Small Molecule Thrombopoietin Receptor Agonist Research Articles

Efficacy and Safety of Avatrombopag in Combination with Standard Immunosuppressive Therapy for Severe Aplastic Anemia

Severe aplastic anemia (SAA) is a life-threatening bone marrow failure disease. The addition of eltrombopag to immunosuppressive therapy (IST) improves the response rate and response quality of SAAs, but its hepatotoxicity is concerning. Avatrombopag (AVA), another small-molecule thrombopoietin receptor agonist without hepatotoxicity, has unknown efficacy in SAA treatment. This retrospective study aimed to assess the efficacy and safety of AVA, a small-molecule thrombopoietin receptor agonist, when added to IST in SAA patients. A total of 42 patients treated with IST and AVA were compared to a historical cohort of 84 patients receiving IST alone, utilizing propensity score matching. The median age was 31.5 (6.0-67.0) years old in Group A and 26 (16.0-45.0) years old in Group B. At 3 months, Group A showed higher complete response (CR) and overall response (OR) rates than Group B (CR: 19.0% vs. 4.8%, P = 0.024; OR: 54.8% vs. 39.3%, P=0.145). Higher CR and OR rates were also found at 6 months in Group A than in Group B (CR 31.0% vs. 14.3%, P=0.145; OR 71.4% vs. 51.2%, P=0.048). In multivariate analysis of Group A, a shorter interval from disease onset to anti-thymocyte globulin (ATG) treatment (≤6 months) (P=0.005) predicted better responses rate at 6 months. Event free survival was also improved in Group A (60.7% vs. 49.6%). AVA was well-tolerated, with no hepatic injury observed during treatment, even in those with pre-existing hepatic impairment. The addition of AVA to IST improves both the response rate and response quality in SAA patients while ensuring safety.

Effectiveness and Safety of Hetrombopag-Containing Therapy in Patients with Severe Aplastic Anemia: A Multicenter Real-World Study

Background: In recent years, immunosuppressive therapy (IST) in combination with thrombopoietin receptor agonist (TPO-RA) with or without other hematopoietic interventions has emerged as the first-line treatment option for patients with severe aplastic anemia (SAA) who are not eligible for hematopoietic stem cell transplantation. Hetrombopag, an innovative orally administered, non-peptide, small-molecule TPO-RA, has shown impressive efficacy and safety as a monotherapy for managing patients with relapsed or refractory SAA. Despite these promising findings, there is a lack of comprehensive real-world evidence on the benefit of hetrombopag in combination with IST-based therapy for patients with SAA. This study aims to fill this knowledge gap by evaluating the effectiveness and safety of hetrombopag-containing therapy for patients with SAA in a real-world setting. Methods: In this multicenter, real-world study, the clinical records of SAA patients who underwent hetrombopag-containing therapy were retrospectively reviewed in six hematological medical centers across China from August 2021 to November 2022. The therapeutic regimen encompassed cyclosporine (CsA) and hetrombopag, with the optional addition of anti-thymocyte globulin (ATG) and/or stanozolol according to the patients' condition. Hetrombopag was initially administered at a daily dose of either 5 or 7.5 mg, which could be escalated to a maximum of 15 mg daily. CsA was introduced at a preliminary dosage of 3-5 mg/kg/day, later tailored to sustain a trough concentration between 150 and 250 μg/L. ATG was given at doses of 2.5-3.5 mg/kg/day for rabbit ATG, or 20-30 mg/kg/day for pig ATG, over five days. Stanozolol was administered at 2-6 mg/day. Hematologic response (HR) was characterized based on evaluations of platelet (PLT), hemoglobin (HGB), and neutrophil (ANC) counts. PLT response was defined as an elevation to 20×10 9/L above the baseline or maintenance ≥20×10 9/L without transfusion for ≥8 weeks. HGB response was defined as an increase by 1.5 g/dL above the baseline, or for those receiving transfusions, an absolute decrease of ≥ 4 units of transfusions over an unbroken 8-week period, relative to that in the 8 weeks preceding treatment. ANC response was classified as a doubling from the baseline, or an increment in ≥ 0.5×10 9/L. Fulfillment of all three response criteria was classified as a complete response (CR), whereas meeting at least one of the three was considered an HR. Results: Our study comprised thirty-two patients diagnosed with SAA, of which 18 were treatment-naive, and 14 were refractory to previous IST. These patients were administered a median dose of hetrombopag of 7.5 mg (range: 5-15 mg) daily for a median duration of 8 months (range: 3-13 months). In treatment-naive SAA patients, the HR and CR rates after three months of hetrombopag-containing therapy were 44.4% and 16.7%, respectively. These rates increased to 87.5% for HR and 25.0% for CR after six months. Meanwhile, refractory SAA patients exhibited HR and CR rates of 50.0% and 14.3% respectively, after three months of therapy, and these rates improved to 60.0% and 40.0% at the six-month mark. Significantly, no patients developed hepatic or renal toxicity of grade 3 or higher. Additionally, no cases of clonal evolution or serious adverse events were documented throughout the treatment period. Conclusions: The hetrombopag-containing therapy demonstrated remarkable effectiveness in both treatment-naïve and refractory SAA patients in the real-world setting, with manageable safety profile. Most notably, the response rates and depth of remission in SAA patients significantly improved over time, signifying the ongoing therapeutic advantage of extended hetrombopag-containing therapy.

Treatment with Hetrombopag for Poor Platelet Engraftment after Allo-HSCT-a Single Center Retrospective, Observational Study

Background: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a common and important treatment for most hematopoietic diseases. Some patients may experience poor platelet engraftment after allo-HSCT, which may lead to transplant failure and is also an important influencing factor for post-HSCT complications such as graft versus host disease (GVHD) and non-relapse mortality (NRM). Thus, exploring methods to improve platelet engraftment is very important. Hetrombopag is a small-molecule thrombopoietin-receptor agonist (TPO-RA) produced in China, stimulates the proliferation and differentiation of megakaryocytes and promotes platelet production through binding to thrombopoietin receptor to stimulate multiple intracellular signaling pathways. It has been reported that hetrombopag was effective in promoting platelet engraftment and decreasing platelet transfusion after allo-HSCT. Here, we studied the efficacy and safety of hetrombopag for poor platelet engraftment after allo-HSCT, of whom did not respond to rhTPO treatment. Aims: To evaluate the efficacy of hetrombopag in patients with poor platelet engraftment after allogeneic hematopoietic stem cell transplantation. Methods: In this retrospective study, data from patients with poor platelet engraftment after allo-HSCT who had been treated firstly with rhTPO and then with hetrombopag at Henan Cancer Hospital from July 1, 2021 to July 1, 2023 were collected. Patients should meet the following criteria to enroll in the study: experienced poor platelet engraftment who had been treated with rhTPO from day +4 post-HSCT. Here we defined poor platelet engraftment as platelet count (PLT) < 20 × 10 9/L beyond day +28 post-HSCT. We analyzed 57 patients mentioned above and divided them into two groups in a ratio of 1:2, 19 of them were given hetrombopag until their PLT exceeded 50 × 10 9/L and maintained for more than 7 days without platelet transfusion (hetrombopag group), another 38 patients were treated without hetrombopag (control group). The initial dose of hetrombopag was 5, or 7.5 mg/d according to the patient's conditions and characteristics (e.g., age, PLT, and bleeding risk). After allo-HSCT, patients administered rhTPO at a dose of 300U/kg·d from day +4. We defined rhTPO as ineffective when PLT was still below 20×10 9/L beyond +21 days post-HSCT after rhTPO administration. At this time, rhTPO was replaced with hetrombopag, or IL-11, decitabine, platelet transfusion, etc. Results: The median ages of the two groups of patients were 38 years (hetrombopag group) and 41 years (control group), respectively. The median baseline platelet count in both groups were 20 × 10 9/L. The proportion of patients with PLT recovery to 50×10 9/L was significantly higher in the hetrombopag group than in the control group (47.3% vs 7.9%, χ2=26.03, P<0.0001). The median time to PLT recovery to 50×10 9/L was 10 (7-48) days in the hetrombopag group and 33 (21-94) days in the control group ( P=0.004). The mean units of platelet transfusion in the hetrombopag group was significantly lower than that in the control group (2.7 vs 6.3 U, P=0.001), and no thrombotic events occurred. There was no statistical difference in the incidence of aGVHD (42.0% vs 44.7%, P=0.850) and NRM (5.2% vs 7.9%, P=0.714) between the two groups, suggesting that hetrombopag had no significant effect on aGVHD and NRM. Conclusion: For allo-HSCT patients who experienced poor platelet engraftment after rhTPO treatment, hetrombopag can rapidly promote PLT recovery, reduce the units of platelet transfusion, and have no risk of the increase of aGVHD and NRM. These results still need further validation in a larger sample prospective confirmatory study in the future.

Avatrombopag Is Effective in First-Line Treatment of Severe Aplastic Anemia: Early Outcomes of a Prospective Study

Acquired severe aplastic anemia (SAA) is a life-threatening bone marrow failure disease and its pathogenesis involves T cell-mediated autoimmunity. Antithymocyte globulin (ATG) and cyclosporine based immunosuppressive therapy (IST) is effective for patients not eligible for hematopoietic stem cell transplant, and the response rate is 60-70%. Complete hematological response (CR) predicts better survival of patients received IST treatment, but only a few patients achieve CR within 6 months (5% at 3 months and 12-17% at 6 months). Thrombopoietin receptor agonist (TPO-RA) eltrombopag improves the overall response (OR) rate and CR rate of SAA patients when combined with IST, but its hepatotoxicity is still worrying. Avatrombopag is another small-molecule TPO-RA without hepatic toxicity. We previously found that SAA patients received avatrombopag and IST as first-line treatment showed both higher CR rate and OR rate at 3 and 6 months. To validate our findings, a prospective, single-arm study of avatrombopag and IST for newly diagnosed SAA was carried out (NCT05720234). There were 25 patients enrolled in the study by June 31, 2023, including 21 SAA patients and 4 very severe aplastic anemia patients. Patients were diagnosed as AA within 6 months and received ATG, cyclosporine and avatrombopag as first-line treatment. Avatrombopag was administered at the first day of ATG initiation at dose of 60mg per day for patients weight ≥ 50kg and 40mg per day for patients weight < 50kg. ATG was given for 5 consecutive days. Cyclosporine was given orally at dose of 3.5-5mg/kg.d. There were 15 males and 10 males, at a median age of 37 years old. Eighteen patients achieved the end-point of 3 months and 10 patients achieved end-point of 6 months. There were 15 patients achieved hematologic response at 3 months (83.3%), including 5 complete responders (27.8%) and 10 partial responders. The overall response rate at 6 months was 80%, and CR rate was 60%. One patient evolved to hemolytic paroxysmal nocturnal hemoglobinuria at 3 months, with normal count of platelet and white blood cell. In conclusion, the addition of avatrombopag to IST as first-line treatment showed earlier hematologic response and higher complete response rate for patients with SAA.

Real-World Effectiveness and Safety of Hetrombopag for Delayed Platelet Engraftment Post-Allogeneic Hematopoietic Stem Cell Transplantation

Background: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) serves as a critical therapeutic approach for various malignant and non-malignant hematopoietic disorders. Notwithstanding successful hematopoietic recovery in most patients following allo-HSCT, a subset may encounter delayed platelet engraftment (DPE), a prevalent and potentially serious complication that stems from myeloablative conditioning. Occurring in approximately 5%-37% of allo-HSCT recipients, DPE is a known harbinger of increased transplant-related mortality and diminished quality of survival. Despite its clinical significance, a well-established standard treatment protocol for post-allo-HSCT DPE remains elusive. Multiple platelet transfusions, often administered in such cases, not only exacerbate the economic burden but also induce toxicities, thereby undermining the patient's quality of life. An alternative to platelet transfusion lies in the utilization of thrombopoietin-receptor agonists (TPO-RAs), advocated for enhancing platelet engraftment. These agents interact with the thrombopoietin receptor, stimulating intracellular signaling pathways inclusive of JAK/STAT, PI3K/AKT, and ERK1/2, which in turn, promote megakaryocyte proliferation and differentiation, thereby augmenting platelet production. Hetrombopag, a novel, orally administered, non-peptide, small-molecule TPO-RA, has been validated to effectively boost platelet engraftment and reduce the necessity for platelet transfusions post-allo-HSCT in a pilot study. Our study sought to investigate the effectiveness and safety of hetrombopag in treating DPE following allo-HSCT within a real-world setting. Methods: In this retrospective study, we evaluated adult patients with hematopoietic disorders who underwent allo-HSCT and subsequently experienced DPE in our center, treated with hetrombopag between March 2022 and April 2023. Given the lack of a consensus definition, we deemed DPE as a platelet count (PLT) < 20 × 10 9/L or a significant and rapid decreasing trend past day 28 post-allo-HSCT. Hetrombopag dosages of 2.5 mg, 5 mg, or 7.5 mg/day were prescribed based on individual patient conditions. Response criteria post-treatment were as follows: complete response: PLT > 50 × 10 9/L without platelet transfusion; partial response: PLT between 20 and 50 × 10 9/L without platelet transfusion; no response: PLT < 20 × 10 9/L. Results: A total of 20 patients were included in the analysis, with a median age of 52, and 60% of them were male. Hetrombopag administration commenced at a median of 58 days following allo-HSCT at a median dose of 5 mg/day, with a median treatment duration of 44 days. The initial platelet count was 24.5 × 10 9/L and serum ferritin levels stood at 3351.1 ng/mL. Post-hetrombopag treatment, platelet counts escalated to 67.5 × 10 9/L while serum ferritin levels decreased to 2726.0 ng/mL. Of the 20 patients, 13 patients (65%) exhibited a complete response, 6 patients (30%) achieved a partial response, and 1 patient (5%) displayed no response. Hetrombopag was well tolerated with only 5 patients reporting increased alanine aminotransferase/aspartate aminotransferase or total bilirubin levels (all grade 1 or 2), and the association with hetrombopag was undetermined. Conclusion: Our findings suggest that hetrombopag yields a sustained response with acceptable tolerability in patients who experienced DPE following allo-HSCT, and could potentially offer a novel approach for managing such patients. Future large-scale, prospective studies are warranted to further assess the potential benefits of hetrombopag for improving patient outcomes following allo-HSCT.

Novel chemical-structure TPOR agonist, TMEA, promotes megakaryocytes differentiation and thrombopoiesis via mTOR and ERK signalings

BackgroundNon-peptide thrombopoietin receptor (TPOR) agonists are promising therapies for the mitigation and treatment of thrombocytopenia. However, only few agents are available as safe and effective for stimulating platelet production for thrombocytopenic patients in the clinic. PurposeThis study aimed to develop a novel small molecule TPOR agonist and investigate its underlying regulation of function in megakaryocytes (MKs) differentiation and thrombopoiesis. MethodsA potential active compound that promotes MKs differentiation and thrombopoiesis was obtained by machine learning (ML). Meanwhile, the effect was verified in zebrafish model, HEL and Meg-01 cells. Next, the key regulatory target was identified by Drug Affinity Responsive Target Stabilization Assay (DARTS), Cellular Thermal Shift Assay (CETSA), and molecular simulation experiments. After that, RNA-sequencing (RNA-seq) was used to further confirm the associated pathways and evaluate the gene expression induced during MK differentiation. In vivo, irradiation (IR) mice, C57BL/6N-TPORem1cyagen (Tpor-/-) mice were constructed by CRISPR/Cas9 technology to examine the therapeutic effect of TMEA on thrombocytopenia. ResultsA natural chemical-structure small molecule TMEA was predicted to be a potential active compound based on ML. Obvious phenotypes of MKs differentiation were observed by TMEA induction in zebrafish model and TMEA could increase co-expression of CD41/CD42b, DNA content, and promote polyploidization and maturation of MKs in HEL and Meg-01 cells. Mechanically, TMEA could bind with TPOR protein and further regulate the PI3K/AKT/mTOR/P70S6K and MEK/ERK signal pathways. In vivo, TMEA evidently promoted platelet regeneration in mice with radiation-induced thrombocytopenia but had no effect on Tpor-/- and C57BL/6 (WT) mice. ConclusionTMEA could serve as a novel TPOR agonist to promote MKs differentiation and thrombopoiesis via mTOR and ERK signaling and could potentially be created as a promising new drug to treat thrombocytopenia.

Combination of Thrombopoietin Receptor Agonist and Recombinant Human Thrombopoietin for Treating Cancer Therapy Induced Thrombopenia

Background Cancer therapy induced thrombopenia (CTIT) refer to thrombopenia caused by various anti-cancer therapy which include chemotherapy, radiotherapy, targeted therapy and immunotherapy. Chemotherapy-induced thrombopenia (CIT) could increase the risk of bleeding, modification of treatment, cost of treatment and even influence overall survival. Recombinant human thrombopoietin (rhTPO) was approved for CIT by national medical products administration (NMPA). However, certain patients still could not benefit from these agents. Hetrombopag, a new orally active small molecule thrombopoietin receptor agonist (TPO-RA), acts through binding to thrombopoietin receptor to stimulate multiple intracellular signaling pathways, including JAK/STAT, PI3K/AKT and ERK1/2. This will stimulate the proliferation and differentiation of megakaryocytes and promote platelet production. Combination of TPO-RA and rhTPO is anticipated to improve the outcome compared with rhTPO alone for treating CTIT in cancer patients. Methods Between January 2021 and June 2022, we conducted a retrospective analysis of patients (18 - 80 years) with cancer therapy induced thrombopenia (platelet count < 50 x 109/L) treated with rhTPO (subcutaneous injection, 300 U/kg/d) alone or combination of rhTPO and hetrombopag (oral, 5 mg/d) at Beijing Luhe Hospital, Capital Medical University. Treatment will discontinue when platelet count increased more than 50 x 109/L or platelet count doubled than baseline. The maximum treatment was 14 days. Results In total, 58 patients were included for analysis (28 patients received rhTPO plus hetrombopag and 30 patients received rhTPO alone). The baseline characteristics were generally similar between two groups. Patients with baseline platelet count less than 30 x109/L were 28.6% vs 10% in rhTPO plus hetrombopag group and rhTPO alone group, respectively. There were 21 patients (75.0%) vs 9 patients (30.0%) achieved response (platelet count increased more than 50 x 109/L or doubled than baseline or reached more than 100 x 109/L without platelet transfusion) within 7-day treatment in rhTPO plus hetrombopag group and rhTPO alone group, respectively. Furthermore, 11 patients (39.3%) and 3 patients (10.0%) reached platelet count ≥100 x 109/L in rhTPO plus hetrombopag group and rhTPO alone group (Table 1). The median platelet count at baseline in two groups were similar. The platelet count of post treatment in two groups were both increased. While the platelet count increase in rhTPO plus hetrombopag group were higher than rhTPO group in day 3, day 5, day 7 and day 9 after treatment (Figure 1). Median time of treatment was 6.5 days (range 4-13) for rhTPO plus hetromnopag group and 9.5 days (range 5-14) for rhTPO group (P < 0.0001). One patient (3.3%) in rhTPO group reported bleeding (WHO bleeding grade 2) while no bleeding events were reported in rhTPO plus hetrombopag group. Five patients (16.7%) and three patients (10.7%) in rhTPO group and rhTPO plus hetrombopag group received platelet transfusion. Cancer patients treated with rhTPO or rhTPO plus hetrombopag were well tolerated, the treatment related adverse events were mainly alanine aminotransferase/aspartate aminotransferase increase or total bilirubin increased (all grade 1/2). The incidence of such adverse event was not significantly different between two groups. Conclusion Compared with rhTPO, combined rhTPO with hetrombopag for treating cancer therapy induced thrombopenia showed faster and deeper response without raise the safety concern. Further study needed to consolidate this result. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Avatrombopag Added to Standard Immunosuppressive Therapy for Severe Aplastic Anemia

Acquired aplastic anemia is immune-mediated bone marrow failure disease. Antithymocyte globulin (ATG) and cyclosporine based immunosuppressive therapy (IST) is effective for severe aplastic anemia (SAA), but only 12-17% of patients achieve complete response at 6 months. Complete hematologic response predicts better survival of patients, so clinicians have been trying to further improve the complete response rate. Addition of eltrombopag improves both the overall response rate and complete response rate of SAA patients, but its hepatotoxicity is still worrying. Avatrombopag is a novel, oral, small-molecule thrombopoietin receptor agonist being developed to provide a predictable increase in platelet counts in immune thrombocytopenia and thrombocytopenia in patients with chronic liver disease. To date, there is no report on the effectiveness of avatrombopag in treating aplastic anemia. Here we enrolled 32 severe and very severe aplastic anemia (SAA/VSAA) patients who received ATG, cyclosporine and avatrombopag as first-line treatment between June 2021 and March 2022. Thirty-one patient received porcine ATG (20mg/kg.d for 5 consecutive days) and one patient received rabbit ATG (3mg/kg.d for 5 consecutive days). Avatrombopag was added within 3 months after ATG initiation at dose of 40-60mg per day and administered for at least 3 months. Cyclosporine was given orally at dose of 3.5-5mg/kg.d. There were 17 SAA patients and 15 VSAA patients. The median neutrophil count was 0.31 (range 0.01-1.01) ×109/L, median reticulocyte count was 8 (range 2-54) ×109/L, and median platelet count was 5 (range 1-16) ×109/L. All patients achieved the end-point of 3 months and 23 patients achieved end-point of 6 months. One patient with VSAA died at 1 month due to infections and was counted as no response at 3 months and 6 months. The rate of complete response was 15.6% and rate of overall response was 46.9% at 3 months. The rate of complete response at 6 months was 30.4% and rate of overall response was 65.2%. The complete response rate at 3 months and 6 months were both higher than historical results of standard IST (ATG and cyclosporine, 5.2% at 3 months and 14.6% at 6 months). Avatrombopag was safe, and there was no drug-related liver dysfunction. No patient discontinued avatrombopag due to adverse events. In conclusion, the addition of avatrombopag to IST was safe and associated with higher complete response rate among patients with SAA/VSAA.

A multicenter phase II study on the efficacy and safety of hetrombopag in patients with severe aplastic anemia refractory to immunosuppressive therapy

Background:In this single-arm phase II study (NCT03557099), we evaluated the efficacy and safety of hetrombopag, a small molecule thrombopoietin (TPO) receptor agonist, in patients with severe aplastic anemia (SAA) who were refractory to standard first-line immunosuppressive therapy (IST).Methods:SAA patients who were refractory to standard first-line IST were given hetrombopag orally at an initial dose of 7.5 mg once daily to a maximum of 15 mg once daily, for a total of 52 weeks. The primary endpoint was proportion of patients achieving hematologic responses in ⩾1 lineage at week 18.Results:A total of 55 eligible patients were enrolled and received hetrombopag treatment. This study met its primary endpoint, with 23 [41.8%, 95% confidence interval (CI) = 28.7–55.9] patients achieving hematologic response in ⩾1 lineage at week 18 after initiation of hetrombopag treatment. Twenty-four (43.6%, 95% CI = 30.3–57.7) and 27 (49.1%, 95% CI = 35.4–62.9) of the 55 patients responded in ⩾1 lineage at weeks 24 and 52, respectively. Median time to initial hematologic response was 7.9 weeks (range = 2.0–32.1). The responses were durable, with a 12-month relapse-free survival rate of 82.2% (95% CI = 62.2–92.2). Adverse events occurred in 54 (98.2%) patients, and 28 (50.9%) patients had treatment-related adverse events. Seventeen (30.9%) patients had adverse events of grade ⩾3. Serious adverse events occurred in 15 (27.3%) patients and three deaths (5.5%) were reported.Conclusion:Hetrombopag showed encouraging efficacy with durable hematologic responses in patients with SAA who were refractory to IST. Hetrombopag was well tolerant and safe for long-term use.ClinicalTrials.gov identifier:NCT03557099

Effects of Lusutrombopag on Post-invasive Procedural Bleeding in Thrombocytopenic Patients with Chronic Liver Disease.

IntroductionThrombocytopenia can increase the bleeding risk in patients with chronic liver disease (CLD) undergoing invasive procedures. Prophylactic platelet transfusion (PT) is often performed to increase platelet counts in patients with CLD undergoing invasive procedures to prevent bleeding. Lusutrombopag, a small-molecule thrombopoietin receptor agonist, is expected to be an alternative therapy to prophylactic PT. This study aimed to compare the effects between lusutrombopag and PT.MethodsData were obtained from a Japanese administrative database (April 2008–May 2019). Patients aged ≥ 18 years who underwent planned invasive procedures after the first CLD diagnosis and were observed for ≥ 30 days prior to invasive procedures were considered eligible. Patients who underwent planned invasive procedures with lusutrombopag prescription at 5–30 days before the procedure were categorized as the lusutrombopag group, whereas those who received PT at 1 day before and/or on the same day as the procedure, without lusutrombopag prescription, were classified as the PT group. Outcomes, including bleeding frequency during hospitalization and average medical costs (costs for prophylactic treatment and total costs between the day of the invasive procedure and 30 days after the invasive procedure), were compared between the groups after matching.ResultsAmong 738,878 patients with CLD, 379 cases for each group were identified after matching. The incidence of bleeding events was lower in the lusutrombopag group than in the PT group (3.7% vs. 8.2%, p < 0.001). Average medical costs were lower in the lusutrombopag group than in the PT group ($6667 as of August 2021 vs. $7170, p = 0.011).ConclusionLusutrombopag is suggested to be effective as a prophylactic treatment for bleeding prevention in patients with CLD undergoing planned invasive procedures.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12325-021-01965-7.

EVALUATION OF THE FREQUENCY OF ARTERIAL AND VENOUS THROMBOSIS AND PREDISPOSING FACTORS IN PATIENTS USING ELTROMBOPAG

Eltrombopag is a small molecule thrombopoietin-receptor agonist used orally for the treatment.There is a high risk of thrombosis associated with the use of Eltrombopag. Our aim in this study is evaluating the incidence of arterial and venous thrombosis in patients using Eltrombopag and followed up in our center with the diagnosis of ITP, MDS and aplastic anemia, and contributing to the literature with the data of Central Black Sea by retrospectively evaluating the predisposing factors. In this study, the data of 144 patients who were treated with Eltrombopag with the diagnosis of ITP, MDS and aplastic anemia at Ondokuz Mayıs University Faculty of Medicine Hematology Clinic between 2009-2019 were analyzed retrospectively. The data of the patients were obtained retrospectively from the hospital management information system. The study included 144 patients who treated with Eltrombopag. 66 (45.8%) of the patients were male and 78 (54.2%) were female. The mean age of the patients was 54.12 ± 20.08 years. 102 (70.8%) of the patient were diagnosed with ITP, 31 (21.5%) with aplastic anemia and 12 (7.6%) with MDS. Thrombosis was observed in 7 (4.9%) of 144 patients who treated with Eltrombopag. Venous thrombosis was found in 6 (4.2%) of these patients and arterial thrombosis was found in one patient (0.7%). Eltrombopag treatment poses a risk for thromboembolic events. The treatment process should be followed closely especially in patients with known risk factors for thrombosis.

Superiority of Avatrombopag to Placebo in Increasing Platelet Counts in Patients with Chronic Liver Disease-Associated Thrombocytopenia Undergoing Scheduled Procedures: Results from 2, Phase 3 Randomized Studies

Background: Thrombocytopenia (TCP) is common in patients with chronic liver disease (CLD). These patients may require platelet transfusions before routine procedures associated with a bleeding risk, thereby exposing them to the risks of transfusion reactions, infections and platelet alloimmunization, while complicating the performance of the procedure and impacting platelet supplies. Avatrombopag (AVA) is an oral, 2ndgeneration, small molecule thrombopoietin receptor agonist being developed to provide a measured increase in platelet counts (PC) as an alternative to platelet transfusions. Two randomized, double-blind, placebo (PBO)-controlled Phase 3 trials evaluated the potential for AVA to increase PC and reduce the need for platelet transfusions in patients with CLD undergoing scheduled procedures.Methods: ADAPT1 (NCT01972529) and ADAPT2 (NCT01976104) enrolled adults with CLD and TCP (mean Baseline PC <50x109/L), scheduled to undergo a procedure. Cohorts were based on Baseline PC (Cohort 1 - <40x109/L, or Cohort 2 - 40 to <50x109/L), and patients randomized 2:1 to receive once-daily oral AVA (Cohort 1- 60 mg; Cohort 2 - 40 mg) or PBO for 5 days with the procedure scheduled 5 to 8 days after the last dose (Day 10 to 13).The primary efficacy endpoint was the proportion of patients not requiring platelet transfusion or any bleeding rescue procedure up to 7 days post-procedure. Secondary endpoints assessed the proportion of patients achieving the target PC of ≥50x109/L by Procedure Day, change in PC from Baseline to Procedure Day, and safety.Results: Together, these studies randomized 435 patients. ADAPT1included 231 patients (median age 57 y; 68% male; Baseline median PC 38x109/L; CLD etiology: alcohol 14%, viral hepatitis 62%, other 23%). In Cohort 1, 90 patients were randomized to AVA and 48 to PBO and in Cohort 2, 59 were randomized to AVA and 34 to PBO. ADAPT2randomized 204 patients (median age 59 y; 62% male; Baseline median PC 39x109/L; CLD etiology: alcohol 15%, viral hepatitis 53%, other 33%). In Cohort 1, there were 70 patients who received AVA and 43 PBO, and in Cohort 2, 58 were randomized to AVA and 33 to PBO.Both studies met their primary efficacy endpoint, demonstrating the superiority of AVA to PBO in increasing the proportion of patients not requiring a platelet transfusion or rescue procedure for bleeding with treatment differences of ADAPT1: Cohort 1 - 42.6% (P<0.001), Cohort 2 - 49.9%, (P<0.0001); ADAPT2: Cohort 1-33.7% (P=0.0006), Cohort 2 - 54.6% (P <0.0001). In addition, a significantly higher proportion of AVA-treated patients successfully achieved the target PC of ≥50x109/L by Procedure Day compared with PBO in both cohorts in ADAPT1 and ADAPT2 (Table). Further, the magnitude of the change in mean PC from Baseline to Procedure Day was significantly larger in AVA-treated compared with PBO-treated patients in both ADAPT1 and ADAPT2in both cohorts (Table). Only 3 AVA-treated subjects achieved PC ≥200x109/L; all were asymptomatic.In both Phase 3 studies, the mean PC in AVA-treated patients started increasing on Day 4 and peaked at ~2 times Baseline PC on Procedure Day (Day 10 to 13); by 7 days post-procedure, mean PC had decreased in both AVA groups, returning to Baseline by Day 35.The most common treatment-emergent adverse events (TEAE) were pyrexia, abdominal pain, nausea, and headache. TEAEs were similar for AVA and PBO arms in both studies. Most TEAEs were mild to moderate in severity; one thrombotic TEAE (partial right portal vein thrombosis) occurred with 40 mg AVA in Cohort 2 in ADAPT2 on Day 7 post-procedure, 14 days after the last AVA dose.Conclusions: Both Phase 3 studies demonstrated the superiority of AVA to PBO in increasing the proportion of patients not requiring a platelet transfusion or any rescue procedure for bleeding. AVA given orally over 5 days resulted in a significant increase in patients achieving the target PC of ≥50x109/L by Procedure Day compared to PBO. The mean change in PC from Baseline to Procedure Day was significantly greater for AVA-treated patients than those who received PBO. In both studies, AVA-treated patients' PC peaked at ~2 times Baseline on Procedure Day, and returned to Baseline by Day 35. AVA was well tolerated, with a safety profile similar to PBO. An agent that provides a measured increase in PC and reduces the need for platelet transfusions may be advantageous for patients with CLD and TCP undergoing invasive procedures to importantly reduce their risks. [Display omitted] DisclosuresTerrault:Merck: Research Funding; AbbVie: Research Funding; Gilead: Research Funding; BMS: Research Funding; Allergan: Research Funding; Eisai: Research Funding. Kuter:Pfizer: Consultancy; Genzyme: Consultancy; Merck: Consultancy; Shire: Consultancy, Research Funding; Protalex: Consultancy, Research Funding; 3SBIO: Consultancy; ONO: Consultancy; BMS: Consultancy, Research Funding; Rigel: Consultancy, Research Funding; Alexion: Consultancy, Research Funding; Dova: Consultancy, Membership on an entity's Board of Directors or advisory committees; Argenx: Consultancy; Incyte: Consultancy, Research Funding; Fujifilm: Consultancy; Zafgen: Consultancy; Amgen: Consultancy; Syntimmune: Consultancy, Research Funding; Novartis: Consultancy. Bibbiani:Eisai, Inc.: Employment.

Protein and Small-Molecule Leucopoiesis and Thrombopoiesis Stimulators.

Pluripotent stem cells of the bone marrow are stimulated by different cytokines to proliferation and differentiation into various types of blood cells. These cytokines are mostly glycoproteins. Erythropoietin stimulates stem cells to the formation of erythrocytes while colony-stimulating factors cause the formation of different types of white blood cells. Stem cell factors play an important role in the maintenance and survival of blood cells of all types. Thrombopoietin stimulates stem cells to proliferation and formation of blood platelets. Granulocyte colony-stimulating factor is probably the most important drug in use. It stimulates stem cells to the formation of neutrophile granulocytes. It is often used in recombinant forms such as filgrastim in the treatment of neutropenia in cancer chemotherapy or AIDS. Its pegylated conjugates such as pegfilgrastim are also available. Its activity can be supported by plerixafor, a small molecule - bicyclam derivative acting as an indirect agonist of stem cells factor. It acts as an antagonist of CXCR4 receptor activation of which brakes hematopoiesis. The treatment of conditions accompanied by thrombocytopenia such as idiopathic thrombocytopenic purpura is currently not performed by thrombopoietin but synthetic agonists of its receptor are preferred. Romiplostim is a peptibody. It consists of a protein part interacting with the thrombopoietin receptor which is, however, different from thrombopoietin, and of Fc fragment of immunoglobulin G1. In contrast, small molecule thrombopoietin receptor agonists represented by eltrombopag can be given orally unlike all of the above.

TET2 Inhibitory Effects of Eltrombopag Contribute Its Hematopoietic Activity

Severe aplastic anemia (sAA) is bone marrow (BM) failure syndrome characterized by immune mediated BM hypoplasia and pancytopenia usually treated with immunosuppressive therapy (IST) or allogeneic BM transplant. Despite the successes of IST in treating acquired, idiopathic sAA, most of the available treatment options only convert severe into non-severe forms of disease. Recently, eltrombopag (Epag), a small molecule thrombopoietin receptor (TPOR) agonist has been introduced into the routine treatment of de-novo and refractory AA with robust clinical response. Epag treatment showed remarkable tri-lineage responses in AA, suggesting an effect on hematopoietic stem and progenitor cells (HSPCs) amplification. The use of hematopoietic growth factors in AA that increases HSPCs has been associated with justified fears of facilitating AA evolution to MDS. Similarly, Epag has parallel effects on the amplification of HSPCs and there has been recent signals that long term treatment of Epag may increase the MDS risk. Using an in-house developed highly stable cell free high throughput screening of bioactive small molecule chemical library, we identified Epag as one of the most potent inhibitor of TET2. TET2 is the most abundant DNA dioxygenase in HSPCs. The loss-of-function mutations of TET2 frequently occurs in myeloid neoplasia. Here using in vitro and in vivo model system we report that effect of Epag, in part, is mediated by its ability to inhibit TET-dioxygenase activity. We demonstrate that Epag directly binds to TET2 in the presence of Fe2+ and inhibits its dioxygenase function in cell free system. In cell culture model we observed that nearly 40% of Epag partitioned into to nucleus suggesting its potential TET2 inhibitory role in cells. To test if TPOR signaling activation by Epag has any impact on TET activity we engineered murine cell lines BaF3 and 32D by introducing human TPOR. Irrespective of the status of TPOR-JAK-STAT pathway activation, as reflected in STAT5 phosphorylation, Epag demonstrated a robust TET-inhibition activity. However, in similar experiments peptide agonist of TPOR or another small molecule TPOR agonist Avotrombopag did not have any TET inhibitory effects. Consistent with these observations, Epag but not TPO or Avotrombopag inhibited TET activity in murine BM. Thus, Epag mediated TET2 inhibition in these cells are specific and independent of TPOR signaling. Consistent with previous reports, we observed that Epag treatment can significantly expand murine HSPCs even in the absence of TPOR signaling activation. The hematopoietic activity of Epag in murine system is dependent on its ability to inhibit TET2 as confirmed by the lack of Epag effects on Tet2-/- HSPCs. We further confirmed that TET-inhibition by Epag is central for its ability to expand HSPCs in murine model under in vivo settings using BM transplant experiments. We transplanted a mixture of cells derived from Tet2+/+ Pep Boy (CD45.1, 95%) and Tet2-/- C57BL/6 (CD45.2, 5%) into lethally irradiated recipient PepBoy mice. Epag treatment of mice reconstituted with the mixture of BM cells increases the fraction of Tet2+/+ BM cells only. Interestingly, Epag mimic loss of Tet2 in vivo as observed in the expansion of myeloid compartments of Tet2+/+ fractions reflected in CD11b-CD11c+, CD11b+CD11c-, CD11b+CD11c-Ly6C+Ly6G- (monocytes) and CD11b+CD11c-Ly6ClowLy6G+ (neutrophils). We did not observe any significant change in B220+, CD4+ or CD8+ lymphoid populations. On the contrary, we observed a growth restrictive effect of Epag treatment on Tet2-/- myeloid cells. Consistent with our hypothesis that Epag inhibits TET-dioxygenase activity, we observed hypermethylation in the mononuclear cells derived AA patients (n= 16) after Epag treatment. This was further confirmed in ex vivo Epag treatment of BM cells derived from healthy donor. Epag treatment significant increase clonogenic expansion of normal BM cells but not TET2 mutant myeloid cells. In summary, here we demonstrate that Epag is a potent inhibitor of TET-dioxygenase and its biological consequences are independent of TPOR-JAK-STAT activation. Epag treatment mimics TET2 loss of function in AA cells, however it restricts clonal expansion of TET2 mutant myeloid cells. Disclosures Patel: Alexion: Other: educational speaker. Nazha:Jazz: Research Funding; Incyte: Speakers Bureau; MEI: Other: Data monitoring Committee; Novartis: Speakers Bureau. Saunthararajah:EpiDestiny: Consultancy, Current equity holder in private company, Patents &amp; Royalties: University of Illinois at Chicago. Sekeres:Pfizer: Consultancy; BMS: Consultancy; Takeda/Millenium: Consultancy. Maciejewski:Alexion, BMS: Speakers Bureau; Novartis, Roche: Consultancy, Honoraria.

Effect of Food on the Pharmacokinetic and Pharmacodynamic Profiles of Hetrombopag in Healthy Volunteers

PurposeHetrombopag, a novel, oral small molecule thrombopoietin receptor agonist, exhibits an obvious thrombocytopoietic effect with good safety. Hetrombopag is currently under clinical development for the treatment of chronic idiopathic thrombocytopenic purpura (ITP). The objectives of this study were to assess the effect of high-fat and high-calorie food on the pharmacokinetic and pharmacodynamic (PK/PD) profiles of hetrombopag in healthy volunteers. MethodsAn independent, single-dose, open-label, randomized-sequence, crossover trial was conducted. Healthy volunteers received hetrombopag 7.5-mg tablets in the fasted state or with a high-fat, high-calorie breakfast. The effects of the high-fat and high-calorie food on the PK/PD profiles of hetrombopag were evaluated by using a noncompartmental analysis and a semi-physiological model. FindingsTwelve Chinese healthy volunteers were enrolled. Mean plasma AUC0–t and Cmax decreased by 98.7% and 95.0%, respectively, when hetrombopag was administered with high-fat and high-calorie food. The semi-physiological PK/PD model analysis showed that the absorption rate constant at the first absorption site was almost halved at the fed condition. The change in platelet counts in the fed condition was not sufficiently as sensitive as that in the fasted condition. ImplicationsHigh-fat and high-calorie food were associated with significantly reduced systemic exposure and platelet count sensitivity. Thus, hetrombopag should be taken in a fasted state to avoid the impact of food on bioavailability and platelet counts. ClinicalTrials.gov identifier: NCT02409394.

Signaling properties of murine MPL and MPL mutants after stimulation with thrombopoietin and romiplostim

Thrombopoietin (THPO) and its receptor myeloproliferative leukemia virus oncogene (MPL) regulate hematopoietic stem cell (HSC) quiescence and maintenance, but also megakaryopoiesis. Thrombocytopenias or aplastic anemias can be treated today with THPO peptide mimetics (romiplostim) or small-molecule THPO receptor agonists (e.g., eltrombopag). These THPO mimetics were designed for human application; however, many preclinical studies are performed in murine models. We investigated the activation of wild-type murine MPL (mMPL) by romiplostim. Romiplostim stimulated AKT, ERK1/2, and STAT5 phosphorylation without preference for one of these pathways, however, with a four- to fivefold lower phosphorylation intensity at high concentration. Faster internalization of mMPL after romiplostim binding could be one explanation of reduced signaling. In vitro megakaryocyte differentiation, proliferation, and maturation by romiplostim was less efficient compared with stimulation with mTHPO. We further dissected mMPL signaling by lentiviral overexpression of mMPL mutants with tyrosine (Y)-to-phenylalanine (F) substitutions in the distal cytoplasmic tyrosines 582 (Y582F), 616 (Y616F), and 621 (Y621F) individually and in combination (Y616F_Y621F) and in truncated receptors lacking 53 (Δ53) or 69 (Δ69) C-terminal amino acids. Mutation at tyrosine residue Y582F caused a gain-of-function with baseline activation and increased ERK1/2 phosphorylation upon stimulation. In agreement with this, proliferation in Y582F-32D cells was increased, yet did not rescue in vitro megakaryopoiesis from Mpl-deficient cells. Y616F and Y621F mutated receptors exhibited strongly impaired ERK1/2 and decreased AKT signaling and conferred reduced proliferation to 32D cells upon mTHPO stimulation but a partial correction of immature megakaryopoiesis in vitro.

Eltrombopag Creates a Transient Chemical Phenocopy of TET2 Loss of Function That Contributes to Hematopoietic Precursor Expansion

Eltrombopag (Epag) is FDA approved for immune thrombocytopenic purpura (ITP) and aplastic anemia (AA), in which it induces tri-lineage responses in primary and refractory settings. These biologic effects suggest that Epag helps to regenerate not only committed megakaryocytic progenitors, but also hematopoietic stem and progenitor cells (HSPCs). Epag is a small molecule thrombopoietin receptor (TpoR) agonist that activates the JAK-STAT pathway to increase platelet counts similar to the polypeptide based TpoR agonist Nplate. In addition, some of Epag's activity may, unlike that of Nplate, be independent of TpoR. Epag increases HSC self-renewal in mice despite the lack of binding to murine TpoR and showed efficacy in a TpoR-deficient strain. Here we show that Epag binds and inhibits TET2 in an iron-chelation independent manner, to in this way increase precursor expansion. Since iron is a key prosthetic component of the TET2 enzyme, we determined if Epag sequestration of iron in HSPCs inhibits TET2 function. In silico modeling indicated that Epag can form a tripartate complex with Fe2+, αKG and TET2 (Fig.A). Epag interacted with TET2 via N1387 and H1984 forming a two-way H-bond and also coordinating Fe2+ sandwiched between N-Oxalylglycine a surrogate for aKG and H1381 residues of TET2 (Fig.A). To experimentally confirm the computational structural model and study the effect of Epag on TET2, we used an ELISA-based TET2 activity assay in a cell-free system. We found that Epag inhibits TET2 in a dose-dependent manner with an IC50 of 1.6±0.1 µM in the presence of 25 µM each of aKG and Fe2+ (Fig.B). Interestingly, this observed IC50 of Epag for TET2 inhibition is 10-fold lower than the plasma Cmax of Epag that is produced in humans at standard clinical doses. Therefore, we performed a dose dependent TET2 rescue experiment by increasing aKG and Fe2+. There was no proportional effect on the TET2 inhibitory IC50 of Epag upon increasing either Fe2+ or αKG suggesting the inhibition of TET2 is independent of both these co-factors (Fig.B). This was consistent with in silico structural model data indicating that Epag specifically binds and traps TET2 in an inactive state, explaining why increasing concentration of Fe2+ or Fe3+ failed to rescue TET2 activity (Fig.C). Also consistent with this model of how Epag inhibits TET2, we did not experimentally observe any significant effect of ascorbic acid (100 µM), known to activate TET2 through maintenance of Fe3+↔Fe2+ homeostasis during TET2 catalysis. Underscoring likely relevance of TpoR independent actions of Epag, Epag treatment of K562 cells displaying undetectable levels of TpoR mRNA as well as protein, significantly reduced levels of 5hmC, while Tpo had no effects on 5hmC (Fig.D). We are currently measuring, after written informed consent on an IRB approved protocol, 5hmc levels serially in patients who are receiving Epag. In summary, we demonstrate TpoR-independent actions of Epag, its direct inhibition of TET2 activity, most likely by locking TET2 in an inactive configuration. Given the fundamental role of TET2 in promoting differentiation, this mechanism-of-action of Epag could be one pathway by which it expands HSPCs, independent of TpoR. In short, Epag creates a transient chemical phenocopy of TET2 loss of function, simultaneously having the capacity to activate JAK-STAT signaling via TpoR. These actions together can explain the clinical potency of Epag. Figure Disclosures Nazha: Abbvie: Consultancy; Tolero, Karyopharma: Honoraria; Daiichi Sankyo: Consultancy; Incyte: Speakers Bureau; MEI: Other: Data monitoring Committee; Novartis: Speakers Bureau; Jazz Pharmacutical: Research Funding. Saunthararajah:Novo Nordisk: Consultancy; EpiDestiny: Consultancy, Equity Ownership, Patents &amp; Royalties. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees. Maciejewski:Novartis: Consultancy; Alexion: Consultancy.

Azacytidine Inhibits Megakaryopoiesis Via the Induction of Immunogenic RNA Species and Activation of Type-I Interferon Signaling

Management of hematologic disease- and therapy-related thrombocytopenia remains a serious clinical issue, especially in patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). The ribonucleoside and DNA-demethylating agent azacytidine (AZA), has proven useful for the treatment of patients with MDS and AML not eligible for stem cell transplantation. While low-dose AZA therapy induces clinical remissions in up to 50% of treated patients, it comes at the cost of aggravating pre-existing thrombocytopenia which is observed in a subset of patients; this can lead to increased bleeding and bleeding-associated mortality, and importantly, often requires dose modifications and delays of therapy. Thus, identification of strategies alleviating ineffective megakaryopoiesis will likely lead to increased therapeutic efficacy for patients with MDS/AML. Eltrombopag (EP), a second-generation small molecule thrombopoietin receptor (TPO-R) agonist was effective in raising platelet counts in patients with MDS as a single agent, as well as in combination with certain standard of care therapies. However, it failed to stimulate platelet production during the first four cycles of AZA treatment as uncovered by a recent phase III placebo-controlled clinical study (SUPPORT; NCT02158936). The goals of this study were to identify the cellular and molecular underpinnings of AZA-associated inhibition of megakaryopoiesis and to assess the ineffectiveness of EP in mitigating AZA treatment-associated thrombocytopenia. Our results demonstrate that at a clinically-equivalent and non-cytotoxic dose, AZA rapidly induces transient activation of interferon type I (IFN-I) signaling in various hematopoietic cell types, including stem and lineage-committed progenitor cells (HSPCs). We detected IFNα and IFNβ production and release using ELISA and intracellular flow cytometry on primary total mononuclear cell- and purified CD34-positive HSPC populations derived from cord blood, bone marrow from healthy volunteers or patients with MDS/AML. AZA-mediated activation of Type I IFNs in healthy control- and MDS/AML cells was preceded by an accumulation of double-stranded RNA (dsRNA) species and decreased total RNA cytosine methylation measured by immunocytochemistry and intracellular FACS analysis; this suggested that AZA triggered the accumulation of immunogenic RNA species which elicit an IFN-I response. In support, we found Toll like receptor 3 (TLR3) activation and phosphorylation of STAT1 in CD34+ HPSC, along with premature activation of Suppressor of Cytokine Signaling 1 (SOCS1), a well-known JAK/STAT-dependent signaling attenuator. This rapid AZA-induced viral mimicry response led to abrogation of thrombopoietin (TPO) or EP-stimulated TPO-R signaling and inhibition of ex vivo megakaryocyte progenitor proliferation quantified by colony formation in semi-solid medium. Importantly, inhibition of IFN-I signal activation using the JAK3 inhibitor decernotinib, the IFNα/β-blocking peptide, B18R, or RNA interference-mediated knock-down of SOCS1 counteracted the inhibitory effects of AZA on TPO-R stimulation and restored megakaryopoiesis. Given these observations, we pre-clinically tested a revised treatment protocol, in which primary cells were first exposed to AZA for four days followed by TPO-R stimulation using TPO or EP. This new treatment strategy alleviated AZA's inhibitory effects at the molecular and cellular levels, demonstrating that upon resolution of the AZA-mediated vial mimicry response, EP and TPO can effectively stimulate TPO-R signaling and megakaryopoiesis. Together, our data reveal a mechanistic basis of AZA-mediated inhibition of megakaryopoiesis in patients with MDS/AML. Additionally, we show that EP cannot overcome the megakaryopoiesis-inhibitory effects of acute IFN-I signaling activation upon AZA exposure. Findings of our study are consistent with and provide a molecular explanation for the observations made in the context of the SUPPORT study. In the future, it will be critical to better understand and potentially counteract the megakaryopoiesis-inhibitory effects by IFN-I pathway activation upon AZA therapy in patients with MDS/AML. Disclosures Okoye-Okafor: Novartis Pharmaceuticals: Research Funding. Pallaud:Novartis Pharmaceuticals: Employment. Marques Ramos:Novartis Pharmaceuticals: Employment. Verma:Janssen: Research Funding; BMS: Research Funding; Celgene: Honoraria; Stelexis: Equity Ownership, Honoraria; Acceleron: Honoraria. Heckman:Celgene: Research Funding; Novartis: Research Funding; Oncopeptides: Research Funding; Orion Pharma: Research Funding. Will:Novartis Pharmaceuticals: Research Funding.

PSU1 LUSUTROMBOPAG CAN SAFELY INCREASE PLATELET COUNT IN PATIENTS WITH CHRONIC LIVER DISEASE PRIOR TO AN INVASIVE PROCEDURE, REDUCING THE NEED FOR PLATELET TRANSFUSIONS AND LOWERING THE RISK OF BLEEDING

Thrombocytopenia complicates management of chronic liver disease (CLD), and may interfere with the performance of invasive procedures. Lusutrombopag (LUSU), an oral, small molecule thrombopoietin receptor agonist, has been studied for the treatment of thrombocytopenia in patients with CLD who are scheduled for invasive procedures. Aiming to further assess its efficacy and safety, a meta-analysis of LUSU randomised controlled trial (RCT) data is presented. A direct random-effects meta-analysis was conducted in Stata 14.2MP, using the method of DerSimonian and Laird, with data from three RCTs enrolling pre-procedure CLD patients with a platelet count (PC) < 50 × 10ˆ9/L. Patients were randomised to receive LUSU 3 mg once daily or placebo (PBO) for up to seven days prior to their invasive procedure, with the procedure performed between day 9 and 14. LUSU is statistically significantly better than PBO in reducing the need for platelet transfusions (PT) prior to and after an invasive procedure (No PT during study: Odds ratio 11.24 (95% CI: 2.83, 44.64); p = 0.001). During the procedure window, patients who received LUSU and no PT had a statistically significant higher increase in PC than patients who received PBO and a PT (mean difference between LUSU and no PT versus PBO with PT at day 12: 34.18 × 10ˆ9/L (95% CI: 30.31, 38.06; p < 0.001)). LUSU significantly reduced the rate of any bleeding (irrespective of severity) during the study compared to PBO (OR 0.45 (95% CI: 0.22, 0.93; p = 0.03)). Overall, there was no significant difference between LUSU and PBO in the rate of treatment emergent adverse events (TEAEs), including splanchnic thrombosis. LUSU can safely increase PC in thrombocytopenic CLD patients prior to an invasive procedure, reducing the need for platelet transfusions and lowering the risk of bleeding.

Lusutrombopag: A Review in Thrombocytopenia in Patients with Chronic Liver Disease Prior to a Scheduled Procedure.

Lusutrombopag (Mulpleta®), an orally bioavailable, small molecule thrombopoietin receptor agonist, is approved for the treatment of thrombocytopenia in adult patients with chronic liver disease who are scheduled to undergo a procedure. In placebo-controlled phase3 clinical trials, lusutrombopag significantly increased the proportion of patients who did not require a platelet transfusion prior to the procedure or rescue therapy for bleeding up to 7days after the scheduled procedure. Lusutrombopag also significantly increased the proportion of patients who were responders (i.e. had a platelet count ≥ 50×109/L and an increase of ≥ 20×109/L from baseline) compared with placebo. Lusutrombopag is well tolerated, with headache being the most common adverse reaction in lusutrombopag recipients in clinical trials. Thus, lusutrombopag represents a promising emerging therapeutic option for the treatment of thrombocytopenia in adult patients with chronic liver disease who are scheduled to undergo a procedure.