Thrombopoietin Receptor Agonist Research Articles

The long-term outcomes and safety of severe aplastic anemia treated with porcine antilymphocyte globulin plus cyclosporine, with or without thrombopoietin receptor agonists: a double-center retrospective study

ABSTRACT Background Porcine antilymphocyte globulin (p-ALG) combined with cyclosporine (CsA) has been commonly used for severe aplastic anemia (SAA) patients, but few studies on the combination of p-ALG and thrombopoietin receptor agonist (TPO-RA). Research design and methods We retrospectively analyzed the data of 85 people with diagnosed SAA who underwent p-ALG plus CsA, with or without TPO-RA from 2014 to 2023. Results The overall response rates were 55.3% and 65.9% at 3 and 6 months, and the TPO-RA group were 66.7% and 72.3% at 3 and 6 months, without TPO-RA group were 27.8% and 55.6%. In multivariate analysis, baseline platelet count of > 10×109/L was a simple predictor of favorable response at 6 months (p = 0.015). The median follow-up time for all patients was 39 months (range 0.4 ~ 104), the 5-year overall survival (OS) rate was 90.6% [95% CI = 82.1–95.2%], and the failure-free survival (FFS) rate was 68.9% [95% CI = 56.6–78.4%]. Having hematologic responses in 6 months was an independent positive predictor for FFS(p = 0.000). 12 patients (14.1%) suffered from serum sickness, and 9.5% of patients had mild hepatic impairment. Conclusions p-ALG along with CsA is an effective choice for patients with SAA. p-ALG combined with TPO-RA may contribute to the early restoration of hematopoiesis.

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.

Thrombopoietin mimetic stimulates bone marrow vascular and stromal niches to mitigate acute radiation syndrome

BackgroundAcute radiation syndrome (ARS) manifests after exposure to high doses of radiation in the instances of radiologic accidents or incidents. Facilitating regeneration of the bone marrow (BM), namely the hematopoietic stem and progenitor cells (HSPCs), is key in mitigating ARS and multi-organ failure. JNJ-26366821, a PEGylated thrombopoietin mimetic (TPOm) peptide, has been shown as an effective medical countermeasure (MCM) to treat hematopoietic-ARS (H-ARS) in mice. However, the activity of TPOm on regulating BM vascular and stromal niches to support HSPC regeneration has yet to be elucidated.MethodsC57BL/6J mice (9–14 weeks old) received sublethal or lethal total body irradiation (TBI), a model for H-ARS, by 137Cs or X-rays. At 24 h post-irradiation, mice were subcutaneously injected with a single dose of TPOm (0.3 mg/kg or 1.0 mg/kg) or PBS (vehicle). At homeostasis and on days 4, 7, 10, 14, 18, and 21 post-TBI with and without TPOm treatment, BM was harvested for histology, BM flow cytometry of HSPCs, endothelial (EC) and mesenchymal stromal cells (MSC), and whole-mount confocal microscopy. For survival, irradiated mice were monitored and weighed for 30 days. Lastly, BM triple negative cells (TNC; CD45−, TER-119−, CD31−) were sorted for single-cell RNA-sequencing to examine transcriptomics after TBI with or without TPOm treatment.ResultsAt homeostasis, TPOm expanded the number of circulating platelets and HSPCs, ECs, and MSCs in the BM. Following sublethal TBI, TPOm improved BM architecture and promoted recovery of HSPCs, ECs, and MSCs. Furthermore, TPOm elevated VEGF-C levels in normal and irradiated mice. Following lethal irradiation, mice improved body weight recovery and 30-day survival when treated with TPOm after 137Cs and X-ray exposure. Additionally, TPOm reduced vascular dilation and permeability. Finally, single-cell RNA-seq analysis indicated that TPOm increased the expression of collagens in MSCs to enhance their interaction with other progenitors in BM and upregulated the regeneration pathway in MSCs.ConclusionsTPOm interacts with BM vascular and stromal niches to locally support hematopoietic reconstitution and systemically improve survival in mice after TBI. Therefore, this work warrants the development of TPOm as a potent radiation MCM for the treatment of ARS.

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

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. 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. 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 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 a 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). 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.

Herombopag for the treatment of persistent thrombocytopenia following hematopoietic stem cell transplantation.

Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) stands as a pivotal treatment for hematologic malignancies, often considered the sole effective treatment option. A frequent complication following allo-HSCT is poor graft function (PGF), with one of its primary manifestations being persistent thrombocytopenia (PT), comprising prolonged isolated thrombocytopenia (PIT) and secondary failure of platelet recovery (SFPR). Conventional treatment methods have had poor efficacy and a high transplantation-associated mortality rate. In recent years, the efficacy of eltrombopag has been reported in the treatment of post-transplantation PT, and additional thrombopoietin receptor agonists (TPO-RA) have been developed. Herombopag is a next-generation TPO-RA which has strong proliferation-promoting effects on human TPO-R-expressing cells (32D-MPL) and hematopoietic progenitor cells in vitro. We reviewed eighteen patients with transplantation-associated thrombocytopenia who received herombopag when eltrombopag was ineffective or poorly tolerated and evaluated its efficacy including effects on survival. Herombopag was administered at a median time of 197 days post-transplantation. Six patients achieved complete response (CR), with a median time to CR of 56 days. Five patients achieved partial response (PR), and the median time to PR was 43 days. Seven patients were considered to have no response (NR). The overall response (OR) rate was 61.1%, and the cumulative incidence (CI) of OR was 90.2%. No patients developed herombopag-associated grade 3-4 toxicity. The median follow-up period was 6.5 months. Twelve patients survived and six patients died, with an overall survival rate of 66.7%. This is the first study to demonstrate the efficacy and safety of herombopag in transplantation-associated thrombocytopenia after failing eltrombopag, introducing a new approach in the treatment of PT following allo-HSCT.

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.

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.

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.