Treatment Of Primary Immune Thrombocytopenia Research Articles

Efficacy and safety of eltrombopag in the treatment of primary immune thrombocytopenia: real-world data from a single medical center

Objective: This study aimed at investigating the efficacy and safety of eltrombopag in the treatment of adult primary immune thrombocytopenia (ITP) and evaluated the factors influencing its efficacy and side effects. Methods: A total of 198 patients with adult ITP who were admitted to Tianjin Medical University General Hospital between January 2018 and March 2022 were retrospectively analyzed. The efficacy of each starting dose of eltrombopag was evaluated, and adverse events were analyzed. The factors influencing efficacy were investigated, including sex, age, adult ITP type, platelet antibodies, and combined drug treatments. Results: Of the 198 patients, 70 males and 128 females with a median age of 45 years (18-88 years) were included; 130 (65.7%) had newly diagnosed adult ITP, 25 (12.6%) had persistent adult ITP, and 43 (21.7%) had chronic adult ITP. The bleeding event scores at baseline were assessed; 84.3% had scores of<4 and 15.7% had scores of ≥4. The eltrombopag response rate (initial response) at 6 weeks was 78.8% (complete response [CR]: 49.0%; CR1: 14.6%; CR2: 15.2%). The median response time to eltrombopag was 7 (7, 14) days. The initial response rates to 25, 50, and 75 mg eltrombopag were 74.1%, 85.9%, and 60.0%, respectively (P=0.031). The initial response rate to the 50 mg dose was significantly higher than that of the 25-mg and 75-mg doses. Two patients received 100 mg as the starting dose, and their initial response was 0. Regarding dose adjustment, 70.7% of the patients remained on the starting dose, 8.6% underwent dose adjustment to 50 mg, and 6.1% underwent dose adjustment to 75 mg. Another two patients underwent dose adjustment to 100 mg. After dose adjustment, the persistent response rates were 83.6%, 85.3%, and 85.7% for the 25-, 50-, and 75-mg doses, respectively, with no significant difference. After dose adjustment, the sustained efficacy rate for the 100-mg dose (4 patients) was 100.0%. After 6 weeks of treatment with eltrombopag, the overall bleeding score of patients with ITP decreased. The number of patients with a score of ≥4 decreased to 0, the number of patients with a score of<4 decreased, and there was no significant change in the number of patients with a score of 1-2. The most common adverse event associated with eltrombopag was impaired liver function (7.7%). No thrombosis events or other adverse events were observed. ITP type and number of megakaryocytes significantly affected the initial response to eltrombopag. The initial response rates to eltrombopag for newly diagnosed adult ITP, persistent adult ITP, and chronic adult ITP were 85.3%, 56.0%, and 76.2%, respectively (P=0.003). For megakaryocytes, the initial response rates were 61.8%, 87.1%, and 84.3% (P=0.009) for the decreased, normal, and increased megakaryocyte groups, respectively. Conclusion: Eltrombopag, as a second-line or higher treatment for adult ITP, has a rapid onset of action and good safety. The initial response rate is significantly higher with a dose of 50 mg than with a dose of 25 mg. Patients with newly diagnosed ITP and those with normal or increased megakaryocyte numbers have a higher initial response rate to eltrombopag.

Clinical and economic effectiveness of thrombopoietin receptor agonists in the treatment of primary immune thrombocytopenia in the Moscow region

Clinical and economic effectiveness of thrombopoietin receptor agonists in the treatment of primary immune thrombocytopenia in the Moscow region

Anti-GPIb/IX Autoantibodies Are Associated with Poor Response to Dexamethasone Combined with Rituximab Therapy in Primary Immune Thrombocytopenia Patients

This retrospective study aimed to evaluate whether anti-glycoproteins (GPs) autoantibodies can be used as predictors of response to high-dose dexamethasone combined with rituximab (DXM-RTX) in the treatment of primary immune thrombocytopenia (ITP) patients. According to the screening criteria (Figure. 1), 126 ITP patients, including 85 (67.5 %) women and 41 (32.5 %) men, were included in the analyses, with a median age was 32 (10 - 80) years, the median duration of disease was 18 (0.1-228.0) months, and the median platelet count at baseline was 6.0 (0-28.0) × 10 9/L. As shown in Table 1, 56.4% (71/126) of patients responded to DXM-RTX at four weeks, including 43 CR and 28 partial responses. The median time to response (TTR) of 71 responded patients was seven days (range: 4-28 days). The OR rate of ITP patients with anti-GPIb/IX positivity was 47.6% (40/84), while that of anti-GPIb/IX autoantibody-negativity was 73.8% (31/42) (χ 2 = 7.808, P = 0.005). In line with the OR rate, a significant difference was found in the CR rate between ITP patients with anti-GPIb/IX positivity and anti-GPIb/IX autoantibody-negativity (26.2% vs. 50.0%, χ 2 = 7.061, P = 0.008). At six months of DXM-RTX therapy, 54.0% (68/126) of patients responded to DXM-RTX, with 39 (31.0%) of CR. The CR and OR rates of anti-GPIb/IX autoantibody-positive patients were also significantly lower than those of negative patients (CR: 45.2% vs. 71.4%, χ 2 = 7.731, P = 0.005; OR: 25.0% vs. 42.9%, χ 2 = 4.178, P = 0.041). No significant difference ( P &amp;gt; 0.05) was found in OR and CR rates between anti-GPIIb/IIIa autoantibody positive and negative patients at four weeks and six months of DXM-RTX therapy. At four weeks of DXM-RTX therapy, a significant difference in OR rate was found among the patients with anti-GPIb/IX single-positivity (37.5%), double-positivity (51.7%), double-negativity (68.4%), and anti-GPIIb/IIIa single-positivity (78.3%) (χ 2 = 9.617, P = 0.022) (Table 2). The further comparison revealed a higher resistance to DXM-RTX in patients with anti-GPIb/IX single-positivity than patients with anti-GPIIb/IIIa single-positivity (OR: 37.5% vs. 78.3%; P &amp;lt; 0.05). A similar trend was also found in the six-month OR rate (29.2% vs. 78.3%, P &amp;lt; 0.05). An analysis of the CR rate at four weeks of therapy showed a significant difference among the four groups (χ 2 = 8.523, P = 0.036) but no significant difference after Bonferroni's correction ( P &amp;gt; 0.05). No significant difference ( P = 0.119) was found in the CR rate among the four groups at six months of combined therapy. In addition, the NR rate of patients with anti-GPIb/IX single-positivity also increased significantly in comparison with the patients with anti-GPIIb/IIIa single-positivity at four weeks (62.5% vs.21.7%, P &amp;lt; 0.05) and six months (70.8% vs.21.7%, P &amp;lt; 0.05) of combined therapy. Multivariate logistic regression analyses revealed that age, sex, duration of disease, liver function, and baseline platelet count were not associated with patient response to DXM-RTX at 4 weeks and 6 months (Table 3). Anti-GPIb/IX autoantibodies and megakaryocytes of DXM-RTX therapy at both 4 weeks and 6 months were associated with the OR rate of patients, with an odds ratio of 0.194 ( P = 0.003, 95% CI: 0.065-0.575) at 4 weeks and 0.189 ( P = 0.003, 95% CI: 0.064-0.563) at 6 months by comparing patients with anti-GPIb/IX autoantibodies to those without anti-GPIb/IX autoantibodies. The factorial design analyses revealed no interaction effect between autoantibodies and showed anti-GPIb/IX autoantibodies at 4 weeks represented the only significant factor affecting OR rate with DXM-RTX therapy (F = 9.128, P = 0.003, Table 4). Therefore, platelet anti-GPIb/IX autoantibodies can predict poor response to DXM-RTX in ITP patients.

CM313, a Novel Anti-CD38 Antibody, As a Potential Treatment for Primary Immune Thrombocytopenia: A Phase II Trial

Background: Primary immune thrombocytopenia (ITP) is an autoimmune disease characterized by autoantibody-mediated platelet destruction. Antiplatelet-specific plasma cells (PCs) have been identified in ITP patients, making PCs depletion a potential treatment for ITP. CM313, a novel anti-CD38 monoclonal antibody currently under investigation in a phase I trial for multiple myeloma, has demonstrated targeted depletion of CD38-positive cells, including PCs. This phase II trial (NCT05694767) was designed to assess the safety and efficacy of CM313 in ITP patients. Methods: The open-label phase II trial consisted of a 4-week screening period, an 8-week treatment period, and a 16-week follow-up period. The main inclusion criteria were patients (age ≥18 years) with ITP and a platelet count &amp;lt;30×10 9/L, who did not response to or relapsed after glucocorticoid therapy and at least one second-line therapy (including rituximab and/or thrombopoietin receptor agonists [TPO-RAs]). Eligible patients received CM313 intravenously at a dose of 16 mg/kg weekly for a total of 8 weeks. The participants were requested to maintain the stable doses of glucocorticoids or TPO-RAs for 4 weeks prior to receiving the first dose without dose escalation during the study. Prophylactic medication, including glucocorticoids, antihistamines, and acetaminophen, was administered to all patients before and after the infusion. The primary endpoints were the percentage of patients with a platelet count ≥50×10 9/L within 8 weeks after the first dose (platelet count must be consecutive on at least 2 occasions with an interval of at least 1 day) and the incidence/severity of adverse events during the study period. Results： As of June 30, 2023, a total of 21 patients had been enrolled in the study and 7 subjects had completed 8 doses of the treatment with at least 8 weeks of follow-up. The 7 subjects consisted of 2 males and 5 females, with a median age of 40 years (range 18-56), a median weight of 62 kg (range 52-93), a median duration of ITP of 30 months (range 12-200) and a median baseline platelet count of 8×10 9/L (range 2-24). Of the 7 patients, 100.0% (7/7) achieved a platelet count ≥50×10 9/L within 8 weeks after the first dose, with a median time to response of 1 week (range 1-3). Furthermore, 4 out of 7 patients (57.1%) maintained a platelet count of ≥50×10 9/L until week 16, while 2 patients experienced a relapse at week 6 and 1 patient had a relapse at week 13. Platelet count (expressed as the median with the interquartile range) of the 7 patients from baseline to week 23 are shown in Figure 1. Of all 21 patients, 6 (6/21, 28.6%) had an infusion-related reaction (IRR) at the first dose but none at subsequent doses. The severity of IRR was grade 1 or 2 (according to CTCAE version 5.0). Conclusion: CM313, a novel anti-CD38 monoclonal antibody, has demonstrated tolerable safety and preliminary efficacy in refractory/relapsed ITP patients. Figure 1: Platelet count in 7 patients.

Cost-per-responder analysis for eltrombopag and rituximab in the treatment of primary immune thrombocytopenia in Spain

ObjectiveSplenectomy, thrombopoietin receptor agonists and rituximab are the second-line treatments for steroid-resistant adult primary immune thrombocytopenia. The last two are becoming the most widely used treatments to avoid splenectomy adverse effects and inconveniences. However, the choice between rituximab and thrombopoietin receptor agonists is unclear. Therefore, the treatment cost may be of particular interest to prioritize the therapy option. Our aim is to determine the cost per responding-patient after 6 months of use of rituximab compared to thrombopoietin receptor agonists eltrombopag in the treatment of chronic primary immune thrombocytopenia in the Spanish National Health Service. MethodA 26-week decision tree model was developed to assess the cost of treatment response of adult patients with chronic-refractory primary immune thrombocytopenia to eltrombopag and rituximab from the perspective of the Spanish National Health System. Effectiveness was obtained from the literature, and cost was obtained from the official rates. Costs were expressed in € (2018). Due to the short period of assessment, no discount rate was applied. ResultsThe average cost per patient after 6 months of treatment was slightly higher for eltrombopag (€13,089.40) than for rituximab (€11,852.60). However, the greater response rate of eltrombopag decreases the bleeding costs, resulting in a 29% higher cost per responding-patient with rituximab (€18,964.15) than for eltrombopag (€14,732.65). This result is consistent with the results of the 15 sensitivity analyses carried out where eltrombopag always represents a lower cost per responding patient, except in the sensitivity analysis in which treatment with eltrombopag is performed at its maximum dose (75mg). Only in this case, the cost per responder of eltrombopag is €48 more expensive than that of rituximab. Likewise, the greatest difference in favor of eltrombopag occurs in the scenario that uses the minimum dose of this drug —25mg— (eltrombopag €7,622.14 compared to €18,964.15 for rituximab). Thus, the cost per responding patient is lower in eltrombopag even if a second cycle of retreatment with rituximab is not performed (€14,732.65 versus €15,298.61). ConclusionsThe treatment cost of rituximab, including monitoring and bleeding costs, is higher than eltrombopag, favoring the latter over rituximab treatment.

Anti-GPIb/IX autoantibodies are associated with poor response to dexamethasone combined with rituximab therapy in primary immune thrombocytopenia patients

This retrospective study aimed to evaluate whether anti-glycoproteins (GPs) autoantibodies can be used as predictors of response to high-dose dexamethasone combined with rituximab (DXM-RTX) in the treatment of primary immune thrombocytopenia (ITP) patients. One-hundred twenty-six ITP patients were included and retrospectively analyzed, 66.7% of anti-GPIb/IX and 65.9% of anti-GPIIb/IIIa autoantibodies. Results showed that overall response (OR) and complete response (CR) rates of patients without anti-GPIb/IX autoantibodies to DXM-RTX were significantly higher than those with anti-GPIb/IX autoantibodies at 4 weeks (OR: 73.8% vs. 47.6%, CR: 50.0% vs. 26.2%; P < 0.05) and 6 months (OR: 71.4% vs. 45.2%, CR: 42.9% vs. 25.0%; P < .05). Furthermore, patients with anti-GPIb/IX single-positivity exhibited higher resistance to DXM-RTX than patients with anti-GPIIb/IIIa single-positivity at 4 weeks (OR: 37.5% vs. 78.3%; P < .05) and 6 months (OR: 29.2% vs. 78.3%; P < .05). Multivariable logistic regression analysis revealed that anti-GPIb/IX autoantibodies and megakaryocytes were associated with the OR rate of patients at both 4 weeks and 6 months, and anti-GPIb/IX autoantibodies at 4 weeks represented the only significant factor affecting OR rate with DXM-RTX (F = 9.128, P = .003). Therefore, platelet anti-GPIb/IX autoantibodies might predict poor response to DXM-RTX in ITP patients.

Low-dose decitabine promotes M2 macrophage polarization in patients with primary immune thrombocytopenia via enhancing KLF4 binding to PPARγ promoter.

The first-line therapy is effective for the treatment of primary immune thrombocytopenia (ITP); however, maintaining the long-term responses remains challenging. Low-dose decitabine (DAC) has been adopted to treat refractory ITP, while its role in macrophage polarization has not been fully understood. We aimed to investigate the mechanistic role of DAC in M2 macrophage polarization and evaluated its therapeutic effect in ITP. The M2 monocytes were identified by flow cytometry from peripheral blood mononuclear cells in healthy controls (HCs) and ITP patients. The expression of PPARγ, Arg-1, DNMT3b and NLRP3, together with IL-10 plasma levels was measured to examine its function. Bisulfite-sequencing PCR was used to evaluate the methylation status of PPARγ promoter, and the binding affinity of KLF4 was measured by Cut&Tag. A sh-PPARγ THP-1 cell line was created to verify if low-dose DAC-modulated M2 macrophage polarization was PPARγ-dependent. The passive ITP models were used to investigate the therapeutic effects of low-dose DAC and its role in modulating polarization and immunomodulatory function of macrophages. NLRP3 inflammasome and reactive oxygen species were also tested to understand the downstream of PPARγ. The M2 monocytes with impaired immunoregulation were observed in ITP. After high-dose dexamethasone (HD-DXM) treatment, M2 monocytes increased significantly with the elevated expression of PPARγ, Arg-1 and IL-10 in CR patients. Low-dose DAC promoted M2 macrophage polarization in a PPARγ-dependent way via demethylating the promoter of PPARγ, especially the KLF4 binding sites. Low-dose DAC alleviated ITP mice by restoring the M1/M2 balance and fine-tuning immunomodulatory function of macrophages. The downstream of the PPARγ modulation of M2 macrophage polarization might physiologically antagonize NLRP3 inflammasome. Low-dose DAC promoted M2 macrophage polarization due to the demethylation within the promoter of PPARγ, thus enhanced the KLF4 binding affinity in ITP.

All-trans retinoic acid added to treatment of primary immune thrombocytopenia: a systematic review and meta-analysis.

All-trans retinoic acid (ATRA) application is a novel treatment approach for primary immune thrombocytopenia (ITP). This study aimed to evaluate the efficacy and safety of ATRA in the treatment of ITP. The databases of PubMed (MEDLINE), EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), and China National Knowledge Internet were searched on August 5, 2022, to find randomized controlled trials (RCTs) and observational studies. Five observational studies and four RCTs from China were included, and 760 Chinese patients were analyzed. In the five observational studies, the pooled overall response rate (ORR) and complete response rate (CRR) were 59.5% (95% confidence interval [CI], 52.4-66.4%) and 20.6% (95% CI, 14.3-27.6%), respectively. In the selected four RCTs, the pooled odds ratios for sustained response rate, ORR, and CRR were 3.00 (95% CI, 1.97-4.57; P < 0.01), 3.21 (95% CI, 2.15-4.78; P < 0.01), and 2.12 (95% CI, 1.17-3.86; P = 0.01), respectively. ATRA was associated with a reduction in relapse rate and salvage treatment rate (odds ratio, 0.30; 95% CI, 0.18-0.50; P < 0.01; 0.36; 95% CI, 0.23-0.56; P < 0.01, respectively). The pooled odds ratios for grade 1-2 dry skin, headache (or dizziness), and rash acneiform were 49.99 (95% CI, 16.05-155.67; P < 0.01), 1.75 (95% CI, 0.98-3.12; P = 0.06), and 0.37 (95% CI, 0.10-1.34; P = 0.13), respectively. This study suggests that ATRA may significantly improve the initial and long-term response of patients with ITP.

Expert consensus on diagnosis and treatment of primary immune thrombocytopenia in pregnancy

原发免疫性血小板减少症（ITP）是一种获得性自身免疫性出血性疾病。妊娠合并ITP患者病情可随妊娠的进展而加重，导致妊娠期及分娩期出血风险增加，部分妊娠合并ITP患者分娩的新生儿可发生新生儿血小板减少症。规范管理妊娠合并ITP可以有效降低ITP患者的出血风险，改善母儿结局。但因妊娠合并ITP发生率较低，缺乏高质量的循证医学证据，临床存在诊疗不规范及过度诊疗现象。为进一步规范ITP的妊娠期管理，中华医学会妇产科学分会产科学组组织多学科专家，在参照国内外相关指南的基础上，共同讨论制定本共识，旨在为我国妊娠合并ITP的诊治提供指导性意见。.

Therapeutic effect of the combination of eltrombopag and low dose hormone in patients with primary immune thrombocytopenia

Purpose: To investigate the clinical effect and side effects of early addition of small-dose eltrombopag in initial treatment of primary immune thrombocytopenia (ITP) patients with decreased platelet count and hormone reduction, and patients with persistent ITP.&#x0D; Methods: Thirty ITP patients newly diagnosed with poor hormonal levels were recruited, along with 36 patients with persistent ITP. The ITP patients were given prednisone in combination with eltrombopag. Blood routine tests, blood pressure, blood sugar, liver and kidney function, and serum ion levels were monitored every two weeks. Adverse events were recorded at 2, 4, and 8 weeks after eltrombopag treatment.&#x0D; Results: After treatment for 2, 4, and 8 weeks, there was obvious effectiveness in 45.0, 39.4, and 40.9 % of patients, respectively, while effectiveness was good in 22.7, 37.9, and 50 % of patients, respectively. Treatment was ineffective in 31.8, 22.7, and 9.1 % of patients, respectively. In the 8th week, 15 patients (22.7 %) had to use prednisone at a dose of more than 20 mg/day to keep their platelet level above 30 x 109/L, while 7 patients (10.6 %) stopped using prednisone completely. Moreover, 4 patients (6.1 %) had their platelet counts maintained above 30 x 109/L after stopping the use of eltrombopag for more than 2 weeks.&#x0D; Conclusion: The combined use of eltrombopag and low-dose hormone is an effective treatment for ITP patients. It produces only a slight side effect, and it is affordable. A larger population study will be required to validate these findings of this new therapeutic option.

A REVIEW ON TREATMENT OF PRIMARY IMMUNE THROMBOCYTOPENIA

A REVIEW ON TREATMENT OF PRIMARY IMMUNE THROMBOCYTOPENIA

A REVIEW ON TREATMENT OF PRIMARY IMMUNE THROMBOCYTOPENIA

A REVIEW ON TREATMENT OF PRIMARY IMMUNE THROMBOCYTOPENIA

Efgartigimod alfa for the treatment of primary immune thrombocytopenia.

Primary immune thrombocytopenia (ITP) is an acquired autoimmune disorder characterized by isolated thrombocytopenia. Most patients with ITP have antiplatelet antibodies of the immunoglobulin G (IgG) subtype which through interaction with platelet and megakaryocyte glycoproteins result in increased platelet destruction and inhibition of platelet production. There are a variety of therapeutic options available for the treatment of ITP including corticosteroids, IVIgG, TPO-RA, rituximab, fostamatinib, and splenectomy. Long-term remissions with any of these therapies can vary widely and patients may require additional therapy. The neonatal Fc receptor (FcRn) plays a pivotal role in IgG and albumin physiology through recycling pathways. Efgartigimod is a human IgG1-derived fragment that has been modified by ABDEG technology to increase its affinity for FcRn at both physiologic and acidic pH. The binding of efgartigimod to FcRn blocks the interaction of IgG with FcRn facilitating increased lysosomal degradation of IgG and decreasing total IgG levels. Based on the mechanism of action and the known pathophysiology of ITP as well as the efficacy of other therapies such as intravenous immunoglobulin (IVIG), the use of efgartigimod in patients with ITP is attractive. This article will briefly discuss the pathophysiology of ITP, current treatments, and the data available on efgartigimod in ITP.

CO13 Evidence Gap Analysis of the Burden of Illness and Treatment of Primary Immune Thrombocytopenia

CO13 Evidence Gap Analysis of the Burden of Illness and Treatment of Primary Immune Thrombocytopenia

Comparison of the efficacy and safety of 2 low-dose rituximab regimens in the second-line treatment of primary immune thrombocytopenia in children

Objective: To compare the efficacy and safety of 2 low-dose rituximab regimens in the treatment of children with primary immune thrombocytopenia (ITP). Methods: A total of 90 ITP children admitted to the Hematology Oncology Center of Beijing Children's Hospital from January 2018 to March 2021 were enrolled in this prospective cohort study. In the single-dose group, rituximab was given with a single dose of 375 mg/m2 (maximum dose 600 mg). In the 4-dose group, rituximab was given with a dose of 100 mg weekly (if body weight of the patient ≥ 30 kg, increase dosage to 200 mg weekly) for 4 weeks. Wilcoxon Mann-Whitney test, Chi-square test and Fisher's exact test were used to analyze the difference in efficacy, safety and treatment burden between two groups. Results: Among the 90 children, 41 were male and 49 were female, and the age of medication was 6.8 (4.1,10.0) years. There were 27 cases in the single-dose group and 63 cases in the 4-dose group.There were no significant differences in overall response rate, complete response rate and partial response rate between the single-dose group and 4-dose group (41% (11/27) vs. 33% (21/63), 26% (7/27) vs. 19% (12/63), 15% (4/27) vs. 14%(9/63), χ2=0.45, 0.54, 0.00, all P>0.05). The single-dose group was earlier to get overall response than the 4-dose group (1 (1, 1) vs. 3 (2, 6) weeks, Z=-3.24, P=0.001). There were no significant differences in the sustained response rate, the overall response rate in 1 year, the complete response rate in 1 year, and the partial response rate in 1 year between the single-dose group and the 4-dose group (33% (9/27) vs. 30% (19/63), 30% (8/27) vs. 24% (15/63), 19% (5/27) vs. 14% (9/63), 11% (3/27) vs. 10% (6/63), χ2=0.09, 0.34, 0.04, 0.00, all P>0.05). There were no significant differences in the duration of overall response, recurrence rate within half a year and one year, recurrence time and rate of adverse events between the single-dose group and 4-dose group (all P>0.05). The number of hospitalizations, the duration of hospital stays and the dosage of the single-dose group were significantly lower than those of the 4-dose group (1 (1, 1) vs. 4 (4, 4) times, 5 (4, 7) vs. 8 (5, 8) d, 400 (250, 500) vs. 400 (400, 800) mg, Z=-8.67, -3.03, -4.05, all P<0.05). Conclusions: The single-dose rituximab regimen is comparable to 4-dose rituximab regimen in effectiveness and safety for treatment of children ITP, but more economical and convenient. The single-dose rituximab regimen is more suitable for the second-line treatment of children ITP.

Human anti-D immunoglobulin preparations: potency standardisation milestones

Human anti-D immunoglobulin preparations derived from human immune plasma are much needed and highly effective for specific anti-D prevention of perinatal complications and treatment of primary immune thrombocytopenia. The effectiveness of immune suppression is a direct function of the active ingredient dose received with the medicinal product. To improve the accuracy of anti-D antibody quantification, it is recommended to use certified reference materials with values assigned in international units (IUs). The aim of this study was to analyse the main stages in the development of the international standards (ISs) for human anti-D immunoglobulin potency testing and to substantiate the need for a national standard for anti-Rho(anti-D) antibody quantification. The article describes the creation of the first and subsequent ISs, the procedure for establishing the IU equivalent for the anti-Rho(anti-D) antibody concentration, the characteristics of the raw materials and preparations used, and the anti-Rho(anti-D) antibody assay methods applied to certify the ISs. According to the study conclusions, it is necessary to develop and certify a national standard for the content of anti-Rho(anti-D) antibodies that will meet the requirements of the corresponding Russian regulations.

Investigation of the mechanism of action of Shengxuexiaoban Capsules against primary immune thrombocytopenia using network pharmacology and experimental validation

BackgroundShengxuexiaoban Capsules (SC) is a classical prescription in traditional Chinese medicine (TCM) and has been clinically adopted in the treatment of primary immune thrombocytopenia (ITP) in China. However, the underlying mechanisms of the actions of SC on ITP remain clear. MethodsA network pharmacology approach was adopted to investigate the underlying molecular mechanism of SC in treating ITP, and the effects of SC on the proliferation, differentiation, and apoptosis of megakaryocyte (MK) and on the ITP animal model were investigated. ResultsNetwork pharmacology analysis found 128 active compounds and 268 targets of these compounds in SC, as well as 221 ITP-related targets. The topological analysis found a central network containing 82 genes, which were significantly associated with the regulation of transcription, cell proliferation, apoptosis processes, the PI3K-AKT signaling pathway, the MAPK signaling pathway, and the ERK1 and ERK2 cascades. It showed that SC increased the proliferation and differentiation of MK, but had no significant impact on MK apoptosis in vivo. The addition of SC increased the gene expression of several potential targets, including STAT3, KDR, CASP3, and TGFB1. In addition, SC administration elevated the protein expression of p-AKT and inhibit the protein expression of p-ERK, but has no impact on the protein expression of p-P38. Moreover, SC could improve haemogram parameters, coagulation indicators, and the proliferation and differentiation of MK in the ITP animal model. ConclusionsThe present study systematically elucidated the underlying mechanisms of SC against ITP and provided an efficient strategy to discover the pharmacological mechanism of TCM. It may strengthen the understanding of SC and facilitate more application of this formula in the treatment of ITP.

S292: SUSTAINED RESPONSE OFF TREATMENT IN ELTROMBOPAG-TREATED PATIENTS WITH ITP WHO ARE REFRACTORY OR RELAPSED AFTER FIRST-LINE STEROIDS: PRIMARY ANALYSIS OF THE PHASE II TAPER TRIAL

Background: Corticosteroids (CSs) are the standard 1st-line treatment for primary immune thrombocytopenia (ITP); however, long-term CS use is associated with high relapse rates and considerable toxicity. Treatments that achieve a sustained response and reduce the need for long-term CS use are needed. Eltrombopag (EPAG) is a thrombopoietin receptor agonist (TPO-RA) indicated in Europe for the treatment of patients (pts) aged ≥1 year with primary ITP lasting ≥6 months who are refractory to other treatments (eg, CSs). Evidence suggests that a proportion of pts treated with TPO-RAs achieve sustained responses that are maintained after TPO-RA tapering and discontinuation; however, much of the evidence is retrospective with only a few prospective studies investigating sustained response off treatment (SRoT). Aims: TAPER (NCT03524612), a Phase II, open-label, prospective, single-arm study, aims to determine whether EPAG can induce SRoT in pts with ITP after 1st-line CS failure. Methods: Adult (≥18 years) pts with ITP who did not respond to or had relapsed after initial CS therapy, with platelet counts <30×109/L and assessed as needing treatment, were included. Patients received a 50 mg/day starting dose of EPAG (25 mg/day for East/Southeast Asian pts; 12.5 mg/day for Japanese pts in Japan), which could be increased up to 75 mg/day (50 mg/day in Japan) if needed. The primary endpoint was the number (%) of pts with SRoT by Month 12; SRoT was defined as achieving a complete response (CR, ie, platelet count ≥100×109/L), then maintaining a stable platelet count (no counts <70×109/L) for 2 months, followed by successful EPAG tapering and discontinuation with platelet counts ≥30×109/L and no bleeding events or rescue therapy. Patients with SRoT at Month 12 were followed for a further year. Secondary outcomes included SRoT duration and platelet count changes from baseline. Data to Month 12 are presented. Results: N=105 pts were enrolled. The median (interquartile range [IQR]) age was 46 (30-65) years; 61% were female. In the 1st 12 months, median (IQR) duration of exposure to EPAG was 5.6 (2.3-11.9) months and median (IQR) EPAG dose was 57.1 (37.5-69.0) mg/day. Overall, 89 pts (85%) achieved CR at least once and 65 pts (62%) maintained a platelet count ≥70×109/L for 2 months after CR. EPAG tapering and discontinuation was achieved in 44 pts (42%). The primary endpoint was met, with 32 pts (30.5% [95% confidence interval, 21.9-40.2]; P<0.001 [H1: P>15%; alpha: 0.05]) achieving SRoT until Month 12 (Fig. 1); SRoT was maintained from last dose to Month 12 for a median (IQR) of 33.3 (25.7-45.3) weeks. The median (IQR) absolute increase in platelet counts from baseline at Month 12 was 77.0×109/L (35.0-145.0). All-grade adverse events (AEs) occurred in 92/105 (88%) pts (grade ≥3 AEs: 33/105 [31%]). Treatment-related AEs occurred in 37 (35%) pts (8 [7.6%] grade ≥3). The most common all-grade AEs were headache (21% of pts with ≥1 event [grade ≥3: 1% of all pts]), thrombocytopenia (17% [10.5%]), and petechiae (11% [1%]). There were 4 deaths (none were considered treatment related): 3 were on-treatment (central nervous system hemorrhage [n=1], intracranial hemorrhage [n=1], metastases to peritoneum [n=1]) and 1 death (malignant neoplasm) occurred 238 days after last dose. Image:Summary/Conclusion: Data from the TAPER study indicate that a significant proportion of pts experience sustained response following tapering and discontinuation of EPAG, even after a relatively short duration of exposure. Overall EPAG was well tolerated with no unexpected AEs.

Serum Copper and Zinc Levels in Primary Immune Thrombocytopenia.

Although the pathogenesis of immune thrombocytopenia is not fully known, oxidative stress is one of the etiological causes. Copper and zinc are elements in the antioxidant system, and their deficiency causes oxidative stress. We aimed to determine the serum copper and zinc levels and their effects on the response to treatment in patients with immune thrombocytopenia. We analyzed 51 patients with primary immune thrombocytopenia and 33 control cases. Age, gender, and platelet values at the time of diagnosis, drugs used for the treatment of immune thrombocytopenia, remission status, and serum copper and zinc levels were recorded. The primary immune thrombocytopenia and control groups were compared in terms of serum copper and zinc levels. In addition, the relationship between the response status to the treatment of patients with immune thrombocytopenia and serum copper and zinc levels was investigated. The serum zinc level in the immune thrombocytopenia group and control group was 10.35 ± 3.28µmol/L and 12.82 ± 2.41µmol/L, respectively (p = 0.01). The serum copper level in patients with immune thrombocytopenia (77.3 ± 22.23µg/dL) was significantly lower than the control group (99.4 ± 20.82µg/dL) (p = 0.01). A significant correlation was found between the response to first-line treatment of primary immune thrombocytopenia and serum copper level (p = 0.005). The serum copper level was significantly lower in relapsed cases (p = 0.001). In conclusion, serum copper and zinc levels are lower in patients with primary immune thrombocytopenia than in healthy cases. Patients with relapsed or unresponsive to immune thrombocytopenia treatment have lower serum copper levels than other patients.

Adapted guideline for the diagnosis and treatment of primary immune thrombocytopenia for Chinese children (2021)

Adapted guideline for the diagnosis and treatment of primary immune thrombocytopenia for Chinese children (2021)