ABSTRACT Avatrombopag maleate (AOG), a thrombopoietin receptor agonist, is a generic drug for which a viable route of synthesis has been identified, in which three nitrosamine drug substance–related impurities (NDSRIs) have been identified. In silico toxicity assessment has been carried out. Being product specific NDSRIs, the specification limit has been defined based on Carcinogenic Potency Categorization Approach (CPCA) approach and selective and sensitive LC‐MS/MS–based analytical method developed and validated for their trace level with predefined parameters with results outcome, which are specificity, linearity with r 2 between 0.9905 and 0.9999, the LOD as 0.34 ppm, and LOQ as 0.67 ppm for all impurities; the obtained recovery was in the range of 94.0%–105.6% with a SD range between 0.6 and 2.8. The overall mean between the method precision and intermediate precision studies was in the range of 6.43–6.81 ppm, and the overall % RSD for the 12 determinations was between 1.3 and 2.4. The method robustness has also been demonstrated with deliberate variations. The solution stability was studied for about 24 h to assess the nature of the solutions prepared. Further, to assess the fate of each NDSRIs, the sample was inflicted to acid, base, oxidative, thermal, and photolytic stress conditions. This intensive stress study concluded that the identified NDSRIs are carried from the starting material of secondary amine scaffolds in the reaction conditions and not a degradation product. Thus, in this current research work, we revealed three new potential NDSRIs for the AOG drug substance, their toxicity assessment, and CPCA scoring to arrive at the specification limit (Category 3 → AI 400 ng/day → 6.6 ppm as target level). The source of the NDSRI formation has also been demonstrated; finally, their selective, sensitive, and stability indicating LC‐MS/MS–based analytical method has been implemented. This wholistic lifecycle approach eliminates the risk‐assessment gaps and ratifies the regulatory requirements, thereby endures the product quality and patients safety.

Background/Objectives: Thrombocytopenia subsequent to antineoplastic therapies leads to bleeding complications, treatment delay or de-intensification, and platelet transfusion requirement. Evidence suggests that thrombopoietin receptor agonists (TPO-RAs) can restore platelet counts in this scenario. Avatrombopag (AVA) is an oral TPO-RA whose efficacy in treating thrombocytopenia in haematological malignancy has been barely addressed. We aimed to evaluate AVA's efficacy in improving platelet recovery and reducing transfusion requirement in haematological patients with thrombocytopenia. Methods: In this retrospective observational study, haematological patients who developed thrombocytopenia persisting for ≥3 weeks and were treated with AVA between November 2023 and December 2024 were recruited. Results: Twenty-three patients were recruited. Nineteen (82.6%) responded to AVA, most within the first 4 weeks: 10 (43.5%) and 9 (39.1%) achieved platelet counts ≥ 30 × 109/L (partial response) and ≥100 × 109/L (complete response), respectively. Response was always maintained for 30 days after AVA withdrawal. Transfusions were significantly fewer than in the previous period: 0 (0-8) vs. 11 (2-15), median (interquartile range [IQR]), p = 0.007. Once on treatment, 13 (56.5%) patients no longer required transfusion. No patient delayed or de-intensified chemotherapy. No safety concerns were reported. Conclusions: AVA shows promise in safely reducing thrombocytopenia-associated transfusion needs in haematological malignancy.

Primary Sjögren’s syndrome (pSS) is an autoimmune disorder characterized by xerostomia and keratoconjunctivitis sicca, with approximately 10%–20% of patients developing concurrent immune thrombocytopenia (ITP). Recent studies suggest the pathogenesis of primary Sjögren’s syndrome - associated immune thrombocytopenia (pSS-ITP) may involve dysregulated TLR7 signaling, B-cell hyperactivation, and autoantibody-mediated platelet destruction. Beyond conventional therapies (e.g., glucocorticoids and intravenous immunoglobulin [IVIG]), emerging treatments have garnered increasing attention, including thrombopoietin receptor agonists (TPO-RAs), B-cell–targeted therapies, and mTOR inhibitors. Predictive models incorporating bone marrow megakaryocyte counts and autoantibody profiles may facilitate individualized treatment selection. Future multicenter clinical studies are warranted to evaluate the long-term efficacy and safety of novel agents and to explore biomarker-guided precision therapy. This review systematically summarizes the pathophysiological mechanisms of pSS- ITP, synthesizes current clinical treatment strategies, and highlights key biomarkers with potential implications for therapeutic response, aiming to provide a theoretical foundation and practical guidance for optimizing individualized therapeutic regimens.

Adult patients with immune thrombocytopenia (ITP) have an increased risk of venous thrombosis as compared to the general population. The management of ITP in the context of anticoagulation is challenging. We conducted an observational study in the prospective, multicenter, national CARMEN-France registry. Adult patients with newly diagnosed ITP between June 2013 and May 2022 were selected. We assessed the cumulative incidence of venous thrombosis during follow-up with death as a competing event, described these events, and assessed patient outcomes depending on management strategies, with a focus on thromboses that occurred during treatment with thrombopoietin receptor agonists (TPO-RA). Among the 1303 patients selected for this study, 53 experienced venous thrombosis. The cumulative incidence of venous thrombosis was 2.6% (95% CI: 1.8-3.7) at 1 year and 8.6% (95% CI: 5.8-12.0) at 5 years. In patients exposed to TPO-RA, the cumulative incidence was 9.3% (95% CI: 6.2-13.2) and 13.4% (95% CI: 8.6-19.2) at 1 and 5 years of exposure, respectively. Patients who experienced thrombosis were older, had more frequently a history of venous thrombosis and secondary ITP, a more severe ITP, and were more frequently treated with TPO-RAs. Twenty (37.7%) of the 53 events were atypical, including five cerebral venous thromboses. Four patients died, and seven experienced major bleeding. The analysis of different managements of ITP after the thrombotic event suggested that the safest strategy was to promptly control ITP to enable early anticoagulation, including using TPO-RAs. Long-term anticoagulation therapy should be considered in patients treated with TPO-RAs and persistent risk factors for thrombosis.

Immune thrombocytopenia (ITP) is a secondary autoimmune complication that can develop in patients with connective tissue diseases (CTDs). Its pathogenesis involves autoantibody-mediated platelet destruction and immune complex deposition, constituting a distinct clinical manifestation of CTD-related autoimmune abnormalities in the hematologic system. Among the subtypes of CTD-related immune thrombocytopenia (CTD-ITP), systemic lupus erythematosus (SLE) and primary Sjögren's syndrome (pSS) are the most prevalent. CTD-ITP occurs within the unique clinical context of being a secondary condition to systemic diseases such as SLE or primary pSS, resulting in more complex clinical management and an increased risk of adverse outcomes. At present, no disease-specific treatment guidelines exist for CTD-ITP, and clinical management is largely based on therapeutic strategies established for primary ITP. However, conventional therapies, including glucocorticoids, often fail to achieve durable clinical remission, and prolonged use is associated with serious adverse effects. In recent years, the introduction of targeted agents such as thrombopoietin receptor agonists (TPO-RAs) and rituximab has markedly improved treatment response rates in CTD-ITP. Meanwhile, emerging targeted therapies, such as spleen tyrosine kinase (Syk) and Bruton's tyrosine kinase (BTK) inhibitors, as well as neonatal Fc receptor (FcRn) inhibitors, have shown considerable clinical promise. This narrative review, based on recent literature, focuses on SLE-ITP and pSS-ITP, summarizing their clinical heterogeneity, disease-specific pathophysiological mechanisms, and recent therapeutic advances. The objective is to provide evidence-based guidance for the personalized management of CTD-ITP.

Thrombocytopenia, a common side effect of chronic liver disease (CLD), increases bleeding risk during invasive procedures. Thrombopoietin receptor agonists (TPO-RAs) offer an effective alternative to platelet transfusions. A systematic review and meta-analysis assessed the efficacy and safety of TPO-RAs in thrombocytopenia patients undergoing elective procedures. A systematic search (PubMed, Google Scholar, Cochrane Library, up to August 2024) evaluated perioperative thrombopoietin receptor agonists in patients with thrombocytopenia undergoing elective procedures. Primary and secondary outcomes included platelet count ≥50 x 10^9/L, bleeding/thrombotic events, platelet transfusions, adverse effects, rescue treatment, discontinuation, death, and serious adverse effects, analyzed via random-effects model. This meta-analysis synthesized evidence from nine trials and 1,409 patients (819 TPO-RAs vs 590 placebo; mean age ~59 years). TPO-RAs significantly increased the likelihood of achieving platelet counts ≥50×10⁹/L compared with placebo (RR 3.93, 95% CI 2.24-6.90; p<0.00001). They also reduced the need for preoperative platelet transfusions (RR 0.34, 95% CI 0.27-0.44; p<0.00001) and lowered the risk of surgical bleeding (RR 0.64, 95% CI 0.49-0.85; p=0.002). In contrast, no statistically significant differences were observed for thrombotic events (RR 1.24, 95% CI 0.57-2.67; p=0.59), treatment-emergent adverse events (RR 0.99, 95% CI 0.89-1.09; p=0.83), study drug discontinuation (RR 0.74, 95% CI 0.32-1.70; p=0.47), rescue treatment use (RR 0.82, 95% CI 0.34-2.03; p=0.67), all-cause mortality (RR 1.23, 95% CI 0.35-4.35; p=0.75), or serious adverse events (RR 1.13, 95% CI 0.70-1.84; p=0.62). TPO-RAs raise platelet counts and reduce transfusions in CLD patients undergoing invasive procedures. However, close monitoring for thrombotic risks is necessary, and further research is needed to optimize dosing.

Allogeneic haematopoietic stem cell transplantation (allo-HSCT) is potentially curative for high-risk haematological diseases but may lead to persistent cytopenias such as poor graft function (PGF) or graft failure (GF). Thrombopoietin receptor agonists (TPO-RAs) like eltrombopag or romiplostim are effective but have pharmacologic and practical limitations. This retrospective study evaluated avatrombopag, a novel oral TPO-RA, in 11 adult patients with persistent thrombocytopenia following allo-HSCT (8 with PGF and 3 with GF). Avatrombopag was initiated at 20 mg/day orally, escalated to 40 mg/day after a median of 21 days and up to 60 mg/day after a median of 36 days as the maximum dose in patients who did not achieve an adequate response. The median time to response was 55 days, with a median treatment duration of 134 days. A haematological response was achieved in all eight patients with PGF, with significant improvements in platelet counts and other haematopoietic lineages. In contrast, no response was documented in patients with GF. No severe adverse events or complications were reported. Notably, these findings suggest that avatrombopag is a promising alternative for PGF, offering practical advantages over other TPO-RAs, although prospective studies are needed with a larger sample size of patients to confirm these results.

Key mechanisms underlying immune thrombocytopenia (ITP) pathophysiology include impaired platelet production and macrophage-mediated platelet destruction, the latter of which is the disease driver in more than half of patients. Traditional sequential treatment approaches achieve suboptimal responses in many patients. This review summarizes ITP pathogenesis and the treatment landscape and proposes a personalized treatment approach for ITP after first-line treatment (corticosteroids, intravenous immunoglobulin, anti-D therapy) based on targeting underlying disease mechanisms with immunomodulatory and bone marrow-supportive therapies (fostamatinib, rituximab, and thrombopoietin receptor agonists [TPO-RAs]) prior to proceeding to later-line therapies. Clinical evidence of monotherapy and real-world studies of combination therapy are reviewed to support mechanism-based treatment selection, focusing on the complementary actions of fostamatinib (to target platelet destruction) and TPO-RAs (to stimulate platelet production). In prior studies, fostamatinib with or without TPO-RAs demonstrated durable platelet responses and manageable safety as second-line or later ITP treatment. The proposed treatment framework augments guidelines by recommending fostamatinib, rituximab, or TPO-RAs as second-line therapy options based on patient-specific disease characteristics and risks. Patients with inadequate response to fostamatinib or TPO-RA monotherapy may combine these therapies to address both platelet destruction and platelet production deficits. This novel framework tailors therapy to patient-specific pathophysiology by preferentially targeting both impaired platelet production and increased platelet destruction to support individualized care.

Abstract Background: Cancer therapy-induced thrombocytopenia (CTIT) is a common complication of anti-tumor therapy and causes treatment delays or interruptions, increased bleeding risk and compromised outcomes. We aimed to evaluate hetrombopag, an oral thrombopoietin receptor agonist that prevented CTIT in breast cancer patients. Methods: In this multi-center, prospective exploratory trial (NCT05394285), breast cancer patients with platelet counts (PLT) &amp;lt; 50×109/L during current anti-tumor treatment cycle (Cycle 1) were enrolled. Those patients were randomized to receive either hetrombopag (7.5 mg daily, n = 30) or subcutaneous recombinant human thrombopoietin (rhTPO, 15000 U daily, n = 30) until their PLT &amp;gt;100×109/L, which was defined as the thrombocytopenia treatment phase (TTP). Eligible patients were scheduled to continue the same anti-tumor regimen in their subsequent treatment cycle (Cycle 2). The secondary prevention phase (SPP) was initiated using a self-controlled design, with prophylactic hetrombopag (7.5 mg/day for 14 days) administration beginning one day after the start of Cycle 2. The primary endpoint was the response rate during the SPP, defined as the proportion of patients meeting all predefined criteria before the next treatment cycle (Cycle 3): 1. no platelet transfusion requirement; 2. no anti-tumor treatment modification (≥20% dose cut, ≥5 days delay, or discontinuation) ; 3. absence of severe thrombocytopenia (PLT &amp;lt;25×109/L, or PLT &amp;lt;50×109/L for ≥7 days). Results: Between Sep 2022 and May 2025, 67 breast cancer patients were enrolled in the study. After excluding 1 patient who withdrew informed consent, 66 patients comprised the full analysis set (FAS). During the trial, 6 patients discontinued participation in the SPP, the remaining 60 patients completed both TTP and SPP, forming the per-protocol (PP) population. In the FAS, 51 (77.3%) patients received antibody-drug conjugates (ADCs) monotherapy, 14 (21.2%) received regimens containing chemotherapy (RCC), and 1 (1.5%) with targeted therapy plus ADC. In the PP population, the response rate in the SPP was 85.0% (51/60). During the TTP, 86.7% (26/30) of patients in the hetrombopag group achieved response, compared to 80% (24/30) in the rhTPO group. No treatment-emergent severe adverse events occurred. Conclusions: As the first prospective trial to evaluate hetrombopag for preventing CTIT in breast cancer patients, this self-controlled exploratory study demonstrated hetrombopag may be a promising option for the secondary prevention of CTIT. The promising response rate observed during the TPP, coupled with a favorable safety profile, supports further large-scale investigation of hetrombopag for the prevention of CTIT in multi-cycle anticancer regimens. Citation Format: H. Sun, H. Lv, W. Chen, Y. Zhao, M. Zhang, L. Niu, Z. Liu, X. Guo, X. Chen, Y. Feng, L. Wang, H. Zeng, J. Wang, Y. Cui, M. Yan. Secondary prevention of cancer therapy-induced thrombocytopenia with hetrombopag in breast cancer: a prospective,multi-center,self-controlled exploratory trial [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS1-03-01.

Unintended First-Trimester Exposure to Two Distinct Thrombopoietin Receptor Agonists in Consecutive Pregnancies Without Maternal or Fetal Harm.

The immune-mediated destruction of hematopoietic stem cells (HSCs) is the most recognized mechanism of aplastic anemia (AA); however, the unfavorable therapeutic effect of immunosuppressive therapy (IST) has shown that the pathogenesis of AA is still unclear. Our previous studies revealed that M1 and M2 macrophages (MΦs) in the bone marrow (BM) microenvironment exert opposite effects on hematopoiesis and that their aberrant polarization is involved in poor hematopoietic reconstitution after transplantation. To determine whether aberrant BM MΦs polarization is involved in the occurrence of AA, we established a classic mouse model of AA and performed a prospective case-control study involving AA patients and age-matched healthy controls (HCs). BM MΦs polarization was analyzed by flow cytometry. RNA-seq, PCR and Western blot were performed to investigate the underlying mechanism involved. To clarify the effect of thrombopoietin receptor agonist (TPO-RA) on BM MΦs polarization and subsequent impact on hematopoiesis and immunity, we established in vitro coculture assays of HSCs/T cells and BM MΦs treated with or without hetrombopag (HET), a novel TPO-RA. We found that in mice with AA, aberrant BM MΦs polarization, characterized by increased M1 MΦs number and decreased M2 MΦs number, accompanied by hematopoietic failure, was observed. Consistently, aberrant BM MΦs polarization, which is related to the downregulation of the PI3K/AKT pathway, was observed in AA patients. HET corrected the aberrant polarization of BM MΦs in AA patients and therefore improved their impaired functions, especially their hematopoiesis-supporting and immune-regulatory abilities, which may be related to the activation of the PI3K/AKT pathway. Although further validation is needed, our data suggest that remodeling BM MΦs polarization may be one of the reasons for the better clinical response to the combination of HET and IST in AA patients.

Eltrombopag is an orally active thrombopoietin receptor agonist indicated for the treatment of thrombocytopenia. The purpose of this randomized study is to evaluate the bioequivalence of test and reference eltrombopag olamine tablets in healthy Chinese subjects after consuming a low-calcium, high-fat, high-calorie breakfast. This was a single-center, randomized, open-label, two-sequence, two-period crossover study. Enrolled subjects were randomly divided into two groups at a 1:1 ratio, with each group randomly receiving either the test or reference eltrombopag olamine tablets per period. The washout period was set to 14 days. The concentration of eltrombopag in plasma was quantified using validated liquid chromatography-tandem mass spectrometry. Safety assessments were conducted throughout the entire trial. This study ultimately included 36 healthy subjects. The geometric mean ratio for maximum plasma concentration between the test or reference eltrombopag olamine tablets was 92.68%; the geometric mean ratio for the area under the concentration-time curve from the time zero to the last measurable concentration was 97.15%; for the area under the concentration-time curve from the time zero to infinity, the geometric mean ratio was 97.30%. The geometric mean ratios and their 90% confidence intervals for the key pharmacokinetic parameters fell within the range of 80.00-125.00%. Within the safety data set of 36 subjects, adverse events were reported in nine subjects, totaling 14 occurrences. All reported adverse events were Grade 1, and no serious adverse events occurred. These findings indicate that a single oral administration of the test eltrombopag is bioequivalent to the reference eltrombopag in healthy subjects after consuming a low-calcium, high-fat, high-calorie breakfast, with both formulations exhibiting a favorable safety profile. These results support the therapeutic interchangeability of the test formulation with the reference product, offering a reliable alternative for clinical use. This trial was registered at the Drug Clinical Trial Registration and Information Disclosure Platform ( http://www.chinadrugtrials.org.cn , CTR20230598) and ClinicalTrials.gov ( https://clinicaltrials.gov , NCT06768619).

Repurposing lusutrombopag: unveiling anti-Staphylococcus aureus activity in a novel oral thrombopoietin receptor agonist.

Guideline on the emergency management of critical bleeding in patients with immune thrombocytopenia.

Thymoma-related aplastic anemia is a rare entity. This article retrospectively analyzes the clinical features and treatment course of a patient who developed aplastic anemia (AA) post-thymectomy, complemented by a systematic review of relevant literature. A 47-year-old female was diagnosed with thymoma, myasthenia gravis (MG), and severe AA (SAA). SAA onset occurred two weeks after total thymectomy, and the patient ultimately succumbed to concurrent COVID-19 infection following allogeneic hematopoietic stem cell transplantation (allo-HSCT). We also reviewed the clinical characteristics, treatment strategies, and prognosis of 47 thymoma-related aplastic anemia patients reported in the literature. AA may present prior to thymoma diagnosis, concurrently with thymoma, or post-thymectomy. Some patients progress to pure red cell aplasia (PRCA) and/or megakaryocytic aplasia, often following prior chemotherapy or radiotherapy. Similar to Good syndrome and PRCA, thymectomy fails to alleviate AA, and spontaneous improvement is rare. Treatment options for thymoma-related aplastic anemia include cyclosporine A (CsA) monotherapy, CsA combined with glucocorticoids, thrombopoietin receptor agonists (TPO-RAs), and allo-HSCT. However, regimens of cyclophosphamide plus methylprednisolone and glucocorticoid monotherapy show limited efficacy. The overall one-year mortality rate is alarmingly high at 29.8%. For young thymoma-related aplastic anemia patients with SAA and suitable donors, allo-HSCT remains the preferred treatment.

Acquired aplastic anemia (AA) is an immune-mediated bone marrow failure in which cytotoxic T lymphocytes (CTLs) target hematopoietic stem cells (HSCs). Approximately 30% of AA patients develop immune escape clones lacking specific HLA class I alleles (HLA[-]) through loss of heterozygosity in chromosome 6p (6pLOH) or somatic loss-of-function mutations. Eltrombopag (EPAG), a thrombopoietin receptor agonist (TPO-RA), demonstrates clinical efficacy in AA in combination with immunosuppressive therapy; however, its impact on HLA(-) HSCs and hematopoietic progenitor cells (HPCs) remains poorly understood. In this study, we evaluated the hematopoietic effects of EPAG using umbilical cord blood-derived HPCs and a humanized hematopoiesis model in immunodeficient (BRGS) mice. Furthermore, we established induced pluripotent stem cell (iPSC)-derived hematopoietic models encompassing five wild-type (WT) clones and seven HLA-lacking clones, differentiated them into HPCs, and assessed their responses to EPAG. EPAG selectively conferred a proliferative advantage to specific hematopoietic fractions in HLA(-) HPCs, distinct from that observed in WT HPCs. Molecular analyses revealed clone-dependent differences in CD110 expression and downstream effectors, including phosphorylated STAT5, FOXM1, and E2F1, indicating differential activation of TPO receptor-mediated signaling pathways among clones. These findings highlight the functional diversity of HLA(-) hematopoiesis and suggest that the hematopoietic response to EPAG is governed by clone-intrinsic signaling programs. Furthermore, our results provide new insights into how eltrombopag modulates clonal competition and hematopoietic recovery in immune-escape hematopoiesis, with potential implications for optimizing therapeutic strategies and predicting clinical response in patients with acquired AA.

Evans syndrome is a rare autoimmune disorder characterized by the simultaneous or sequential occurrence of autoimmune cytopenia. The disease is chronic, relapsing, and frequently refractory to standard therapies. Typical symptoms include anemia-related fatigue, pallor, and jaundice due to hemolysis and petechiae, and purpura and mucosal bleeding due to thrombocytopenia. Treatment often involves a stepwise escalation of immunosuppressive treatments (e.g., corticosteroids, anti-CD20 monoclonal antibodies) and/or stimulants (e.g., thrombopoietin receptor agonists). However, sustained remission remains elusive in many patients. We report the case of a 69-year-old woman with a 19-year history of Evans syndrome, presenting with a life-threatening relapse marked by severe thrombocytopenia and strong hemolytic activity. The patient had previously undergone multiple treatment regimens and had developed comorbidities that both complicated disease management and treatment strategies. Despite repeated therapeutic interventions with various immunosuppressant agents, she remained transfusion-dependent and clinically unstable and experienced various treatment complications. Additionally, targeting antibody-producing plasma cells with daratumumab (anti-CD38) led to a rapid fall in transfusion dependency, clinical stabilization, and transition to outpatient care. Unfortunately, the patient later succumbed to infectious complications after a femoral fracture. This case underscores the therapeutic complexity of multirefractory Evans syndrome and the limitations of conventional therapy. The addition of daratumumab, resulting in depletion of CD38 + plasma cells, helped achieve hematologic stabilization in this refractory case.

Immune thrombocytopenia (ITP) is an autoimmune disorder that occurs in children and adults, and it is characterized by a reduced platelet count. Hetrombopag, a novel thrombopoietin receptor agonist (TPO-RA) for second-line ITP treatment, lacks thorough efficacy and safety evaluation in paediatric patients. In this study, we assessed complete response (CR), response (R), overall response (OR), no response (NR), durable response (DR), relapse and treatment-free response (TFR) rates in 93 paediatric ITP patients who were treated with hetrombopag. The results demonstrated that the CR rate, R rate, OR rate, NR rate, DR rate, relapse rate and TFR rate were 61.3%, 15.1%, 76.3%, 23.7%, 76.1%, 26.8% and 52.1% respectively. Patients with newly diagnosed ITP exhibited a higher TFR rate than those with persistent or chronic ITP. Furthermore, among the nine patients who switched from other TPO-RAs, seven patients achieved OR during initial treatment, including three patients who achieved CR and four patients who achieved R. The overall incidence of adverse events was 37.6%, with no serious adverse events reported. Our findings highlight that hetrombopag is both safe and effective in paediatric patients and may serve as a viable option for patients for whom first-line therapy fails.

Background/Objectives: Eltrombopag, a thrombopoietin receptor agonist, is widely used in the treatment of relapsed or refractory (R/R) immune thrombocytopenia (ITP). This study aimed to compare the efficacy, safety, and tolerability of generic eltrombopag (Rompag®) with original eltrombopag (Revolade®) in adult patients with R/R ITP. Methods: In this prospective, multicenter study conducted at 10 centers, 104 adult ITP patients were followed for at least 3 months. A total of 35 (33.7%) patients received Rompag® and 69 (66.3%) received Revolade®. The primary endpoint was platelet (PLT) response, defined as achieving a PLT count ≥50 × 109/L and at least a twofold increase from baseline, without the need for rescue therapy or transfusion. Secondary endpoints included bleeding rates, fatigue-related quality of life, adverse events (AEs), and rescue therapy requirements. Results: PLT response was achieved in 94.2% of patients in the Revolade® group and 85.7% in the Rompag® group (p = 0.16). Bleeding rates decreased significantly in both groups (Revolade®: 56.5% to 2.9%, p < 0.001; Rompag®: 62.9% to 2.9%, p < 0.001). Although overall AE rates were similar (30.4% in the Revolade® group and 42.9% in the Rompag® group; p = 0.22), arthralgia (28.6% vs. 7.2%, p = 0.01) and vomiting (11.4% vs. 0%, p = 0.008) were more frequent with Rompag®. Conclusions: Both generic and original eltrombopag demonstrated no statistically significant difference in efficacy in achieving PLT response, reducing bleeding, and improving fatigue-related quality of life in adult patients with R/R ITP. Although minor differences in AE profiles were observed, particularly arthralgia and vomiting, both formulations showed acceptable safety and tolerability.

IntroductionParagangliomas (PGLs) are rare neuroendocrine tumors. Atypical manifestations such as skin lesions mimicking vasculitis secondary to catecholamine-induced vasoconstriction are extremely rare. Both hypoxia observed in cyanotic congenital heart disease, like tetralogy of Fallot (TOF), and succinate dehydrogenase B (SDHB) germline mutations can activate hypoxia-inducible factor (HIF) pathways, leading to tumor proliferation.Clinical CaseA 34-year-old female patient, with a history of TOF repair, hypothyroidism, hypertension, carotid body tumor surgery, and autoamputation of two toes in the right foot, presented with necrotic, ulcerative lesions on her extremities. The patient was treated with steroids and methotrexate for 3 months. Examination revealed blood pressure of 100/70 mmHg, a diastolic murmur in the pulmonary area, pretibial edema, right third toe gangrene, and multiple skin lesions (Figure 1). Rheumatologic tests for vasculitis were negative, and the skin biopsy was inconclusive. Abdominopelvic CT performed for vascular imaging and detected a retroperitoneal mass (80x46 mm) in the posterior of the pancreas. 18F-FDG PET/CT showed intense uptake. Significant increase in urinary normetanephrine (10-fold) and norepinephrine (18-fold) levels was detected. 68Ga Dotatate PET/CT revealed intense somatostatin receptor activity. Focal uptake was seen on the MIBG scan. The tumor was inoperable due to involvement of the superior mesenteric and celiac arteries. Genetic analysis identified a pathogenic heterozygous SDHB gene variant (c.262A>C; p.Thr88Pro).Given the ineffectiveness of vasculitis treatment, it was discontinued. The gangrenous toe was amputated, and the patient was managed with hyperbaric oxygen therapy along with alpha blockade therapy. The treatment resulted in the healing of necrotic lesions. 177Lu-Dotatate therapy resulted in partial tumor regression and biochemical response, but it was discontinued due to pancytopenia. Therapy was resumed with thrombopoietin receptor agonist support but later discontinued due to recurrent cytopenia.131I-MIBG therapy was administered. However, despite these interventions, the patient developed progressive cardio-renal complications and died due to sudden arrhythmia.ConclusionThis case highlights the rare hypoxia-related PGL phenotype in a patient with TOF and SDHB mutation. Although SDHB mutations are sufficient to initiate PGL development via pseudohypoxia, the accompanying chronic systemic hypoxia due to TOF may have exerted a synergistic effect by further stabilizing HIF signaling, thereby accelerating tumorigenesis and contributing to the unusual clinical presentation. Cutaneous lesions mimicking vasculitis may be attributed to catecholamine-induced vasoconstriction and ischemia. Recognition of atypical findings may allow for early diagnosis and intervention. Multidisciplinary management is essential in inoperable cases with complex comorbidities.Figure 1:Necrotic cutaneous lesions of the patient’s lower extremity