Tapering and Sustained Remission of Thrombopoietin Receptor Agonists (TPO-RAs): Is it Time for Paediatric ITP?

Thrombopoietin receptor agonists (TPO-Ras; romiplostim/eltrombopag/avatrombopag) have demonstrated high efficacy rates (59-88%) and a good safety profile in clinical trials with adult patients with immune thrombocytopenia (ITP). Similar efficacy and safety results have been observed with romiplostim and eltrombopag in paediatric cohorts. Continuous treatment with TPO-RAs has shown durable responses with long-term use, up to 3 years. The effect of TPO-RAs was generally considered transient, as platelet counts tended to drop to baseline values after a short period of time (about 2 weeks), unless treatment was maintained. Several groups have reported successful discontinuation of TPO-RAs without the need for concomitant treatments. This is referred to as sustained remission off treatment (SROT). Both short- and medium-term treatment with TPO-RAs may reduce costs to our healthcare systems and, more importantly, may reduce the potential side effects that may be associated with continuous TPO-RA treatment. The issue of tapering and discontinuation of TPO-RAs in paediatric patients with ITP has received little attention to date. Given that paediatric ITP has much higher rates of spontaneous remission than ITP in adults, we consider that the possibility of SROT of TPO-RAs in paediatric patients with ITP is a neglected but very relevant issue in this subtype of the disease.

Real-world experience of thrombopoietin receptor agonists in pediatric immune thrombocytopenia: a report from a Chinese tertiary children's hospital.

Background: Primary immune thrombocytopenia (ITP) is the most common bleeding disorder in children. There are approximately 20% pediatric ITP patients respond poor to corticosteroids as first-line treatment. Recently thrombopoietin receptor agonists (TPO-RAs) have been used to treat refractory ITP and have achieved certain therapeutic effects. To investigate the efficacy and safety of TPO-RAs in the treatment of pediatric ITP, we conducted this real-world study. Methods: Fifty-three pediatric patients with ITP who did not respond well to corticosteroids were treated with TPO-RAs. Clinical data, including therapeutic response rate, changes in platelet (PLT) count, and adverse events (AEs) were collected. Results: Of the 51 evaluable patients, 37 (72.5%) responded to TPO-RAs. Patients aged >4 years had a higher response rate than those aged ≤4 years (81.1% vs. 50.0%, P=0.04). There was no effect of sex, duration of disease, prior therapy, Mycoplasma pneumoniae (MP) immunoglobulin M (IgM) positivity, antinuclear antibody (ANA) positivity, CD4/CD8 ratio or baseline PLT count on the response rate (P>0.05). Other than 10 patients with PLT counts that exceeded the upper limit of normal, AEs were sporadic, including increased aminotransferase levels, cough, headache, and vomiting. Conclusions: TPO-RAs exhibited good clinical efficacy in pediatric ITP patients who failed to respond to first-line treatment, especially patients aged >4 years, and the side effects were minor.

Translating mechanisms into therapeutic strategies for immune thrombocytopenia (ITP): Lessons from clinical trials.

Immune thrombocytopenia (ITP) is an autoimmune disorder that causes a significant reduction in peripheral blood platelet count. Fortunately, due to an increased understanding of ITP, there have been significant improvements in the diagnosis and treatment of these patients. Over the past decade, there have been a variety of proven therapeutic options available for ITP patients, including intravenous immunoglobulins (IVIG), Rituximab, corticosteroids, and thrombopoietin receptor agonists (TPO-RAs). Although the effectiveness of current therapies in treating more than two-thirds of patients, still some patients do not respond well to conventional therapies or fail to achieve long-term remission. Recently, a significant advancement has been made in identifying various mechanisms involved in the pathogenesis of ITP, leading to the development of novel treatments targeting these pathways. It seems that new agents that target plasma cells, Bruton tyrosine kinase, FcRn, platelet desialylation, splenic tyrosine kinase, and classical complement pathways are opening new ways to treat ITP. In this study, we reviewed the pathophysiology of ITP and summarized updates in this population's management and treatment options. We also took a closer look at the 315 ongoing trials to investigate their progress status and compare the effectiveness of interventions. May our comprehensive view of ongoing clinical trials serve as a guiding beacon, illuminating the path towards future trials of different drugs in the treatment of ITP patients.

Primary and secondary immune thrombocytopenia (ITP): Time for a rethink.

There are not many publications that provide a holistic view of the management of primary and secondary ITP as a whole, reflecting the similarities and differences between the two. Given the lack of major clinical trials, we believe that comprehensive reviews are much needed to guide the diagnosis and treatment of ITP today. Therefore, our review addresses the contemporary diagnosis and treatment of ITP in adult patients. With respect to primary ITP we especially focus on establishing the management of ITP based on the different and successive lines of treatment. Life-threatening situations, "bridge therapy" to surgery or invasive procedures and refractory ITP are also comprehensively reviewed here. Secondary ITP is studied according to its pathogenesis by establishing three major differential groups: Immune Thrombocytopenia due to Central Defects, Immune Thrombocytopenia due to Blocked Differentiation and Immune Thrombocytopenia due to Defective Peripheral Immune Response. Here we provide an up-to-date snapshot of the current diagnosis and treatment of ITP, including a special interest in addressing rare causes of this disease in our daily clinical practice. The target population of this review is adult patients only and the target audience is medical professionals.

Sustained Remission Off-Treatment (SROT) of TPO-RAs: The Burgos Ten-Step Eltrombopag Tapering Scheme.

Background and Objectives: TPO-RAs (romiplostim/eltrombopag/avatrombopag) have broadly demonstrated high efficacy rates (59-88%), durable responses (up to three years) and a satisfactory safety profile in clinical trials. The effect of TPO-RAs is classically considered to be transient because platelet numbers usually dropped rapidly to baseline unless therapy was maintained. However, several groups have reported the possibility of successfully discontinuing TPO-RAs in some patients without further need for concomitant treatments. This concept is usually referred as sustained remission off-treatment (SROT). Materials and Methods: Unfortunately, we still lack predictors of the response to discontinuation even after the numerous biological, clinical and in vitro studies performed to study this phenomenon. The frequency of successful discontinuation is matter of controversy, although a percentage in the range of 25-40% may probably be considered a consensus. Here, we describe all major routine clinical practice studies and reviews that report the current position on this topic and compare them with our own results in Burgos. Results: We report our Burgos ten-step eltrombopag tapering scheme with which we have achieved an elevated percentage rate of success (70.3%) in discontinuing treatment. Conclusions: We hope this protocol may help successfully taper and discontinue TPO-RAs in daily clinical practice.

Efficacy and safety of treatments in newly diagnosed adult primary immune thrombocytopenia: A systematic review and network meta-analysis.

Background: Immune thrombocytopenia is an autoimmune disease characterised by decreased platelet count. In recent years, novel therapeutic regimens have been investigated in randomised controlled trials (RCTs). We aimed to compare the efficacy and safety of different treatments in newly diagnosed adult primary immune thrombocytopenia. Methods: We did a systematic review and network meta-analysis of RCTs involving treatments for newly diagnosed primary immune thrombocytopenia. PubMed, Embase, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov databases were searched up to April 31, 2022. The primary outcomes were 6-month sustained response and early response. Secondary outcome was grade 3 or higher adverse events. This study is registered with PROSPERO (CRD42022296179). Findings: Eighteen RCTs (n = 1944) were included in this study. Pairwise meta-analysis showed that the percentage of patients achieving early response was higher in the dexamethasone-containing doublet group than in the dexamethasone group (79.7% vs 68.7%, odds ratio [OR] 1.82, 95% CI 1.10-3.02). The difference was more profound for sustained response (60.5% vs 37.4%, OR 2.57, 95% CI 1.95-3.40). Network meta-analysis showed that dexamethasone plus recombinant human thrombopoietin ranked first for early response, followed by dexamethasone plus oseltamivir or tacrolimus. Rituximab plus prednisolone achieved highest sustained response, followed by dexamethasone plus all-trans retinoic acid or rituximab. Rituximab plus dexamethasone showed 15.3% of grade 3 or higher adverse events, followed by prednis(ol)one (4.8%) and all-trans retinoic acid plus dexamethasone (4.7%). Interpretation: Our findings suggested that compared with monotherapy dexamethasone or prednis(ol)one, the combined regimens had better early and sustained responses. rhTPO plus dexamethasone ranked top in early response, while rituximab plus corticosteroids obtained the best sustained response, but with more adverse events. Adding oseltamivir, all-trans retinoic acid or tacrolimus to dexamethasone reached equally encouraging sustained response, without compromising safety profile. Although this network meta-analysis compared all the therapeutic regimens up to date, more head-to-head RCTs with larger sample size are warranted to make direct comparison among these strategies. Funding: National Natural Science Foundation of China, Major Research Plan of National Natural Science Foundation of China, Shandong Provincial Natural Science Foundation and Young Taishan Scholar Foundation of Shandong Province.

Current approaches for the diagnosis and management of immune thrombocytopenia.

Immune thrombocytopenia (ITP), is an acquired autoimmune disorder characterized by the destruction of platelets and megakaryocytes, resulting in thrombocytopenia (platelet count <100 × 109/L). This review focuses on the diagnosis and current management of ITP. The diagnosis of ITP is based principally on the exclusion of other causes of isolated thrombocytopenia using patient history, physical examination, blood count, and evaluation of the peripheral blood film. The clinical treatment goals should be to resolve bleeding events and to prevent severe bleeding episodes. The platelet count should be improved to attain a minimum of > 20-30 × 109/L. Therapy should be given as an inpatient in newly diagnosed ITP with a platelet count of > 20 × 109/L or if there is active bleeding. Corticosteroids are considered the standard initial treatment for newly diagnosed patients. Subsequent medical therapies with robust evidence include thrombopoietin receptor agonists (TPO-RAs), rituximab and fostamatinib. Surgical therapy with splenectomy may be considered for patients failing medical therapy. The choice between therapy options is highly dependent upon patient values and preferences.

Effect of Thrombopoietin Receptor Agonist on Pregnant Mice.

Thrombopoietin receptor agonists (TPO-RAs) are an effective treatment for refractory immune thrombocytopenia (ITP). However, the use of TPO-RAs is limited for ITP in pregnant women due to concerns about fetal toxicity. In this study, we examined the effects of romiplostim, one of the TPO-RAs, on pregnant mice. The mice were injected subcutaneously with romiplostim (1, 5, 10, 30, and 100 µg/kg) on gestational days (GD) 1, 8, and 15. We evaluated maternal and fetal platelet and megakaryocyte counts (MK), fetal weight at birth, placental morphology, and miscarriage rates. Romiplostim increased platelet and MK counts in pregnant mice at all doses and in fetuses at doses above 10 µg/kg. Fetal weight at birth was slightly reduced at a dose of 100 µg/kg, but there were no significant differences in placental weight, spiral artery wall thickness, placental growth factor signal changes, or the rate of resorption at that dosage. The dose of romiplostim used clinically for ITP patients (1-10 µg/kg) did not show any adverse effects on pregnant mice. Although the results of the present study are encouraging, until there are more conclusive data, the use of romiplostim should be evaluated individually in severe, life-threatening cases, and all relevant ethical aspects should be considered.

Efficacy and safety of thrombopoietin receptor agonists in the treatment of thrombocytopenia after hematopoietic stem cell transplantation: a meta-analysis and systematic review.

Thrombocytopenia is a tough complication after hematopoietic stem cell transplantation (HSCT) with elusive pathogenesis and lack of well-established therapies. Thrombopoietin receptor agonists (TPO-RAs) have been used for thrombocytopenia post HSCT in recent years, but the outcomes remain debatable. We conducted this meta-analysis and systematic-review to evaluate the efficacy and safety of TPO-RAs for platelet recovery after HSCT. We searched PubMed, EMBASE, and Cochrane databases for studies on the application of TPO-RAs (eltrombopag and romiplostim) in the settings of primary or secondary thrombocytopenia after HSCT by 17 March 2021. Efficacy outcomes included response rate and survival rate, and adverse events were also evaluated. A total of 19 studies involving 378 patients were included. The pooled response rate was 73% (95%CI: 68-78%), which was significantly higher than recombinant human thrombopoietin (rhTPO) (27.8%). The pooled survival rate was 66% (95%CI: 54-77%), and infection was found to be the main cause of death. In addition, the pooled rate of adverse events was 3% (95%CI: 1-7%), with no severe adverse events reported. TPO-RAs could effectively and safely promote the recovery of platelets in patients after HSCT.

Markers of endothelial cell activation and neutrophil extracellular traps are elevated in immune thrombocytopenia but are not enhanced by thrombopoietin receptor agonists.

INTRODUCTION: Patients with immune thrombocytopenia (ITP) are at increased risk of thrombosis, which seems to be further enhanced by treatment with thrombopoietin-receptor-agonists (TPO-RAs). The underlying mechanisms of thrombosis in ITP are not fully understood. Endothelial cell activation and neutrophil extracellular traps (NETs) play important roles in thrombosis, however, their roles in ITP itself, or in TPO-RA-treatment, have not yet been fully explored. We aimed to investigate whether endothelial cell activation and NETs are involved in the hypercoagulable state of ITP, and whether TPO-RA-treatment enhances endothelial cell activation and NET formation. MATERIAL AND METHODS: We measured markers of endothelial cell activation including intercellular adhesion molecule-1 (ICAM-1), vascular adhesion molecule-1 (VCAM-1) and thrombomodulin in 21 ITP patients, and E-selectin in 18 ITP patients. Markers of NET formation, citrullinated histone H3-DNA (H3Cit-DNA) and cell-free DNA (cfDNA), were measured in 15 ITP patients. All markers were measured before, and 2 and 6 weeks after initiation of TPO-RA-treatment in ITP patients, and in matched controls. RESULTS: Higher levels of ICAM-1, thrombomodulin, and H3Cit-DNA were found in ITP patients, both before and after TPO-RA-treatment, compared with controls. No differences were found for VCAM-1, E-selectin or cfDNA. TPO-RA-treatment did not further increase markers of endothelial cell activation or NET formation. CONCLUSIONS: This study showed that ITP patients have increased endothelial cell activation and NET formation, both of which may contribute to the intrinsic hypercoagulable state of ITP. TPO-RA-treatment, however, did not further increase endothelial cell activation or NET formation indicating that other drug-associated prothrombotic mechanisms are involved.

Circulating microRNAs in patients with immune thrombocytopenia before and after treatment with thrombopoietin-receptor agonists.

MicroRNAs (miRNAs) are small non-coding RNAs involved in the regulation of gene expression. Dysregulated expression of several miRNAs has been found in primary immune thrombocytopenia (ITP) suggesting that miRNAs are likely involved in the pathogenesis of ITP. We aimed to explore the differential expression of miRNAs in patients with ITP before and after starting treatment with thrombopoietin-receptor agonists (TPO-RAs) to clarify their roles in the pathophysiology of ITP, and as potential diagnostic and prognostic markers of this disorder.We performed a profiling study where 179 miRNAs were analyzed in eight ITP patients before and during treatment with TPO-RAs and in eight controls using miRNA PCR panel; 81 miRNAs were differentially expressed in ITP patients compared to controls, and 14 miRNAs showed significant changes during TPO-RA-treatment. Ten miRNAs were selected for validation that was performed in 23 patients and 22 controls using droplet digital PCR. Three miRNAs were found to be differentially expressed in ITP patients before TPO-RA-treatment compared to controls: miR-199a-5p was down-regulated (p = 0.0001), miR-33a-5p (p = 0.0002) and miR-195-5p (p = 0.035) were up-regulated. Treatment with TPO-RAs resulted in changes in six miRNAs including miR-199a-5p (p = 0.001), miR-33a-5p (p = 0.003), miR-382-5p (p = 0.004), miR-92b-3p (p = 0.005), miR-26a-5p (p = 0.008) and miR-221-3p (p = 0.023); while miR-195-5p remained unchanged and significantly higher than in controls, despite the increase in the platelet count, which may indicate its possible role in the pathophysiology of ITP. Regression analysis revealed that pre-treatment levels of miR-199a-5p and miR-221-3p could help to predict platelet response to TPO-RA-treatment. ROC curve analysis showed that the combination of miR-199a-5p and miR-33a-5p could distinguish patients with ITP from controls with AUC of 0.93.This study identifies a number of differentially expressed miRNAs in ITP patients before and after initiation of TPO-RAs with potential roles in the pathophysiology, as well as with a possible utility as diagnostic and prognostic biomarkers. These interesting findings deserve further exploration and validation in future studies.