Diagnosis Of Immune Thrombocytopenia Research Articles

Comprehensive analysis and prediction model of mitophagy and ferroptosis in primary immune thrombocytopenia.

Primary immune thrombocytopenia (ITP) is linked to specific pathogenic mechanisms, yet its relationship with mitophagy and ferroptosis is poorly understood. This study aimed to identify new biomarkers and explore the role of mitophagy and ferroptosis in ITP pathogenesis. Techniques such as differential analysis, Mfuzz expression pattern clustering, machine learning, gene set enrichment analysis, single-cell RNA sequencing (scRNA-seq) and immune infiltration analysis were employed to investigate the molecular pathways of pivotal genes. Two-sample Mendelian randomization (TSMR) assessed the causal effects in ITP. Key genes identified in the training set included GABARAPL1, S100A8, LIN28A, and GDF9, which demonstrated diagnostic potential in validation sets. Functional analysis indicated these genes' involvement in ubiquitin phosphorylation, PPAR signalling pathway and T-cell differentiation. Immune infiltration analysis revealed increased macrophage presence in ITP, related to the critical genes. scRNA-seq indicated reduced GABARAPL1 expression in ITP bone marrow macrophages. TSMR linked S100A8 with ITP diagnosis, presenting an OR of 0.856 (95% CI = 0.736-0.997, p = 0.045). The study pinpointed four central genes, GABARAPL1, S100A8, LIN28A, and GDF9, tied to mitophagy and ferroptosis in ITP. It posits that diminished GABARAPL1 expression may disrupts ubiquitin phosphorylation and PPAR signalling, impairing mitophagy and inhibiting ferroptosis, leading to immune imbalance.

Incidence and risk factors of systemic lupus erythematosus in patients with primary immune thrombocytopenia: a systematic review and meta-analysis.

Immune disorders and autoantibodies has been noted in both primary immune thrombocytopenia (ITP) and systemic lupus erythematosus (SLE). Whether the two disorders are correlated is unclear. The lack of evidence on the incidence of and risk factors for SLE in primary ITP patients poses a challenge for prediction in clinical practice. Therefore, we conducted this study. The protocol was registered with PROSPERO (CRD42023403665). Web of Science, Cochrane, PubMed, and EMBASE were searched for articles published from inception to 30 September 2023 on patients who were first diagnosed with primary ITP and subsequently developed into SLE. Furthermore, the risk factors were analyzed. Study quality was estimated using the Newcastle-Ottawa Scale. The statistical process was implemented using the R language. This systematic review included eight articles. The incidence of SLE during the follow-up after ITP diagnosis was 2.7% (95% CI [1.3-4.4%]), with an incidence of 4.6% (95% CI [1.6-8.6%]) in females and 0 (95% CI [0.00-0.4%]) in males. Older age (OR = 6.31; 95% CI [1.11-34.91]), positive antinuclear antibody (ANA) (OR = 6.64; 95% CI [1.40-31.50]), hypocomplementemia (OR = 8.33; 95% CI [1.62-42.91]), chronic ITP (OR = 24.67; 95% CI [3.14-100.00]), organ bleeding (OR = 13.67; 95% CI [2.44-76.69]), and female (OR = 20.50; 95% CI [4.94-84.90]) were risk factors for subsequent SLE in ITP patients. Patients with primary ITP are at higher risk of SLE. Specific follow-up and prevention strategies should be tailored especially for older females with positive ANA, hypocomplementemia, or chronic ITP. In subsequent studies, we need to further investigate the risk factors and try to construct corresponding risk prediction models to develop specific prediction strategies for SLE.

Pathophysiology, Clinical Manifestations and Diagnosis of Immune Thrombocytopenia: Contextualization from a Historical Perspective.

Immune thrombocytopenia (ITP) is an autoimmune disease characterized by an isolated decrease in the platelet count and an increased risk of bleeding. The pathogenesis is complex, affecting multiple components of the immune system and causing both peripheral destruction of platelets and impaired central megakaryopoiesis and platelet production in the bone marrow. Here, we intend to contextualize the current knowledge on the pathophysiology, terminology, epidemiology, clinical manifestations, diagnosis, and prognosis of ITP from a historical perspective and the first references to the never-stopping garnering of knowledge about this entity. We highlight the necessity to better understand ITP in order to be able to provide ITP patients with personalized treatment options, improving disease prognosis and reducing the incidence or frequency of refractoriness.

Evaluation of vitamin D status in adult patients with newly diagnosed immune thrombocytopenia.

It has been shown that 25-OH vitamin D not only preserves calcium and bone homeostasis but also has immunomodulatory effects. The purpose of this study was to assess the association between adult patients with recently diagnosed immune thrombocytopenia (ITP) and vitamin D levels. Retrospective technique was employed in this study. The associations between 25(OH)D value and platelet count, as well as the clinical symptoms of ITP upon diagnosis and 25(OH)D value, were our main findings. A total of 60 patients diagnosed and followed up in our clinic were included in the study. Forty-one patients (68.3%) were female and 19 (31.7%) were male. The median age of the patients was 52.5 (19-88). The median vitamin D level of all patients at diagnosis of ITP was 11.5 (3-86). There was no statistically significant difference between the patients divided into three groups according to their vitamin D levels, in terms of laboratory parameters. There was no statistically significant difference in clinical findings according to vitamin D status in ITP patients. There was no statistically significant difference in terms of relapse-free survival in all three groups (p = 0.71). In conclusion, in our study, no correlation was found between laboratory and clinical findings at diagnosis and vitamin D levels in adult ITP patients. Additional investigations, particularly randomized controlled trials, are required to examine the relationship between 25(OH)D and the incidence and severity of ITP.

Изменения качества жизни у пациентов с хронической иммунной тромбоцитопенией в процессе терапии ромиплостимом, его эффективность и безопасность в условиях реальной клинической практики: результаты многоцентрового наблюдательного исследования

Aim. To study the quality of life in patients with chronic immune thrombocytopenia (ITP) in the process of romiplostim therapy and to assess the efficacy and safety of this drug in real-world setting.
 Materials & Methods. The study enrolled adult patients with the confirmed chronic ITP diagnosis and indications for romiplostim therapy. Clinical parameters, RAND SF-36 and FACT-Th6 quality of life as well as FACIT-Fatigue scores were evaluated prior to romiplostim administration vs. 3, 6, and 12 months after the treatment onset. Patient satisfaction checklist was also administered at all study points after the start of therapy. The clinical efficacy of romiplostim was analyzed along with assessing response and time to response. To study the quality of life and fatigue changes, the Generalized Estimating Equation (GEE) method was used during the observation period. Significant fatigue changes were determined and compared in terms of the perception differences from patient’s and physician’s perspective.
 Results. The study enrolled 60 chronic ITP patients treated with romiplostim in the real-world setting (mean age 51.9 years, 70 % women). The median thrombocyte count prior to romiplostim therapy was 18.5 × 109/L (interquartile range 10.8–22.3 × 109/л). On the enrollment date, 90 % of patients showed hemorrhagic syndrome. Overall response to romiplostim therapy was 98.3 % (complete response was achieved in 93.3 % of patients). After 6 months of therapy, 89.5 % of patients preserved response. After 3 months of therapy, hemorrhagic syndrome was eliminated in 81 % of patients, after 6 months the same was achieved in 93 % of patients. The median time to response was 4.4 weeks (95% confidence interval 3.6–5.3 weeks). Adverse events of grades 1/2 associated with romiplostim were reported in 6.7 % of patients. On romiplostim therapy, pronounced positive changes in quality of life were shown by all scales of the general questionnaire SF-36 and the targeted questionnaire FACT-Th6 (p < 0.001). The clearest improvements were observed in role-physical and role-emotional functioning. Already after 3 months of therapy, a considerable fatigue reduction was observed and sustained for the next 6 and 12 months of romiplostim administration (p < 0.001). During the therapy, the proportion of patients with fatigue impacting various aspects of functioning became considerably smaller. The vast majority of patients (85 %) were satisfied with the treatment. Discrepancies between patients’ and physicians’ evaluations of fatigue were also identified during the treatment.
 Conclusion. The results of the present multi-center observational study demonstrate high efficacy and safety of romiplostim for chronic ITP patients in the real-world setting. Romiplostim therapy yields considerable quality of life improvement and fatigue reduction. To optimize the patient monitoring system and patient-centered ITP treatment in the real-world setting, it is advisable to use the standardized questionnaires assessing quality of life and fatigue.

Excellent response to treatment with hydroxychloroquine in pediatric patients with SLE-related immune thrombocytopenia.

Pediatric immune thrombocytopenia (ITP) may precede systemic autoimmune disorders. In adolescent patients with ITP, routine screening for systemic lupus erythematosus (SLE) may be performed by testing for antinuclear antibody (ANA) titer. Hydroxychloroquine (HCQ) is a safe and effective immunomodulatory drug in patients with SLE but rarely used in ITP. We analyzed the platelet count response and safety of HCQ in treating pediatric patients with SLE-related ITP. A retrospective study including pediatric patients with ITP and definite or incomplete SLE, who were treated with HCQ during 2010-2021. SLE was defined by ANA titer≥1:160 as measured by immunofluorescence and ≥10 points according to the 2019 EULAR/ACR 2019 classification criteria, while patients with incomplete SLE achieved a score<10. Complete response (CR) of the platelet count was defined as platelet count>100 × 109/L; partial response (PR) as platelet count 30-100 × 109/L and exceeding≥twice baseline counts. Of the 17 patients included (median age 15.5 years; IQR 3.6), 15 (88.2%) were female, 13 had definite SLE, and four had incomplete SLE. HCQ was initiated at a median of 17 months after ITP diagnosis with a median platelet count of 38 × 109/L (IQR 28). At 8weeks, 8 (47.1%) patients responded, including 6 (35.3%) achieving CR. After one year, the overall response was 82.4%, with the remaining patients having stable platelet counts requiring no additional ITP therapy. The response was maintained at a median follow-up of 42 months. No adverse effects to HCQ were noted. Pediatric patients with SLE-related ITP may benefit from treatment with HCQ.

Risk of fractures and use of bisphosphonates in adult patients with immune thrombocytopenia-A nationwide population-based study.

Corticosteroids remain the first-line treatment of immune thrombocytopenia (ITP), but increase the risk of osteoporosis and fractures. Bisphosphonates are used for the treatment of osteoporosis, but their usage among patients with ITP has not been systemically described. We investigated the risk of fractures and the use of bisphosphonates in adult patients with primary (pITP) and secondary ITP (sITP) compared with matched comparators in a nationwide registry-based cohort study. We identified 4030 patients with pITP (median age 60 years [IQR, 40-74]), 550 with sITP (median age 59 years [IQR, 43-74]) and 182 939 age-sex-matched general population comparators. All individuals were followed for incident fractures. Bisphosphonate use was estimated for calendar-years and in temporal relation to the ITP diagnosis. Adjusted cause-specific hazard ratio (csHR) for any fracture was 1.37 (95% confidence interval [CI] 1.23; 1.54) for pITP and 1.54 (1.17; 2.03) for sITP. The first-year csHR was 1.82 (1.39; 2.40) for pITP and 2.78 (1.58; 4.91) for sITP. Bisphosphonate use over calendar-years and in the early years following ITP diagnosis was higher among patients with ITP diagnosis compared with the general population. In conclusion, the risk of fractures and the use of bisphosphonates are higher in patients with ITP compared with the general population.

Proposal of New Diagnostic Criteria for Primary Immune Thrombocytopenia

Primary immune thrombocytopenia (ITP) is an autoimmune disorder characterized by isolated thrombocytopenia due to accelerated platelet destruction and impaired platelet production. Diagnosis of ITP is still challenging because ITP has been diagnosed by exclusion. Exclusion of thrombocytopenia due to bone marrow failure is especially important in Japan because of high prevalence of aplastic anemia compared to Western countries. Hence, we propose new diagnostic criteria involving the measurement of plasma thrombopoietin (TPO) levels and percentage of immature platelet fraction (RP% or IPF%) as shown in Fig. 1. These biomarkers reflect the pathology of ITP, in which shortened platelet lifespan associated with increased platelet destruction and relatively maintained platelet production. Diagnostic criteria is as follows: 1. ALL of the following *1 ・Thrombocytopenia (＜100,000/μL) ・Absence of anemia (excluding anemia due to bleeding and/or iron deficiency) ・Normal leukocyte count (but may present with mild abnormal leukocyte count) ・No morphological evidence of dysplasia in any blood cell type in a blood smear 2. Normal or slightly increased plasma TPO level (&amp;lt;cutoff) 3. Elevated percentage of immature platelet fraction (RP% or IPF%; &amp;gt; upper limit of normal) 4. Absence of other conditions that potentially cause thrombocytopenia including secondary ITP ⋆2 ● A diagnosis of ITP is made if conditions 1 - 4 above are all met (ITP) ● Cases in which criterion 2 or 3 is not met or unavailable are defined as “possible ITP, pITP”. A diagnosis of ITP can be made if the patient is a glycoprotein (GP)-specific platelet-antibody positive, increased GP-specific platelet antibody-producing B cells, or typical clinical course. (Footnotes) *1 Bone marrow examination is strongly recommended to rule out other diseases if peripheral blood demonstrates any of the following findings: leukocyte count &amp;lt;3,000 or ≥10,000/μL, MCV ≥110, neutrophils &amp;lt;30% or lymphocytes ≥50%, presence of immature leukocytes *2 Includes drug-related thrombocytopenia, radiation injury, aplastic anemia, myelodysplastic syndrome (MDS), paroxysmal nocturnal hemoglobinuria (PNH), systemic lupus erythematosus (SLE), leukemia, malignant lymphoma, bone marrow metastasis of cancer cells, disseminated intravascular coagulation (DIC) , thrombotic thrombocytopenic purpura (TTP), hypersplenism, megaloblastic anemia, sepsis, infections (tuberculosis, etc.), sarcoidosis, and huge hemangioma such as Kasabach-Merritt syndrome. Congenital diseases involving thrombocytopenia include Bernard-Soulier syndrome, Wiskott-Aldrich syndrome, MYH9-related disease and Upshaw-Schulman syndrome. Sensitivity and specificity analysis of this criteria was performed by using data of previously performed prospective study (Kuwana et al. J Thromb Haemost 2006). In this study plasma TPO level were measured by R&amp;D Systems ELISA Kit and RP% were measured by flow cytometry. 112 thrombocytopenic patients who were initially suspected ITP (final diagnosis: ITP 88, aplastic anemia 11, MDS 10, others 3) were included in the study. The sensitivity and specificity of “ITP” who met all 4 conditions of the new criteria were 53.4% (47/88) and 95.8% (23/24), respectively. If cases of diagnosed as “ITP” or “pITP” by the new criteria were considered as ITP, sensitivity and specificity were 94.3% (83/88) and 75.0% (18/24), respectively. More importantly, these criteria exclude aplastic anemia completely from true ITP. For clinical diagnostic use, new CLEIA-based TPO measurement kit (MBL, Japan) has recently been developed in Japan. However, it is still crucial to carefully differentiate ITP from other thrombocytopenic diseases before applying these biomarkers. These new criteria enable us to clearly differentiate ITP from aplastic anemia and other forms of hypoplastic thrombocytopenia, and can be highly useful in clinical practice for avoiding unnecessary bone marrow examination as well as for appropriate selection of treatments.

Predictors of Response to Rituximab in Chronic Immune Thrombocytopenia: Do Race, Gender and ABO Blood Type Matter?

Introduction: Immune thrombocytopenia (ITP)is characterized by immune mediated destruction of platelets causing isolated thrombocytopenia with a peripheral blood platelet count &amp;lt;100,000/microL in the absence of other causes that may be associated with thrombocytopenia. It remains a diagnosis of exclusion. Corticosteroids are the first-line treatment for ITP and more than 75% of adults with ITP will respond to them. However, approximately 70-80% of adult patients with ITP will experience treatment failure with corticosteroids or become dependent on them and require second-line therapy. Various options in the second line setting include thrombopoietin receptor agonists, rituximab, and splenectomy. In one study rituximab was noted to result in an overall platelet count response in 62.5% of adults. However not all patients remain in remission and clinical factors that are predictive of response are lacking. Racial disparities are known to predict response to rituximab in other hematologic disorders such as immune mediated thrombotic thrombocytopenic purpura (Mezapa et al, 2022). Herein, we are examining the effect of race, gender and ABO blood type on response to rituximab in patients diagnosed with ITP. Methods: This retrospective cohort study included adult patients, aged 18 and above, with a diagnosis of ITP who had received single agent rituximab within a multihospital academic healthcare system between January 2015 and December 2022. Initially 196 patients were identified but only 127 of those were included in the study. We excluded patients with missing response data, and those with combined rituximab and other therapies (stable or decreasing doses of steroids were allowed). Our primary end point was any response to rituximab by day 180 after starting rituximab. Any response was defined as complete response or partial response. Complete response was defined as platelet count ≥ 100,000 /microL and absence of bleeding. Partial response was defined as platelet count of at least 30,000/microL after week 4 from rituximab administration or doubling of platelet count from baseline without administration of any platelet increasing therapy. Our secondary end point was relapse rate which was defined as platelet count below 100,000/microL if complete response had been attained or below 30,000/microL or less than 2 fold increase of baseline platelet count. We also investigated clinical and socioeconomic predictors of response. Exploratory analysis was performed. Summary statistics are presented as percentages for categorical data and median with interquartile range for quantitative data. Chi square test was used to compare percentages and t-test was used to compare means. Univariate and multivariate regression models were used to analyze the predictors of any response to rituximab. Kaplan-Meier method was used to calculate estimates of relapse-free survival, and log-rank test was used to compare these estimates. Result: We identified 127 patients diagnosed with ITP who received rituximab. The median age was 64 years (IQR 48-74), there were 46.5% females. The majority of the patients were Caucasians (95.3%), and rituximab was most commonly received as a second line therapy (73.2%). Median initial platelet count was 28,000/microL. Complete response was observed in 50% of African American patients compared with 43.0% in Caucasian patients (p-value 0.63). No predictors for any response on univariate or multivariate analyses were found. Race (OR 0.30, 95CI 0.03-3.25, p-value 0.32) and female gender (OR 0.76, 95CI 0.33-1.76, p-value 0.51) did not affect response to rituximab in our patient cohort. Relapse rate was 60% in African American patients versus 67.5% in Caucasians (p-value 0.72), and 68.7% in males versus 64.9% in females (p-value 0.71). ABO blood type also did not predict a response to Rituximab in our patient population (Table 1) Conclusion: In our study, race and gender did not affect response or relapse rates after rituximab treatment in chronic ITP. Patient's ABO blood type also did not predict a difference in response to Rituximab. However, our study was limited by a small sample size and further multi-institutional analysis is warranted to confirm the findings of our study.

The Risk of Infections in Adults with Primary Immune Thrombocytopenia (ITP)

Background Immunosuppressive treatment has remained a cornerstone in the management of primary ITP (pITP) for decades. Infections are known complications to immunosuppressive therapy, but the actual risk is not well studied in ITP. We have previously shown that the overall mortality risk is increased in pITP patients and specifically that death due to infections is 1.5-2.4-fold elevated compared to the general population. In this study,we aimed at quantifying the risk of infection, including infection subtypes, in adults with pITP and matched comparators from the general population. Study design We constructed a nationwide cohort of patients ≥18 years with pITP using the Danish Civil Registration System (CRS) and the Danish National Patient Registry (DNPR). We identified ITP patients using the specific ICD-10 diagnosis registration and age-sex matched these with up to 40 comparators without ITP from the general population. We excluded prevalent ITP, non-ITP thrombocytopenic disorders, and secondary ITP defined as one or more associated diagnosis registered any time before or up to 30 days after diagnosis of ITP. The latter included ITP in combination with hematological malignancies, autoimmune disorders etc. Hospital registered infections were identified through the DNPR, prior to 1995 using ICD-8 and ICD-10 diagnoses codes thereafter. Diagnosis codes were grouped, defining the following seven types or sites of infection: respiratory, urogenital, bloodstream, gastrointestinal, tissue and musculoskeletal, central nervous system (CNS), candidiasis and other fungal infections. Date of first registration of pITP marked start of follow-up and comparators were assigned the same start date. Patients and comparators were followed to the first of following events in each of the seven subgroups: infection, emigration, death, or end of study period (31 st of December 2016). Infections occurring before start date were categorized as prevalent. We computed 1-year, 5-year, and 10-year as well as overall cumulative incidences. In addition, relative increases in risk were estimated using Cox-specific hazard (csHR) and Fine-Gray subhazard ratios (subHR) with and without equivalent time-splits, and death as competing event. Results We identified 4,030 pITP patients and 161,020 matched comparators. In the combined group of all types of infections total follow-up time was 22,075 person-years (average 5.5 years) for pITP patients and 1,118,304 person-years (average 6.9 years) for comparators. Median age was 60 years [IQR 40-74]. Previous hospital registered infections had occurred in 37% of patients and 27% of comparators. Comorbidity was more frequent among pITP patients than among comparators. The 1-year cumulative incidences in all subgroups of infections were higher in patients compared with the general population (Figure 1). For blood stream infections the 1-year cumulative incidence reached 3.36% [95% CI 2.83-3.96] in patients and 0.47% [95% CI 0.44-0.51] in comparators. The cumulative incidences for all subtypes of infections remained higher for patients than comparators throughout the study period, but differences decreased over time. During the first year adjusted csHR for infections overall was 2.82 [95%CI 2.61-3.05] and the adjusted subHR was 2.20 [95% CI 2.01-2.41]. Blood stream infections had the relative highest risk with an adjusted csHR of 6.58 [95% CI 5.46-7.92] and adjusted subHR of 2.08 [95% CI 1.71-2.54] (Figure 2). Risks of the other types of infections were also increased during first year but diminished over time in general (Figure 2). For the entire study period the overall adjusted csHR of all infections was 1.51 [95% CI 1.35-1.67] with a subHR of 1.34 [95% CI 1.20-1.49]. Blood stream infections continued having the highest risk in the period between 6 th-10 th year with a csHR of 1.40 [95% CI 1.03-1.91]. Conclusion The risk of incident infection in patients with pITP is increased compared with the general population. This risk is especially elevated within the first year after diagnosis but remains higher than the general population also in subsequent years. The risk of blood stream infection is especially high within the first year after diagnosis, but remains higher even 20 years after diagnosis. These data may help clinicians to improve management of ITP and support shared decision making with patients.

Efficacy and Safety of Fostamatinib for Immune Thrombocytopenia in Clinical Practice in Spain: Interim Results of Fostames, Our National Fostamatinib Registry

Background: Fostamatinib is a splenic tyrosine kinase (SYK) inhibitor that prevents antibody-mediated platelet destruction. This drug has demonstrated to be effective and safe in immune thrombocytopenia (ITP). However, clinical trials may not accurately reflect what happens in clinical practice. Here we evaluated the efficacy and safety of eltrombopag in ITP in a real-world setting. Aims: To assess the management of adult patients with immune thrombocytopenia (ITP) with fostamatinib (Tavlesse®) in routine clinical practice outside controlled clinical trials. Methods: Multicentre, retrospective and prospective observational study at national level to evaluate the management of fostamatinib (Tavlesse®) in adult patients with ITP. An interim analysis of the medical records of all patients treated with fostamatinib (Tavlesse®) and suffering from ITP at each center was performed. Data were obtained in a retrospective and prospective observational, non-interventional manner to fulfil the exclusively scientific objective of this study, by conducting a review of the patient's clinical history. Thus, a total of 46 adult patients with ITP from 19 Spanish centers, who had been treated with fostamatinib, were evaluated. Results: The median age of our cohort was 74 yr (interquartile range, IQR, 60-81 yr). 25/46 (54%) were women. 43 of them were Primary ITP, 2 Secondary ITP and only one Evans Syndrome. 20 (47.6%) had ≥ 1 comorbidity of the Charlson Comorbidity Index. At the time of ITP diagnosis, the median platelet count was 8 x 10 9/L (IQR, 4-21 x 10 9/L) while 31 (69%) patients had hemorrhages. The median time with a diagnosis of ITP at initiation of fostamatinib was 61 months (IQR, 9-160 months). The median number of therapies prior to fostamatinib was 4 (IQR, 3-6). Of the entire cohort of 46 patients, 35 had been exposed to eltrombopag, 33 to romiplostim, 23 to intravenous immunoglobulins (IVIG), and 21 to rituximab. Only eight and two patients had received avatrombopag and splenectomy prior to fostamatinib treatment, respectively. 26/46 patients (56.5%) were treated with fostamatinib monotherapy throughout ITP. Twenty-three patients (50%) had signs/symptoms of bleeding in the month prior to treatment initiation. The median platelet count at baseline on fostamatinib was 12 × 10 9/L (IQR, 6-28 × 10 9/L), while the median platelet count to best response achieved after fostamatinib treatment was 84 × 10 9/L (IQR, 28-187 × 10 9/L). The median time from initiation of fostamatinib to maximum response to treatment was 2 months (IQR, 0-3.25). Similarly, the median duration of treatment with fostamatinib was 2 months (IQR, 1-4.25). The median time from initiation of fostamatinib to dose increase to 150 mg twice a day was 16 days (IQR, 8-38). A total of 32/46 patients (69.5%) responded to fostamatinib. Thus, 21 patients (45.7%) achieved a complete response (platelet count &amp;gt; 100 x 10 9/L) and 11 achieved a response. Twenty-one patients (45.6%) experienced adverse events, mainly grade 1-2, with diarrhea (n=13) and hypertension (n=8) being the most frequent. Twenty-five patients (54.3%) discontinued fostamatinib treatment: 18 did so due to inefficacy with three exitus due to severe bleeding in the context of refractory ITP. On the contrary, only three patients discontinued the drug due to toxicity/severe adverse events. Summary/Conclusion: Fostamatinib was used in heavily treated patients. However, fostamatinib proved to be effective and well tolerated in unselected patients with primary and secondary ITP. The association of fostamatinib with other drugs or its use in earlier lines of therapy may be associated with higher platelet response rates.

Efficacy and Safety of Dapsone in Primary Immune Thrombocytopenia. Results of a Randomized, Placebo-Controlled Multicenter Trial and of a Single-Arm, Emulated Trial in the Prospective, Multicenter Carmen-France Registry

Introduction: Adults treated for immune thrombocytopenia (ITP) usually respond to 1 st-line therapy but the majority of them eventually relapse and need a second-line treatment to spare corticosteroids. Dapsone is an antibiotic drug with immunomodulatory properties that has shown some efficacy in various autoimmune diseases including ITP in several retrospective studies. The aim of this study was to assess the efficacy and the safety of dapsone given as second-line for primary ITP. Methods DAPS-ITP was a prospective multicenter randomized open-label controlled trial aimed to assess the efficacy and safety of dapsone as a second-line option in adult ITP. Adult patients with primary and newly diagnosed or persistent ITP with previous transient response to corticosteroids and/or IVIg and a platelet count ≤30x10 9/L (or &amp;lt;50x10 9/L with bleeding manifestations) were eligible. After randomization (1/1 ratio), patients received either dapsone at 100 mg/day in combination with prednisone for 3 weeks (arm A) or just the 3 weeks course of prednisone (arm B). The primary outcome was the overall response rate (R + CR) in intention to treat at week 52 in the absence of any rescue therapy after week 6 and/or any other treatment for ITP over the study period. Complete response (CR) was defined by a platelet count &amp;gt;100x 10 9/L on dapsone (arm A) or off treatment (arm B) and response (R) by a platelet count &amp;gt;30x10 9/L with a least a doubling of the baseline count. We also conducted a single-arm, emulated trial in the prospective, multicenter CARMEN-France registry to provide real world evidence about the efficacy and the safety of dapsone in ITP. The CARMEN-France is a prospective, multicenter registry of adult patients with a new diagnosis of ITP in France. We selected the patients included in the registry between 2013 and 2022 with a primary ITP, exposed to dapsone, who met the inclusion criteria of the DAPS-ITP trial. We assessed the same outcomes than in the DAPS-ITP trial. Results In total, 93 patients (51% of females, median age 51 years [range: 33-66]) were included and randomized (46 in arm A and 47 in arm B) in DAPS-ITP trial. Median platelet count at inclusion was 25x 10 9/L [17-36], median ITP duration was 0.31 years [0.18-0.90]. Forty-two (arm A) and 45 patients (arm B) were followed up to week 52. In intention to treat (see figure), the overall response-rate (ORR) was respectively 8.70% [2.78%-18.93%] (arm A) and 4.26% [0.78%-12.81%] (arm B) at week 52 (primary outcome, p value = 0.78)). At week 24, the ORR was 25% [11.06%-41.78%] in arm A and 12.77% [5.18%-23.89%] in arm B (p value = 0.57). One death (intracranial hemorrhage) occurred in arm A, none in arm B; 36/46 patients (78%) from arm A had to discontinue prematurely dapsone, mostly for inefficacy with the need of other ITP treatment (n =10/36, 27.7%) or for various safety issues (n=26/36, 72%) including anemia ± gastro-intestinal manifestations (n=6); high methemoglobinemia (n=4); toxidermia (n=3) and others miscellaneous causes (n =13). In the CARMEN registry, 127 patients were exposed to dapsone. Among them, 50 met the inclusion criteria of the DAPS-ITP trial and had a 52-week follow-up after the initiation of dapsone. Patients characteristics were similar to those included in the DAPS-ITP trial. Three patients had no platelet count measured at W52 ± 4 weeks and were withdrawn from the primary outcome assessment. Overall, 5/47 achieved R or CR at W52 without any concomitant ITP treatment, resulting in an ORR of 10.6%; 95% CI: 3.5-23.1. At W24, 9/45 patients achieved R or CR (ORR: 20.0%; 95% CI: 9.6 -34.6; 5 patients had no platelet count at W24 ± 4 weeks in the real world). Seventeen (34.0%) experienced 19 adverse drug reactions (ADRs) including 8 hemolytic anemia, 4 methemoglobinemia and 3 cutaneous rash. Twelve patients discontinued dapsone due to an ADR. Conclusion Among adult patients with primary ITP and a platelet count &amp;lt;30 x 10 9/L treated with dapsone as a second-line treatment, only a minority of patients achieved a sustained response at W52. The low rate of durable response may be at least in part due to an unexpectedly high rate of early discontinuation observed in the dapsone arm (DAPS-ITP trial) due to the occurrence of ADRs, some of which could have been easily manageable outside a clinical trial. Further studies are needed to better define who are the few patients who may still benefit from dapsone, in a cost-effectiveness perspective.

Real World Practices of Thrombopoietin Receptor Agonist Use and Discontinuation in Pediatric Patients with Immune Thrombocytopenia (ITP): A Single Center Retrospective Review

Introduction Thrombopoietin Receptor Agonists (TPO-RAs) are becoming widely used as second-line treatment in patients with immune thrombocytopenia (ITP). These can be weaned/discontinued in adults. There is a paucity of literature on weaning and discontinuation practices in pediatric ITP. Methods We performed a retrospective review of pediatric patients aged 0-18 years with ITP treated with TPO-RAs at our institution over an eight-year period (2015-2022). Weaning and discontinuation practices were compared between patients based on timing of TPO-RA initiation: &amp;lt;3 months from diagnosis (group A), ≥3 to &amp;lt;12 months from diagnosis (group B), &amp;lt;12 months from diagnosis (group AB) or ≥12 months from diagnosis (group C). Results There were 11, 12 and 32 patients in group A, B, and C respectively (table 1). As of last follow up, 10 patients successfully weaned and discontinued their TPO-RA. Eighteen patients were weaning their TPO-RA monotherapy and 15 continued a TPO-RA at maximal dose or required the addition of another agent, such as an immunosuppressant, to permit TPO-RA weaning. Five patients discontinued their TPO-RA due to poor response. Seven patients had stopped the TPO-RA due to an alternate reason (family preference, side effects, etc.). There was no difference in any of these outcomes based on timing of TPO-RA initiation. In patients whose platelet count responded to TPO-RAs, the dose was weaned at the provider's discretion. The dose was generally not weaned for a platelet count &amp;lt;50k. Among only patients in which the TPO-RA monotherapy was weaned, patients in group AB had a shorter duration of TPO-RA treatment than patients in group C (IQR 12.1-48.9 months vs 37.5-88.0 months; p=0.019). While not statistically significant, after the start of the TPO-RA dose weaning, patients in group A weaned their TPO-RA at a faster rate (IQR 4.7-20.5% of maximal dose per month) compared to patients in groups B and C (IQR 1.8-5.1% of maximal dose per month and 1.5-5.5% of maximal dose per month). The 10 patients who fully weaned their TPO-RA had a shorter duration of TPO-RA use compared to the 18 patients who partially weaned their TPO-RA monotherapy (IQR 11.5-38.6 months vs 27.6-82.1 months; p=0.018). Once the wean of TPO-RA dose was started, patients who fully weaned their TPO-RA did so at a faster rate than patients who partially weaned (IQR 5.6-29.6% of maximal dose per month vs 1.0-3.4% of maximal dose per month; p=0.017; figure 1). Seven patients who fully weaned their TPO-RA had follow up CBCs between one and three months after discontinuation. Of these, five patients had platelet counts &amp;gt;100k, while the other two had platelet counts &amp;gt;40k that continued to rise to &amp;gt;80k within a year of discontinuation without further treatment. Of the remaining three patients, two had CBCs more than three months post TPO-RA discontinuation with platelet counts &amp;gt;100k without additional treatment and one had no follow up CBC after TPO-RA discontinuation. Two patients with follow-up had transient ITP exacerbations with platelet counts &amp;lt;10k at 14 and 31 months after TPO-RA discontinuation that were treated with anti-D/steroids and IVIG respectively with subsequent sustained improvement in platelet counts that did not require any further intervention. There was no difference in the number of rescue medications (IVIG, anti-D, steroids) required between patient groups based on timing of TPO-RA initiation or type of agent used. Patients who were treated with both romiplostim and eltrombopag required adjunctive therapies (such as immunosuppressants) more than patients treated with either agent alone (p=0.022). Conclusion TPO-RAs were weaned and successfully discontinued in 10 of 55 (18.2%) pediatric patients with ITP in our small cohort with a low rate of subsequent ITP exacerbation. There was no difference in TPO-RA discontinuation rate in patients with a good platelet response based on timing of TPO-RA initiation. Patients who started a TPO-RA within 12 months of their ITP diagnosis had a shorter duration of TPO-RA use than patients who started a TPO-RA more than 12 months after diagnosis. Patients who started a TPO-RA within three months of diagnosis were able to wean their TPO-RA dose at a faster rate than patients who started a TPO-RA more than three months after diagnosis. TPO-RA dose was weaned at a faster rate in patients who fully weaned their TPO-RA compared to patients who were partially weaned. This data should be validated in a larger study.

Interim Analysis of Treatment Satisfaction from a Prospective Phase 4 Study in Adult Immune Thrombocytopenia (ITP) Subjects after Switching from Eltrombopag or Romiplostim to Avatrombopag

Background: Recently, the Thrombopoietin-Receptor Agonist (TPO-RA) Patient experience survey (TRAPeze) determined that the characteristics which influence preference towards TPO-RA treatments the most were the method of administration and drug-food interactions. Specifically, participants were more likely to select an oral tablet over a subcutaneous injection and a treatment without food restrictions rather than one with food restrictions (McDonald V, et al, 2021). A majority of patients in a real-world analysis who switched from eltrombopag (ELT) or romiplostim (ROMI) to avatrombopag (AVA) did so due to perceived convenience benefits (Al-Samkari H, et al, 2022). The ongoing AVA-ITP-401 prospective interventional study is evaluating treatment satisfaction and on-therapy convenience in patients immediately switching to AVA from either ELT or ROMI and aims to provide valuable patient-reported outcomes. Safety and platelet count (PC) response to AVA following a switch from the other two TPO-RAs are also being evaluated. In a separate abstract submission, the mean/median PCs are reported to either be improved or maintained with AVA treatment over 90 days. Methods: This is an interim analysis of a prospective, multi-center, open-label Phase 4 study being conducted in the US (NCT04638829) since March 2021. Subjects who have been receiving ELT or ROMI for ≥90 days prior to study entry are enrolled and immediately switched to AVA at a starting dose of 20 mg daily. Key inclusion criteria: age ≥18 years; subjects have been undergoing treatment for primary ITP with ELT or ROMI for ≥90 days prior to the screening visit; subjects have had a previous response to either ELT or ROMI. The primary endpoint is occurrence of adverse events and serious adverse events. A key secondary endpoint is the change from baseline in each of the 4 domains of the self-administered Treatment Satisfaction Medication Questionnaire (TSQM) Version 1.4 (convenience, global satisfaction, effectiveness, and side effects) to Day 90 (D90) or End of Study (EOS). An increase in domain mean score indicates an increased patient preference to a given therapy in that domain. Clinic Visits were mandated per protocol at Days 15 (D15), 30 (D30), 60 (D60), and 90/End of Study (D90/EOS) with PCs obtained at each timepoint. The TSQM was assessed at baseline (BL), D30, and D90/EOS. Results: As of April 1, 2023, 51 patients were screened with 47 enrolled. 35 completed the study, 3 dropped out, and 6 are on-going. The mean age at enrollment was 58 years, the median (min,max) time since ITP diagnosis was 2.88 years (0.2,31.0), 60% were female, 72% were Caucasian, and 11% had a previous history of splenectomy. 62% of patients were switched to AVA from ELT (median prior treatment duration 42 weeks (range 12 - 442); median daily dose 50 mg) and 38% from ROMI (median prior treatment duration 81 weeks (range 12 - 468); median weekly dose ≤3 µg). Safety results will be reported when the study is complete. TSQM individual domain BL, D30, and D90/EOS mean values and mean percent change from BL following the switch from either ELT or ROMI to AVA are summarized in Table 1. In the Total Population, scores at BL in all four domains were generally high reflecting patient satisfaction to their prior therapy. Following the switch to AVA, however, there was measurable improvement in satisfaction across all domains-most pronounced in the effectiveness, convenience, and global satisfaction domains. This improvement began at D30 and was maintained through D90/EOS. The increase in patient-reported satisfaction was greater in ELT-switchers than with ROMI-switchers; however, improvement in satisfaction was observed by EOS across all four domains in the ROMI-switching population as well. Summary/Conclusion: Despite high patient satisfaction scores at BL from prior therapy (ELT or ROMI), patients reported higher satisfaction following a switch to AVA across all domains of the TSQM (effectiveness, side effects, convenience, and global satisfaction) over 90 days. In a population of patients who were generally responding to TPO-RAs prior to a switch to AVA, mean/median PCs were also either improved or maintained with AVA treatment for the duration of the study (reported in a separate abstract submission), suggesting that some patients may experience sustained effectiveness paired with enhanced overall treatment satisfaction when switching from ELT or ROMI.

Interim Analysis of Platelet Response in a Prospective Phase 4 Study in Adult Immune Thrombocytopenia (ITP) Subjects after Switching from Eltrombopag (ELT) or Romiplostim (ROMI) to Avatrombopag (AVA)

Background: Three thrombopoietin receptor agonists (TPO-RAs) [eltrombopag, romiplostim, and avatrombopag] are currently approved in the United States (US) and Europe for the treatment of ITP in adult patients. ROMI is administered via injection whereas ELT and AVA are oral medications. Polyvalent cations significantly limit the bioavailability of ELT; therefore, patients must follow rigid dietary restrictions. AVA is taken with meals and does not have food-type or timing restrictions, aligning with reported patient preferences for ITP treatments. 1 A recent retrospective study of heavily pre-treated ITP patients at 4 large US tertiary care medical centers demonstrated that 91% of AVA patients who switched from ELT and 94% who switched from ROMI achieved a platelet response (platelet count (PC) ≥50 x 10 9/L) regardless of the reason for switch. 2 This study required a &amp;lt; 30-day gap between ELT or ROMI discontinuation and initiation of AVA. Platelet count response to AVA following an immediate switch from another TPO-RA has not been previously reported in a prospective study. The current study aims to evaluate the safety and efficacy of immediately switching to AVA from other TPO-RAs as well as capture patient-reported outcomes of treatment satisfaction and convenience. Methods: This is an interim analysis of a prospective, multi-center, open-label Phase 4 study conducted in the US (NCT04638829). Subjects who have been receiving ELT or ROMI ≥90 days prior to study entry are enrolled and immediately switched to AVA. The main inclusion criteria: age ≥18 years; subjects have been undergoing treatment for primary ITP with ELT or ROMI for at least 90 days prior to the screening visit and have a desire to switch therapy; subjects have had a previous response to either ELT or ROMI, defined as at least 2 platelet counts ≥50×10 9/L. The primary endpoint is occurrence of adverse events and serious adverse events. Clinic Visits were mandated per protocol at Baseline (BL), Days 15 (D15), 30 (D30), 60 (D60), and 90/End of Study (D90/EOS), and PCs were obtained at each timepoint. The interim analyses reported here evaluate the PC response to AVA following the switch from either ELT or ROMI. Results: As of April 1, 2023, 51 patients were screened and 47 enrolled. 35 completed the study, 3 dropped out, and 6 are on-going. The mean age at enrollment was 58 years, the median (min,max) time since ITP diagnosis was 2.88 years (0.2,31.0), 28/47 (60%) were female, 34/47 (72%) were Caucasian, and 5/47 (11%) had a previous history of splenectomy. 62% of patients were switched to AVA from ELT (median prior treatment duration 42 weeks (range 12 - 442 weeks); median daily dose 50 mg) and 38% from ROMI (median prior treatment duration 81 weeks (range 12 - 468 weeks); median weekly dose ≤3 µg). Baseline platelet counts revealed that patients were generally well-controlled on prior TPO-RA therapies when switched with a mean platelet count of 152×10 9/L and median platelet count of 130×10 9/L in the overall study population. Safety results will be reported when the study is complete. PC values for the Entire Population, as well as the ELT- and ROMI-switching subpopulations are summarized in Table 1. Median PC values over time are represented in Figure 1 for the Entire Population. For the Entire Population, after switching to AVA 20mg daily, there was an initial early increase in median PC from baseline noted on day 15, with median PC remaining well above 50 x10 9/L at each subsequent time point with less variability compared with day 15. ROMI-switched patients had a higher BL median PC than ELT-switchers (170 vs 76 x10 9/L).; median PC in patients switching from ELT rose from BL, whereas those switched from ROMI maintained a similar median PC throughout, with the minimum PC observed being similar to the minimum BL value (27 vs 24×10 9/L). Summary/Conclusion: In a population of patients who were generally responding to TPO-RAs prior to a switch to AVA, mean/median PCs were either improved or maintained with AVA treatment over 90 days. Importantly, patient satisfaction was also higher across each domain of the TSQM-9 with AVA treatment (convenience, global satisfaction, safety, and effectiveness) than with the prior TPO-RA (results reported in related abstract submission) suggesting that some patients may experience sustained effectiveness paired with enhanced overall treatment satisfaction when switching from ELT or ROMI.

Initial Report of Povetacicept, an Enhanced Dual BAFF/APRIL Antagonist, in Autoimmune Cytopenias: The RUBY-4 Study

Introduction: BAFF and APRIL are cytokines with key roles in B cell development, survival, differentiation into antibody-secreting cells (ASCs; plasmablasts and plasma cells), and production of antibodies, making them promising targets for the treatment of autoantibody-associated diseases such as immune thrombocytopenia (ITP), warm autoimmune hemolytic anemia (wAIHA), and cold agglutinin disease (CAD). Patients with ITP or AIHA have elevated serum BAFF and APRIL levels and belimumab, a BAFF inhibitor, has exhibited encouraging efficacy in the treatment of lupus-associated ITP as well as alone or in combination with rituximab for the treatment of primary ITP. Due to their overlapping but non-redundant roles, inhibition of both BAFF and APRIL may be required for optimal efficacy in autoimmune cytopenias. In preclinical studies, dual BAFF/APRIL inhibition achieved superior suppression of ASCs and immunoglobulin levels vs inhibitors of BAFF or APRIL alone or an anti-CD20 antibody, suggesting the potential of this novel mechanism to modify the underlying pathogenesis of autoimmune cytopenias. Povetacicept (ALPN-303) is a TACI-Fc fusion protein engineered for potent dual BAFF/APRIL inhibition. In a mouse model of AIHA, povetacicept suppressed anti-erythrocyte autoantibodies and increased hematocrit (ASH 2022 abstract #3763). In a first-in-human study in healthy volunteers, povetacicept was well tolerated and reduced levels of circulating ASCs and immunoglobulins. This is an initial report of an open-label study of povetacicept in autoimmune cytopenias (RUBY-4; NCT05757570). Methods: RUBY-4 is a phase 1b, group-sequential, parallel-cohort study evaluating povetacicept in participants aged ≥18 years with a documented diagnosis of primary ITP, wAIHA, or CAD of ≥12 weeks in duration (Figure). Eligible participants must have sustained thrombocytopenia (ITP cohort) or sustained symptomatic anemia (wAIHA/CAD cohorts)-i.e., platelet count &amp;lt;30 × 10 9/L or hemoglobin ≤10 g/dL on 2 occasions ≥7 days apart during screening-and a history of failure or relapse on ≥2 prior treatments (including a thrombopoietin receptor agonist for the ITP cohort). Background therapy, including corticosteroids, is allowed but must remain at stable doses for the durations specified in the protocol. Participants receive povetacicept 240 mg subcutaneously once every 4 weeks for 24 weeks, with an optional 24-week treatment extension, followed by an 8-week off-treatment follow-up period. The primary objective is safety and tolerability; secondary objectives include pharmacokinetics, pharmacodynamics, immunogenicity, and efficacy. Results: As of 31 July 2023, 1 participant with ITP has enrolled and received 2 doses of povetacicept 240 mg without incident. Initial, preliminary observations include expected reductions in B cells and immunoglobulin levels. The RUBY-4 study continues to enroll in the US, Canada, Australia, and Turkey. At the time of presentation, available data including safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy (e.g., platelet or hemoglobin response rate, duration of response, and time to response) findings will be reported. Conclusions: To our knowledge, povetacicept is the first dual BAFF/APRIL inhibitor to be evaluated for the treatment of autoimmune cytopenias. Previous preclinical and healthy volunteer studies suggest the potential of povetacicept for suppression of the pathogenic autoimmunity that mediates platelet/erythrocyte destruction in ITP, wAIHA, and CAD, which may lead to more durable responses and improved outcomes for patients.

Predictors of Immune Thrombocytopenic Purpura in COVID-19 Positive Elderly Admitted in the Pre-Vaccination Era of the Pandemic; An Analysis Via the 2020 National Inpatient Sample

Introduction: Immune thrombocytopenia (ITP) involves an autoimmune destruction of platelets secondary to factors such as lupus erythematosus or viral conditions, e.g., COVID-19. With the onset of the pandemic in 2020, several reports of ITP in COVID-19 patients were published. However, to date, very limited information exists on the factors influencing the odds of ITP among the elderly who were COVID-19-positive before the introduction of mass vaccination campaigns. Hereby, we seek to bridge the knowledge gap via an in-depth analysis of hospitalization records. Methods: Our retrospective analysis via the 2020 National Inpatient Sample included admissions of patients ages≥60 years with a primary diagnosis of COVID-19. As the COVID-19 vaccination began on a large scale in December 2020 in the US and the ICD-10 code ‘U071‘ was introduced in April, we restricted our sample to admissions between April to November 2020 for better accuracy of results. Logistic regression models were used to estimate various patient characteristics that affected the odds of a diagnosis of ITP. Results: Between 1st April 2020 and 30th November 2020, there were 507860 patients of 60 and more years hospitalized primarily for COVID-19. An estimated 830 cases developed ITP, with an incidence rate of 163 cases per 100,000 COVID-19-positive patients. Multiple comorbidities such as a history of autoimmune conditions (aOR 1.982, 95% CI 1.483-2.648, p&amp;lt;0.01), chronic kidney disease (aOR 1.652, 95% CI 1.375-1.984, p&amp;lt;0.01), and cirrhosis (aOR 4.119, 95% CI 2.964-5.724, p&amp;lt;0.01) showed higher odds of ITP. Racial disparities were also noted as compared to Whites, Blacks (aOR 0.523, 95% CI 0.417-0.657, p&amp;lt;0.01) and Hispanics (aOR 0.461, 95% CI 0.355-0.600, p&amp;lt;0.01) showed reduced odds. Furthermore, Medicaid insurers also had lower odds (aOR 0.411, 95% CI 0.244-0.694, p&amp;lt;0.01) than those insured by Medicare. Hypertension (aOR 0.747, 95% CI 0.624-0.894, p&amp;lt;0.01) and long-term aspirin use(aOR 0.700, 95% CI 0.572-0.856, p&amp;lt;0.01) also showed fewer events of ITP (Table 1, Figure 1). The mean Charlson Comorbidity Index (CCI) score was higher among those who had ITP (mean score of 4.20 vs. 3.08, p&amp;lt;0.01). Furthermore, patients with ITP also experienced a longer stay (12.29 days vs. 8.34 days, p&amp;lt;0.01). Events of ITP among the elderly with COVID-19 were linked with a poorer prognosis as 27.1% of all patients died (vs. 15.2% in the non-ITP group, aOR mortality 1.880, 95% CI 1.585-2.230, p&amp;lt;0.01). Conclusion: Our results provide the first report of factors linked with the risk of ITP among the elderly with COVID-19. Various conditions such as autoimmunity and racial disparities have previously been reported to influence events of ITP, as also seen in our study. We further report higher odds among patients with cirrhosis and chronic kidney disease, while those with hypertension and long term aspirin use had lower odds. ITP also led to a higher mortality rate. Broader studies can help understand the impact of our findings during the pre-vaccination era, which can help set a template for protocols among the elderly in future pandemics.

Health Related Quality of Life in Patients with Primary ITP Compared with Population Norms: A Multicenter Retrospective Analysis of Data from Norwegian ITP Registry

Introduction: Immune thrombocytopenia (ITP) is characterized by thrombocytopenia and varying grades of bleeding manifestations. Many patients develop a fear of bleeding, which can impact their health-related quality of life (HRQoL). In addition, often necessary lifestyle adjustments as well as treatment-related side effects may further reduce HRQoL. Aims: to estimate HRQoL in adult patients diagnosed with ITP and to compare their HRQoL to that of the general population using the EuroQol-5 Dimensions-3 Levels (EQ-5D-3L) questionnaire. Methods: Data from the Norwegian ITP (NOR-ITP) Registry was used. Adult ITP patients registered in NOR-ITP from Dec 2016 to May 2023 were included in this study. Patients included in NOR-ITP complete the EQ-5D-3L questionnaire, when included in the registry and then annually as part of their scheduled follow-up. In patients who had completed several EQ-5D-3L questionnaires, the most recent one was used. The age-adjusted Norwegian EQ-5D-3L populations norms were used as reference values for Index and VAS scores. Missing data were replaced using multiple imputation. Results: Median (IQR) age of 247 patients was 57 years (34); M:F ratio = 1:1.5. ITP was newly diagnosed in 18 (7%), persistent in 14 (6%), and chronic in 215 (87%) patients. Platelet count was &amp;gt;50*10 9/L in 166 (67%) patients, between 31 and 50*10 9/L in 15 (6%), and &amp;lt; 30*10 9/L in 18 (7%), unknown for 19% (48). Thirty-nine (16%) patients were never treated for ITP, 80 (32%) patients had remission induced by glucocorticoids +/- IVIGs, and 128 (52%) were treated with second-line agents. Ongoing treatment was an immunosuppressive agent (i.e. glucocorticoids +/- IVIGs, rituximab (received during the last 3 months), azathioprine, cyclosporine-A, mycophenolate mofetil) in 43 (17%) patients, a thrombopoietin receptor agonist in 42 (17%) patients, while 162 (66%) were off-ttraetment. Median time from diagnosis of ITP to most recent EQ-5D questionnaire was 4 (10) years. Figure1a displays the frequency of reported problems (levels 2 and 3) in ITP patients compared to the population norms. ITP patients reported significantly more problems in 4 out of 5 domains. EQ-5D index score was significantly lower in ITP patients compared to the general population [Mean (SD) = 0.790 (0.23) vs 0.830 ([0.041); p-value 0.007]. Likewise, we found VAS to be significantly lower in ITP patients compared to the general population [Mean (SD) = 70.82 (21.09) vs 77.32 (5.554); p-value 0.0001). Within the ITP cohort, we found significantly lower VAS scores in ITP patients receiving ongoing treatment compared to those off treatment (p-value 0.01), as shown in figure1b. However, no significant difference was found concerning Index scores when comparing patients with ongoing to off-treatment. Comparing index scores and VAS according to platelet count category (&amp;lt;30; 31-50; &amp;gt;50*109/L) and the phase of ITP did not reveal any significant differences. Conclusion: This study is the first to evaluate HR-QoL using EQ-5D in a well-characterized cohort of patients with ITP. In line with existing evidence, using other HRQoL instruments, we found significantly reduced HRQoL in ITP patients compared to the general population. ITP patients receiving ongoing treatment had worse HRQoL compared to those off-treatment. Limitations of this study are the the long time period between diagnosis and completing the questionnaire, the observational and retrospective study design, and the lack of predictors for HRQoL.

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

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

Interim Baseline Characteristics of Adult Patients with Immune Thrombocytopenia Enrolled in the Observational Multicenter Phase 4 Adopt Study to Evaluate the Use and Effectiveness of Avatrombopag

Background: Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by low platelet counts and increased bleeding rate. Current first-line ITP treatments include corticosteroids and immunoglobulins. If first-line therapy fails, subsequent treatment options include the thrombopoietin receptor agonists (TPO-RAs). Avatrombopag (AVA), the most recently approved TPO-RA, is a small molecule, administered orally with no food-type restrictions, and no significant hepatotoxicity. AVA was approved by FDA in 2019 and EMA in 2021, for the treatment of chronic ITP in adult patients who are refractory to other treatments. The Phase 4 ADOPT study (NCT04943042) will generate data on the real-world effectiveness and safety of AVA in routine clinical practice in Europe. Described here are the interim baseline characteristics of patients enrolled in the ADOPT study. Study objective and methods: ADOPT is a multicenter, observational study with the primary objective to describe the real-world effectiveness of AVA treatment over a prospective period of 12 months. Prospective data will be collected at routine clinical visits. In addition, retrospective data will be collected from patients' medical records for up to 12 months prior to AVA treatment start. Eligible patients must be ≥18 years of age, have provided informed consent, have an established and well documented ITP diagnosis, and are treated with, or initiating treatment with AVA for ITP, at enrollment. Exclusion criteria include enrollment in other clinical interventional studies, or intake of an investigational medicinal product, ≤3 months prior to inclusion. The primary endpoint is the cumulative number of weeks with a platelet count ≥30×10 9/L. Platelet counts during rescue medication use and within 4 weeks after stopping a rescue medication or following splenectomy are considered non-response and thus not included in the primary endpoint cumulative number. Secondary endpoints supporting the primary objective include cumulative number of weeks with a platelet count ≥50×10 9/L, patients (n [%]) with a platelet count ≥30×10 9/L and ≥50×10 9/L for at least 8 consecutive weeks, patients (n [%]) experiencing WHO bleeding grade ≥2, patients (n [%]) requiring rescue medication, and time from AVA treatment start to platelet count ≥30×10 9/L and ≥50×10 9/L. Additional secondary endpoints are AVA dose and dosing frequency, reason for ITP treatment discontinuation or change from one ITP treatment to another (prior to and during the study), use of concomitant ITP medications, physicians' satisfaction with outcome of AVA treatment (5-point scale), physician assessment of clinically meaningful effects (Clinical Global Impression of Change scale), healthcare resource use, as well as a number of patient reported outcomes (PROs). Secondary safety endpoints include serious adverse events and adverse events of special interest (thromboembolic events [TEEs] and significant bleeding events). Results: Fifty-six patients have been enrolled in the study as of July 2023, and demographic and baseline characteristics information were available for 39 patients (Table 1). The mean age (SD) was 52.2 (18.10) years and 20 patients were male (51.3%). Nine patients had a baseline PC &amp;lt;30x10 9/L. Eight patients (20.5%) reported newly diagnosed/persistent ITP with &amp;lt;12 months disease duration since diagnosis; 31 (79.5%) had chronic ITP. A majority of patients (n=22; 56.4%) had no previous exposure to TPO-RAs. One patient was splenectomized (2.6%), and seven had experienced prior TEEs (17.9%). Conclusions: This baseline interim data set from the ADOPT Phase 4 study provides important insight into the types of ITP patients who are being prescribed avatrombopag across European centers. More than half of enrolled patients were TPO-RA naïve, and over 20% did not have chronic ITP although the mean duration of ITP was 7.6 years and median duration of 4 years at the time of first AVA treatment. Though previous clinical trials excluded patients with newly diagnosed/persistent ITP and prior TEEs, this real-world evidence study does not exclude such patients. We look forward to presenting safety and efficacy data, as well as multiple PROs, from this observational study at future scientific meetings. Study status: The study was initiated in January 2022, will include approximately 60 sites in Europe, and enroll 150 patients in total.