Recombinant Human Thrombopoietin Research Articles

Abstract C067: Immune thrombocytopenia induced by PD-1/PD-L1 inhibitors in a patient with non-small cell lung adenocarcinoma: A case report and literature review

Abstract Introduction: The introduction of immunotherapy, particularly programmed cell death protein 1 (PD-1) and programmed cell death-ligand 1 (PD-L1) inhibitors, has transformed the treatment paradigm for non-small cell lung adenocarcinoma (NSCLC), significantly improving patient survival rates. However, alongside their immune-activating effects, these agents can also lead to immune-related adverse events (irAEs), affecting various organ systems. Among these, immune thrombocytopenia (ITP) is a rare but potentially life-threatening complication characterized by the destruction of platelets by autoantibodies, resulting in decreased platelet counts and an increased risk of bleeding. While ITP has been identified as a complication of immunotherapy, particularly PD-1 or PD-L1 inhibitors, its incidence, clinical presentation, and management remain poorly understood. Case Presentation: The 73-year-old female with stage IIIA poorly differentiated NSCLC who received chemotherapy with Taxol/Carboplatin and concurrent radiation therapy followed by a right upper lobectomy, initiated on immunotherapy with durvalumab, a PD-L1 inhibitor, developed severe thrombocytopenia (grade 4) after receiving two cycles of durvalumab. Despite steroid treatment, her condition persisted, indicating immune-related adverse events (irAEs). After confirming the diagnosis through further investigation, including molecular analysis, the patient was treated with intravenous immunoglobulin (IVIG), which significantly increased her platelet counts. Durvalumab was discontinued, and fostamatinib, a spleen tyrosine kinase (SYK) inhibitor, was initiated to manage the irAEs effectively. Discussion: ITP is recognized as an immune-related adverse event (irAE) associated with PD-1 or PD-L1 inhibitors, although it remains rare and poorly understood. Several case reports have highlighted the occurrence of ITP induced by these inhibitors, demonstrating varied clinical presentations and responses to treatment. Mechanisms underlying ITP induction by PD-1/PD-L1 inhibitors are not fully elucidated but may involve immune dysregulation, including CD4+ and CD8+ T cell activation, production of antiplatelet antibodies, and increased expression of PD-L1 on platelets. Management strategies for ITP induced by PD-1/PD-L1 inhibitors include steroids, intravenous immunoglobulin (IVIG) therapy, recombinant human thrombopoietin (TPO), interleukin-6 (IL-6) receptor antagonists, and immunosuppressive agents. However, the effectiveness of these treatments varies among patients, highlighting the need for individualized approaches and further research to optimize management strategies. Conclusion: The prompt recognition and management of ITP induced by PD-1/PD-L1 inhibitors are essential for ensuring favorable patient outcomes. Further research is needed to understand the underlying mechanisms and develop effective prevention and management strategies for this rare but serious immune-related adverse event. Citation Format: Aliya M Khan, Richa Dawar. Immune thrombocytopenia induced by PD-1/PD-L1 inhibitors in a patient with non-small cell lung adenocarcinoma: A case report and literature review [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C067.

Efficacy and safety of recombinant human thrombopoietin for the treatment of chronic primary immune thrombocytopenia in children and adolescents: A multicentre, randomized, double-blind, placebo-controlled phase III trial.

The efficacy and safety of recombinant human thrombopoietin (rhTPO) in children and adolescent patients with chronic primary immune thrombocytopenia (ITP) remains unclear. A multicentre, randomized, double-blind, placebo-controlled phase III trial was performed. Patients aged 6-17 years, diagnosed with ITP and resistant or relapsed to corticosteroid treatment were included. For the trial, part 1 was exploratory and part 2 was the main analysis, with part 1 determining whether part 2 was stratified by age. Patients in part 1 were treated with rhTPO (the 6- to 11-/12- to 17-year-old groups; 1:1). Patients in part 2 were randomized (3:1) to receive either rhTPO treatment or placebo. Patients received rhTPO or placebo at a dose of 300 U/kg once daily for up to 14 days. A total of 68 patients were included [part 1 (12 patients), part 2 (56 patients)]. The total response rate (TRR) in part 1 was 50.0% (95% CI: 21.09%-78.91%). For part 2, the TRR was 58.5% (95% CI: 42.11%-73.68%) and 13.3% (95% CI: 1.66%-40.46%) in the rhTPO and placebo groups (FAS) respectively. The difference in TRR between the rhTPO group and placebo group was 45.2% (95% CI: 22.33%-68.08%) and 44.6% (95% CI: 21.27%-67.85%) on the FAS and per-protocol set (PPS), respectively, which indicates the superiority of rhTPO treatment.

Efficacy and safety of avatrombopag in the treatment of thrombocytopenia after umbilical cord blood transplantation.

Delayed platelet engraftment is a common complication after umbilical cord blood transplantation (UCBT), and there is no standard therapy. Avatrombopag (AVA) is a second-generation thrombopoietin (TPO) receptor agonist (TPO-RA) that has shown efficacy in immune thrombocytopenia (ITP). However, few reports have focused on its efficacy in patients diagnosed with thrombocytopenia after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We conducted a retrospective study to evaluate the efficacy of AVA as a first-line TPO-RA in 65 patients after UCBT; these patients were compared with 118 historical controls. Response rates, platelet counts, megakaryocyte counts in bone marrow, bleeding events, adverse events and survival rates were evaluated in this study. Platelet reconstitution differences were compared between different medication groups. Multivariable analysis was used to explore the independent beneficial factors for platelet implantation. Fifty-two patients were given AVA within 30days post-UCBT, and the treatment was continued for more than 7days to promote platelet engraftment (AVA group); the other 13 patients were given AVA for secondary failure of platelet recovery (SFPR group). The median time to platelet engraftment was shorter in the AVA group than in the historical control group (32.5days vs. 38.0days, Z=2.095, P=0.036). Among the 52 patients in the AVA group, 46 achieved an overall response (OR) (88.5%), and the cumulative incidence of OR was 91.9%. Patients treated with AVA only had a greater 60-day cumulative incidence of platelet engraftment than patients treated with recombinant human thrombopoietin (rhTPO) only or rhTPO combined with AVA (95.2% vs. 84.5% vs. 80.6%, P<0.001). Patients suffering from SFPR had a slightly better cumulative incidence of OR (100%, P=0.104). Patients who initiated AVA treatment within 14days post-UCBT had a better 60-day cumulative incidence of platelet engraftment than did those who received AVA after 14days post-UCBT (96.6% vs. 73.9%, P=0.003). In summary, compared with those in the historical control group, our results indicate that AVA could effectively promote platelet engraftment and recovery after UCBT, especially when used in the early period (≤14days post-UCBT).

Discovery of an unconventional lamprey lymphocyte lineage highlights divergent features in vertebrate adaptive immune system evolution

Lymphocyte receptors independently evolved in both jawed and jawless vertebrates with similar adaptive immune responses. However, the diversity of functional subtypes and molecular architecture in jawless vertebrate lymphocytes, comparable to jawed species, is not well defined. Here, we profile the gills, intestines, and blood of the lamprey, Lampetra morii, with single-cell RNA sequencing, using a full-length transcriptome as a reference. Our findings reveal higher tissue-specific heterogeneity among T-like cells in contrast to B-like cells. Notably, we identify a unique T-like cell subtype expressing a homolog of the nonlymphoid hematopoietic growth factor receptor, MPL-like (MPL-L). These MPL-L+ T-like cells exhibit features distinct from T cells of jawed vertebrates, particularly in their elevated expression of hematopoietic genes. We further discovered that MPL-L+ VLRA+ T-like cells are widely present in the typhlosole, gill, liver, kidney, and skin of lamprey and they proliferate in response to both a T cell mitogen and recombinant human thrombopoietin. These findings provide new insights into the adaptive immune response in jawless vertebrates, shedding new light on the evolution of adaptive immunity.

Effect and safety of recombinant human thrombopoietin on haematopoietic reconstitution after allogeneic haematopoietic cell transplantation

Delayed platelet engraftment (DPE) and thrombocytopenia are common complications following myeloablative conditioning in the advanced stage of allogeneic haematopoietic cell transplantation (allo-HCT), and they are associated with transplantation-related mortality and poor prognosis. Therefore, promoting haematopoietic reconstitution after allo-HCT plays a key role in improving patient outcomes. The aim of this retrospective study was to assess the effectiveness and safety of recombinant human thrombopoietin (rhTPO) in promoting haematopoietic reconstruction after allo-HCT. The study included 210 patients who underwent transplantation, with 158 in the rhTPO group and 52 in the control group. Of the total patient population, 120 were males and 90 were females, with a median age of 31 years (range=6 to 59 years). The results showed that the rhTPO group had a median platelet engraftment time that was 14.1 days shorter than that of the control group (14.1 days vs. 21.9 days; P < 0.001). The time for platelet count recovery to 50 × 10^9/L was also shorter in the rhTPO group than in the control group (21.7 days vs. 30.3 days; P<0.001). Additionally, the granulocyte engraftment time was shorter in the rhTPO group (14.3 days vs. 18.2 days; P<0.001). There was no significant difference in overall survival (OS) between the rhTPO group and the control group at 2 years after transplantation (77.2% vs. 65.4%; P=0.08). Furthermore, there were no significant differences in the amount of platelet transfusions, the rate of platelet engraftment, the rate of DPE, or the incidence of Grade 4 haemorrhage between the groups. Moreover, no adverse reactions were found in the rhTPO group. This study demonstrated that rhTPO administration after allo-HCT effectively reduced the time required for platelet and granulocyte engraftment and was safe.

Clinical observation study of recombinant human thrombopoietin in the prevention of chemotherapy-induced thrombocytopenia in patients with aggressive lymphoma.

e19056 Background: Recombinant human thrombopoietin (rhTPO) has demonstrated efficacy in elevating platelet counts in lymphoma patients suffering from chemotherapy-induced thrombocytopenia. However, the optimal timing for its administration remains to be established. Methods: This prospective, observational, non-randomized, multicenter study aimed to identify the optimal timing for rhTPO intervention in patients with aggressive lymphoma experiencing chemotherapy-induced thrombocytopenia. Participants aged between 18 and 70 years, diagnosed with aggressive lymphoma and chemotherapy-induced thrombocytopenia, were divided into three groups based on their baseline platelet counts. Group 1 received rhTPO when platelet counts fell below 50×109/L but remained above 25×109/L; Group 2 was treated with rhTPO at platelet counts ≥ 50×109/L and &lt; 75×109/L; and Group 3 received rhTPO treatment for platelet counts ≤ 25×109/L. Treatment was discontinued once platelet counts reached ≥ 100×109/L. The primary endpoint was the proportion of patients achieving normalization of platelet counts, the secondary outcomes including platelet nadir values, the incidence of platelet transfusions, and adverse events. Results: Eighty-eight patients were enrolled, with 36 in Group 1, 22 in Group 2, and 30 in Group 3. The groups were comparable in clinical manifestation of age, gender, comorbidities, lymphoma classification, and bone marrow involvement. Normalization of platelet counts was achieved in 69.44%, 81.82%, and 36.67% of patients in Groups 1, 2, and 3, respectively, with Groups 1 and 2 showing significantly higher rates than Group 3 (P&lt;0.05). The mean platelet nadir values were significantly higher in Groups 1 and 2 (28.39±10.19×109/L and 43.23±14.97×109/L, respectively) compared to Group 3 (11.13±6.21×109/L, P&lt;0.01). The incidence of platelet transfusions was notably lower in Groups 1 and 2 (19.44% and 13.64%, respectively) than in Group 3 (70.00%, P&lt;0.01). There were no significant differences in adverse event rates across the groups. Conclusions: Early administration of rhTPO significantly enhances platelet recovery and reduces the need for platelet transfusions in aggressive lymphoma patients with chemotherapy-induced thrombocytopenia.

Single-dose Administration of Recombinant Human Thrombopoietin Enhances Survival and Hematopoietic Reconstruction in Canines Irradiated with 3 Gy Gamma Radiation.

We conducted this study to investigate the radioprotective effects of recombinant human thrombopoietin (rhTPO) on beagle dogs irradiated with 3.0 Gy 60Co gamma rays. Fifteen healthy adult beagles were randomly assigned to a control group with alleviating care, and 5 and 10 μg/kg rhTPO treatment group. All animals received total-body irradiation using 60Co γ-ray source at a dose of 3.0 Gy (dose rate was 69.1 cGy/min). The treatment group received intramuscular injection of rhTPO 5 and 10 μg/kg at 2 h postirradiation, and the control group was administrated the same volume of normal saline. The survival rate, clinical signs, peripheral hemogram, serum biochemistry, and histopathological examination of animals in each group were assessed. Single administration of 10 μg/kg rhTPO at 2 h postirradiation promoted the recovery of multilineage hematopoiesis and improved the survival rate of beagles irradiated with 3 Gy 60Co γ rays. The administration of 10 μg/kg rhTPO alleviated fever and bleeding, reduced the requirement for supportive care, and may have mitigated multiple organ damage.

Recombinant human thrombopoietin in alleviating endothelial cell injury in sepsis

BackgroundTo evaluate the effect of recombinant human thrombopoietin (rhTPO) on clinical prognosis by exploring changes in endothelial cell injury markers and inflammatory factors in patients with sepsis after treatment with rhTPO. MethodsThis retrospective observational study involved patients with sepsis (diagnosed according to Sepsis 3.0) admitted to Shanghai General Hospital intensive care unit from January 1, 2019 to December 31, 2022. Patients were divided into two groups (control and rhTPO) according to whether they received rhTPO. Baseline information, clinical data, prognosis, and survival status of the patients, as well as inflammatory factors and immune function indicators were collected. The main monitoring indicators were endothelial cell-specific molecule (ESM-1), human heparin-binding protein (HBP), and CD31; secondary monitoring indicators were interleukin (IL)-6, tumor necrosis factor (TNF)-α, extravascular lung water index, platelet, antithrombin III, fibrinogen, and international normalized ratio. We used intraperitoneal injection of lipopolysaccharide (LPS) to establish a mouse model of sepsis. Mice were randomly divided into four groups: normal saline, LPS, LPS + rhTPO, and LPS + rhTPO + LY294002. Plasma indicators in mice were measured by enzyme-linked immunosorbent assay. ResultsA total of 84 patients were included in the study. After 7 days of treatment, ESM-1 decreased more significantly in the rhTPO group than in the control group compared with day 1 (median=38.6 [interquartile range, IQR: 7.2 to 67.8] pg/mL vs. median=23.0 [IQR: −15.7 to 51.5] pg/mL, P=0.008). HBP and CD31 also decreased significantly in the rhTPO group compared with the control group (median=59.6 [IQR: −1.9 to 91.9] pg/mL vs. median=2.4 [IQR: −23.2 to 43.2] pg/mL; median=2.4 [IQR: 0.4 to 3.5] pg/mL vs. median=−0.6 [IQR: −2.2 to 0.8] pg/mL, P <0.001). Inflammatory markers IL-6 and TNF-α decreased more significantly in the rhTPO group than in the control group compared with day 1 (median=46.0 [IQR: 15.8 to 99.1] pg/mL vs. median=31.2 [IQR: 19.7 to 171.0] pg/mL, P <0.001; median=17.2 [IQR: 6.4 to 23.2] pg/mL vs. median=0.0 [IQR: 0.0 to 13.8] pg/mL, P=0.010). LPS + rhTPO-treated mice showed significantly lower vascular von Willebrand factor (P=0.003), vascular endothelial growth factor (P=0.002), IL-6 (P <0.001), and TNF-α (P <0.001) than mice in the LPS group. Endothelial cell damage factors vascular von Willebrand factor (P=0.012), vascular endothelial growth factor (P=0.001), IL-6 (P <0.001), and TNF-α (P=0.001) were significantly elevated by inhibiting the PI3K/Akt pathway. ConclusionrhTPO alleviates endothelial injury and inflammatory indices in sepsis, and may regulate septic endothelial cell injury through the PI3K/Akt pathway.

Effect of Recombinant Human Thrombopoietin on Platelet Reconstitution after Autologous Peripheral Blood Stem Cell Transplantation in Patients with Multiple Myeloma

To analyze the effect of recombinant human thrombopoietin (rhTPO) on platelet (PLT) reconstitution after autologous peripheral blood stem cell transplantation (APBSCT) in patients with multiple myeloma (MM). The clinical data of 147 MM patients who were diagnosed in the First Affiliated Hospital of Soochow University and received APBSCT as the first-line therapy were retrospectively analyzed. According to whether rhTPO was used during APBSCT, the patients were divided into rhTPO group (80 cases) and control group (67 cases). The time of PLT engraftment, blood product infusion requirements, the proportion of patients with PLT recovery to≥50×109/L and≥100×109/L at +14 days and +100 days after transplantation, and adverse reactions including the incidence of bleeding were compared between the two groups. There were no significant differences between the two groups in sex, age, M protein type, PLT count at the initial diagnosis, median duration of induction therapy before APBSCT, and number of CD34+ cells reinfused (all P >0.05). The median time of PLT engraftment in the rhTPO group was 10 (6-14) days, which was shorter than 11 (8-23) days in the control group (P < 0.001). The median PLT transfusion requirement in the rhTPO group during APBSCT was 15(0-50)U, which was less than 20 (0-80)U in the control group (P =0.001). At +14 days after transplantation, the proportions of patients with PLT≥50×109/L in the rhTPO group and the control group were 66.3% and 52.2%, while the proportions of patients with PLT≥100×109/L were 23.8% and 11.9%, respectively, with no significant differences (all P >0.05). At +100 days after transplantation, the proportion of patients with PLT≥50×109/L in rhTPO group and control group was 96.3% and 89.6%, respectively (P >0.05), but the proportion of patients with PLT≥100×109/L in rhTPO group was higher than that in control group (75.0% vs 55.2%, P =0.012). There was no difference in the overall incidence of bleeding events in different locations during period of low PLT level of patients between the two groups. In rhTPO group, the rhTPO administration was well tolerated, and the incidences of abnormal liver and kidney function and infection were similar to those in the control group. When MM patients undergo first-line APBSCT, subcutaneous injection of rhTPO can shorten the time of platelet engraftment, reduce the transfusion volume of blood products, and be well tolerated, moreover, more patients have achieve a high level of PLT recovery after transplantation, which is very important for ensuring the safety of APBSCT and maintenance therapy.

Recombinant Human Thrombopoietin Promotes Platelet Engraftment in Severe Aplastic Anemia Patients Following Treatment With Haploid Hematopoietic Stem Cell Transplantation using Modified Post-Transplantation Cyclophosphamide

BackgroundRecombinant human TPO (rhTPO) promotes platelet engraftment in patients after allogeneic HSCT (allo-HSCT). However, the effects of rhTPO on platelet recovery after Haplo-HSCT in patients with severe aplastic anemia (SAA) have not been intensively studied. ObjectiveWe aimed to evaluate the efficacy of rhTPO on platelet engraftment in patients with SAA who were treated with Haplo-HSCT using post-transplantation cyclophosphamide (PTCy). Study DesignSAA patients who received Haplo-HSCT plus PTCy regimen were divided into the rhTPO group (with subcutaneous injection of rhTPO, n = 28) and Control group (no rhTPO administration, n = 27). The engraftment of platelet/neutrophil, platelet infusion amount, and transplant-related complications between the 2 groups were compared. ResultsAll 55 patients showed successful hematopoietic reconstitution. The median time of platelet engraftment was 11 (9 to 29) days in the rhTPO group and 14 (9 to 28) days in the Control group (P = .003). The rhTPO group had a significantly reduced amount of infused platelets compared to the Control group (2 (1 to 11.5) versus 3 (1 to 14) therapeutic doses; P = .004). There was no significant difference between the 2 groups regarding median time of neutrophil engraftment, incidence of acute graft-versus-host disease (aGVHD) and chronic GVHD (cGVHD), incidence of cytomegalovirus or Epstein–Barr virus reactivation, 3-yr overall survival rate, and failure-free-survival rate. No obvious adverse reactions were observed in the rhTPO group. ConclusionrhTPO promoted platelet engraftment, reduced the amount of transfused platelets, and demonstrated good safety profiles without evidence of adverse reactions in patients with SAA who received Haplo-HSCT using PTCy regimen.

Effect of recombinant human thrombopoietin on platelets in rats with D-galactosamine salt-induced acute liver failure

To evaluate the effects of recombinant human thrombopoietin (rhTPO) on platelet count (PLT) and liver function in acute liver failure (ALF) rats by observing the dynamic changes of PLT, thrombopoietin (TPO) and liver function during ALF. Twenty-four male Sprague-Dawley (SD) rats were divided into model group, TPO group and interleukin-11 (IL-11) group using a random number table method, with eight rats in each group. All rats were intraperitoneally injected with D-galactosamine (D-GalN, 1 500 mg/kg, dosed within 72 hours) to induce the ALF model. After modeling, rats in TPO group was received subcutaneous injection of 15 μg/kg of rhTPO for 5 days, and rats in IL-11 group was received subcutaneous injection of 0.45 mg/kg of IL-11 for 5 days. Venous blood samples were collected before and at 1, 3, 5, 7 and 12 days after molding for whole blood cell detection. The level of TPO in serum was detected by enzyme-linked immunosorbent assay (ELISA). Liver function indexes including serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBil) and albumin (ALB) were measured before and at 1, 3 and 5 days after modeling. The rats were sacrificed 12 days after the modeling, and the pathological changes of liver tissue were observed by hematoxylin-eosin (HE) staining. Two rats in each group died within 24-48 hours after modeling. HE staining showed that all three groups of ALF rats showed large flake necrosis of hepatocytes, disorder of hepatic lobular structure, mesh scaffold collapse, hepatic sinus congestion and hemorrhage, and flake infiltration of inflammatory cells on day 12 after modeling. The levels of serum ALT, AST and TBil of rats in each group were significantly increased 1 day after modeling and then decreased. The level of ALB decreased significantly on the first day after modeling and then increased, but there was no significant difference in the trend of liver function indexes among the three groups. PLT in the three groups decreased rapidly on day 1 after modeling, and then recovered gradually with the improvement of liver function. The PLT of the TPO group rose to the peak value 7 days after molding and was significantly higher than that of the model group [PLT (×109/L): 1 673.3±347.5 vs. 855.3±447.0, P < 0.05], while there was no significant difference between the IL-11 group and the model group [PLT (×109/L): 1 350.3±386.6 vs. 855.3±447.0, P > 0.05]. The level of serum TPO of the three groups increased significantly on day 1 after modeling, then decreased, and dropped to the lowest value on day 5, but there was no significant difference in the trend of serum TPO level among the three groups. PLT in ALF rats decreased rapidly in the early stage and recovered gradually with the improvement of liver function, and the serum TPO level increased first and then decreased. Injection of rhTPO can significantly increase PLT in ALF rats, but has no significant effect on liver function and survival rate.

Effectiveness and economic evaluation of rhTPO and rhIL-11 in the treatment of cancer therapy induced thrombocytopenia based on real-world research.

Objective: Based on real-world research, we aimed to evaluate the effectiveness and economy of recombinant human thrombopoietin (rhTPO) and recombinant human interleukin 11 (rhIL-11) in the treatment of cancer therapy induced thrombocytopenia (CTIT). Methods: We retrospectively collected clinical data of patients with CTIT who were treated with rhTPO or rhIL-11 in a single cancer hospital from January 2020 to December 2021. Propensity score matching (PSM) was applied to eliminate confounding factors. The measurements of effectiveness analysis were the platelet compliance rate, days of medication, days of compliance, highest platelet count after medication, platelet count elevation before and after medication, and the lowest platelet count after next-cycle cancer therapy. The economic evaluation was performed according to the results of the effectiveness evaluation. At the same time, patients were stratified according to type of tumor and grade of thrombocytopenia for subgroup analysis. Results: A total of 262 patients were collected and 174 patients were enrolled after PSM, 87 in the rhTPO group and 87 in the rhIL-11 group. In all patients, there were no significant differences in the platelet compliance rate, mean days of medication, median days of compliance, median highest platelet count after medication, and the median platelet count elevation before and after medication between the two groups (p > 0.05), but the median lowest platelet count after next-cycle cancer therapy in the rhTPO group was lower than that in the rhIL-11 group (p = 0.014). The subgroup analysis showed that the rhTPO group had longer mean days of medication than the rhIL-11 group in patients with hematological malignancies (p = 0.042), and a lower median lowest platelet count after next-cycle cancer therapy in patients with grade I/II thrombocytopenia than rhIL-11 group (p = 0.022), with no significant difference in other outcome indicators (p > 0.05). As there was no statistically significant difference in platelet compliance rate between the two groups, the cost-minimization analysis showed that the rhIL-11 group had lower treatment costs than the rhTPO group. Conclusion: RhTPO and rhIL-11 showed similar effectiveness in the treatment of CTIT, but rhIL-11 was more advantageous in economic cost.

Thrombopoietin Receptor Agonists in Post-Hematopoietic Cell Transplantation Complicated by Prolonged Thrombocytopenia: A Comprehensive Review.

Hematopoietic cell transplantation (HCT) is a well-established procedure that has become a therapeutic mainstay for various hematological conditions. Prolonged thrombocytopenia following HCT is associated with a significant risk of morbidity and mortality, yet no universally recognized treatment protocol exists for such a complication. First-generation thrombopoietin receptor (TpoR) agonists as well as second-generation agents are known for their role in enhancing platelet production, and their use is expanding across various thrombocytopenic conditions. Therefore, we conducted this comprehensive review of the literature to provide an updated evaluation of the use of TpoR agonists and explore their efficacy and safety in the treatment of extended post-HCT thrombocytopenia. The literature search was conducted using PubMed database from 1996 through December 2023, using a predefined strategy with medical subject headings terms. We identified 64 reports on the utility of TpoR agonists, five of them were randomized controlled trials and the rest were retrospective observational studies and case series, with a total number of 1730 patients. Second-generation TpoR agonists appear more convenient than subcutaneous recombinant human thrombopoietin (rhTpo) as they can be orally administered and exhibit similar efficacy in platelet recovery, as indicated by recent trial results. Among these agents, avatrombopag, unlike eltrombopag, does not require any dietary restrictions, which could be more favorable for patients. However, eltrombopag remains the most extensively studied agent. TpoR agonists had promising effects in the treatment of post-HCT thrombocytopenia with a good safety profile so far, highlighting the potential benefit of their use.

High- vs regular-dose recombinant human thrombopoietin plus cyclosporine A in patients with newly diagnosed non-severe aplastic anemia: a retrospective cohort study

ABSTRACT Background: Cyclosporine A (CsA) and regular doses of recombinant human thrombopoietin (rhTPO) can accelerate platelet recovery in patients with non-severe aplastic anemia (NSAA). However, it is unclear whether CsA plus rhTPO at a higher dose can further increase the efficacy. Methods: Data from patients with newly diagnosed NSAA, who had been treated with CsA in combination with different doses of rhTPO between February 2021 and August 2021 at Peking Union Medical College Hospital, were reviewed. All the enrolled patients had been treated with CsA at 3–5 mg/(kg/d), and patients were further classified into high-dose (with rhTPO 30000U qd × 14 days for 2 months) group or regular-dose (with rhTPO 15000U qd × 7days for 3 months) group. The treatment response and therapy-related adverse events were compared. Results: 36 patients including 16 (44.4%) in the high-dose and 20 (55.6%) in the regular-dose group were enrolled. The baseline characteristics were compatible between the two groups. The platelet counts were significantly higher at 1/3/6 months in the high-dose group (p = 0.028, 0.0063 and p = 0.040, respectively). The high-dose group had a significantly shorter time to platelet transfusion independence ([1 (0.5–6) months vs 2.5 (1–12) months, p = 0.040]). There was no significant difference in overall response and complete response rate between the two groups at 1/3/6/12 months (p > 0.05). Treatment-related morbidities were similar between the two groups (p > 0.05). Conclusions: Adding a higher dose of rhTPO can further accelerate platelet recovery and platelet transfusion independence in patients with newly diagnosed NSAA.

Efficacy and safety of QL0911 in adult patients with chronic primary immune thrombocytopenia: A multicenter, randomized, double-blind, placebo-controlled, phase III trial.

QL0911, a recombinant human thrombopoietin mimetic peptide-Fc fusion protein, is a romiplostim (Nplate®) biosimilar used to treat primary immune thrombocytopenia (ITP). This phase III study aimed to assess the efficacy and safety of QL0911 in adult patients with chronic primary ITP over a 24-week treatment period. We conducted a double-blind, placebo-controlled, phase III study in patients diagnosed with primary ITP for at least 12 months who had received at least one first-line ITP treatment with no response or recurrence after treatment, or who relapsed after splenectomy at 44 sites in China. Patients were randomly allocated (2:1 ratio) to QL0911 or placebo injection subcutaneously once weekly at an initial dose of 1 μg/kg for 24 weeks. The doses were adjusted to maintain the target platelet counts from 50 × 109/L to 200 × 109/L. Patients and investigators were blinded to the assignment. The primary endpoints were the proportion of patients who achieved a durable platelet response at week 24 (platelet count, ≥ 50 × 109/L during 6 of the last 8 weeks of treatment) and safety. The study was registered at ClinicalTrials.gov (NCT05621330). Between October 2019 and December 2021, 216 patients were randomly assigned (QL0911,144; placebo,72). A durable platelet response was achieved by significantly more patients in the QL0911 group (61.8%, 95% CI: 53.3-69.8; P < 0.0001) than in the placebo group (0%). The mean duration of platelet responses was 15.9 (SE: 0.43) weeks with QL0911, and 1.9 (SE:0.26) week with placebo. Consistent results were achieved in subgroup analyses categorized by baseline splenectomy status (yes/no), concomitant ITP treatment (yes/no), and baseline platelet count (≤ 10 × 109/L, > 10 × 109/L, ≤ 20 × 109/L, > 20 × 109/L, and < 30 × 109/L). The incidence of TEAEs was comparable between the QL0911 and the placebo groups (91.7% and 88.9%, respectively). The most common adverse events overall were ecchymosis (28.5% for QL0911 vs. 37.5% for placebo), upper respiratory tract infections respiratory tract infections (31.9% for QL0911 vs. 27.8% for placebo), and gingival bleeding (17.4% for QL0911 vs. 26.4% for placebo). QL0911 was well-tolerated and increased and maintained platelet counts in adults with ITP. QL0911, a biosimilar to romiplostim (Nplate®), may be a novel treatment option for patients with ITP who have failed or relapsed from first-line treatment in China. Ongoing studies will provide further data on long-term efficacy and safety in such patient populations.

Short-Term Efficacy of Combination Therapy with Recombinant Human Thrombopoietin (rh-TPO) and Thrombopoietin Receptor Agonists (TPO-Ra) in Patients with Severe Immune Thrombocytopenia

Introduction: Bleeding manifestations in patients with immune thrombocytopenia (ITP) range from mild skin bruises to lifethreatening intracranial hemorrhage. When the risk of bleeding is becoming high or life-threatening bleeding events occurs, we often use a combination of therapies to rapidly raise platelets to the safe range, including platelet transfusions, high-dose glucocorticoid, and intravenous immunoglobulins. Recombinant human thrombopoietin (rh-TPO) and thrombopoietin receptor agonists (TPO-Ra) are two kinds of thrombopoietic drugs commonly used in China. In patients with severe ITP refractory to glucocorticoids, we lack experience with the use of rh-TPO and TPO-Ra in this emergency situation. Patients and methods： We included ITP patients with platelets &amp;lt;10*10 9/L and bleeding symptoms requiring treatment, who were refractory to glucocorticoids and used thrombopoietic drugs. The bleeding score was calculated with reference to the Chinese guidelines for adult ITP. The patients were divided into three groups according to the medication used: rh-TPO group(rh-TPO 30000IU Qd), TPO-Ra group(Eltrombopag 25mg-75mg/d or Avatrombopag 2.5mg-7.5mg/d or Hetrombopagolamine 20mg-60mg/d), and rh-TPO+TPO-Ra group(combination of two drugs at the same dosage). The platelet count should be rechecked every 1-2 days during the treatment. Platelet transfusion and hemostatic drugs can be used as needed. According to the standardized and international criteria, and taking into account the characteristics of this study, platelet counts were classified as short-term Complete Response(sCR), short-term Response(sR), and short-term No Response (sNR), based on the highest value of platelet counts from the start of treatment to the time of hospital discharge, short-term Overall Response(sOR)=sCR+sR. The three groups were compared the effective time(defined as the time to first sCR/sR after treatment) , peak platelet count after treatment, time to peak platelet count after treatment and other short-term efficacy indicators. Results Nineteen patients were include in this study, with 68.4% (13/19) was female. The median age was 58 years [range 17-79]. 15.8%(3/19) were newly diagnosed with ITP, 10.5%(2/19) had persistent ITP, and 73.7%(14/19) had chronic ITP. All patients were treated with glucocorticoids prior to this treatment, but they had a poor response. The median platelet count was 3*10 9/L [range 1-9] and the median bleeding score was 4 [range 2-9] before treatment. The common bleeding sites were skin ecchymosis and oral mucous membrane hemorrhage in 100%(19/19)and 47.3%(9/19), respectively. Severe bleeding symptoms were the manifestation in 3 cases: including 2 heavy menstrual flow and 1 hemoptysis and gastrointestinal. 100%(19/19) achieved a sOR and 31.6%(6/19) achieved a sCR. The median bleeding score was 0[0-2] after treatment and none had active bleeding symptoms. Platelet transfusion and hemostatic drugs were administered to all patients. Further details are provided in Table 1. Among 19 patients, 7(36.8%) used rh-TPO alone, 6(31.6%) TPO-Ra alone and 6(31.6%) used rh-TPO+TPO-Ra. There was no statistically significant difference in Clinical characteristics, including ages, gender, platelet counts and bleeding score among the three groups of patients before treatment (P=0.727, 0.594, 0.719, 0.299). In terms of treatment efficacy, we were unable to perform a statistical analysis of sOR rates because all three groups reached 100%. The sCR and the peak platelet count after treatment of rhTPO+TPO-Ra group was higher than the other two groups, 28.6%(2/7), 16.7%(1/6) and 50%(3/6) of patients achieved sCR respectively, the peak platelet counts after treatment in the three groups were 62*10 9/L, 72*10 9/L, 79.5*10 9/L respectively in this treatment, but there was no statistically significant difference (P=0.425，0.924). In addition, the effective time and time to peak platelet count after treatment of the three group are also no statistically significant difference(p=0.692,0.505). Further details are provided in Table 2. Conclusion This retrospective study suggests that the patients with severe ITP who were refractory to glucocorticoids, the use of rh-TPO and TPO-Ra may rapidly increase to safe ranges, but the combination is not necessary.

Efficacy and Safety of Avatrombopag in the Treatment of Chemotherapy-Induced Thrombocytopenia Refractory to Rhtpo in Patients with Lymphoma

Background: Chemotherapy-induced thrombocytopenia (CIT) is a common cause of chemotherapy dose reductions and treatment delays. With applications of recombinant human interleukin 11 (rhIL-11) and recombinant human thrombopoietin (rhTPO), outcomes of patients with CIT have improved significantly. however，some patients with severe thrombocytopenia still have poor responses to the above therapies. Avatrombopag is an orally administered thrombopoietin receptor agonist and can stimulate thrombopoiesis in haematopoietic stem cells. Avatrombopag has been approved in the USA, Europe, and China for thrombocytopenia in patients with chronic liver disease who are scheduled to undergo a surgery. It also has been approved for patients with chronic immune thrombocytopenia who are unresponsive to previous treatments in the USA and Europe. The aim of this study is to evaluate the efficacy and safety of avatrombopag in the treatment of refractory CIT. Methods: The clinical data of 23 lymphoma patients with grade 3/4 CIT unresponsive to rhTPO treatment for 7-10 days were collected from April 2022 to May 2023. All patients received avatrombopag orally at a dose of 40 to 60 mg / day combined with subcutaneous injection of rhTPO (300 U/kg/day). Response (R) was defined as a platelet count≥ 50 × /L, or doubling of the baseline platelet count, and absence of bleeding. Platelet transfusion was allowed when the platelet count was less than 10×109/L or with bleeding events. When the platelet count recovered to ≥100 ×10 9/L or increased 50 ×10 9/L from baseline, treatments of avatrombopag and rhTPO were stopped. Results: The median age of the 23 patients with refractory CIT was 57 (range 17‒83) years. The pathological subtypes were diffuse large B cell lymphoma (DLBCL) (n=10), Burkitt lymphoma (n=4), angioimmunoblastic T-cell lymphoma (AITL) (n=3), follicular lymphoma (FL) (n=2), extranodal NK/T cell lymphoma (ENKTL) (n=1), anaplastic large cell lymphoma (ALCL) (n=1), B-lymphoblastic lymphoma (n=1), and mantle cell lymphoma (MCL) (n=1). The treatment consisted of CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) (n=11), Hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone), high-dose methotrexate with cytarabine (n=6), liposomal mitoxantrone-containing regimen (n=4), bendamustine-containing regimen (n=1), and peg-asparaginase-based regimens (n=1). At baseline, 19 patients experienced grade 3 and 4 patients experienced grade 4 thrombocytopenia after chemotherapy. The median lowest platelet level was 12×10 9/L (range 2‒44×10 9/L). Two patients developed grade 1 bleeding events and one patient occurred grade 2 bleeding events. Nineteen patients received platelet transfusion. After receiving the combination therapy of avatrombopag, 73.9% (17/23)of patients achieved the primary end point of corrected platelet counts (≥50×10 9/L )and were free from platelet transfusion. The median time to response was 11 (range 5‒25) days. No treatment-related adverse events such as elevated aminotransferases, thrombosis, fatigue, fever and dizziness were noticed during administration. Two patients received avatrombopag as secondary prophylactic treatment, and there were no grade 4 thrombocytopenia or bleeding events during subsequent cycles of chemotherapy. Conclusion: Avatrombopag is effective and safe in the management of CIT for lymphoma and it can be used as an alternative / combination treatment for the patients who refractory to rhTPO. The further clinical research is still needed to confirm this conclusion.

Early Efficacy of IST in Combination with Hetrombopag and Rhtpo As First-Line Treatment for Naïve Severe Aplastic Anemia

BACKGROUND: Immunosuppressive therapy (IST) (anti-thymocyte immunoglobulin (ATG) and cyclosporine (CSA)) is the treatment of choice for patients with acquired severe aplastic anemia (SAA) who are ineligible for hematopoietic stem cell transplantation (HSCT), which results in a hematological response (HR) in about 60-70% of SAA patients. TPO is a hepatic-secreted hematopoietic growth factor that specifically regulates platelet production, induces hematopoietic stem cell differentiation to megakaryocytes by binding to the TPO receptor (MPL), stimulates megakaryocyte proliferation and differentiation, and promotes platelet production and release. Several previous studies have shown that IST combined with rhTPO or hetrombopag can improve the early hematologic response of SAA patients, especially the proportion of good hematologic response (good HR) in the early stage. RhTPO and TPORA have different binding sites with thrombopoietin receptor (c-MPL) and do not have competitive binding, which may produce synergistic effect. A retrospective study showed that eltrombopag combined with rhTPO increased the IST HR and improved the quality of hematologic remission in SAA with mild adverse effects. Therefore the combination of TPORA and rhTPO in SAA patients undergoing IST treatment may result in faster and higher HR rates. Clinical studies have confirmed that hetrombopag, act similarly to eltrombopag in SAA, but there are no clinical studies of hetrombopag in combination with rhTPO in SAA. OBJECTIVE: To evaluate the early-efficacy and safety profile of IST in combination with hetrombopag, and rhTPO in patients with primary, severe aplastic anemia. METHODS: This study was designed for patients with primary aplastic anemia major aged 14-70 years after January 2023 from a single center. This group were planned to be get treat of IST combination with rhTPO 15000U/d for 8 weeks from the first day of ATG and hetrombopag 15mg/d for at least 6 months. The primary endpoint was to observe the good response rate, blood product transfusion and safety profile of the study regimen for the treatment of primary SAA for 3 months. Efficacy Criteria：Complete response (CR): HGB&amp;gt;100 g/L, PLT&amp;gt; 100×10 9/L and ANC&amp;gt;1.5×10 9/L; ② Good partial response (GPR): HGB&amp;gt;80g/L, PLT&amp;gt; 50×10 9/L and ANC&amp;gt;1.0×10 9/L; ③ Partial response (PR): withdrawal from blood product transfusion dependence (HGB&amp;gt;70g/L, PLT&amp;gt; 20×10 9/L), hematologic tests improved and no longer met the SAA criteria, but blood count did not meet the GPR criteria. ④No response to treatment (NR): Continuous transfusion dependency was classified as no response. and/or blood count still met SAA criteria. We defined CR+GPR+PR as HR and CR+GPR as good HR. RESULTS: The trial group proposes to enroll 39 patients and currently includes 8 patients who can be evaluated for 3-month efficacy of IST treatment. And the control group includes two groups of IST combined rhTPO group and IST combined HPAG group in our previous center, and the cohort study of the results of the three groups. In this study, the HR rate of 8 patients can be assessed at present as 75% (6/8), and the rate of good HR was 50% (4/8). The HR of 33 patients in the control IST+rhTPO group was 66.67% (22/33), and the rate of good HR was 36.4% (12/33); the HR rate of 32 patients in the control IST+HPAG group was 46.9% (15/32), and the rate of good HR was 21.9%. The HR rate and good HR rate of the trial group were higher than those of the IST+rhTPO group and the IST+HPAG group (75%v66.67%v46.9%; 50%v36.4%v21.9%). None of the 8 patients enrolled in the trial group had any transformation of myelofibrosis, myelodysplastic syndrome and acute myeloid leukemia during the follow-up period. CONCLUSION: HR was obtained at 3 months in 6 of the 8 patients with severe remodeling IST+rhTPO+ hetrombopag in this study, with a good HR rate of 50%, which is the highest good efficacy response we know of in a prospective study of Chinese SAA patients to date. This confirms that rhTPO combined with hetrombopag can synergize the recovery of bone marrow hematopoietic function in SAA patients treated with IST, and its clinical effect is superior to that of various TPO-Ras or rhTPO that have been widely used. It is expected that more cases will be included in the later stages and that better results will be obtained. 【Keywords】severe aplastic anemia; recombinant human thrombopoietin; hetrombopag ; immunosuppression treatment.

IST Combined with Full-Dose Rhtpo in the Treatment of Severe Aplastic Anemia -a Prospective Single-Center Clinical Study

BACKGROUND: Immunosuppressive therapy (IST) (anti-thymocyte immunoglobulin (ATG) and cyclosporine (CSA)) is the treatment of choice for patients with acquired severe aplastic anemia (SAA) who are ineligible for hematopoietic stem cell transplantation (HSCT), which results in a hematological response (HR) in about 60-70% of SAA patients, while 1/3 of patients fail to achieve a hematological response. TPO is a hepatic-secreted hematopoietic growth factor that specifically regulates platelet production, induces hematopoietic stem cell differentiation to megakaryocytes by binding to the TPO receptor (MPL), stimulates megakaryocyte proliferation and differentiation, and promotes platelet production and release. Previous retrospective studies have demonstrated that IST combined with rhTPO improves the early hematologic response in SAA patients, but efficacy reported by centers varied depending on the dose and duration of rhTPO. There are no prospective studies of rhTPO application in SAA to confirm its efficacy. So this study was designed to observe the early feeicacy and safety of the SAA patients who were treated with IST combination with full-dose rhTPO. METHODS: This study was a single-center, single-arm, prospective cohort clinical study, enrolling 33 naive SAA patients aged between 14-70 years who diagnosed after April 2021 in our study center. The patients treated with IST combined with full-dose rhTPO (300U/kg.d) for 8 weeks starting from the first day of ATG. The primary endpoint of the observational study protocol good response rate, blood product transfusion volume and safety profile at 3 months of treatment of initial SAA. The patients were also evaluated for total hematologic response rate and adverse effects of drug application, clonal shift rate, and recurrence rate at 3 and 6 months after treatment. Efficacy Criteria：Complete response (CR): HGB&amp;gt;100 g/L, PLT&amp;gt; 100×10 9/L and ANC&amp;gt;1.5×10 9/L; ② Good partial response (GPR): HGB&amp;gt;80g/L, PLT&amp;gt; 50×10 9/L and ANC&amp;gt;1.0×10 9/L; ③ Partial response (PR): withdrawal from blood product transfusion dependence (HGB&amp;gt;70g/L, PLT&amp;gt; 20×10 9/L), hematologic tests improved and no longer met the SAA criteria, but blood count did not meet the GPR criteria. ④No response to treatment (NR): Continuous transfusion dependency was classified as no response. and/or blood count still met SAA criteria. We defined CR+GPR+PR as HR and CR+GPR as good HR. RESULTS: The rhTPO group enrolled 33 patients, and the control group was 99 patients who applied the caliper value of 0.2 to match the previous unapplied TPO treatment of SAA. At 3 months after IST treatment efficacy, the HR rate of 33 patients in the rhTPO group was 66.67% (22 /33 ), and the rate of good HR was 36.4% (12/33). The HR rate in the control group was 32.32% (32 /99 ), and the rate of good HR was 12.12% (12/99). The HR rate and the good HR rate between the two group were significantly statistical differences (66.67% v 32.32%; 36.4% v 12.12%), (P value=0.001; 0.002). At 6 months after IST treatment, the HR rate and good HR rate in the rhTPO group had a significantly higher than those of the control group (66.67% v 32.32%; 36.4% v 12.12%), (P value=0.001; 0.002). No disease transformation such as myelofibrosis, myelodysplastic syndrome and acute myeloid leukemia occurred in all enrolled patients during the follow-up period. CONCLUSION: 22 of the 33 SAA patients in this study achieved HR at 3 months after IST treatment, including 36.4% cases achived good HR , which is the highest good efficacy response in a prospective study of SAA patients in China known to us to date. This confirms that full-dose rhTPO, as a macromolecular peptide, can also promote the recovery of bone marrow hematopoietic function, significantly improved the rapidity and strength of HR in SAA patients. And its clinical effect is no less than that of the various TPO-Ras that have been widely used so far, and may even be higher. 【Keywords】severe aplastic anemia; recombinant human thrombopoietin; immunosuppression treatment.

Effect of Hetrombopag Combined with Rhtpo in Patients with Severe Immune Thrombocytopenia

Background: Severe Immune Thrombocytopenia (ITP) is a life-threatening acquired hemorrhagic disease with dramatically decreased platelet number and clinical bleeding symptoms. Some patients with severe ITP did not respond to first-line treatment including steroids and Intravenous Immunoglobulin (IVIG). It was critical for them to use effective treatments to promote platelet and reduce the risk of fatal bleeding. Clinical practice guidelines have recommended the use of thrombopoietin receptor agonist (TPO-RA) as a second-line treatment for ITP. Recombinant human thrombopoietin (rhTPO) and hetrombopag are two distinct TPO-RAs with different mechanisms. As reported, there remains no study assessing the efficacy and safety of hetrombopag combined with rhTPO in the treatment of ITP. Therefore, the present study aimed to investigate the efficacy of hetrombopag plus rhTPO in Chinese patients with severe ITP, focusing on the short rather than the long-term efficacy, such as quickly increasing platelet count and significantly reducing bleeding, which would be more meaningful for severe patients whose platelet count &amp;lt;10 × 10 9/L. Methods: This was a prospective, open-label, single-center study with a planned enrollment of 30 patients. The inclusion criteria were patients ≥ 18 years, diagnosed with primary immune thrombocytopenia, platelet count &amp;lt;10 × 10 9/L, or bleeding score ≥ 5. Patients receiving other ITP drugs as maintenance therapy were eligible if previous glucocorticoid therapy doses were stable, and rituximab was used for at least 2 months and other immunosuppressants were stable for at least 4 weeks. Patients who had received IVIG, avatrombopag, eltrombopag, or romiplostim within 2 weeks prior to enrollment were excluded. Histories of platelet transfusion one week before treatment were excluded. Hetrombopag was given at 5 mg/day for 28 days, while rhTPO was administered at 300 U/kg subcutaneously daily for 14 days. When PLT &amp;gt; 100 × 10 9/L, rhTPO should be discontinued. When PLT &amp;gt; 150 × 10 9/L, the dosage of hetrombopag was reduced to 2.5mg/day, and it would be discontinued if PLT &amp;gt; 250 × 10 9/L. The primary endpoints were proportion of subjects with platelet count ≥30×10 9/L and at least doubled the baseline platelet count within 28 days. Secondary endpoints included bleeding score, incidence of thrombotic events, and adverse events (AEs). Results: As to July 27, 2023, a total of 20 patients were included in this study, with a median age of 36 years and a male proportion of 50%. Among them, 70% (14 cases) were newly diagnosed ITP patients. 50% of patients have received ≥ 1 line of previous treatment, of which 2 patients have received IVIG treatment and both have achieved CR (PLT ≥ 100 × 10 9/L). The baseline median platelet count was 5 × 10 9/L, and 95% (19 cases) of patients had active bleeding with a bleeding score of ≥ 1 point. The median duration for hetrombopag at dose of 5mg is 8.0 days, and rhTPO is 6.5 days. After combined treatment, the median time for platelet counts reached 30, 50, and 100 × 10 9/L was 4.5 days, 6 days, and 7 days, respectively. Among them, the median platelet count reached 103 × 10 9/L after 7 days treatment and 214.5 × 10 9/L after 15 days. Within 15 days of combined treatment, 15% (3 cases) of patients achieved partial platelet reaction (PLT &amp;gt; 50 × 10 9/L, without bleeding), and 85% (17 cases) achieved complete platelet reaction (PLT &amp;gt; 100 × 10 9/L, without bleeding). In terms of safety, two patients experienced liver function abnormalities, both of which were grade 1-2. One was related to treatment drugs, and the other was associated with underlying autoimmune liver disease. No thrombotic events occurred in all patients. Conclusion: This study innovatively explores the efficacy and safety of combination therapy with hetrombopag and rhTPO in the treatment of severe ITP. It is preliminarily confirmed that this combination therapy can effectively and quickly improve the early platelet response of ITP patients, avoid bleeding damage, and is expected to become a new treatment choice for severe ITP patients. We also look forward to the overall efficacy evaluation results of all patients after completing treatment in the future.