Use Of Thrombopoietin Receptor Agonists Research Articles

Can COVID-19 Increase Platelet in Adult Immune Thrombocytopenia During the TPO-RA Administration? A Real-World Observational Study.

COVID-19 infection has brought new challenges to the treatment of adult patients with immune thrombocytopenia (ITP). In adult ITP patients, there have been no relevant reports exploring the incidence, clinical characteristics, and risk factors of platelet elevation after COVID-19 infection. A total of 66 patients with previously diagnosed ITP from December 2022 to February 2023 in a single-center were collected and analyzed for this real-world clinical retrospective observational study. In the platelet count increased group (n = 19), 13 patients (68.4%) were using thrombopoietin receptor agonists (TPO-RA) treatment at the time of COVID-19 infection; the median platelet count was 52 (2-207) ×109/L at the last visit before infection and 108 (19-453) ×109/L at the first visit after infection. In the platelet count stable group (n = 19) and platelet count decreased group (n = 28), 9 (47.4%) and 8 (28.6%) patients were using TPO-RA at the time of infection, respectively. ITP patients treated with TPO-RA had a significantly higher risk of increased platelet count than those not treated with TPO-RA at the time of infection (platelet count increased group vs platelet count decreased group: OR: 5.745, p = 0.009; platelet count increased group vs the non-increased group: OR: 3.616, p = 0.031). In the platelet count increased group, the median platelet count at 6 months post-infection was 67 (14-235) × 109/L, which was significantly higher than the platelet level at the last visit before infection (p = 0.040). This study showed that some adult ITP patients had an increase in platelet count after COVID-19 infection, and this phenomenon was strongly associated with the use of TPO-RA at the time of infection. Although no thrombotic events were observed in this study, it reminds clinicians that they should be alert to the possibility of thrombotic events in the long-term management of adult ITP patients during the COVID-19 pandemic.

Complications of thrombopoietin receptor agonists therapy in patients with immune thrombocytopenia

Immune thrombocytopenia (ITP) is an autoimmune disease characterized by increased platelet destruction and decreased platelet production. The formation of antibodies to platelet and megakaryocyte glycoproteins plays a major role in the pathophysiology of ITP. All treatment strategies for ITP attempt to increase platelet count and reduce the risk of bleeding complications. Corticosteroids remain the most commonly used first-line therapy for ITP, but their long-term use is limited due to the development of severe complications. Today the new treatment methods including the use of thrombopoietin receptor agonists (TPO-RA) romiplostim, eltrombopag and avatrombopag with a number of advantages over standard therapy are of great interest. These drugs are recommended for use in the second-line therapy and show high efficacy in patients with ITP, particularly in real clinical practice. In most cases TPO-RA provide stable and long-term remission of the disease, allowing you to reduce or discontinue the use of glucocorticosteroids and avoid splenectomy. Many studies of the mechanism of action, efficacy and toxicity of TPO-RA have been performed. the research results significantly expand our knowledge about these agents. This review provides comparative data of the TPO-RA safety and the main aspects of their clinical use. The features of the new drug avatrombopag, recently approved for use in the Russian federation, are described. the overview presents the advantages and limitations of each drug, possible adverse events and methods for their control.

Novel Perspectives on Thrombopoietin Receptor Agonists Applications.

Second-generation thrombopoietin receptor agonists (TPO-RAs), romiplostim, eltrombopag, and avatrombopag, have been proved to be significant stimulators of megakaryopoiesis and, in the last decade, they have been incorporated in the treatment options against refractory immune thrombocytopenia in children and adults that do not respond to conventional therapy. Additionally, given their beneficial impact on hematopoiesis, they have successfully been applied in cases of non-immune thrombocytopenia, such as aplastic anemia, HCV-related thrombocytopenia, chronic liver disease, and most recently acute radiation syndrome. During the past years, a wide variety of clinical studies have been performed, in regard to the use of TPO-RAs in various thrombocytopenic settings, such as malignant hematology and hematopoietic stem cell transplantation, hereditary thrombocytopenias, and chemotherapy-treated patients with solid organ tumors. Although data indicate that TPO-RAs may be an effective and safe option for managing disease- or treatment-related thrombocytopenia in these patients, further research is needed to determine their efficacy and safety in these settings. Furthermore, recent studies have highlighted novel properties of TPO-RAs that render them as potential treatment candidates for reducing tumor burden or fighting infections. Herein, we discuss the potential novel applications of TPO-RAs and focus on data regarding their efficacy and safety in these contexts.

Real-world use of thrombopoietin receptor agonists for the management of immune thrombocytopenia in adult patients in the United Kingdom: Results from the TRAIT study.

Few studies have reported the real-world use of both romiplostim and eltrombopag in immune thrombocytopenia (ITP). TRAIT was a retrospective observational study aimed to evaluate the platelet responses and adverse effects associated with the use of these thrombopoietin receptor agonists (TPO-RAs) in adult patients with ITP in the United Kingdom. Of 267 patients (median age at diagnosis, 48 years) with ITP (primary ITP [n = 218], secondary ITP [n = 49]) included in the study, 112 (42%) received eltrombopag and 155 (58%) received romiplostim as the first prescribed TPO-RA. A platelet count ≥30 × 109 /L was achieved in 89% of patients with the first TPO-RA treatments, while 68% achieved a platelet count ≥100 × 109 /L. Treatment-free response (TFR; platelet count ≥30 × 109 /L, 3 months after discontinuing treatment) was achieved by 18% of the total patients. Overall, 61 patients (23%) switched TPO-RAs, most of whom achieved platelet counts ≥30 × 109 /L with the second TPO-RA (23/25 who switched from eltrombopag to romiplostim [92%]; 28/36 who switched from romiplostim to eltrombopag [78%]). TFR was associated with secondary ITP, early TPO-RA initiation after diagnosis, the presence of comorbidity and no prior splenectomy or treatment with steroids or mycophenolate mofetil. Both TPO-RAs had similar efficacy and safety profiles to those reported in clinical studies.

Current Understanding of Immune Thrombocytopenia: A Review of Pathogenesis and Treatment Options.

The management of immune thrombocytopenia (ITP) and the prediction of patient response to therapy still represent a significant and constant challenge in hematology. ITP is a heterogeneous disease with an unpredictable evolution. Although the pathogenesis of ITP is currently better known and its etiology has been extensively studied, up to 75% of adult patients with ITP may develop chronicity, which represents a significant burden on patients' quality of life. A major risk of ITP is bleeding, but knowledge on the exact relationship between the degree of thrombocytopenia and bleeding symptoms, especially at a lower platelet count, is lacking. The actual management of ITP is based on immune suppression (corticosteroids and intravenous immunoglobulins), or the use of thrombopoietin receptor agonists (TPO-RAs), rituximab, or spleen tyrosine kinase (Syk) inhibitors. A better understanding of the underlying pathology has facilitated the development of a number of new targeted therapies (Bruton's tyrosine kinase inhibitors, neonatal Fc receptors, strategies targeting B and plasma cells, strategies targeting T cells, complement inhibitors, and newer TPO-RAs for improving megakaryopoiesis), which seem to be highly effective and well tolerated and result in a significant improvement in patients' quality of life. The disadvantage is that there is a lack of knowledge of the predictive factors of response to treatments, which would help in the development of an optimized treatment algorithm for selected patients.

Glucocorticosteroid-induced complications in patients with idiopathic thrombocytopenic purpura

Glucocorticosteroids (GCS) are the first-line treatment for idiopathic thrombocytopenic purpura (ITP). Despite their high efficacy in patients with newly diagnosed ITP, an adequate level of platelets remains after GCS withdrawal in only less than 20 % of patients. Additionally, GCS use is associated with an increased risk of different adverse reactions, including serious and life-threatening ones. Thrombopoietin receptor agonists represent a relatively new class of drugs for treating ITP as a second-line therapy. This paper reviews the risks of GCS pharmacotherapy, as well as the evidence supporting the use of thrombopoietin receptor agonists as both first-line and second-line treatment for patients with ITP.

A Phase 3 Study of Eltrombopag Vs. Standard First-Line Management for Newly Diagnosed Immune Thrombocytopenia in Children: Trial in Progress Update

Background: Immune thrombocytopenia (ITP) causes low platelet counts, variable bleeding symptoms, and reductions in health-related quality of life (HRQoL). Despite this, novel therapies for newly diagnosed ITP have not been introduced in over 30 years. Eltrombopag, a thrombopoietin receptor agonist (TPO-RA), was FDA approved for children with chronic ITP in 2015. The use of eltrombopag for adults with newly diagnosed ITP has been described in two small single-center trials (Tripathi et al, Int J Hematol, 2014; Gόmez-Almaguer et al, Blood, 2014), and pediatric hematologists do use TPO-RAs off-label in some cases of newly diagnosed ITP (Neunert et al, Pediatr Blood Cancer, 2016). TPO-RAs may be an efficacious and more durable first-line therapy for children with newly diagnosed ITP who require treatment. This abstract provides a 4-year interval update on the Pediatric ITP Newly diagnosed patients Eltrombopag vs Standard therapy (PINES) trial in progress. Study Design and Methods: The PINES trial, NCT03939637, is an investigator-initiated prospective, open label, randomized, multi-center trial sponsored by the ITP Consortium of North America (ICON) and funded by Novartis. The primary objective is to determine if the proportion of patients with a platelet response, defined as ≥3 of 4 platelet counts >50 x10 9/L during weeks 6-12 without rescue treatment, is significantly greater in patients with newly diagnosed ITP treated with eltrombopag compared to those treated with standard first-line therapy. Patients (n=162) from 30 ICON centers (Figure) are randomized 2:1, stratified by age and treatment status, to receive the experimental treatment, eltrombopag, or investigator's choice of 3 standard first-line therapies: prednisone, intravenous immune globulin or anti-D globulin at standardized doses. Eligible patients are ages 1 to <18 with primary ITP, within 3 months of diagnosis, with platelet count <30 x10 9/L who require pharmacologic treatment from the perspective of the treating clinician. Baseline treatment status is 1) upfront treatment, or patients within 10 days of ITP diagnosis with no prior treatment, and 2) treatment failure, or patients previously managed with observation or a first-line standard agent. Patients are ineligible if they can be observed without medication or have severe bleeding. A one-sided z-test, at alpha=0.025, will be used to compare the proportion of patients who have a platelet response between the two treatment arms. All randomized patients will be analyzed in the intention-to-treat analysis. Secondary objectives include treatment arm comparison of bleeding scores (WHO Bleeding Scale and Modified Buchanan Score), changes in HRQoL (measured by the Kids ITP Tool, Hockenberry Fatigue Scale, PROMIS, and Global Change Scale), and changes in percentage of CD4 +25 +Foxp3 + regulatory T (Treg) cells. Due to challenges related to recruitment and the logistics and safety of obtaining frequent assessments during the COVID-19 pandemic, the primary endpoint was re-defined in 2021 to what is considered a clinically equivalent definition of response, from ≥6 of 8 weekly to ≥3 of 4 biweekly platelet counts >50 x10 9/L during weeks 6-12. Baseline Characteristics: Since first site activation in 2019, 100 patients have been enrolled (Table). Subjects include 42 patients aged 1-<6 years, 34 patients aged 6-<12 years, and 24 patients aged 12-<18 years. Thirty-six patients received upfront treatment and 64 patients had treatment failure prior to enrollment. Median baseline platelet count at enrollment was 5 x10 9/L (range 1 - 28 x10 9/L). Median WHO Bleeding Scale at enrollment was 1 (range 0 - 3) and median modified Buchanan Overall Score was 3 (range 0 - 3). Baseline HRQoL surveys have been obtained for >80% of eligible subjects. Treg samples have been obtained for 95% of subjects, and 74% of subjects have consented to optional biology studies. Conclusion: Despite historical difficulty completing interventional trials in pediatric ITP and pandemic-related enrollment challenges, PINES trial enrollment is progressing successfully and will ultimately provide definitive data regarding the efficacy of eltrombopag in children with newly diagnosed ITP. There are no current data supporting the use of TPO-RAs for newly diagnosed ITP in children, or as monotherapy for newly diagnosed ITP in adults. Results from this trial therefore carry the potential to change management practices in ITP.

Effect of Hetrombopag Combined with Rhtpo in Patients with Severe Immune Thrombocytopenia

Background: Severe Immune Thrombocytopenia (ITP) is a life-threatening acquired hemorrhagic disease with dramatically decreased platelet number and clinical bleeding symptoms. Some patients with severe ITP did not respond to first-line treatment including steroids and Intravenous Immunoglobulin (IVIG). It was critical for them to use effective treatments to promote platelet and reduce the risk of fatal bleeding. Clinical practice guidelines have recommended the use of thrombopoietin receptor agonist (TPO-RA) as a second-line treatment for ITP. Recombinant human thrombopoietin (rhTPO) and hetrombopag are two distinct TPO-RAs with different mechanisms. As reported, there remains no study assessing the efficacy and safety of hetrombopag combined with rhTPO in the treatment of ITP. Therefore, the present study aimed to investigate the efficacy of hetrombopag plus rhTPO in Chinese patients with severe ITP, focusing on the short rather than the long-term efficacy, such as quickly increasing platelet count and significantly reducing bleeding, which would be more meaningful for severe patients whose platelet count <10 × 10 9/L. Methods: This was a prospective, open-label, single-center study with a planned enrollment of 30 patients. The inclusion criteria were patients ≥ 18 years, diagnosed with primary immune thrombocytopenia, platelet count <10 × 10 9/L, or bleeding score ≥ 5. Patients receiving other ITP drugs as maintenance therapy were eligible if previous glucocorticoid therapy doses were stable, and rituximab was used for at least 2 months and other immunosuppressants were stable for at least 4 weeks. Patients who had received IVIG, avatrombopag, eltrombopag, or romiplostim within 2 weeks prior to enrollment were excluded. Histories of platelet transfusion one week before treatment were excluded. Hetrombopag was given at 5 mg/day for 28 days, while rhTPO was administered at 300 U/kg subcutaneously daily for 14 days. When PLT > 100 × 10 9/L, rhTPO should be discontinued. When PLT > 150 × 10 9/L, the dosage of hetrombopag was reduced to 2.5mg/day, and it would be discontinued if PLT > 250 × 10 9/L. The primary endpoints were proportion of subjects with platelet count ≥30×10 9/L and at least doubled the baseline platelet count within 28 days. Secondary endpoints included bleeding score, incidence of thrombotic events, and adverse events (AEs). Results: As to July 27, 2023, a total of 20 patients were included in this study, with a median age of 36 years and a male proportion of 50%. Among them, 70% (14 cases) were newly diagnosed ITP patients. 50% of patients have received ≥ 1 line of previous treatment, of which 2 patients have received IVIG treatment and both have achieved CR (PLT ≥ 100 × 10 9/L). The baseline median platelet count was 5 × 10 9/L, and 95% (19 cases) of patients had active bleeding with a bleeding score of ≥ 1 point. The median duration for hetrombopag at dose of 5mg is 8.0 days, and rhTPO is 6.5 days. After combined treatment, the median time for platelet counts reached 30, 50, and 100 × 10 9/L was 4.5 days, 6 days, and 7 days, respectively. Among them, the median platelet count reached 103 × 10 9/L after 7 days treatment and 214.5 × 10 9/L after 15 days. Within 15 days of combined treatment, 15% (3 cases) of patients achieved partial platelet reaction (PLT > 50 × 10 9/L, without bleeding), and 85% (17 cases) achieved complete platelet reaction (PLT > 100 × 10 9/L, without bleeding). In terms of safety, two patients experienced liver function abnormalities, both of which were grade 1-2. One was related to treatment drugs, and the other was associated with underlying autoimmune liver disease. No thrombotic events occurred in all patients. Conclusion: This study innovatively explores the efficacy and safety of combination therapy with hetrombopag and rhTPO in the treatment of severe ITP. It is preliminarily confirmed that this combination therapy can effectively and quickly improve the early platelet response of ITP patients, avoid bleeding damage, and is expected to become a new treatment choice for severe ITP patients. We also look forward to the overall efficacy evaluation results of all patients after completing treatment in the future.

Nationwide Survey on the Use of Thrombopoietin Receptor Agonists (TPO-RA) for the Management of Immune Thrombocytopenia in Current Clinical Practice in Italy.

Two thrombopoietin receptor agonists (TPO-RA), romiplostim and eltrombopag, are currently widely adopted as second-line ITP therapy even in the absence of robust evidence on their comparative advantages over rituximab or splenectomy or their preferential use in some specific clinical contexts. An online survey was distributed between May 2021 and June 2021 to collect standardized information on TPO-RA use in Italy. Eighty-eight hematologists from 79 centers completed the survey. Eighty-four percent would use TPO-RA earlier than formally indicated, without a preference for young or elderly in 82% of respondents. No clear preference for either romiplostim or eltrombopag was indicated. Seventy-two percent would use TPO-RA in young patients aiming at a complete response followed by tapering, a strategy considered by only 16% in the elderly. Switching between the two agents was considered appropriate in case of insufficient response or intolerance. Tapering schedule by reducing the dosage and prolonging the intervals between administrations was preferred by 73% of respondents. TPO-RA was considered a risk factor for thrombosis by only 35%, and 94% would administer TPO-RA in elderly patients also in the presence of other thrombotic risk factors. Thirty-three percent of respondents would withdraw TPO-RA in case of thrombosis. The TPORA administration has been reported to be preferred over anti-CD20 or splenectomy by about half of the participants due to the ongoing COVID-19 pandemic. Significant discrepancies in TPO-RA use emerged from the survey, and participants would appreciate consensus-based specific guidance on the practical use of TPO-RA.

Use of thrombopoietin receptor agonists in adults with immune thrombocytopenia: a systematic review and Central European expert consensus

There are currently three thrombopoietin receptor agonists (TPO-RAs) approved in Europe for treating patients with immune thrombocytopenia (ITP): romiplostim (Nplate®), eltrombopag (Revolade®), and avatrombopag (Doptelet®). However, comparative clinical data between these TPO-RAs are limited. Therefore, the purpose of this study was to perform a literature review and seek expert opinion on the relevance and strength of the evidence concerning the use of TPO-RAs in adults with ITP. A systematic search was conducted in PubMed and Embase within the last 10 years and until June 20, 2022. A total of 478 unique articles were retrieved and reviewed for relevance. The expert consensus panel comprised ITP senior hematologists from eight countries across Central Europe. The modified Delphi method, consisting of two survey rounds, a teleconference and email correspondence, was used to reach consensus. Forty articles met the relevancy criteria and are included as supporting evidence, including five meta-analyses analyzing all three European-licensed TPO-RAs and comprising a total of 31 unique randomized controlled trials (RCTs). Consensus was reached on seven statements for the second-line use of TPO-RAs in the management of adult ITP patients. In addition, the expert panel discussed TPO-RA treatment in chronic ITP patients with mild/moderate COVID-19 and ITP patients in the first-line setting but failed to reach consensus. This work will facilitate informed decision-making for healthcare providers treating adult ITP patients with TPO-RAs. However, further studies are needed on the use of TPO-RAs in the first-line setting and specific patient populations.

Feasibility and Efficacy of Romiplostim for the Treatment of Persistent Thrombocytopenia after Allogeneic Stem Cell Transplantation. a Single Centre Experience

Introduction. Persistent thrombocytopenia (PT) due to delayed primary platelet recovery or secondary graft failure with prolonged thrombocytopenia is a relevant and relatively common complication after allogeneic stem cell transplantation (alloSCT). It can result in transfusion dependence and hemorrhagic events, leading to increase of morbidity and mortality. Concomitant causes of PT after alloSCT are several and can include viral infections, graft-versus-host disease (GvHD), drug toxicity, thrombotic microangiopathy (TMA) and immune thrombocytopenia (ITP). Together with the treatment of the primary cause and the support with platelet transfusion, the use of thrombopoietin receptor agonists (TPO-RAs), which proved to be effective in several scenarios (e.g. ITP or aplastic anemia), is gaining a fundamental role also in the post alloSCT setting. To date, the use of TPO-RAs after transplant has been investigated in small studies or case reports. In this study, we evaluated the use of romiplostim in a larger patient cohort to determine its safety, efficacy and potential predictors of response. Materials and methods. We conducted a retrospective study on consecutive patients undergoing alloSCT and receiving romiplostim for the treatment of PT at the bone marrow transplantation unit of the University Hospital of Ulm. PT was defined as a platelet count < 20 Giga/l for 7 consecutive days after engraftment, the need for continuous transfusion during the post-transplant follow-up or a not rapidly reversible decrease of >50% of the platelet count not due to relapse of underlying hematological disease. Response to treatment was defined as a platelet count >50 Giga/l for at least 7 consecutive days without transfusion. Patients with residual bone marrow involvement of primary hematological disease were excluded. Univariate analysis was conducted using Fisher's exact test or Mann-Whitney-U-test. Results. Between 01/2019 and 12/2021 we identified a total of 119 out of 255 transplanted patients (46,7%) with PT receiving, as a part of the treatment, romiplostim during the post-transplant follow-up. Patient characteristics are listed in Table 1. The median platelet count at baseline was 32 Giga/l (r = 0 - 88). We started with romiplostim 250μg on a weekly basis, in 46,2% of cases the dose was escalated to 500 µg during treatment. Seventy-three percent showed a clinical response to treatment with a median time to response of 40 days (r = 7 - 565). We observed adverse events like thrombosis, pain syndrome, dizziness in only 8,4% of patients. The median duration of treatment was 168 days (r = 18 - 761). In patients with response, the median platelet count was 91 Giga/l (r = 53 - 212). In univariate analysis, we evaluated potential risk factors associated with poor response to romiplostim. While the presence of a viral reactivation (like CMV, EBV, BKV, HSV1) requiring systemic treatment was associated with a significant lower response rate (47.6% versus 79.6%, respectively for patients with or without reactivation, p= 0.005), the presence of active GvHD (also in case of steroid-refractory (SR) forms), of TMA and the number of CD34-positive stem cells of the graft did not play a role in determining the efficacy of romiplostim. We also evaluated the influence of graft cryopreservation, which was performed increasingly during the SARS-CoV-2 pandemic, on the rate of efficacy of romiplostim in PT treatment. We could not identify a significant difference as compared to the non-cryopreserved grafts. Conclusion. Our results indicate that romiplostim is overall well tolerated and represents a reasonable and effective treatment for PT after alloSCT. We observed that viral infections requiring systemic antiviral treatment could represent a predictor of worse response, which could potentially be explained by the myelotoxicity induced not only by the virus itself but also as a consequence of antiviral substances. Of note, especially considering that SR GvHD or TMA did not seem to impair the efficacy of romiplostim, the stimulation of TPO receptor could play a role in reducing the rate of morbidity and mortality associated with such severe complications of the post transplant follow-up. Also, cryopreservation did not impact on the rate of success of TPO-RAs based treatment strategy. These preliminary results need to be further validated in larger and prospective cohorts. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Switching from Eltrombopag to Hetrombopag in Patients with Primary Immune Thrombocytopenia (ITP): Post-Hoc Analysis of a Multicenter, Randomized Phase III Trial

Introduction: Primary immune thrombocytopenia (ITP) is an autoimmune disorder characterized by a low platelet count resulting from platelet destruction and impaired platelet production. In the last decades, thrombopoietin receptor agonists (TPO-RAs) demonstrated a high rate of response in ITP and are licensed for use in persistent or chronic patients who have had an insufficient response to first line treatment with corticosteroids or Intravenous Immunoglobulin (IVIG). Some evidence suggests that switching to the alternate TPO-RA can be an appealing treatment option in patients with ITP for efficacy or safety issues; however, much of the evidence is retrospective and only a few prospective studies investigating alternate use of TPO-RAs. Hetrombopag is the first small molecule, nonpeptide oral TPO-RA developed in China and its efficacy has been demonstrated in a multicenter phase III trial (NCT03222843). Here we conducted a post hoc analysis of this phase III trial to assess the response in patients who switched from eltrombopag to hetrombopag. Methods：A multicenter phase III study included a randomized, double-blind, placebo-controlled, 10-week treatment period (hetrombopag or placebo), sequentially followed by an open-label 14-week treatment period, during which patients who received placebo switched to eltrombopag with an initial dosage of 25 mg once daily and can be adjusted to a maximum of 75 mg once daily. Patients who completed eltrombopag 14-week treatment could directly continue additional 24-week hetrombopag treatment initiated at 2.5, 3.75, 5, or 7.5 mg once daily at the discretion of the investigator. Patients were assessed for efficacy and safety at every scheduled visit. In this post-hoc analysis, we investigated the response switching from eltrombopag to hetrombopag in ITP patients. Results: All 63 (74.1%) patients who completed the initial 24-week treatment (10-week placebo and 14-week eltrombopag) entered a prespecified additional 24-week hetrombopag treatment period. At enrollment, the median age was 43 years (range 18-70) and 47 (74.6%) patients were female, the duration of ITP was three years or longer in 40(63.5%) patients. The median baseline platelet count before switching to hetrombopag was 69.0×109/L (range 6.0-278.0×109/L ) and one third patients had not achieved a sustained response (platelet count≥50×109/L) after eltrombopag treatment. The median dose of the prior eltrombopag at the time of switching was 50 mg daily. As of data cutoff on November 19, 2020, 58 (92%) patients completed the hetrombopag treatment period, the median exposure to hetrombopag was 169.0 days (range, 53.0-176.0); 28 (44.4%) patients received the maximum dose of 7.5 mg once daily and the final dose of the other 16 (25.4 %) patients was 5 mg once daily. Overall, 56/63 (88.9%) achieved a platelet response (platelet count≥50×109/L) after switching from eltrombopag to hetrombopag. Among 12 patients with prior platelet count lower than 30×109/L, eight patients (66.7%) achieved response. For nine patients with prior platelet count between 30×109/L and 50×109/L, eight patients (88.9%) achieved response (Table 1). The median platelet count was 70 ×109/L after 2 weeks of switching and ranged between 62.5 ×109/L and 110 ×109/L across every scheduled visit during 24-week treatment with hetrombopag, highlighting that consistent platelet response could be maintained after switching from eltrombopag to hetrombopag. (Figure 1). The median maximum continuous duration of response was 78 days (range 8-165) and the median total duration of response was 104 days (range, 8-165) after switching to hetrombopag. In addition, 5(7.9%) patients received protocol-defined rescue therapy and 3(4.8%) patients had bleeding symptoms (All were grade 1 according to WHO bleeding scale) during hetrombopag treatment. Conclusion：In this one of the largest evaluations of switching between different TPO-RAs. Hetrombopag was effective following prior eltrombopag treatment, with high response rates even in patients with inadequate response to the prior therapy. Our results confirm the reported efficacy of TPO-RA switch in ITP patients and the lack of cross-resistance between the two available TPO-RAs. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Arterial Thromboembolism Is Prevalent and Often Suboptimally Managed in Immune Thrombocytopenia

Background: Adults with chronic immune thrombocytopenia (ITP) have increased risk of arterial thromboembolism (TE) compared to the general population. Adequate therapy with antiplatelets, anticoagulants or revascularization may be limited by thrombocytopenia and bleeding risk. Few studies have examined the quality of arterial TE management in ITP, and outcomes such as bleeding and cardiovascular deaths. Aims: To examine acute inpatient management and outcomes of arterial TE in relapsed/refractory ITP. Methods: This multicentre retrospective cohort study included all chronic ITP patients ≥18 years who received second-line therapy (2012-2020) in the province of Alberta, Canada. Demographics, ITP disease characteristics, traditional vascular risk factors, and history of TE were collected. We also collected ITP-related thrombotic risk factors including splenectomy status, antiphospholipid antibody syndrome (APS), and use of thrombopoietin receptor agonists (TPO-RA) at the time of TE. The incidence rate was calculated by dividing the number of TE events by the person-years of follow-up since ITP diagnosis. For each TE event, we examined the initial and nadir platelet counts, acute ITP-directed therapy, and quality of TE management (antiplatelets, anticoagulants, revascularization) during hospitalization. We assessed outcomes including 30-day mortality, cardiovascular deaths, and bleeding from TE event to last follow-up or death. Research ethics approval was obtained. Results: During 2713 person-years of follow-up since ITP diagnosis, 46/329 patients (14%) developed a total of 53 incident arterial TE events, 9 of whom also developed venous thromboembolism. TE events included 27 (51%) acute coronary syndromes (ACS), 25 (47%) ischemic strokes or transient ischemic attacks (TIA), and 1 (2%) acute limb ischemia. The incidence rate of arterial TE was 2.0 (95% CI 1.5-2.6) per 100 person-years. The median age at time of arterial TE was 67 years (IQR 61-77), 22 (42%) were men (Table 1). Risk factors for arterial TE included: history of atherosclerotic disease (18; 34%), 3 or more traditional vascular risk factors (17; 32%), post-splenectomy status (23; 43%), concurrent TPO-RA use (16; 30%), and APS (5; 9%). Most (37; 70%) were not on antiplatelets or anticoagulants at presentation. Of these, 7 had interruption or discontinuation of prior antiplatelets/anticoagulants due to bleeding risk, and subsequently developed ischemic stroke/TIA. A platelet count <50 x 109/L was observed in 21 (40%) arterial TE events throughout hospitalization. Acute ITP therapies to maintain platelet >50 x 109/L included: IVIG (9/21; 43%), platelet transfusions (7; 33%), TPO-RA (6; 29%), corticosteroids (4; 19%), and rituximab (4; 19%). Of the 27 ACS events, over half (15; 56%) underwent revascularization with either PCI (5 bare metal stents, 6 drug-eluting stents, 1 catheter-directed thrombolysis) or coronary artery bypass graft (3). Patients with platelet count >50 x 109/L showed a non-significant trend towards higher likelihood of revascularization (10/15, 67%) compared to those with platelet count <50 x 109/L (5/11, 45%; P=0.28). Three patients received neither antiplatelets nor revascularization due to severe thrombocytopenia (<30 x 109/L). Of the 25 stroke/TIA events, 6 (24%) underwent revascularization. Antiplatelet or anticoagulants were not offered in 5 cases, mostly due to thrombocytopenia and/or hemorrhagic transformation. At last follow-up, 26/46 (57%) patients died at a median age of 74 (IQR 64-80) years, from cardiovascular deaths (n=10), other TE (n=2), infection (n=7), bleeding (n=1) and other causes (n=6). The 30-day mortality following TE was 10%. Major bleeding occurred in 6 (11%) individuals, at a median of 18 days (IQR 14-32) after TE. Conclusion: Patients with chronic ITP receive suboptimal management of arterial TE including a lower likelihood of receiving antiplatelet/anticoagulants or revascularization. With the advent of newer lines of ITP therapies including three TPO-RAs and fostamatinib, aggressive ITP control is critical to avoid withholding antiplatelet/anticoagulants, and to reduce the risk of bleeding, recurrent TE, and cardiovascular deaths. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Diagnosis of disorders in the coagulation system, assessment of the risk of hemorrhagic complications in severe cirrhosis/liver diseases according to global screening tests of the hemostasis system and principles for their correction: guidelines

Hemostasis disorders in cirrhosis / severe liver disease are complex, as they affect both pro- and anticoagulant factors, as well as pro- and antifibrinolytic components. Most of the tests that are used in clinical practice to assess coagulation do not take into account the compensatory capabilities of this system as a whole. This document provides guidance for the optimal application and interpretation of global screening tests in the assessment of hemostasis in cirrhosis/severe liver disease, analysis of risk factor of spontaneous and perioperative hemorrhagic complications in these patients, and possible ways to correct them. Thrombocytopenia is one of the most common hematological abnormalities in cirrhosis/ severe liver disease. The frequency of thrombocytopenia in such patients at the stage of liver cirrhosis is 70%, at the pre-cirrhotic stage – 6%. The latest scientific data on the use of thrombopoietin receptor agonists in chronic liver diseases are presented: which patients are the best candidates for a such of therapy. The rationality and limitations in prescribing blood components to patients with liver cirrhosis/severe liver diseases are described. Emphasis is placed on the fact that a number of hemorrhagic complications develop for other non-coagulopathic reasons: decompensated portal hypertension, traumatization of a varicose vein with trophic wall disorders, etc. Data are presented on the use of viscoelastic tests to optimize the management of patients with liver cirrhosis, which simultaneously assess the four main known components of the hemostasis system: the coagulation cascade, platelets, anticoagulant mechanisms and the fibrinolysis system. These tests allow optimization of transfusion of blood components in such patients and should be further studied. Research in this very complex area of hepatology is ongoing and must continue.

Eltrombopag may induce bone marrow fibrosis in allogeneic hematopoietic stem cell transplant recipients with prolonged thrombocytopenia

Poor graft function (PGF) and secondary failure of platelet recovery (SFPR) are significant causes of transplant related morbidity and mortality. Although thrombopoietin receptor agonists (TPO-RA), particularly Eltrombopag (EPAG), have been reported to be efficacious in the treatment of prolonged thrombocytopenia, potential long term adverse effects remain to be elucidated. This retrospective study was performed to determine the efficacy and toxicity profile of TPO-RAs in allogeneic hematopoietic stem cell transplant (alloHCT) recipients. Medical records of 27 patients [median age: 55(21−73) years; male/female: 15/12] who received posttransplant EPAG for SFPR or PGF were analysed. Eltrombopag was started on day 110(33−670) after transplant. Median initial dose was 25(25−50) mg/day which was properly escalated to a maximum dose of 75(50−100) mg/day. Duration of the treatment was median 120(31−377) days. Overall response rate (ORR) was 59.3% in the study population. Time-to-treatment response was 42(3−170) days. Mild-to-moderate bone marrow fibrosis was detected in the posttreatment biopsies of 12/22 patients (54.5%), 9 of whom did not represent any grade of myelofibrosis in their inital biopsies. The grade of posttreatment fibrosis was significantly increased when time-to-treatment response was longer (p = 0.008). Long term use of TPO-RAs may be considered as a potential cause of myelofibrosis in alloHCT recipients.

Use of eltrombopag in treatment programs for patients with aplastic anemia

Introduction. The use of thrombopoietin receptor agonists, especially eltrombopag, in the treatment of aplastic anemia (AA) patients who did not respond to the previous immunosuppressive therapy (IST), is accompanied by the development of a hematological response in 40–60 % of patients.Aim — to study the effi cacy of using eltrombopag in treatment programs for AA patients refractory to previous IST.Methods. The study included 20 AA patients who were treated at the National Research Center for Hematology from 2015 to 2020. These patients did not respond to the conducted IST (ATG + CsA). Eltrombopag was administered at a dose of 150 mg/day. The results of treatment were assessed at 3 and 6 months: the achievement of hematological improvement, partial and complete remission, as well as the identifi cation of possible clonal evolution were determined.Results. Eleven out of 20 (55 %) patients responded to treatment: 2 patients developed hematological improvement, 6 patients — partial remission, 3 patients — complete remission. All 11 patients responded to treatment within 12 months from the start of eltrombopag, but further positive dynamics of hematological parameters are possible. The median duration of treatment with eltrombopag was 11 (1–48) months. Most of the patients were treated with eltrombopag in combination with CsA. The duration of the course of treatment with eltrombopag depended on the response received (stable hematological improvement, remission, as well as the detection of clonal evolution) or its absence and the need for ATG or BMT. An aberrant karyotype was found in 2 AA patients who received eltrombopag: in one patient monosomy of chromosome 7 was detected 1 month after the start of treatment, in another patient, 37 months later, a clone with a derivative of chromosome 16 from t(1;16) and subclone with complex disorders of the karyotype without signs of myelodysplasia in the bone marrow.Conclusion. The inclusion of the TPO receptor agonist eltrombopag in the treatment program for AA patients allows for a stable hematological response and remission of AA for patients who have not responded to IST. The effectiveness of eltrombopag is determined by adherence to the treatment algorithm, the optimal duration of the course, and the dose of the drug used. There is still a need for long-term observation of the patient and control morphological and cytogenetic studies.

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.

Thrombopoietin receptor agonists and rituximab for treatment of pediatric immune thrombocytopenia: A systematic review and meta-analysis of prospective clinical trials.

Children with immune thrombocytopenia (ITP) may require second-line ITP therapies. The high remission rate in pediatric patients, need for extended-duration use of thrombopoietin receptor agonists (TPO-RAs), drug adherence, potential side effects, monitoring, and cost effectiveness are factors that should be considered in decision-making about second-line therapies. Rituximab (RTX) has been used off-label for years to treat ITP but there are limited studies about its efficacy and safety in children. To date, no studies have directly compared TPO-RAs with RTX for the treatment of childhood ITP. This systematic review analyzed the overall platelet response, durability of treatment effect, and safety for RTX use in comparison to TPO-RAs in pediatric ITP. MEDLINE/PubMed, EMBASE, Cochrane Library, and Web of Science databases were searched through December 2020 and meta-analysis was conducted using proportions of success/failure for each intervention in the selected studies. The proportion of participants achieving the primary endpoint of a platelet response above 50,000 was similar for TPO-RAs (proportion=0.71, 95% CI: 0.63-0.78) and RTX (proportion=0.68, 95% CI: 0.53-0.82). However, considerable variation was found between the two groups with regards to the sustainability of the response and other secondary outcomes such as need for rescue and adverse events. RTX was associated with higher rates of rescue therapy. In this analysis of prospective pediatric ITP studies, RTX and TPO-RAs had similar rates of overall platelet response but differed in other important measures. Prospective comparative studies are needed to better characterize second-line treatments for pediatric ITP.

Practice Guidelines of the Central European Hepatologic Collaboration (CEHC) on the Use of Thrombopoietin Receptor Agonists in Patients with Chronic Liver Disease Undergoing Invasive Procedures.

Background: Second-generation thrombopoietin receptor agonists (TPO-RAs) are emerging as the new standard for managing thrombocytopenia (TCP) in patients with chronic liver diseases (CLDs) undergoing scheduled procedures. However, practical guidance for their routine use in CLD patients undergoing specific invasive procedures is lacking. Methods: These practice guidelines were developed by the Initiative Group for Central European Hepatologic Collaboration (CEHC), composed of nine hepatologist/gastroenterologist experts from Central Europe. Using an adapted Delphi process, the CEHC group selected ten invasive procedures most relevant to the hepatology/gastroenterology setting in the region. Consensus recommendations for each invasive procedure are reported as a final percentage of expert panel responses. Results: A consensus was agreed that TPO-RAs should be considered for raising platelet count in CLD patients undergoing scheduled abdominal surgery, high-bleeding risk dentistry, endoscopic polypectomy, endoscopic variceal ligation, liver biopsy, liver surgery, liver transplantation and percutaneous ablation, but it was also agreed that they are less beneficial or not necessary for endoscopy without intervention and paracentesis. Conclusions: Using a modified Delphi method, experts reached an agreement for TCP management in CLD patients undergoing ten invasive procedures. These practice guidelines may help with decision making and patient management in areas where clinical evidence is absent or limited.

Cost-Effectiveness of Second-Line Therapies in Adult Patients with Chronic Immune Thrombocytopenia

Introduction: Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by accelerated platelet clearance and impaired platelet production. Up to 75% of cases in adults assume a chronic course. Standard second-line treatment options include rituximab, thrombopoietin receptor agonists (TPO-RAs), and splenectomy. The 2019 American Society of Hematology (ASH) guidelines provide three dichomotous evaluations of these treatments with conditional recommendations for 1) splenectomy or TPO-RA, 2) rituximab over splenectomy, and 3) TPO-RA over rituximab. The guideline panel noted that there were no studies available to evaluate the cost-effectiveness of these therapies. We sought to address this knowledge gap by conducting the first cost-effectiveness analysis of second-line therapies for chronic ITP. Methods: We built a Markov model comparing the cost-effectiveness of all six treatment pathways utilizing rituximab, TPO-RA (romiplostim or eltrombopag), and splenectomy. We assumed a median age of 50 at diagnosis and a 20-year time-horizon. Costs were assessed from the health system perspective. Effectiveness was calculated in quality-adjusted life-years (QALYs). The costs of splenectomy treatment included the cost of surgery, postoperative care, accessory spleen imaging and repeat splenectomy, treatment for post-splenectomy sepsis and thromboembolism. The annual risks of post-splenectomy sepsis and thromboembolism were assumed to be the highest reported, every post-splenectomy infectious complication was assumed to be severe septic shock, and patients with thromboembolism accrued the costs of indefinite anticoagulation. To minimize bias against TPO-RAs, TPO-RA therapy was assumed to have no adverse events, a constant high overall response without any loss of effectiveness, and the highest reported rate of successful TPO-RA therapy discontinuation after two years, which we assumed to be permanent. Rituximab treatment was assumed to have no adverse events and overall response rates as previously reported. Cost-effectiveness of each treatment pathway was calculated as the incremental cost-effectiveness ratio (ICER), calculated as ratio of costs to QALYs. The ICER was compared against a 2019 US willingness-to-pay (WTP) threshold of $195,300. We then performed one-way deterministic sensitivity analyses varying all parameters including the costs of splenectomy, TPO-RA, rituximab, splenectomy complications, splenectomy complete response rates, TPO-RA and rituximab overall response rates, utilities of the well and diseases states, annual post-splenectomy septic shock mortality and perioperative splenectomy mortality. We concluded with a probabilistic sensitivity analysis running 10,000 Monte Carlo simulations. Results: The most cost-effective treatment pathway was #5 (splenectomy->rituximab->TPO-RA; Figure). The next most cost-effective pathway was #4 (rituximab followed by splenectomy and then TPO-RA therapy), with an ICER of $369,289. All four remaining treatment pathways (#1-3, 6) utilizing TPO-RA therapy early (first or second) had an ICER above $1 million, far above the US WTP of $195,300, and/or were dominated. Of these, pathways #1 and #3 were externally dominated and #2 was absolutely dominated. No parameter change in one-way deterministic sensitivity analysis in any of the 4 pathways featuring TPO-RA early brought down the ICER to under $1 million. In the probabilistic sensitivity analysis, pathway #5 was favored in 100% of 10,000 Monte Carlo simulations. The cost of TPO-RA would have to be decreased to under $20,000 annually (e.g., >80% reduction in the cost of eltrombopag or romiplostim) before it could become cost-effective in any TPO-early treatment pathway.Conclusion: Four treatment pathways (#1-#4) are consistent and two pathways (#5-#6) are at variance with the ASH guidelines. Although it does not align with the ASH guidelines, pathway #5 (splenectomy->rituximab->TPO-RA) was most cost-effective. Over a 20-year time-horizon, all pathways featuring early use of a TPO-RA exceeded an ICER >$1 million or were dominated. Because our model was designed to maximize the cost-effectiveness of TPO-RA, it is likely that the actual ICER of pathways featuring early use of TPO-RA are higher than what we report here. Preferred second-line treatment strategies in adults with chronic ITP may be worth considering in light of our findings. [Display omitted] DisclosuresCuker: Synergy: Consultancy; Novo Nordisk: Research Funding; Alexion: Research Funding; UpToDate: Patents & Royalties; Novartis: Research Funding; Bayer: Research Funding; Takeda: Research Funding; Pfizer: Research Funding; Sanofi: Research Funding; Spark Therapeutics: Research Funding.