efficacy and side effects. Recent advances in our understanding of ITP pathogenesis have highlighted the role of impaired platelet production, which has led to the advent of a new generation of thrombopoietin (TPO)-receptor agonist therapies, including eltrombopag and romiplostim. The oral, non-peptide TPO-receptor agonist eltrombopag has shown considerable promise in both preclinical and clinical trials. Eltrombopag has a unique mechanism of action and binds to a transmembrane region of the TPO receptor that is distant from the TPO binding site. As such, eltrombopag may confer synergistic effects with endogenous TPO rather than competing for binding. Eltrombopag also induces activation of the TPO receptor and downstream signalling in a distinct manner to TPO and does not have a significant impact on platelet function. Clinical evidence demonstrates that eltrombopag produces a rapid and sustainable increase in platelet counts that significantly reduces bleeding and is well tolerated in patients with ITP. Eltrombopag therefore represents an important addition to the therapeutic armamentarium for ITP.

A multi-centric study on the efficacy of eltrombopag in management of refractory chronic immune thrombocytopenia

“…Immune thrombocytopenia (ITP) is an acquired disorder characterized by a transient or persistent decrease in platelets accompanied with an increased risk of bleeding [1,2,3]. The estimated incidence of ITP is 100 cases per 1 million people annually [4].…”

“…As a consequence, the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway stimulates megakaryocytopoiesis, while autoantibody generation is not detected [10]. Furthermore, eltrombopag does not influence agonist-induced platelet aggregation or activation [1]. Eltrombopag produces a quick and sustainable increase in platelet counts and is generally well tolerated in patients with chronic ITP.…”

Prolonged haematologic toxicity in CAR‐T‐cell therapy: A review

“…Thrombopoietin receptor agonists (TPO‐RAs) are used for treatment of ITP, AA, chemotherapy‐induced thrombocytopenia and thrombocytopenia post stem cell transplantation 71–74 . TPO‐RAs bind to MPL (also known as TPO receptor), leading to its conformational change and activating a wide range of downstream signalling pathways, such as JAK2/STAT3/5, ERK1/2 and PI3K/Akt, and ultimately increasing megakaryocyte differentiation and maturation and platelet production 75,76 . Furthermore, as the TPO receptor is expressed on stem cells, these agents have a critical role in stem cell proliferation and maintenance 77 .…”

“… 71 , 72 , 73 , 74 TPO‐RAs bind to MPL (also known as TPO receptor), leading to its conformational change and activating a wide range of downstream signalling pathways, such as JAK2/STAT3/5, ERK1/2 and PI3K/Akt, and ultimately increasing megakaryocyte differentiation and maturation and platelet production. 75 , 76 Furthermore, as the TPO receptor is expressed on stem cells, these agents have a critical role in stem cell proliferation and maintenance. 77 Eltrombopag, romiplostim and rhTPO are all TPO‐RAs and bind to MPL, activating similar signalling pathways.…”

Biometric Image Analysis for Quantitation of Dividing Platelets

“…For these patients, many therapeutic options can be considered, ranging from corticosteroid treatment to surgical removal of the spleen [10]. Recently, chemical therapeutics that mimic the action of natural hematopoietic substances promoting platelet production were introduced to manage refractory patients [11,12]. However, even the latest treatment modality is imperfect, and undesirable side effects, including bone marrow fibrosis, have been reported [13].…”