Aplasticanemia (AA) is an autoimmune-mediated bone marrow failure syndrome characterized by excessive T-cell activation and destruction of hematopoietic stem and progenitor cells. Eltrombopag (ELT), a thrombopoietin receptor agonist, has been shown to promote hematopoiesis and exert immunomodulatory effects. However, its role in regulating T cells in AA remains unclear. This study aimed to investigate whether ELT modulates the T-cell functional phenotype via the oxidative metabolism pathway. Using single-cell RNA sequencing of AA mouse models under different treatment regimens, we identified differentially expressed genes in T-cell subsets associated with oxidative stress. ELT treatment effectively reduced reactive oxygen species (ROS) levels in both CD4⁺ and CD8⁺ T cells, reshaped T-cell subset composition, and attenuated cytotoxic activity. Mechanistically, Western blot analysis confirmed that ELT significantly upregulated ENPP1 and ENTPD5, which are involved in oxidative metabolism. Collectively, these findings reveal a previously unrecognized mechanism through which ELT restores T-cell homeostasis by fine-tuning oxidative metabolism, highlighting its therapeutic potential beyond hematopoietic stimulation in AA.

Real-world data on treatment response after switching between thrombopoietin receptor agonists are limited for patients with immune thrombocytopenia (ITP). The objective of this study is to describe treatment patterns and outcomes in patients with primary ITP who switched from eltrombopag (ELT) or romiplostim (ROMI) to avatrombopag (AVA). We conducted a retrospective chart review study of adults with primary ITP who initiated ELT or ROMI on or after 1 July 2019, switched to AVA within 30 days of ELT/ROMI discontinuation and had ≥6 months follow-up after AVA initiation. Patients were followed from AVA initiation until last contact, death or study end (21 March 2025), whichever occurred earliest. Response was defined as achieving ≥1 platelet count (PC) of ≥30 × 109/L, ≥50 × 109/L or ≥100 × 109/L in the absence of rescue therapy. Response durability was the percentage of time on AVA with PCs above the response threshold among responders. Patients (N = 201) most commonly discontinued ELT/ROMI due to lack of efficacy (59.2%). Among patients with baseline PCs <30 × 109/L (n = 79), 98.7% and 94.9% achieved PCs ≥30 × 109/L and ≥50 × 109/L on AVA respectively. Median response durability was 93.8%, 89.6% and 67.4% for ≥30 × 109/L, ≥50 × 109/L and ≥100 × 109/L respectively. Most patients who switched to AVA from ELT or ROMI achieved or maintained a clinically meaningful and durable platelet response throughout the study period.

Eltrombopag (ELT) is a second-line therapy for pediatric immune thrombocytopenia (ITP), but inter-individual variability in metabolism leads to wide plasma concentration differences at the same dose, affecting efficacy and adverse drug reactions (ADRs). To validate the feasibility of individualized drug regimens based on blood drug concentration guidance in pediatric persistent/chronic ITP (P/CITP) and to provide a new method of individualized treatment with eltrombopag for pediatric P/CITP. This prospective, observational cohort study enrolled 70 children with refractory persistent/chronic ITP (P/CITP) to evaluate the feasibility and value of plasma concentration–guided individualized dosing. Patients were assigned to a conventional group (dose titration by platelet counts and bleeding events) or an individualized group (dose adjustments additionally guided by ELT concentrations), with 6-month follow-up. Although no statistical significance was observed, the individualized group achieved a higher overall response rate (82.9% vs. 71.4%) and complete response rate (65.7% vs. 48.6%), with more stable platelet counts, fewer bleeding events, reduced requirements for concomitant/rescue therapy, and a lower incidence of ADRs (17.1% vs. 37.1%). Similarly, though not statistically significant, the individualized group had lower direct medical costs and improved cost-effectiveness. These findings suggest that plasma concentration-guided individualized ELT therapy may enhance therapeutic efficacy, improve safety profiles, and reduce medical costs, which represents a meaningful step toward precision medicine in the field of pediatric hematology.

Left panel: Scheme of the XPAG-immune thrombocytopenia trial. The dexamethasone (DEX) arm consisted of DEX 40 mg/day for days 1-4 for one to three cycles every 28 days to a maximum of 12 weeks, cycles 2 + 3 were optional. Patients randomised to eltrombopag (ETB) + DEX received eltrombopag in combination with a short course of high-dose DEX beginning on day 1 (40 mg/day during days 1-4). The starting dose of ETB was 50 mg/day for 2 weeks; thereafter, the ETB dose was increased by 25 mg for all patients who did not achieve the target platelet count of ≥50 × 109/L. The ETB tapering was performed by decreasing the dose by 25 mg every 2 weeks to a minimum dose of 25 mg every other day for all patients. Right upper panel: Clinical outcomes in patients treated with first-line ETB + DEX. Patients displayed a qualitatively longer response duration and qualitatively reduced usage of rescue medication. Right lower panel: The immunological T-cell response was different in treatment responders and non-responders. Patients with sustained response (responders) displayed a high T-cell clonality at baseline. Clones are depicted as bubbles (right side).

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.

Left panel: Scheme of the XPAG-ITP trial. The dexamethasone monotherapy (DEX) arm consisted of DEX 40 mg/day for days 1-4 for one to three cycles every 28 days to a maximum of 12 weeks, cycles 2 + 3 were optional. Patients randomised to eltrombopag combined with dexamethasone (ETB + DEX) received eltrombopag (ETB) in combination with a short course of high-dose DEX beginning on day 1 (40 mg/day during days 1-4). The starting dose of ETB was 50 mg/day for 2 weeks; thereafter, the ETB dose was increased by 25 mg for all patients who did not achieve the target platelet count of ≥50 × 109/L. The ETB tapering was performed by decreasing the dose by 25 mg every 2 weeks to a minimum dose of 25 mg every other day for all patients. Right upper panel: Clinical outcomes in patients treated with first-line ETB + DEX. Patients displayed a qualitatively longer response duration and qualitatively reduced usage of rescue medication. Right lower panel: The immunological T-cell response was different in treatment responders and non-responders. Patients with sustained response (responders) displayed a high T-cell clonality at baseline. Clones are depicted as bubbles (right side).

SummaryThe efficacy of a triple combination of rabbit anti‐human thymocyte immunoglobulin (rATG), ciclosporin and eltrombopag (EPAG) was prospectively evaluated in patients with severe or transfusion‐dependent non‐severe aplastic anaemia (SAA) across 29 institutions in Japan. Sixty patients were enrolled, of whom 48 had SAA. The primary end‐point, the haematological overall response rate at 12 weeks, was 52.6% (95% confidence interval, 39.0%–66.0%), increasing to 67.9% at 26 weeks. The most frequent grade 3/4 adverse event was febrile neutropenia (20.0%). One elderly patient with severe neutropenia died of sepsis. Progression to myelodysplastic syndrome (MDS) or acute myeloid leukaemia (AML) was observed in one patient each. There was no association between the haematological response and high thrombopoietin levels, presence of paroxysmal nocturnal haemoglobinuria‐type cells or Human Leukocyte Antigen (HLA) class I allele‐lacking cells. Five patients (8.5%) had chromosomal abnormalities at baseline with no subsequent progression to MDS or AML. By 26 weeks, chromosomal abnormalities had emerged or expanded in eight patients (17.4%), although abnormalities of chromosome 7 were not observed within 52 weeks. These results suggest that triple therapy with rATG may be as effective as that with horse anti‐human thymocyte immunoglobulin. Notably, the addition of EPAG did not induce chromosomal abnormalities associated with poor prognosis.

The utilization of eltrombopag (EPAG) in the management of post allogenic hematopoietic cell transplant (HCT) cytopenia has exhibited promising outcomes. Isolated thrombocytopenia and poor graft function (PGF) are factors that adversely influence transplant outcomes and patient well-being. This retrospective study aims to assess EPAG efficacy in this context as a primary outcome and evaluate early EPAG tapering post complete response (CR) for cost efficiency and response durability as a secondary outcome. We analyzed 39 patients who underwent allogeneic HCT; EPAG was administered to 89.7% of patients for PGF and 10.3% for isolated thrombocytopenia. The overall response rate (ORR) after 4 weeks of EPAG treatment was 71.8%, with 48.7% achieving a complete response (CR). Early tapering of EPAG post-CR was explored for cost benefit among responders. Early tapering was defined as the start of tapering after 4 weeks of achieving CR and was found to be associated with significant response durability with a trend towards cost effectiveness. Eltrombopag response was independent of megakaryocyte number or density prior to drug initiation. The study suggests EPAG as a safe treatment for PGF and isolated thrombocytopenia post-allogeneic HCT and proposes early drug tapering as a potentially cost-beneficial approach.

UCB. Graft source was bone marrow (n=26), peripheral blood (n=6) and cord blood (n=3).Myeloablative conditioning consisting of Cyclophosphamide/ATG was used in all MSD/autologous recipients, MUD recipients received Cyclophosphamide/Fludarabine/ATG with five also receiving TBI .Fourteen patients underwent upfront HSCT, while twenty had received prior immunosuppressive therapy (IST).Results: Engraftment was achieved in 30/34 (86%) patients.Median neutrophil and platelet engraftment times was 20 and 23 days respectively.Four patients experienced Primary Graft Failure, with 2 achieving engraftment after a second and third transplant respectively.aGvHD occurred in 8/34 patients (23.5%) (6 with Grade II-III, 2 with Grade IV).Immune reconstitution was observed in all 25 evaluable patients by 12 months.Median follow-up was 76.6 months.25/34 patients are alive with normal blood counts.Estimated 5-year Overall Survival was 76% in the entire cohort; 93% in the MSD group (95% CI, 61%-99%) (p = 0.02).TRM at 30 days and 12 months was 6% (95% CI, 1.5%-21.5%)and 21% (95% CI, 10%-38%) respectively.Cause of death was infection (6/9), refractory GvHD (2/9) and cardiac complications (1/9).In univariate analysis Donor type and the presence of aGvHD were the strongest predictors impacting OS.Prior IST did not impact outcome.Conclusions: HSCT for SAA showed excellent outcomes in MSD recipients.Donor type and aGvHD were key survival predictors.Notably, prior IST had no significant impact on outcomes, suggesting upfront HSCT may offer an advantage by avoiding associated burdens and delays.The favorable outcomes observed with haploidentical HSCT using TCR+/CD19+ depletion show promise in expanding donor options.

BackgroundTo compare the efficacy of eltrombopag (EPAG) combined with standard immunosuppressive therapy (IST), EPAG with cyclosporine or cyclosporine alone in children with severe aplastic anemia (SAA).MethodsThis is a retrospective study. The patients were categorized as three groups: Group A (EPAG + rabbit antithymocyte globulin + cyclosporine, n = 12), Group B (EPAG + cyclosporine, n = 13), and Group C (cyclosporine alone, n = 16). The overall remission rate (ORR) of each group at 1, 3, 6, and 12 months of treatment was evaluated.ResultsThere was no significant difference in the ORR among Groups A, B, and C at 1, 3, 6 and 12 months (P > 0.05). The incidence rates of adverse reactions in each group at 6 months were 36.4% (4/11), 58.3% (7/12), and 69.2% (9/13), respectively (P = 0.264). Patients with a duration from diagnosis to receiving EPAG treatment of ≤ 60 days, a diagnosis of SAA, a platelet (PLT) count ≥ 15 × 109/L, a white blood cell (WBC) count of ≥ 2.0 × 109/L, N% of ≥ 40%, a lymphocyte count of ≥ 1.0 × 109/L, and a CD4+/CD8+ ratio of ≥ 1.5 were more likely to achieve a hematopoietic response. No clonal evolution was observed in any of the patients.ConclusionEPAG combined with IST shows comparable efficacy to cyclosporine alone in children with SAA, along with a favorable safety profile. Patients with earlier initiation of EPAG and preserved residual hematopoietic function are more likely to achieve remission, without serious adverse reactions or significant clonal evolution.

Outcomes of eltrombopag combined with immunosuppressive therapy in adults with severe aplastic anemia: A large, propensity-matched retrospective analysis

Aplastic anemia treatment in older adults in resource-limited settings: Can rabbit ATG bridge the gap?

Abstract Introduction Eltrombopag (ELT) is a thrombopiotin receptor agonist approved for treatment of pediatric immune thrombocytopenia (ITP) and severe aplastic anemia (SAA) with reported hepatobiliary adverse events (AE). We assessed the frequency and clinical determinants of hepatobiliary AE in patients with ITP or SAA receiving ELT therapy. Methods we retrospectively reviewed the records of 61 patients aged from 1 to 18 years receiving ELT; 42 patients with ITP and 19 with SAA. Patients were categorised according to hepatobiliary toxicity into three groups: no toxicity (group A), isolated hyperbilirubinemia (group B), and transaminitis with/without hyperbilirubinemia (group C). Results we observed our patients along the first three courses of treatment. The mean duration of the 1st course in group A, B and C was 8.2, 9.5 and 7 months, respectively. While, the mean duration of the 2nd course in group A, B and C was 2.6, 2.8 and 2.1 months, respectively. Also, the mean duration of the 3rd course in group A, B and C was 5.2, 1.7 and 8.9 months, respectively. Overall, 36% of patients developed hepatobiliary toxicity (24.6% had isolated hyperbilirubinemia while 11.5% had transaminitis with/without hyperbilirubinemia). Most patients (93%) in isolated hyperbilirubinemia group had SAA, in contrast to transminitis group in which 40% out of 54.29% had ITP (p &amp;lt; 0.001). Isolated hyperbilirubinemia occurred at similar doses in ITP and SAA (50-75mg), while transaminitis devleoped in ITP at a lower dose (50- 75 mg) than those with SAA (100-125mg). Ten patients discontinued treatment for toxicity; one with liver cell failure. All patients showed normalization of their liver function tests after discontinuation of treatment. Conclusion hepatobiliary toxicity represents a common occurrence with ELT therapy, and it requires regular follow up of liver function tests.

BackgroundImmune thrombocytopenia (ITP) in children is an autoimmune disorder in which a significant subset develops persistent or chronic disease requiring second-line therapies, yet the optimal sequencing of agents such as rituximab (RTX) and eltrombopag (ELT) to achieve sustained remission off-treatment remains (SRoT) undefined.ObjectivesThis study assessed whether RTX-first sequential therapy outperforms upfront ELT monotherapy in achieving durable remission for pediatric persistent/chronic ITP (p/cITP) after first-line failure.MethodsThis nonrandomized multicenter prospective cohort study enrolled 55 children (April 2020 to July 2023) with refractory p/cITP until first-line therapy. They were assigned to RTX-first (RfG, n = 35: single RTX dose, then ELT for nonresponders) or ELT monotherapy (ELT-first group [EfG], n = 20) groups, with 12-month follow-up. Primary endpoints were SRoT and treatment duration (TD), and secondary endpoints were response rate and safety. The study is registered at ChiCTR2100048162.ResultsAmong the 55 enrolled children (RfG = 35, EfG = 20), RfG had superior SRoT (30%; 95% CI, 15.6%-48.7%) than ELT-monotherapy group (0%; 95% CI, 0%-18.7%; P = .016), although 12-month remission rates were comparable (84.8% vs 87.5%; P = .804). RfG had a shorter TD (median 18 vs 34 weeks; P = .009), even in severe cases (baseline platelets 20 ×109/L vs 29 ×109/L; P = .034). Early ELT (≤96 days) in RfG nonresponders improved outcomes (P = .024). Both treatments had favorable safety (grade 1-2 adverse events, <15%).ConclusionsRTX-first treatment yields a better SRoT and shorter TD than ELT monotherapy for pediatric p/cITP, with comparable remission and safety.

The Janus kinase (JAK)/signal transducer and activatorof transcription(STAT) signaling pathway is a key therapeutic target for inflammatoryand neoplastic diseases such as rheumatoid arthritis (RA) and certaintypes of cancer. Although several inhibitors have been approved formedical use, their associated adverse effects limit their therapeuticuse. Therefore, it is essential to search for new, safer inhibitors.In this work, we applied computer-aided approaches consisting of consensusmolecular docking and molecular dynamics using the JAK2 structureas a filter of 3330 drugs approved by the Food and Drug Administration(FDA) retrieved from the ZINC20 database. The best predicted virtualhits were evaluated in an ex vivo STAT1,3 phosphorylationfunctional model in human lymphocytes induced by IL-6 stimulation.The docking-based consensus-scoring strategy allowed the selectionof pitavastatin (PIT), eltrombopag (ELT), flavoxate (FLA), and empagliflozin(EMP) as potential JAK2 inhibitors. Their stability was confirmedby running independent molecular dynamics simulations of 200 ns intriplicate, which showed comparable stability with baricitib (BAR)and showed that hydrogen bonding is involved in their binding withkey amino acids of the ATP-binding site. In the ex vivo evaluations, pitavastatin (0.5004 μM), eltrombopag (0.2548μM), flavoxate (0.1536 μM), and empagliflozin (0.2548μM) affected the phosphorylation of downstream STAT1 and STAT3signaling molecules, similarly to tofacitinib citrate (TOF) (1.2 nM). These results encourage further in-depth preclinical experimentsaimed at exploring the additional effects of the JAK2-STAT1/3 signalingpathway.

BackgroundDifferences in the clinical efficacy and adverse drug reactions (ADRs) of eltrombopag (ELT) in children with immune thrombocytopenia (ITP) may be positively correlated with the serum trough concentration of ELT. Individual pharmacokinetic variations primarily contribute to differences in ELT concentration among individuals. This study is the first to establish an expected concentration reference range for ELT in treating pediatric persistent/chronic ITP (P/CITP) across different age-groups.MethodsA total of 94 patients with 111 serum trough concentrations were analyzed to validate this range. The median age of patients was 7.68 (5.35, 10.21) years, and 44.7% (42/49) of them were male.ResultsSubgroup analyses revealed significant differences in ELT concentration related to the age, efficacy, and ADR occurrence. The expected concentration reference range was determined using the dose-related concentration (DRC) factor combined with the ELT dosage. The DRC factor ranges were as follows: 0.083–0.216 (mg/L)/mg in children aged 1–6 years, 0.058–0.125 (mg/L)/mg in children aged 7–12 years, and 0.043–0.097 (mg/L)/mg in children aged 13–18 years. Among patients with measured trough concentrations within the expected reference range, 84.3% (59/70) achieved response/complete response (R/CR) and 88.6% (62/70) did not experience ADR.ConclusionSerum trough concentration monitoring based on the established reference ranges could enhance the precision of individualized ELT therapy in pediatric ITP patients.

Objective: This research investigated the interaction between Eltrombopag (EB) and Human Serum Albumin (HSA) by fluorescence spectroscopy and voltammetry while explaining the quenching mechanism. Material and Method: The electrochemical studies were conducted in an acetate buffer solution (AB) at pH 4 by differential pulse voltammetry (DPV). For the fluorescence studies, EB, HSA, and a mixture of EB and HSA solutions were designed with a pH of 4.7, AB containing 20% DMSO. Result and Discussion: The interaction between EB and HSA was examined by fluorescence and electrochemical titrations, which showed a quenching effect and peak shifting. Fluorescence titrations indicate that EB’s HSA quenching process is static and has a hypsochromic shift. Analysis of thermodynamic parameters and higher binding constants concluded a strong and spontaneous interaction. Electrochemical titrations show the intercalation of EB into HSA.

Eltrombopag (EPAG) added to standard immunosuppressive therapy (IST) has been associated with higher overall response (OR) and complete response (CR) rates in adult patients with treatment-naïve severe aplastic anemia (SAA), but clinical evidence on the efficacy of EPAG in children with acquired aplastic anemia is limited and controversial. This retrospective study aimed to determine the efficacy and safety of EPAG combined with IST in pediatric patients with SAA compared to a standard IST group. We compared the efficacy and safety of EPAG combined with IST (n=38) versus IST alone (n=57) as frontline treatment for pediatric patients with SAA. The EPAG+IST group had higher CR and OR rates at 3 and 6 months, although the 1-year OR, CR, and partial response rates showed no significant difference between the two groups. Older age at diagnosis (>8.95 years) was associated with a higher OR rate at 6 months and 1 year in the EPAG+IST group (p=0.007 and p=0.005, respectively). The addition of EPAG to IST did not achieve superiority over IST alone in terms of overall survival (OS) and event-free survival (EFS) in this study, with 1-year EFS of 81.1% for EPAG+IST and 71.3% for IST, and 1-year OS of 89.2% versus 80.4%, respectively. EPAG+IST induced a faster response compared to IST alone without increasing toxic effects, but EPAG did not confer additional benefits regarding OS or relapse rates in children. Notably, older age at diagnosis was significantly associated with improved response rates in the EPAG+IST group.

Comparison of Haploidentical-Hematopoietic Stem Cell Transplantation Using Modified Post-Transplantation Cyclophosphamide and Eltrombopag Combined With Immunosuppression for the Treatment of Severe Aplastic Anemia.

Persistent pulmonary hypertension of the newborn (PPHN) represents a life-threatening cardiopulmonary condition characterized by hypoxia-driven pulmonary vascular remodeling. While transcription factor EB (TFEB), a master regulator of cellular adaptation to hypoxia, has been implicated in vascular pathologies, its mechanistic role in PPHN remains undefined. This study elucidates the molecular interplay of TFEB in hypoxia-induced PPHN pathogenesis. Fetal rat models of hypoxia-induced PPHN, including untreated hypoxic models and hypoxic models treated with the TFEB inhibitor Eltrombopag (EO), as well as a hypoxia-induced human pulmonary artery endothelial cell (HPAEC) model, were established. Multimodal assessments, including histopathology, qRT-PCR, JC-1 staining, immunofluorescence, flow cytometry, and Western blotting, were employed to evaluate the effects of TFEB on mitophagy and NLRP3 inflammasome. In the hypoxia group, significant thickening of the pulmonary arterioles and right ventricular wall was observed. Immunostaining revealed a significant increase in the relative staining density of TFEB-positive, NLRP3-positive, and LC3-positive cells, alongside elevated expression of mitophagy-proteins and NLRP3 inflammasome-related proteins. TFEB inhibition downregulated the expression of PINK1, TOMM20, COX IV, P62, and LC3II/I ratio, impairing mitophagy, while upregulating eNOS, NLRP3, and GSDMD, thereby enhancing NLRP3 activation and pyroptosis. In the EO group, fetal rats exhibited more pronounced pulmonary arteriole thickening, intensified fluorescence signals for NLRP3, caspase-1, and GSDMD, reduced mitophagy-related protein expression, and further elevated NLRP3 inflammasome-related protein and GSDMD expression. TFEB exerts a protective effect in PPHN by inhibiting NLRP3 inflammasome activation through PINK1/Parkin-mediated mitophagy, highlighting TFEB’s potential as a therapeutic target for hypoxia-induced PPHN.