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.

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). Twelve 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.

Essential thrombocythaemia: A contemporary approach with new drugs on the horizon.

Essential thrombocythaemia (ET) is a myeloproliferative neoplasm characterized by an increased risk of vascular complications and a tendency to progress to myelofibrosis and acute leukaemia. ET patients have traditionally been stratified into two thrombosis risk categories based on age older than 60 years and a history of thrombosis. More recently, the revised IPSET-thrombosis scoring system, which accounts for the increased risk linked to the JAK2 mutation, has been incorporated into most expert recommendations. However, there is increasing evidence that the term ET encompasses different genomic entities, each with a distinct clinical course and prognosis. Moreover, the effectiveness and toxicity of cytoreductive and anti-platelet treatments differ depending on the molecular genotype. While anti-platelets and conventional cytoreductive agents, mainly hydroxycarbamide (hydroxyurea), anagrelide and pegylated interferon, remain the cornerstone of treatment, recent research has shed light on the effectiveness of novel therapies that may help improve outcomes. This comprehensive review focuses on the evolving landscape of treatment strategies in ET, with an emphasis on the role of molecular profiling in guiding therapeutic decisions. Besides evidence-based management according to revised IPSET-thrombosis stratification, we also provide specific observations for those patients with CALR-, MPL-mutated and triple-negative ET, as well as cases with high-risk mutations.

Thrombopoietin Receptor Agonists and Other Second-Line Therapies for Immune Thrombocytopenia: A Narrative Review With a Focus on Drug Access in Canada.

INTRODUCTION: Immune thrombocytopenia (ITP) is an autoimmune disease characterized by low platelet counts and increased risk of bleeding. After corticosteroids with or without intravenous immune globulin (first-line treatment), second-line treatment options include rituximab, splenectomy, thrombopoietin receptor agonists (TPO-RAs), and fostamatinib. In Canada, the choice of second-line therapy is influenced by access to medications. The goals of this narrative review are to 1) summarize the evidence for the use of TPO-RAs and other second-line therapies in ITP and 2) highlight differences in public funding criteria for TPO-RAs across provinces and territories in Canada. METHODS: We conducted a literature review of second-line therapies for ITP. We solicited information on public funding programs for TPO-RAs in Canada from health care providers, pharmacists, and provincial ministries of health. RESULTS: Head-to-head trials involving TPO-RAs, rituximab, splenectomy, and fostamatinib are lacking. There is substantial evidence of effect for TPO-RAs in improving platelet count levels, health-related quality of life, bleeding, and fatigue from placebo-controlled trials and observational studies; however, access to TPO-RAs through provincial funding programs in Canada is variable. Splenectomy failure is a prerequisite for the funding of TPO-RAs in Ontario, Manitoba, and Saskatchewan, but not in Alberta or Quebec. Other provinces either do not have access to public funding or funding is provided on a case-by-case basis. DISCUSSION: TPO-RAs are effective second-line therapies for the treatment of ITP; however, access is variable across Canada, which results in health disparities and poor uptake of international treatment guidelines.

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.

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.

The problem of immune thrombocytopenia refractory to both eltrombopag and romiplostim.

Immune thrombocytopenia refractory to multiple thrombopoietin receptor agonists remains a challenging clinical problem. This commentary discusses and contextualizes the recent report on this entity from Moulis and colleagues, and how to move forward with these patients. Commentary on: Moulis et al. Difficult-to-treat primary immune thrombocytopenia in adults: Prevalence and burden. Results from the CARMEN-France Registry. Br J Haematol 2024;204:1476-1482.

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.

Face validity of the Kids' ITP Tools (KIT) in the era of thrombopoietin receptor agonists.

The Kids' ITP Tools (KIT) is a questionnaire to assess quality of life of children with immune thrombocytopenia (ITP). The aim of this study was to update this previously validated tool to align with changes in clinical practice, specifically, treatment with thrombopoietin receptor agonists (TPO-RAs). Children aged 1-18 with ITP and/or their families were recruited to participate in interviews to review the KIT. Twenty-six interviews were conducted. Based on interview data from children and families, current guidelines, and expert opinion, five changes were made to the KIT in order to improve its face validity.

Optimal management of chemotherapy-induced thrombocytopenia with thrombopoietin receptor agonists.

Chemotherapy-induced thrombocytopenia (CIT) is a common complication of antineoplastic therapy, resulting in antineoplastic therapy dose reductions, treatment delays, treatment discontinuation, and morbid bleeding events. Despite several decades of research into thrombopoietic growth factors in CIT, there are presently no available U.S. FDA- or EMA-approved agents to treat CIT. However, a respectable body of evidence has been published evaluating the thrombopoietin receptor agonists (TPO-RAs) for the management and prevention of CIT in patients with solid tumors, and critical studies are ongoing with the TPO-RAs romiplostim and avatrombopag. When employed in the appropriate patient population and used properly, TPO-RAs can successfully and safely manage CIT for extended periods of time with minimal apparent risks. This comprehensive review discusses the evidence for TPO-RAs in CIT in patients with solid tumors, provides detailed guidance for their use in the clinic, and discusses ongoing essential clinical trials in management of CIT.

Efficacy and safety of thrombopoietin receptor agonists in solid tumors with chemotherapy-induced thrombocytopenia: a meta-analysis.

OBJECTIVE: To evaluate the efficacy and safety of thrombopoietin receptor agonists (TPO-RAs) in solid tumors with chemotherapy-induced thrombocytopenia (CIT). METHODS: We conducted a comprehensive search of PubMed, FMRS, Cochrane Library, Web of Science, EMBASE, and ClinicalTrials.gov for randomized controlled trials (RCTs) reporting the efficacy and safety of TPO-RAs in solid tumors with CIT. The search was limited to articles published before April 30, 2022. Primary outcomes included chemotherapy dose reduction or delays, platelet transfusion, the incidence of grade 3 or 4 thrombocytopenia, and bleeding events. Secondary outcomes encompassed the incidence of platelet count > 400 × 109/L, adverse events (AEs), serious AEs, thrombosis, and mortality. RESULTS: Our analysis encompassed six studies: five rigorous RCTs and one unique study comparing romiplostim to an observation group, involving a total of 489 patients. For primary outcomes, TPO-RAs significantly reduced the incidence of grade 3 or 4 thrombocytopenia (RR = 0.69, 95% CI: 0.52-0.91). After applying the Bonferroni correction for multiple comparisons, the significance of the reduction in grade 3 or 4 thrombocytopenia incidence persisted (P = 0.008). TPO-RAs showed no significant impact on chemotherapy dose reduction or delays (RR = 0.81, 95% CI: 0.65-1.01), platelet transfusion (RR = 1.04, 95% CI: 0.48-2.27), or bleeding events (RR = 0.50, 95% CI: 0.23-1.10). In terms of safety, there were no significant difference in the incidence of any AEs (RR = 0.98, 95% CI:0.92-1.04), serious AEs (RR = 0.79, 95% CI:0.45-1.40), thrombotic events (RR = 1.20, 95% CI:0.51-2.84) and mortality (RR = 1.15, 95% CI:0.55-2.41). CONCLUSIONS: This meta-analysis suggests that TPO-RAs are generally well-tolerated. However, their efficacy in solid tumors with CIT appears limited, as they only demonstrate a reduction in the incidence of grade 3 or 4 thrombocytopenia.

Immune thrombocytopenia secondary to primary cytomegalovirus infection after renal transplantation treated with a thrombopoietin receptor agonist: a case report.

BACKGROUND: Immune thrombocytopenia (ITP) is an acquired disorder characterised by a low platelet count due to immune-mediated destruction and impaired platelet production. Here we report a rare case of primary cytomegalovirus (CMV) infection followed by thrombocytopenia after renal transplantation (RT). CASE PRESENTATION: A 24-year-old male patient with end-stage kidney disease secondary to hereditary focal segmental glomerulosclerosis was treated with peritoneal dialysis and received ABO-compatible living-related RT from his aunt. Nine months after the RT, the patient was diagnosed with primary CMV infection. After initiating treatment for primary CMV infection, the patient developed thrombocytopenia. After excluding other diseases or drugs that may cause thrombocytopenia, the patient was finally diagnosed with ITP, administered prednisolone (PSL), and started on Helicobacter pylori eradication therapy. Tapering the PSL dose was difficult, but thrombopoietin receptor agonists (TPO-RAs) were effective. CONCLUSIONS: In this case, the patient was diagnosed with ITP, and other causes of thrombocytopenia after RT were successfully ruled out. This case report demonstrates that RT recipients can develop ITP after CMV infection, and, in such cases, TPO-RAs may be an attractive option as a second-line therapy.

Markers of refractory primary immune thrombocytopenia.

Refractory immune thrombocytopenia (ITP) is a challenging disease that can be defined by refractoriness to second-line treatments. In this review, we list and comment available evidence about clinical and biological factors associated with refractoriness to splenectomy, thrombopoietin receptor agonists (TPO-RAs), rituximab and fostamatinib, as well as those associated with multirefractory ITP (active disease with failure of rituximab, TPO-RAs and splenectomy).

Treatment of immune thrombocytopenia during pregnancy with thrombopoietin receptor agonists.

The introduction of thrombopoietin receptor agonists (TPO-RAs) led to a paradigm shift in the management of immune thrombocytopenia (ITP). However, TPO-RAs are not approved for use during pregnancy due to the absence of evidence and concerns for possible effects on the fetus due to their expected transplacental transfer. This comprehensive review examines the safety and efficacy of TPO-RA in 45 pregnancies of women with ITP (romiplostim n = 22; eltrombopag n = 21; both in the same pregnancy n = 2). Mothers experienced failure of the median of three treatment lines during pregnancy prior to TPO-RA administration. A platelet response (>30 × 109 /L) was seen in 86.7% of cases (including a complete response >100 × 109 /L in 66.7%) and was similar between eltrombopag and romiplostim (87.0% and 83.3%, p = 0.99). The maternal safety profile was favourable, with no thromboembolic events encountered. Neonatal thrombocytopenia was noted in one third of cases, with one case of ICH grade 3, and neonatal thrombocytosis was observed in three cases. No other neonatal adverse events attributable to TPO-RAs were seen. This review suggests that the use of TPO-RA during pregnancy is associated with a high response rate and appears safe. Nevertheless, TPO-RA should not be routinely used in pregnancy and should be avoided in the first trimester until further evidence is accumulated.

Real-world use of avatrombopag in patients with chronic liver disease and thrombocytopenia undergoing a procedure.

The phase 4 observational cohort study assessed the effectiveness and safety of the thrombopoietin receptor agonist avatrombopag in patients with chronic liver disease (CLD) and thrombocytopenia undergoing a procedure. Patients with CLD may have thrombocytopenia, increasing the risk of periprocedural bleeding. Prophylactic platelet transfusions used to reduce this risk have limitations including lack of efficacy and transfusion-associated reactions. Prophylactic thrombopoietin receptor agonists have been shown to increase platelet counts and decrease platelet transfusions. Effectiveness was assessed by change from baseline in platelet count and proportion of patients needing a platelet transfusion. Safety was assessed by monitoring adverse events (AEs). Of 50 patients enrolled, 48 were unique patients and 2 patients were enrolled twice for separate procedures. The mean (standard deviation) change in platelet count from baseline to procedure day was 41.1 × 109/L (33.29 × 109/L, n = 38), returning to near baseline at the post-procedure visit (change from baseline -1.9 × 109/L [15.03 × 109/L], n = 11). The proportion of patients not requiring a platelet transfusion after baseline and up to 7 days following the procedure was 98% (n = 49). Serious AEs were infrequent (n = 2 [4%]). No treatment-emergent AEs were considered related to avatrombopag. There were 2 mild bleeding events, no thromboembolic events or deaths, and no patients received rescue procedures (excluding transfusions). This study found that in a real-world setting, treatment with avatrombopag was well tolerated, increased the mean platelet count by procedure day, and reduced the need for intraoperative platelet transfusions in patients with CLD and thrombocytopenia.

[Consensus on the clinical diagnosis, treatment and prevention of cancer treatment-induced thrombocytopenia in China (2023 edition)].

Cancer treatment-induced thrombocytopenia (CTIT) is a common adverse event during anti-tumor treatment, of which incidence is related to tumor classification, regimens, course of chemotherapy, etc. CTIT may result in a series of events including bleeding, dose intensity reduction, chemotherapy delay, and in severe cases, even the need for platelet transfusion, ultimately affecting the implementation of treatment plan, increasing the cost of treatment, reducing treatment effect and quality of life, and leading to a poor prognosis. The treatment of CTIT should first identify the cause, assess the risk of bleeding, and then adopt treatment strategies according to the cause and severity of CTIT. The main treatments of CTIT include platelet transfusion, application of various types of platelet-producing drugs, and measures to reduce the additional loss of platelets. Among them, platelet-producing drugs mainly refer to platelet-stimulating factors, including recombinant human thrombopoietin (rhTPO), recombinant human interleukin 11(rhIL-11), and thrombopoietin receptor agonists (TPO-RAs). In addition, traditional Chinese medicine also has some assistance in raising platelets. Pharmacological prophylaxis in high-risk patients may help reduce the incidence and severity of CTIT. This consensus aims to support Chinese oncologists in the diagnosis and treatment of CTIT in China, reduce the risk of bleeding and improve the quality of life of patients.