Eltrombopag is intended to be used for the treatment of cytopenias in patients with severe aplastic anaemia who have had an insufficient response to immunosuppressive therapy. If licensed, eltrombopag will offer a treatment option for this patient group. Eltrombopag is a non-peptidyl thrombopoietin (TPO) receptor agonist. TPO is the principal cytokine involved in the regulation of megakaryopoiesis and platelet production and acts through the activation of the TPO receptor. Eltrombopag mimics the effect of TPO thereby stimulating platelet production. Eltrombopag is licensed in the EU for the treatment of chronic immune (idiopathic) thrombocytopenic purpura in adult splenectomised patients who are refractory to other treatments, second line treatment of thrombocytopenia in adult non-splenectomised patients where surgery is contraindicated, and for the treatment of thrombocytopenia in adult patients with chronic hepatitis C virus infection. Aplastic anaemia is a rare condition and its precise incidence is difficult to determine due to the imprecision in establishing a diagnosis. However, estimates indicate that annual incidence is around two cases per million population. The incidence of aplastic anaemia varies throughout the world and is 2-3 times more common in Southeast Asia. In England, there were 12,987 admissions due to forms of aplastic anaemia in 2012-13, resulting in 14,390 finished consultant episodes and 19,658 bed days. In 2012, forms of aplastic anaemia accounted for 216 deaths in England and Wales. Treatment for aplastic anaemia aims to correct the hypo-cellular bone marrow of the patient while providing supportive care where appropriate. The main two effective treatments for those with acquired severe aplastic anaemia are allogeneic bone marrow stem cell transplantation and immunosuppressive therapy. Supportive care can include platelet and red blood cell transfusions, growth factors and antibiotics. Eltrombopag is currently in uncontrolled phase II clinical trials to determine its effect on haematological response in patients with severe aplastic anaemia. These trials are expected to complete in December 2016.

Eltrombopag is intended to be used for the treatment of chronic immune thrombocytopenic purpura (ITP) in children. If licensed, it will provide a treatment option for this patient group, for whom there are currently no licensed therapies available. Eltrombopag is a non-peptidyl thrombopoietin (TPO) receptor agonist. TPO is the principal cytokine involved in the regulation of megakaryopoiesis and platelet production and acts through the activation of the TPO receptor. Eltrombopag mimics the effect of TPO thereby stimulating platelet production. Eltrombopag is licensed in the EU for the treatment of adult ITP and thrombocytopenia in adults with chronic hepatitis C virus infection. ITP is an acquired autoimmune disorder of adults and children characterised by increased platelet destruction, and in some cases, inadequate platelet production. The incidence of ITP in children is around 4 per 100,000 population, and it is more common in two groups: young children and young adults. Approximately 25% of children develop chronic disease, which is often a mild disorder that does not significantly interfere with daily life. However in some children, frequent and serious haemorrhages may occur, including intracranial haemorrhage, which is fatal in around 50%. In 2012-13, there were 1,094 finished consultant episodes due to ITP in children in England, and in 2012, one death was registered in England and Wales. Most children with ITP do not require specific treatment. Treatment is dependent on a range of factors including the presence and severity of bleeding, co-morbidities, specific instances such as surgery, and the side effects of treatment. Current options include intravenous immunoglobin, steroids, rituximab, thrombopoeitin receptor agonists, platelet transfusion or splenectomy. Eltrombopag is currently in a phase II clinical trial comparing its effect on platelet counts against treatment with placebo. The completion date of this trial has not reported.

BACKGROUND: The pathogenesis of chronic idiopathic thrombocytopenic purpura (ITP) involves antibody-mediated platelet destruction and reduced platelet production. Stimulation of platelet production may be an effective treatment for this disorder. METHODS: We conducted a trial in which 118 adults with chronic ITP and platelet counts of less than 30,000 per cubic millimeter who had had relapses or whose platelet count was refractory to at least one standard treatment for ITP were randomly assigned to receive the oral thrombopoietin-receptor agonist eltrombopag (30, 50, or 75 mg daily) or placebo. The primary end point was a platelet count of 50,000 or more per cubic millimeter on day 43. RESULTS: In the eltrombopag groups receiving 30, 50, and 75 mg per day, the primary end point was achieved in 28%, 70%, and 81% of patients, respectively. In the placebo group, the end point was achieved in 11% of patients. The median platelet counts on day 43 for the groups receiving 30, 50, and 75 mg of eltrombopag were 26,000, 128,000, and 183,000 per cubic millimeter, respectively; for the placebo group the count was 16,000 per cubic millimeter. By day 15, more than 80% of patients receiving 50 or 75 mg of eltrombopag daily had an increased platelet count. Bleeding also decreased during treatment in these two groups. The incidence and severity of adverse events were similar in the placebo and eltrombopag groups. CONCLUSIONS: Eltrombopag increased platelet counts in a dose-dependent manner in patients with relapsed or refractory ITP. (ClinicalTrials.gov number, NCT00102739.) 2007 Massachusetts Medical Society

BACKGROUND: Late graft failure after allogeneic haematopoietic cell transplantation (HCT) can result from the failed engraftment of long-term engrafting cells. The use of thrombopoietin (TPO) receptor agonists (TRA) has been extensively studied and remains an important component of experimental ex vivo stem cell expansion protocols, but its use in allogeneic transplantation is still evolving. METHODS: We describe the use of eltrombopag, a TRA, to stimulate the rescue of late graft failure in a patient following allogeneic HCT, and we performed a systematic review of published studies describing the use of TRAs following allogeneic transplantation. RESULTS: A total of eight publications were identified from our systematic search and included observational case studies (five studies, total of seven patients) that primarily addressed ITP or isolated thrombocytopenia at various time points after allogeneic HCT and prospective clinical trials (three studies, total of 177 patients with 95 patients receiving TRAs). No studies reported specifically on the use of TRAs for the treatment of trilineage graft failure as a means of in vivo stem cell expansion. The use of TRAs following allogeneic HCT appears safe and promising. CONCLUSION: The use of eltrombopag or other TRAs to treat poor graft function after allogeneic HCT is intriguing and warrants further study.

BACKGROUND: Eltrombopag is an oral thrombopoietin receptor agonist for the treatment of thrombocytopenia. We aimed to compare the response to once daily eltrombopag versus placebo in patients with chronic immune thrombocytopenia during a 6-month period. METHODS: We undertook a phase 3, double-blind, placebo-controlled study in adults with previously treated immune thrombocytopenia of more than 6 months' duration who had baseline platelet counts lower than 30,000 per μL. Patients were randomly allocated (in a 2:1 ratio) treatment with local standard of care plus 50 mg eltrombopag or matching placebo once daily for 6 months. Randomisation was done centrally with a computer-generated randomisation schedule and was stratified by baseline platelet count (≤ 15,000 per μL), use of treatment for immune thrombocytopenia, and splenectomy status. Patients, investigators, and those assessing data were masked to allocation. Dose modifications were made on the basis of platelet response. Patients were assessed for response to treatment (defined as a platelet count of 50,000-400,000 per μL) weekly during the first 6 weeks and at least once every 4 weeks thereafter; the primary endpoint was the odds of response to eltrombopag versus placebo. Analysis was by intention to treat. This study is registered at ClinicalTrials.gov, number NCT00370331. FINDINGS: Between Nov 22, 2006, and July 31, 2007, 197 patients were randomly allocated to treatment groups and were included in the intention-to-treat analysis (135 eltrombopag, 62 placebo). 106 (79%) patients in the eltrombopag group responded to treatment at least once during the study, compared with 17 (28%) patients in the placebo group. The odds of responding were greater in patients in the eltrombopag group compared with those in the placebo group throughout the 6-month treatment period (odds ratio 8·2, 99% CI 3·59-18·73; p<0·0001). 37 (59%) patients receiving eltrombopag reduced concomitant treatment versus ten (32%) patients receiving placebo (p=0·016). 24 (18%) patients receiving eltrombopag needed rescue treatment compared with 25 (40%) patients receiving placebo (p=0·001). Three (2%) patients receiving eltrombopag had thromboembolic events compared with none in patients on placebo. Nine (7%) eltrombopag-treated patients and two (3%) in the placebo group had mild increases in alanine aminotransferase concentration, and five (4%) eltrombopag-treated patients (vs none allocated to placebo) had increases in total bilirubin. Four (7%) patients taking placebo had serious bleeding events, compared with one (<1%) patient treated with eltrombopag. INTERPRETATION: Eltrombopag is effective for management of chronic immune thrombocytopenia, and could be particularly beneficial for patients who have not responded to splenectomy or previous treatment. These benefits should be balanced with the potential risks associated with eltrombopag treatment. FUNDING: GlaxoSmithKline. Copyright © 2011 Elsevier Ltd. All rights reserved.

BACKGROUND: Eltrombopag is an oral, non-peptide, thrombopoietin-receptor agonist that stimulates thrombopoiesis, leading to increased platelet production. This study assessed the efficacy, safety, and tolerability of once daily eltrombopag 50 mg, and explored the efficacy of a dose increase to 75 mg. METHODS: In this phase III, randomised, double-blind, placebo-controlled study, adults from 63 sites in 23 countries with chronic idiopathic thrombocytopenic purpura (ITP), platelet counts less than 30 000 per muL of blood, and one or more previous ITP treatment received standard care plus once-daily eltrombopag 50 mg (n=76) or placebo (n=38) for up to 6 weeks. Patients were randomly assigned in a 2:1 ratio of eltrombopag:placebo by a validated randomisation system. After 3 weeks, patients with platelet counts less than 50 000 per microL could increase study drug to 75 mg. The primary endpoint was the proportion of patients achieving platelet counts 50 000 per microL or more at day 43. All participants who received at least one dose of their allocated treatment were included in the analysis. This study is registered with ClinicalTrials.gov, number NCT00102739. FINDINGS: 73 patients in the eltrombopag group and 37 in the placebo group were included in the efficacy population and were evaluable for day-43 analyses. 43 (59%) eltrombopag patients and six (16%) placebo patients responded (ie, achieved platelet counts >/=50 000 per microL; odds ratio [OR] 9.61 [95% CI 3.31-27.86]; p<0.0001). Response to eltrombopag compared with placebo was not affected by predefined study stratification variables (baseline platelet counts, concomitant ITP drugs, and splenectomy status) or by the number of previous ITP treatments. Of the 34 patients in the efficacy analysis who increased their dose of eltrombopag, ten (29%) responded. Platelet counts generally returned to baseline values within 2 weeks after the end of treatment. Patients receiving eltrombopag had less bleeding at any time during the study than did those receiving placebo (OR 0.49 [95% CI 0.26-0.89]; p=0.021). The frequency of grade 3-4 adverse events during treatment (eltrombopag, two [3%]; placebo, one [3%]) and adverse events leading to study discontinuation (eltrombopag, three [4%]; placebo, two [5%]), were similar in both groups. INTERPRETATION: Eltrombopag is an effective treatment for managment of thrombocytopenia in chronic ITP.

Eltrombopag, an orally administered, small-molecule non-peptide thrombopoietin receptor agonist, selectively binds to the transmembrane domain of the thrombopoietin receptor on the surface of platelets, megakaryocytes and megakaryocyte precursor cells. The drug acts via the Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) pathway to activate megakaryocyte proliferation and differentiation in bone marrow progenitor cells, similar to those observed with endogenous thrombopoietin. Platelet counts are increased as a result of eltrombopag therapy, and the drug has shown good clinical efficacy in adults with chronic immune (idiopathic) thrombocytopenic purpura (ITP) in randomized, double-blind, placebo-controlled, multicentre, phase II dose-finding and phase III trials. After 6 weeks of therapy in the phase III trial, eltrombopag 50 mg/day was associated with a significantly higher response rate (proportion of patients with a platelet count of >or=50 000 cells/microL at day 43; primary endpoint) than placebo in adult patients with chronic ITP. In addition, the proportion of patients with ITP achieving a platelet count of >200 000 cells/microL and discontinuing treatment due to protocol-defined treatment-cessation criteria, was approximately 8-fold higher with eltrombopag than with placebo. Eltrombopag therapy for 6 weeks also significantly decreased the incidence of WHO-defined bleeding compared with placebo. Eltrombopag was generally well tolerated in clinical trials, with an adverse events profile that did not differ significantly from that with placebo.

Good's syndrome is a rare acquired immunodeficiency associated with thymoma. Eltrombopag is a thrombopoietin receptor agonist and has been shown to be a valuable supplement to the treatment of several types of refractory cytopenias. In this paper, we describe a male patient suffering from Good's syndrome with immune-mediated T-cell driven pancytopenia and absence of megakaryopoiesis. He was successfully treated with eltrombopag resulting in a multilineage clinical response.

BACKGROUND: Eltrombopag is an oral thrombopoietin receptor agonist that stimulates the production of normally functioning platelets. The aim of this meta-analysis is to synthesize evidence about the safety and efficacy of eltrombopag for both adult and children with primary immune thrombocytopenia (ITP). METHODS: A computer literature search of PubMed, Scopus, Web of Science, and Cochrane Central was conducted. Records were screened for eligible studies, and data were extracted and synthesized using Review Manager for Windows. Subgroup analysis and sensitivity analysis were conducted to investigate whether treatment effect varies significantly between adults and children. RESULTS: Six randomized controlled trials (N = 611 patients) were included in the final analysis. The overall effect estimates favored eltrombopag group in terms of overall platelet response (relative risk [RR]: 3.42; 95% confidence interval [CI]: 2.51-4.65; P < .0001), incidence of significant bleeding (RR: 0.56; 95% CI: 0.41-0.77; P = .0004), and number of cases needed to rescue treatment (RR: 0.45; 95% CI: 0.32-0.65; P < .0001). The efficacy of eltrombopag did not differ significantly between children and adults except for incidence of any bleeding (RR: 0.83 vs 0.51; P = .008). CONCLUSION: Eltrombopag is a tolerable and effective drug for the management of chronic ITP in children and adults.

OBJECTIVES: Immune thrombocytopenia (ITP) causes increased platelet destruction and suboptimal platelet production, increasing risk of bleeding. This analysis uses a Bayesian metaregression model to indirectly compare effectiveness of the thrombopoietin mimetics romiplostim and eltrombopag for increasing platelet counts, and contrasts the results with those of non-Bayesian approaches. METHODS: Ten databases were searched during 2010. Placebo-controlled trials of 24 weeks' duration were included. An indirect comparison was undertaken using Bayesian metaregression, which includes all trials in a single model. This was compared with previous analyses in which data for each intervention were combined using simple pooling, logistic regression or meta-analysis, followed by indirect comparison of pooled values using the Bucher method. RESULTS: Two trials of romiplostim and one of eltrombopag were included. The indirect evidence suggests romiplostim significantly improves overall platelet response compared with eltrombopag. Bayesian metaregression gave an odds ratio (OR) for eltrombopag versus romiplostim of 0.11 (95 percent credible interval 0.02-0.66); p values and Bayesian posterior probabilities ranged from 0.01 to 0.05 for all analyses. There was no significant difference in durable platelet response in any of the analyses, although the direction of effect favored romiplostim (OR = 0.15; 95 percent credible interval, 0.01-1.88); p values and Bayesian posterior probabilities ranged from 0.08 to 0.40 across analyses. Results were relatively consistent between analyses. CONCLUSIONS: Bayesian metaregression generated similar results to other indirect comparison methods, and may be considered the most robust as it incorporates all data in a single model and accounts appropriately for parameter uncertainty.