Treatment of Immune Thrombocytopenia (ITP) with Eltrombopag - Results of the 4 th Interim Analysis of the German Non-Interventional Trial RISA

Background: Immune thrombocytopenia (ITP) is an acquired autoimmune disorder with increased platelet destruction and impaired platelet production. Patients present with bleeding complications of various severity. Another common symptom of ITP is fatigue, which can severely affect patient's quality of life. Eltrombopag (EPAG) is an oral thrombopoietin receptor agonist, which is proved to be effective and safe in the treatment of ITP. In Europe, it is approved for the therapy of patients who were diagnosed with ITP at least 6 months ago and who have not responded to other treatments. Here we present data from the 4 th interim analysis of the RISA study. Methods: RISA is a prospective multicenter non-interventional trial in Germany. It was launched in December 2015, and it will be continued until December 2023. In accordance with the inclusion criteria, adults with persisting or chronic pITP (primary ITP) have been enrolled. Patients with pre-treatment could only be included if it was terminated 4 weeks prior to the patient's consent to participate in the study. Exclusion criteria comprised pregnancy, hepatitis C infection and severe aplastic anaemia. Dosage of EPAG and treatment of patients follows the SmPC and the routine of treating physicians. According to the study protocol, patient questionnaires must be completed at 0,1,3,6,9,12,18 and 24 months. Fatigue is assessed using the FACIT-F score, which includes a score range from 0 to 52, with score values <30 indicating severe fatigue. Statistical elaboration is predominantly descriptive. Calculations of confidence intervals and significance values are performed only for explorative purposes. Results: Data cutoff for this 4 th interim analysis was 23.02.2021. 275 patients were enrolled. 261 of them received at least one dose of EPAG and completed one post baseline assessment. Mean duration of participation was 5.2 years. Mean±SD age was 62.7±17.6 years. 54.8% of the patients were female. Median (range) duration of ITP at baseline was 5.3 (0.0-44.9) years. Comorbidity was present in 80.5% of all patients. 79 (28.7%) patients completed all scheduled visits before data cutoff. Median treatment duration was 395.0 days. Treatment with EPAG was carried out at a median dosage of 50 mg daily. In 255 patients, baseline platelet counts were available. The proportion of patients with a platelet count ≥50x10 9/L was 30.6% at baseline. With EPAG treatment, it increased to 75.4% within the first month (N=224) and to 89.0% within 24 months (N=73) from baseline. 12.6% of the patients who completed at least one assessment visit after baseline were pre-treated with the thrombopoietin receptor agonist romiplostim. Within this subgroup as well, platelet counts responded well to EPAG treatment. In 35.6% of patients, at least one bleeding event had occurred in the 12 months prior to baseline. During EPAG therapy, the incidence of bleeding events per patient year was reduced from 1.40 before baseline to 0.60 and 0.13 within the first and second treatment year respectively. This corresponds to a relative reduction in bleeding events of 57% and 91% respectively. Over the entire two years treatment period, the average incidence of bleeding events per patient year accounted for 0.44, which is 69% below the incidence at baseline. Bleeding events were mostly of low severity. (Tab.) Median FACIT-F score was 37.0 at baseline (N=202; mean 36.0±11.0) and 42.5 after 24 months (N=48; mean 38.1±12.1). This difference was not statistically significant. According to exploratory calculations, severity of fatigue was not correlated to platelet count, hemoglobin concentration or incidence of bleeding events. Discussion: In line with previously published randomized controlled trials (Birocchi et al. Platelets 2021), this non-interventional study confirmed the effectiveness of EPAG in adults with persistent or chronic ITP in a routine care setting. During treatment with EPAG, the prevalence and severity of thrombocytopenia, as well as the incidence of bleeding events, decreased. We could also confirm that fatigue is a significant issue in patients with ITP. A FACIT-F score of 37.0 is comparable to average score values in cancer patients (Montan et al. Value Health 2018). Under treatment with EPAG, we observed a decrease in fatigue that was clinically relevant but not statistically significant. Further research is needed to explore possible additional effects of EPAG, for example on fatigue. Figure 1 Figure 1. Disclosures Meyer: Swedish Orphan Biovitrum: Consultancy, Honoraria; Grifols: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Stauch: Novartis: Honoraria, Research Funding; Amgen: Honoraria. Willy: Novartis Pharma: Current Employment.

Sequential Use of Romiplostim after Eltrombopag for Refractory Thrombocytopenia in Hydrocarbon-Induced Myelodysplasia

We describe the clinical course of a 65-year-old male patient who suffered from hydrocarbon-induced myelodysplasia and was successfully treated with the thrombopoietin receptor agonist (TPO-RA), romiplostim. Myelodysplastic syndromes (MDS) are characterized by ineffective hematopoiesis, cytopenias, and increased risk of leukemic transformation. Here, we present a clinical vignette of MDS-associated thrombocytopenia refractory to first-line drugs as well as the TPO-RA, eltrombopag. To date, romiplostim is an U.S. Food and Drug Administration (FDA)-approved drug for idiopathic thrombocytopenic purpura and thrombocytopenia secondary to liver disease. Of note, currently the FDA advises against its use in MDS based on previous long-term safety concerns. Since the therapeutic options for thrombocytopenia in MDS patients are sparse, repurposing and reassessing romiplostim in this setting have been the focus of recent studies. At the time of writing, no published double-blind randomized clinical trials have conducted a head-to-head comparison between romiplostim and eltrombopag in thrombocytopenic MDS patients. To the best of our knowledge, for a thrombocytopenic patient in the setting of MDS, this is the first documented report of refractory clinical response after a 2-year use of eltrombopag in which replacement of treatment with romiplostim resulted in sustained physiological counts of thrombocytes within four weeks.

Quality of Life Improvements Following Eltrombopag Treatment in Children with Chronic Immune Thrombocytopenia: Case Report

The present case series described six chronic immune thrombocytopenia patients (cITP), with a median age of 7.7 (7.0 to 13.0) years and low platelet count at 15,500 (7,000 to 20,000)/uL. They were suffering from bleeding symptoms and side effects of treatment. After enrollment, they were treated with thrombopoietin receptor agonist (eltrombopag). Five patients responded positively, showing a median platelet count of 115,000 (39,000 to 433,000)/uL. The median dose of eltrombopag used was 1.3 (0.8 to 2.2) mg/kg/day. The quality of life (QoL) improved for all patients, with their median overall score using a Pediatric QoL questionnaire showing 25.0% improvement. Median scores also showed improvements in each sphere of life functioning as physical (30.8%), emotional (26.4%), social (16.4%), and school (21.4%). The present report demonstrated that a select group of cITP patients, with low platelet count and bleeding symptoms, benefitted from treatment with eltrombopag, as shown by increased platelet counts and improved QoL. Keywords: Chronic ITP, Thrombopoietin receptor agonist, Children

Thrombopoietin Receptor Agonist Eltrombopag Prevents Insulin Resistance and Synaptic Pathology via HIF1α/COX2/Sirt1 Signaling Pathway

Background: Insulin resistance has been reported to be closely correlated with the pathogenesis of MHE. The mechanism underlying the effects of thrombopoietin receptor agonist eltrombopag (ELT) on synaptic activity and formation involved in MHE pathogenesis remains unclear. Methods: The effect of ELT on neurodegeneration and insulin resistance was examined in the primary rat neurons and an MHE rat model. Results: We found that the level of thrombopoietin receptor c-MPL (MPL) expression was decreased in MHE brains, and ELT administration improved insulin resistance, alleviated the destruction of synaptic formation and enhanced learning and memory in the MHE rats, indicating the relationship between dowregulated ELT and insulin resistance. Then in vitro, ELT treatment ameliorated the impairment of glucose uptake, indicating the reduction of insulin resistance. High dose of glucose inhibited insulin-stimulated downregulation of Hypoxia-inducible factor-1α (HIF1α) expression, the inhibition of inflammatory response and upregulation of sirtuin-1 (Sirt1), destruction of synaptic formation and activity, which were all reversed by ELT treatment in insulin resistant neurons.Conclusions: These results indicate that ELT is a promising potential therapeutic agent for insulin resistance and defect in learning and memory.

A multicenter, randomized phase III trial of hetrombopag: a novel thrombopoietin receptor agonist for the treatment of immune thrombocytopenia

Background Hetrombopag, a novel thrombopoietin receptor agonist, has been found in phase I studies to increase platelet counts and reduce bleeding risks in adults with immune thrombocytopenia (ITP). This phase III study aimed to evaluate the efficacy and safety of hetrombopag in ITP patients. Methods Patients who had not responded to or had relapsed after previous treatment were treated with an initial dosage of once-daily 2.5 or 5 mg hetrombopag (defined as the HETROM-2.5 or HETROM-5 group) or with matching placebo in a randomized, double-blind, 10-week treatment period. Patients who received placebo and completed 10 weeks of treatment switched to receive eltrombopag, and patients treated with hetrombopag in the double-blind period continued hetrombopag during the following open-label 14-week treatment. The primary endpoint was the proportion of responders (defined as those achieving a platelet count of ≥ 50 × 109/L) after 8 weeks of treatment. Results The primary endpoint was achieved by significantly more patients in the HETROM-2.5 (58.9%; odds ratio [OR] 25.97, 95% confidence interval [CI] 9.83–68.63; p < 0.0001) and HETROM-5 (64.3%; OR 32.81, 95% CI 12.39–86.87; p < 0.0001) group than in the Placebo group (5.9%). Hetrombopag was also superior to placebo in achieving a platelet response and in reducing the bleeding risk and use of rescue therapy throughout 8 weeks of treatment. The durable platelet response to hetrombopag was maintained throughout 24 weeks. The most common adverse events were upper respiratory tract infection (42.2%), urinary tract infection (17.1%), immune thrombocytopenic purpura (17.1%) and hematuria (15%) with 24-week hetrombopag treatment. Conclusions In ITP patients, hetrombopag is efficacious and well tolerated with a manageable safety profile. Trial registration Clinical trials.gov NCT03222843, registered July 19, 2017, retrospectively registered.

Thrombopoietin receptor agonist eltrombopag alleviates cognitive impairment via NRG1/ErbB4 signaling

Background Patients with minimal hepatic encephalopathy (MHE) show mild cognitive impairments. Thrombopoietin (TPO) has been shown to be neuroprotective. This study aimed to explore the therapeutic effect of Thrombopoietin receptor agonist eltrombopag (ELT) on MHE and the involvement of NRG1 signaling using primary rat neurons and a MHE rat model. Methods We explored the effects of ELT stimulation on NRG1/ErbB4 signaling and synapse formation in the primary rat neurons. Furthermore, we explored the cerebral TPO expression level and the effect of TPO replacement therapy in an MHE rat model. Results The results showed that ELT stimulation activated NRG1/ErbB4 signaling and enhanced synaptic protein expression in the primary rat neurons via sirtuin 1. An anti-NRG1 antibody, ErbB4 inhibitor, or knockdown of NRG1 or ErbB4 could significantly abolish ELT-induced upregulation of synaptic protein expression in the primary rat neurons. MHE rats had significantly decreased cerebral ELT expression compared with normal rats. ELT activated NRG1/ErbB4 signaling in MHE rat brains. Administration or overexpression of ELT or TPO promoted synapse formation and alleviated cognitive impairments in MHE rats. Conclusions These data suggest that ELT promotes synapse formation in vitro and in vivo via activating NRG1/ErbB4 signaling, serving as a promising therapeutic agent for MHE treatment.

Thrombopoietin receptor agonist eltrombopag prevents insulin resistance-mediated synaptic pathology via HIF1α/GSK3β/Sirt1 pathway

Background Minimal hepatic encephalopathy (MHE) is characterized by impaired cognitive function and memory loss, which are often the result of synaptic pathology. Insulin resistance has been reported to be closely correlated with the pathogenesis of MHE. Methods The effect of thrombopoietin receptor agonist eltrombopag (ELT) on neurodegeneration and insulin resistance was examined in the primary rat neurons and an MHE rat model. Results We found that the level of thrombopoietin receptor c-MPL (MPL) expression was decreased in MHE brains, and ELT administration improved insulin resistance, alleviated the destruction of synaptic formation and enhanced learning and memory in the MHE rats, indicating the relationship between dowregulated ELT and insulin resistance. Then in vitro, ELT treatment ameliorated the impairment of glucose uptake, indicating the reduction of insulin resistance. High dose of glucose inhibited insulin-stimulated downregulation of Hypoxia-inducible factor-1α (HIF1α) expression, the phosphorylation of GSK3β (pGSK3 β), upregulation of sirtuin-1 (Sirt1), destruction of synaptic formation and activity, which were all reversed by ELT treatment in insulin resistant neurons. Conclusions These results indicate that ELT is a promising potential therapeutic agent for insulin resistance and defect in learning and memory.