Thrombopoietin Receptor Agonist Research Articles

Lusutrombopag Reduces the Risk of Hemoperitoneum Caused by Percutaneous Radiofrequency Ablation for Hepatocellular Carcinoma Compared with Platelet Transfusion

Introduction: Patients with liver cirrhosis develop thrombocytopenia and an increased risk of bleeding events after invasive procedures. Lusutrombopag, a thrombopoietin receptor agonist, can increase the platelet count. This study assessed whether lusutrombopag reduces the risk of hemoperitoneum following percutaneous radiofrequency ablation for hepatocellular carcinoma, compared with platelet transfusion. Methods: Participants in the present study comprised patients with severe thrombocytopenia (platelet count <50,000/μL) enrolled between November 2012 and March 2020, excluding patients with idiopathic thrombocytopenia or anticoagulant use. Hemoperitoneum rate, hemostasis rate, hemoglobin reduction rate, rate of achieving a platelet count ≥50,000/μL, and increases in platelet count and factors contributing to hemoperitoneum were retrospectively analyzed. Results: This study enrolled 41 patients, comprising 18 patients administered lusutrombopag and 23 patients who received platelet transfusion. The major hemoperitoneum rate after RFA was tend to be lower in the lusutrombopag group (0%) than in the platelet transfusion group (21.7%). All of the major hemoperitoneum was observed in the platelet transfusion group. Hemoglobin reduction rate was lower in the lusutrombopag group (−0.17%) than in the platelet transfusion group (6.79%, p = 0.013). Hemostasis rate was lower in the lusutrombopag group (0%) than in the platelet transfusion group (21.7%, p = 0.045). The rate of achievement of platelet counts ≥50,000/μL the day after RFA was higher in the lusutrombopag group (100%) than in the platelet transfusion group (60.9%, p = 0.005). Conclusion: Lusutrombopag may be able to perform RFA more safely with respect to the hemoperitoneum caused by percutaneous radiofrequency ablation compared with platelet transfusion.

A practical guide to the management of immune thrombocytopenia co-existing with acute coronary syndrome.

Immune thrombocytopenia (ITP) management with co-existing acute coronary syndrome (ACS) remains challenging as it requires a clinically relevant balance between the risk and outcomes of thrombosis and the risk of bleeding. However, the literature evaluating the treatment approaches in this high-risk population is scarce. In this review, we aimed to summarize the available literature on the safety of ITP first- and second-line therapies to provide a practical guide on the management of ITP co-existing with ACS. We recommend holding antithrombotic therapy, including antiplatelet agents and anticoagulation, in severe thrombocytopenia with a platelet count < 30 × 109/L and using a single antiplatelet agent when the platelet count falls between 30 and 50 × 109/L. We provide a stepwise approach according to platelet count and response to initial therapy, starting with corticosteroids, with or without intravenous immunoglobulin (IVIG) with a dose limit of 35 g, followed by thrombopoietin receptor agonists (TPO-RAs) to a target platelet count of 200 × 109/L and then rituximab. Our review may serve as a practical guide for clinicians in the management of ITP co-existing with ACS.

The Challenge for a Correct Diagnosis of Refractory Thrombocytopenia: ITP or MDS with Isolated Thrombocytopenia?

Immune thrombocytopenia (ITP) is an autoimmune disease characterized by isolated thrombocytopenia. It is diagnosed in patients with a platelet count below 100,000 per cubic millimeter in whom other causes of thrombocytopenia have been ruled out, and its diagnosis is generally one of exclusion. Clinical manifestations of patients may vary from asymptomatic disease to mild mucocutaneous or life-threatening bleeding. Glucocorticoids are used as first-line treatment for ITP, while other second-line medications, mainly thrombopoietin-receptor agonists (TPO-RA) and rituximab, are given to patients in whom ITP does not remit, or relapses soon after glucocorticoid treatment. Refractoriness of ITP strongly questions its diagnosis and necessitates a thorough clinical and laboratory work-up to decide whether that is the case of refractory ITP or a misdiagnosis. The aim of this review is to summarize the conditions associated with isolated thrombocytopenia and highlight the characteristics of confusing cases. Even though the case of a myelodysplastic syndrome presented with isolated thrombocytopenia (MDS-IT) is relatively rare and not well-established in the literature, it constitutes one of the most predominant misdiagnoses of refractory ITP. MDS-IT patients are thought to present with multilineage dysplasia, normal karyotype and low risk prognostic score, based on IPSS-R. It has been shown that a significant proportion of MDS-IT patients are misdiagnosed as having the more common ITP. Therefore, it is crucial that in confusing cases of persistent thrombocytopenia a detailed diagnostic work-up is applied-including evaluation of peripheral-blood smear, bone marrow examination and cytogenetic testing-to avoid unnecessary therapy delay.

Platelet-derived TGF-β1 induces functional reprogramming of myeloid-derived suppressor cells in immune thrombocytopenia

AbstractPlatelet α-granules are rich in transforming growth factor β1 (TGF-β1), which is associated with myeloid-derived suppressor cell (MDSC) biology. Responders to thrombopoietin receptor agonists (TPO-RAs) revealed a parallel increase in the number of both platelets and MDSCs. Here, anti-CD61 immune-sensitized splenocytes were transferred into severe combined immunodeficient mice to establish an active murine model of immune thrombocytopenia (ITP). Subsequently, we demonstrated that TPO-RAs augmented the inhibitory activities of MDSCs by arresting plasma cells differentiation, reducing Fas ligand expression on cytotoxic T cells, and rebalancing T-cell subsets. Mechanistically, transcriptome analysis confirmed the participation of TGF-β/Smad pathways in TPO-RA–corrected MDSCs, which was offset by Smad2/3 knockdown. In platelet TGF-β1–deficient mice, TPO-RA-induced amplification and enhanced suppressive capacity of MDSCs was waived. Furthermore, our retrospective data revealed that patients with ITP achieving complete platelet response showed superior long-term outcomes compared with those who only reach partial response. In conclusion, we demonstrate that platelet TGF-β1 induces the expansion and functional reprogramming of MDSCs via the TGF-β/Smad pathway. These data indicate that platelet recovery not only serves as an end point of treatment response but also paves the way for immune homeostasis in immune-mediated thrombocytopenia.

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.

Challenges in treating primary immune thrombocytopenia patients undergoing COVID-19 vaccination: A retrospective study.

Since the outbreak of COVID-19 in December 2019, countries around the world, including China, have been administering COVID-19 vaccines in response to the pandemic. Our center has observed that treating patients with primary immune thrombocytopenia (ITP) has become more challenging in this context. This study compared the treatment response of 25 de novo ITP patients who had received a COVID-19 vaccination (Group 1) with an equal number of de novo ITP patients randomly selected from the 2 years prior to the COVID-19 pandemic (Group 2) by using the Mann-Whitney U test and Fisher's exact. Patients in both groups had predominantly female gender with similar age and baseline platelet counts. However, on Day 3, the median platelets were 22 and 49 × 109/L, and on Day 7, they were 74 and 159 × 109/L, respectively (P < 0.05). Compared to Group 2, Group 1 showed a suboptimal short-term response to glucocorticoid monotherapy, with a higher proportion of patients requiring combination therapy with other drugs including intravenous immunoglobulin, thrombopoietin receptor agonists, and rituximab. After subgroup analysis, a significant difference was observed in the proportion of patients requiring second-line therapy between the two groups. Our study suggests that COVID-19 vaccination may lead to a lower response rate to first-line treatment in de novo ITP patients. Nevertheless, it is crucial to acknowledge the inherent limitations in this conclusion. Further studies are needed to confirm these findings and investigate the underlying mechanisms.

Abstract 1381: Characterization of the 12-lipoxygenase expression in the megakaryoblastic cell line, Dami

Abstract Megakaryocytes are myeloid cells produced primarily in the bone marrow and are best known for releasing platelets in the blood stream. In the platelet production process, megakaryocytes transfer their bioactive content, including the 12-lipoxygenase (12-LO) enzyme, into newly formed platelets. The 12-LO has been shown to be implicated in platelet activation and is overexpressed in several chronic inflammatory conditions, including several types of cancers. The 12-LO is responsible for the conversion of the arachidonic acid into the 12(S)-hydroxyeicosatetraenoic acid (12(S)-HETE), a key lipid mediator implicated in several steps of the metastatic cascade. While 12-LO is expressed in mature human megakaryocytes, we recently identified two megakaryoblast cell lines isolated from leukemia patients lacking 12-LO expression. However, only one of the two cell lines expresses functional 12-LO protein upon megakaryocyte maturation. The goal of this study is to characterize the 12-LO expression during the megakaryocyte maturation process. We hypothesize that 12-LO expression is increased during cell maturation and that inhibition of the 12-LO expression will result in dysfunctional platelets. Both the Dami cell and MEG-01 cells were induced with the co-incubation of both phorbol myristate acetate and eltrombopag, a thrombopoietin receptor agonist. The maturation and viability of the cells were confirmed by flow cytometry. Expression of the 12-LO was assessed by RT-qPCR and immunoblot. Quantification of the 12(S)-HETE was performed by reversed-phase high performance liquid chromatography. Platelet release was quantified by flow cytometry using CD41 fluorescent labelled antibodies. We observed a 3-fold increase in 12-LO protein expression following cell maturation in the Dami cell line. Interestingly, mRNA expression between the undifferentiated Dami cells and mature Dami cells remained unchanged. Furthermore, we did not detect any 12-LO protein expression in the MEG-01 after the cell’s maturation. Finally, we identified a specific 12-LO antisens non-coding RNA that is implicated in the regulation of the protein expression in megakaryocytes. Our study reports the first mechanistic regulation of 12-LO expression implicated in the megakaryocyte maturation process. Since both platelets and platelet-specific 12-LO play an important role in cancer biology, it is important to better understand how megakaryocytes package the enzyme inside these small cells. It remains elusive whether 12-LO enrichment in platelet correlates with the disease severity. Citation Format: Luc H. Boudreau, Vanessa L. Gauvin, Jaël Richard, Marie-France N. Soucy, Mathieu P.A. Hébert, Eric P. Allain. Characterization of the 12-lipoxygenase expression in the megakaryoblastic cell line, Dami [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1381.

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.

Treatment of refractory/relapsed Diamond-Blackfan anaemia with eltrombopag.

Diamond-Blackfan anaemia (DBA) is a rare, inherited bone marrow failure syndrome with a ribosomal defect causing slowed globin chain production with normal haem synthesis, causing an overabundance of reactive iron/haem and erythroid-specific cellular toxicity. Eltrombopag, a non-peptide thrombopoietin receptor agonist, is a potent intracellular iron chelator and induced a robust durable response in an RPS19-mutated DBA patient on another trial. We hypothesized eltrombopag would improve RBC production in DBA patients. We conducted a single-centre, single-arm pilot study (NCT04269889) assessing safety and erythroid response of 6 months of daily, fixed-dose eltrombopag for DBA patients. Fifteen transfusion-dependent (every 3-5 weeks) patients (median age 18 [range 2-56]) were treated. One responder had sustained haemoglobin improvement and >50% reduction in RBC transfusion frequency. Of note, 7/15 (41%) patients required dose reductions or sustained discontinuation of eltrombopag due to asymptomatic thrombocytosis. Despite the low response rate, eltrombopag has now improved erythropoiesis in several patients with DBA with a favourable safety profile. Dosing restrictions due to thrombocytosis may cause insufficient iron chelation to decrease haem production and improve anaemia in most patients. Future work will focus on erythropoiesis dynamics in patients and use of haem synthesis inhibitors without an impact on other haematopoietic lineages.

Impurity assessment, development and validation of an RP-HPLC method for the determination of eleven potential impurities of eltrombopag precursor

Eltrombopag is an oral non-peptide thrombopoietin receptor (TPO-R) agonist indicated for the treatment of thrombocytopenia in patients with persistent or chronic immune thrombocytopenia (idiopathic thrombocytopenic purpura, ITP) or chronic hepatitis C infection and the treatment of severe aplastic anemia. The purpose of this research was to assess the possible impurities that may carry over to eltrombopag from its precursor Eltro-1 (3′-amino-2′-hydroxy-[1,1′-biphenyl]-3-carboxylic acid) and to develop a specific analytical method for the determination of these impurities. Eltro-1 samples synthesized by two different synthesis routes were investigated during the evaluation and method development studies. Besides the expected process-related impurities (Eltro-1A – Eltro‐1J), e.g., starting materials, intermediates, and/or compounds formed from their further reactions, an unknown impurity detected above 0.10% was identified by LC-MS, synthesized and fully characterized by NMR, MS and FTIR (Eltro‐1K). Accordingly, an HPLC-RP method for the determination of eleven impurities (Eltro-1A – Eltro‐1K) in Eltro-1 was developed and validated according to ICH Q2. The control limits for impurities in Eltro-1 were set at ≤ 0.15% for Eltro-1A – Eltro‐1J and ≤ 1.0% for Eltro‐1K based on fate, spike-purge and carryover studies and in accordance with the ICH M7 classification for impurities in drug substance. Eltro-1 and eleven impurities at the specification limit were separated from each other and the diluent peaks with sufficient resolution without interference. Separation was performed on a Waters XBridge C18 column (150 × 4.6 mm, 3.5 μm) at 40 °C with a 10 µL injection volume at a detection wavelength of 220 nm and 15 °C sample temperature. The gradient elution is performed at a flow rate of 1.0 mL/min for 40 min with mobile phase A (0.1% orthophosphoric acid in water) and B (acetonitrile) according to the following program: Time (min) / Acetonitrile (%): 0/0, 35/70, 36/0, 40/0. Test and standard solutions were prepared at a concentration of 1.0 mg/mL and 1.0 µg/mL, respectively, using a mixture of mobile phase A and acetonitrile (75/25) as diluent. This is the first specific, selective, sensitive, linear, precise, accurate, and robust HPLC method for the determination of Eltro-1A – Eltro‐1K in Eltro-1, which showed no significant degradation under thermal stress, photostability (UV and VIS), and standard accelerated and long-term stability conditions.

Cytotoxic T lymphocyte‐associated antigen‐4 (CTLA-4) gene polymorphisms in a cohort of Egyptian patients with immune thrombocytopenia (ITP)

BackgroundImmune thrombocytopenia (ITP) is characterized by immune response dysregulations. Cytotoxic T lymphocyte‐associated antigen‐4 (CTLA‐4) plays a central role in immune checkpoint pathways and preventing autoimmune diseases by regulating immune tolerance. We aimed to explore the potential association between CTLA-4 gene polymorphisms and ITP as well as study their impact on the response to therapy.MethodsWe investigated two CTLA-4 single‐nucleotide polymorphisms (SNPs; rs: 231775 and rs: 3087243) using real-time PCR as well as the plasma levels of CTLA-4 by ELISA in 88 patients with ITP and 44 healthy participants (HC).ResultsCTLA-4 (rs: 3087243) A > G polymorphism analysis showed most HC had the homozygous AA genotype, which was statistically significant compared to patients with ITP. Plasma levels of CTLA4 were statistically lower in patients with acute ITP. There was no correlation between CTLA-4 (rs: 231775 and rs: 3087243) A/G SNPs were not correlated to the response to all lines of therapy assessed (corticosteroids, thrombopoietin receptor agonists, splenectomy, and rituximab).ConclusionCTLA-4 CT 60 A/G may affect the susceptibility of ITP, but both CTLA-4 + 49 A/G and CT60 A/G did not impact the response of patients with ITP to different lines of therapy.

Rapid, Simple and Low-Cost Analytical Method Development for Quantification of Eltrombopag Olamine in Tablet Dosage by UV Spectroscopy Method.

Eltrombopag Olamine is a drug used to treat thrombocytopenia, a disorder where blood platelet counts get lower and severe aplastic anemia. It serves as a thrombopoietin receptor agonist, which give rise to platelet production in the bone marrow. The objective of this study is to develop a simple, specific, accurate, precise and economical Ultraviolet spectroscopy method to estimate the amount of Eltrombopag Olamine in bulk and tablet dosage form. The developed method was performed using methanol for identification and physicochemical characterization of the drug. The validation parameters like linearity, precision, accuracy, robustness limits of detection and quantitation, and specificity were assessed as per ICH Q2 (R2). The maximum absorbance wavelength (λmax) of the drug was found at 247 nm in methanol. The linearity was found in the concentration range of 2-14 μg/ml with regression equation y = 0.0619x - 0.0123 and r² = 0.999. The standard addition method was used to determine the accuracy of the developed method. The result was found in the % recovery range of 98-99%. The precision was done on λmax with respect to the parameters such as repeatability, intraday, and interday. The method was found to be precise as the % RSD value was found to be <2%. The detection limit value (LOD) and quantitation limit value (LOQ) were 0.0524 μg/ml and 0.1588 μg/ml, respectively. The developed method is simple, economical, accurate and selective. The developed method was adaptable for the estimation of Eltrombopag Olamine analysis in pharmaceutical dosage form and routine quality control laboratory.

Chronic liver disease-associated severe thrombocytopenia in Spain: Results from a retrospective study using machine learning and natural language processing

BackgroundPatients with chronic liver disease (CLD) often develop thrombocytopenia (TCP) as a complication. Severe TCP (platelet count<50×109/L) can increase morbidity and complicate CLD management, increasing bleeding risk during invasive procedures. ObjectivesTo describe the real-world scenario of CLD-associated severe TCP patients’ clinical characteristics. To evaluate the association between invasive procedures, prophylactic treatments, and bleeding events in this group of patients. To describe their need of medical resource use in Spain. MethodsThis is a retrospective, multicenter study including patients who had confirmed diagnosis of CLD and severe TCP in four hospitals within the Spanish National Healthcare Network from January 2014 to December 2018. We analyzed the free-text information from Electronic Health Records (EHRs) of patients using Natural Language Processing (NLP), machine learning techniques, and SNOMED-CT terminology. Demographics, comorbidities, analytical parameters and characteristics of CLD were extracted at baseline and need for invasive procedures, prophylactic treatments, bleeding events and medical resources used in the follow up period. Frequency tables were generated for categorical variables, whereas continuous variables were described in summary tables as mean (SD) and median (Q1–Q3). ResultsOut of 1,765,675 patients, 1787 had CLD and severe TCP; 65.2% were male with a mean age of 54.7 years old. Cirrhosis was detected in 46% (n=820) of patients and 9.1% (n=163) had hepatocellular carcinoma. Invasive procedures were needed in 85.6% of patients during the follow up period. Patients undergoing procedures compared to those patients without invasive procedures presented higher rates of bleeding events (33% vs 8%, p<0.0001) and higher number of bleedings. While prophylactic platelet transfusions were given to 25.6% of patients undergoing procedures, TPO receptor agonist use was only detected in 3.1% of them. Most patients (60.9%) required at least one hospital admission during the follow up and 14.4% of admissions were due to bleeding events with a hospital length of stay of 6 (3, 9) days. ConclusionsNLP and machine learning are useful tools to describe real-world data in patients with CLD and severe TCP in Spain. Bleeding events are frequent in those patients who need invasive procedures, even receiving platelet transfusions as a prophylactic treatment, increasing the further use of medical resources. Because that, new prophylactic treatments that are not yet generalized, are needed.

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.

Progress in medical therapy in aplastic anemia: why it took so long?

The treatment of aplastic anemia (AA) has significantly advanced in the last 50years, evolving from a fatal condition to one where survival rates now exceed 80-85%. Hematopoietic stem cell transplantation (HSCT) and immunosuppressive therapy (IST) have become the primary treatments, with the latter widely adopted due to factors like the scarcity of compatible donors, patient age, comorbidities, and limited HSCT access. A therapy breakthrough was the introduction of antithymocyte globulin (ATG), with its effectiveness further boosted by cyclosporine. However, it took years to achieve another major milestone in management. Initially, treatments aimed to intensify immunosuppression following the success of the ATG-cyclosporine combination, but these methods fell short of expectations. A major turning point was combining immunosuppression with stem cell stimulation, surpassing the efficacy of IST alone. Earlier, growth factors had shown limited success in AA treatment, but thrombopoietin receptor agonists represented a significant advancement. Initially applied alone as salvage, these were later combined with IST, forming the most effective current regimen for medically managing SAA. Horse ATG is the preferred formulation combined with cyclosporine and eltrombopag. This progress in AA treatment offers improved outcomes for patients afflicted with this once-lethal disease.

Long-term treatment with rilzabrutinib in patients with immune thrombocytopenia

AbstractImmune thrombocytopenia (ITP) is an autoimmune disease associated with autoantibody-mediated platelet destruction and impaired platelet production, resulting in thrombocytopenia and a predisposition to bleeding. The ongoing, global phase 1/2 study showed that rilzabrutinib, a Bruton tyrosine kinase inhibitor specifically developed to treat autoimmune disorders, could be an efficacious and well-tolerated treatment for ITP. Clinical activity, durability of response, and safety were evaluated in 16 responding patients who continued rilzabrutinib 400 mg twice daily in the long-term extension (LTE) study. At LTE entry, the median platelet count was 87 × 109/L in all patients, 68 × 109/L in those who had rilzabrutinib monotherapy (n = 5), and 156 × 109/L in patients who received concomitant ITP medication (thrombopoietin-receptor agonists and/or corticosteroids, n = 11). At a median duration of treatment of 478 days (range, 303-764), 11 of 16 patients (69%) continued to receive rilzabrutinib. A platelet count of ≥50 × 109/L was reported in 93% of patients for more than half of their monthly visits. The median percentage of LTE weeks with platelet counts ≥30 × 109/L and ≥50 × 109/L was 100% and 88%, respectively. Five patients discontinued concomitant ITP therapy and maintained median platelet counts of 106 × 109/L at 3 to 6 months after stopping concomitant ITP therapy. Adverse events related to treatment were grade 1 or 2 and transient, with no bleeding, thrombotic, or serious adverse events. With continued rilzabrutinib treatment in the LTE, platelet responses were durable and stable over time with no new safety signals. This trial is registered at www.clinicaltrials.gov as #NCT03395210 and www.clinicaltrialsregister.eu as EudraCT 2017-004012-19.

Efficacy and safety of avatrombopag in Chinese children with persistent and chronic primary immune thrombocytopenia: A multicentre observational retrospective study in China.

Avatrombopag (AVA) is a novel thrombopoietin receptor agonist (TPO-RA) that has been recently approved as a second-line therapy for immune thrombocytopenia (ITP) in adults; however, its safety and efficacy data in children are lacking. Here, we demonstrated the efficacy and safety of AVA as second-line therapy in children with ITP. A multicentre, retrospective, observational study was conducted in children with persistent or chronic ITP who did not respond to or relapsed from previous treatment and were treated with AVA for at least 12 weeks between August 2020 and December 2022. The outcomes were the responses (defined as achieving a platelet count ≥30 × 109/L, twofold increase in platelet count from baseline and absence of bleeding), including rapid response within 4 weeks, sustained response at weeks 12 and 24, bleeding control and adverse events (AEs). Thirty-four (18 males) patients with a mean age of 6.3 (range: 1.9-15.3) years were enrolled. The median number of previous treatment types was four (range: 1-6), and 41.2% patients switched from other TPO-RAs. Within 4 weeks, overall response (OR) was achieved in 79.4% patients and complete response (CR, defined as a platelet count ≥100 × 109/L and the absence of bleeding) in 67.7% patients with a median response time of 7 (range: 1-27) days. At 12 weeks, OR was achieved in 88.2%, CR in 76.5% and sustained response in 44% of patients. At 24 weeks, 22/34 (64.7%) patients who achieved a response and were followed up for 24 weeks were evaluated; 12/22 (54.55%) achieved a sustained response. During AVA therapy, median platelet counts increased by week 1 and were maintained throughout the treatment period. The proportion of patients with grade 1-3 bleeding decreased from 52.95% at baseline to 2.94% at 12 weeks, while concomitant ITP medications decreased from 36.47% at baseline to 8.82% at 12 weeks, with only 9 (26.47%) patients receiving rescue therapy 23 times within 12 weeks. There were 61.8% patients with 59 AEs: 29.8% with Common Terminology Criteria for Adverse Events grade 1 and the rest with grade 2. These findings show that AVA could achieve a rapid and sustained response in children with persistent or chronic ITP as a second-line treatment, with good clinical bleeding control and reduction of concomitant ITP therapy, without significant AEs.

Thrombopoietin receptor agonist and rituximab combination therapy in patients with refractory primary immune thrombocytopenia.

The aim of our study was to evaluate the efficacy of this therapy in patients with refractory primary immune thrombocytopenia. It is crucial to develop alternative treatment methods for this patient group in order to achieve better response. This combination therapy combines two different mechanisms of action, which is promising in terms of targeting pathophysiology of immune thrombocytopenia. We conducted a retrospective study, which included all patients who were diagnosed with refractory primary immune thrombocytopenia and received TPO-RA and rituximab at the General Hematology Department, Copernicus Memorial Hospital in Lodz, Poland. We assessed the response, time to response and treatment-free remission (TFR). After 1 month of treatment, the complete response (CR1, PLT >100 g/l) was achieved in 62.5% patients, and response (R1, PLT >30 g/l) was achieved in 62.5% patients. The median PLT was 175 × 10 9 /l. Within 1 month of treatment, 87.5% of patients achieved TFR. Adequately, after 6 months, CR6 and R6 was 62.5 and 75%. The median PLT was 182 × 10 9 /l. Treatment-free remission 6 months after completion was in 50% of patients. The study group achieved response to treatment, which suggests that combination of TPO-RA and rituximab is effective and relatively well tolerated. Prospective study on larger group of patients is needed to better evaluate the efficiency and safety of this treatment.

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.

Epidemiology and Management of Immune Thrombocytopenia in Adult Patients in Algeria: A Non-interventional, Longitudinal, Nationwide Estimation Study

Introduction: Globally, immune thrombocytopenia (ITP) affects more women than men with a higher incidence in older patients. However, data on the epidemiology and treatment regimen for ITP is limited and varies across different countries. In this non-interventional, longitudinal, nationwide estimation study, we present incidence (by age, sex, and diagnosis stage), prevalence, characteristics, and treatment regimens of ITP in Algeria.Methods: Patients ≥16 years of age with prevalent (diagnosed before September 3, 2017) or incident (diagnosed between September 3, 2017–August 30, 2018) ITP were involved in this study. Patient data were collected from public hospitals and the incidence and prevalence estimates were made using Poisson distributions (95% confidence interval [CI]). Results: Of 1,746 patients from 16 hematology departments, 1,159 were included in the study; 173 (14.9%) were incident and 986 (85.1%) were prevalent patients with ITP. The median (quartiles) age of patients at diagnosis was 36 (25, 50) years; 895 (77.2%) were women. At inclusion, 88.2% of patients were asymptomatic and 3.8% had severe bleeding. The national incidence was 0.85 (0.75–0.96) and prevalence was 5.65 (5.39–5.93) per 100,000 population. The incidence of ITP in women (1.18 [1.02–1.37]/100,000 population) was higher versus men (0.54 [0.43–0.67]/ 100,000 population). The incidence of ITP was four times higher in the ≥75 years cohort (2.37 [1.60–3.51]/100,000 population) versus that observed in the 15–35-years age cohort (0.54 [0.43–0.68]/100,000 population). First-line treatments included corticosteroids (80.8%), intravenous immunoglobulin (3.4%), and rituximab (1.3%); 17.4% of patients underwent splenectomy as a third-line procedure. Conclusion: The overall incidence rate of ITP in Algeria was low. However, the incidence trends are similar to those reported globally, with high incidence reported in women and older patients. Corticosteroids were the most prescribed therapy, and few patients were prescribed thrombopoietin receptor agonists before opting for splenectomy.