Thrombopoietin Receptor Agonist Research Articles

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.

Eltrombopag Plus Rhtpo for Corticosteroid-Resistant or Relapsed ITP: A Prospective Observed Study

During the COVID-19 pandemic, the classical subsequent treatment regimen for immune thrombocytopenia (ITP) of immunosuppressants and/or steroids might increase patients' susceptibility of virus infections. To minimize ITP patients' risk during the COVID-19 global crisis and to improve treatment efficacy, non-immunosuppressive therapies, mainly including thrombopoietin mimetics, such as eltrombopag or recombinant human thrombopoietin (rhTPO), may be better for them. Eltrombopag, a small molecule agonist of thrombopoietin receptor (TPO-RA), was recommended as the subsequent treatment for ITP patients, which also already showed robust efficacy. However, inefficacy, loss of response and fluctuation of platelet counts during treatment were the serious problems in eltrombopag treatment for corticosteroid-resistant or relapsed ITP.RhTPO is a full-length glycosylated-TPO produced by Chinese hamster ovary cells, which showed its effectiveness in ITP in a variety of studies.For the difference of rh-TPO and eltrombopag , it had distinct molecular structures, treatment mechanisms, and pharmacokinetic characteristics and thus different response patterns and side effect profile. Previous studies have confirmed the safety and effectiveness of switching between rh-TPO and eltrombopag for ITP patients who had no response to or experienced adverse events with their first TPO-RA.However, no study has focused on the safe and effectiveness of the combination therapy of eltrombopag and rhTPO.The investigators hypothesized that the combination of these two agents could be a promising option for ITP treatment. Methods This is a prospective observed study to investigate the efficacy and safety of eltrombopag plus rhTPO as treatment for corticosteroid-resistant or relapsed ITP during the COVID-19 pandemic. Participation Criteria The inclusion criteria were as follows:Clinically confirmed corticosteroid-resistant or relapsed primary ITP;Platelet count less than 30×10^9/L on two occasions or platelets above 30×10^9/L combined with bleeding manifestation (WHO bleeding scale 2 or above);≥ 18 years. Exclusion Criteria: with secondary ITP such as drug-related thrombocytopenia, viral infection-induced thrombocytopenia, or a known diagnosis of another autoimmune disease; with other possible causes of thrombocytopenia, such as leukaemia, myelodysplastic syndrome, and aplastic anaemia; impaired renal function as indicated by a serum creatinine level > 2.0 mg/dL;inadequate liver function as indicated by a total bilirubin level > 2.0 mg/dL and/or an aspartate aminotransaminase or alanine aminotransferase level > 3×upper limit of normal; with a New York Heart Classification III or IV heart disease; with a history of severe psychiatric disorder or are unable to comply with study and follow-up procedures; pregnant or lactating women, or plan to become pregnant or impregnated within 12 months of receiving study drug; previous splenectomy; with previous or concomitant malignant disease; expected survival of < 2 years;not willing to participate in the study. Procedure For the patients with the combination therapy of eltrombopag and rhTPO, they received eltrombopag 25-75 mg oral daily and rh-TPO 300U/kg subcutaneous injection once daily for 7 consecutive days, followed by a tapering dose in maintenance therapy to maintain the platelet count between 50-150×10 9/L. Results From September 2nd, 2020, to July 1st, 2023, a total of 29 patients with corticosteroid-resistant or relapsed ITP were enrolled to receive eltrombopag plus rhTPO treatment, which included 11 male and 18 female patients.The median age were 55 (23-91) years old. The baseline platelete count was 7 (1-17)×10 9/L. Most patients (69.0%) were with severe ITP (platelet counts≤10×10 9/L or bleeding score ≥5).Response was defined as the achievement of platelet counts ≥30 × 10 9/L and ≥2 times the baseline platelet count at least once with treatment.The response rates at 1 week (early response) and 1 month ( initial response) were 37.9%(11/29) and 62.1%(18/29), respectively. After 6 weeks' treatment, 82.8% (25/29) of patients achieved response, and the improvement of bleeding symptoms were observed in most patients (89.7%).No thromboembolic events occurred during treatment. Conclusion Elrtombopag and rhTPO was a safe and effective therapy for corticosteroid-resistant or relapsed ITP, especially for severe ITP.

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

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

Time to Achieve Platelet Count Response after Intravenous Efgartigimod in Adults with Primary Immune Thrombocytopenia: A Phase 3, Multicenter, Double-Blinded, Placebo-Controlled, Randomized Clinical Trial (ADVANCE IV)

Background In primary immune thrombocytopenia (ITP), immunoglobulin G (IgG) anti-platelet autoantibodies contribute to platelet clearance and impair platelet production. IgG homeostasis is regulated by the neonatal Fc receptor (FcRn), which binds to IgG in a pH-dependent manner and recycles bound IgG. Efgartigimod (EFG), a human IgG1 Fc fragment, is a natural ligand of FcRn engineered to bind competitively to FcRn with high affinity, preventing recycling of endogenous IgG, thereby reducing IgG levels, including pathogenic IgG autoantibody levels. Methods Intravenous (IV) EFG was evaluated in ADVANCE IV, a phase 3, multicenter, randomized, double-blinded, placebo (PBO)-controlled trial (NCT04188379) in adults with persistent or chronic ITP (Broome CM, et al. ASH 2022). Participants who received 2 prior or 1 prior and 1 concurrent ITP therapy with an average of 2 platelet (PLT) counts of <30×10 9/L during screening were randomized 2:1 to receive EFG IV 10 mg/kg or PBO IV for 24 weeks. Concurrent oral corticosteroids, immunosuppressants, dapsone, danazol, fostamatinib, and oral thrombopoietin receptor agonists were permitted but required to remain at the entry dosage and frequency. Participants received weekly dosing of either EFG or PBO (weeks 1-4) followed by response-dependent weekly or every-other-week dosing (weeks 5-16) and then maintained their dosing regimen from weeks 17-24. PLT counts were measured weekly starting at day 7 after treatment initiation. The extent of disease control, defined as cumulative weeks with PLT counts of ≥50×10 9/L in the chronic ITP population, was assessed as a key secondary endpoint. This analysis evaluates trends in time to response in ADVANCE IV. The time to achieve 2 consecutive PLT counts of ≥50×10 9/L was evaluated as a secondary endpoint. Time to 2 consecutive PLT counts of ≥100×10 9/L and time to single counts of ≥50×10 9/L and 100×10 9/L were analyzed as defined a priori. Post hoc Kaplan-Meier (KM) analyses, including time to a single PLT of ≥30×10 9/L and time to the International Working Group (IWG) response, were also performed. Change from baseline in mean PLT counts over time was evaluated based on a mixed model for repeated measurements. Results One hundred thirty-one participants (118 chronic ITP, 13 persistent ITP) were randomized (86 EFG, 45 PBO). Least-squares mean estimate changes from baseline in PLT counts were significantly different in EFG group compared with PBO group starting at day 7 (22×10 9/L vs -1×10 9/L; P=0.0293) and remained significant at most time points throughout the study. 38.4% of EFG-treated participants compared with 11.1% of PBO treated participants achieved a PLT count of ≥30×10 9/L in 7 days. The EFG group showed a higher proportion of PLT count responders ≥50×10 9/L on ≥4 occasions until week 12 compared with PBO (34.9% vs 4.4%, respectively). Based on KM analysis, 31.8% of participants receiving EFG and 2.2% of those receiving PBO achieved 2 consecutive PLT counts of ≥50×10 9/L by day 42 (Figure). 41.5% of participants receiving EFG vs 11.4% of those receiving PBO achieved the first PLT count ≥50×10 9/L by day 42. 22.5% of participants receiving EFG vs 2.2% of those receiving PBO achieved the first PLT count ≥100×10 9/L by day 42 (Table). The cumulative number of weeks in disease control was significantly higher in the EFG group compared with PBO (mean [SD]: 6.1 [7.66] vs. 1.5 [3.23]; P=0.0009) (Broome CM, et al. ASH 2022).KM estimates for IWG response by day 42 in the overall (chronic and persistent ITP) population were 29.7% in participants receiving EFG vs 4.6% in those receiving PBO. Overall, EFG was well tolerated; most adverse events were mild or moderate in severity. Conclusions In ADVANCE IV, EFG demonstrated a rapid PLT count increase, as early as the first time point measured (7 days after EFG treatment). Irrespective of the specific measure of response utilized, these data demonstrate that at all time points evaluated more participants in the EFG group achieved response compared with the PBO group. In addition to this early response, significantly more sustained responses were observed in the EFG group compared with the PBO group. The response rate, regardless of definition, in participants who received EFG continued to increase over time suggesting that some participants may have delayed responses to EFG. These data further demonstrate early and sustained responses with EFG in ITP.

The Efficacy of Hetrombopag Combined with Cyclosporine a in Patients with Transfusion-Dependent Non-Severe Aplastic Anemia

Objective: Thetherapeutic approach for transfusion-dependent non-severe aplastic anemia (TD-NSAA) is undetermined. Though the British guideline recommended intensive immunosuppressive therapy (IST) as front-line therapy for TD-NSAA ( Killick SB, et al. British Journal of Haematology. 2016; 172(2): 187-207), the cost and risk were relatively high. Hetrombopag is a thrombopoietin receptor agonist approved for IST-refractory severe aplastic anemia (SAA) by the China Food and Drug Administration in 2021 ( Peng G, et al. Ther Adv Hematol. 2022; 13: 20406207221085197). This study aimed to evaluate the efficacy of hetrombopag plus cyclosporine A (CsA) for TD-NSAA. Methods: 24 eligible patients receiving hetrombopag plus CsA from September 2021 to July 2023 were collected by prospective registration (ChiCTR2100045895) in the Chinese Eastern Collaboration Group of Anemia (CECGA). A historical cohort (n=79) receiving CsA alone from December 2013 to January 2017 in the CECGA was used as a comparator (Table 1). Primary endpoint was overall response at 24 weeks, defined as hematologic response in ≥ 1 lineage. Secondary endpoints were overall response at 12 and 48 weeks, complete response at 48 weeks, overall survival, transformation to SAA and treatment-related adverse events. Results: At 24 weeks, the overall response rate was 74% in hetrombopag plus CsA cohort and 16% in CsA cohort (odds ratio [OR]: 14.7; 95% confidence interval [CI]: 4.1 ~ 52.4; p＜0.001). The overall response rates at 12 and 48 weeks were also significantly higher in hetrombopag plus CsA cohort than those in CsA cohort (43% vs 8%, OR: 9.1, 95% CI: 2.7 ~ 31.1, p＜0.001; 85% vs 30%, OR: 13.0, 95% CI: 2.5 ~ 66.2, p = 0.001, respectively). At 48 weeks, the complete response rate was 23% in hetrombopag plus CsA cohort and 2% in CsA cohort (OR: 13.8; 95% CI: 1.3 ~ 146.8; p = 0.029). The median time to initial response was 11.6 [95% CI: 2.9~20.3] weeks in hetrombopag plus CsA cohort, significantly shorter than that in CsA cohort (hazard ratio: 5.0; 95% CI: 2.1 ~ 12.1; p＜0.0001) (Figure 1). The median time to erythroid, platelet and neutrophil responses in hetrombopag plus CsA cohort were 20.6 [95% CI: 9.1 ~ 32.0], 16.4 [95% CI: 3.0 ~ 29.9] and 23.0 [95% CI: 10.6 ~ 35.4] weeks, respectively. The 1-year survival rates in hetrombopag plus CsA cohort and in CsA cohort were similar (90% vs 94%; hazard ratio: 1.9; 95% CI: 0.2 ~ 15; p = 0.5). The percentage of patients transforming to SAA was 8% in hetrombopag plus CsA cohort and 34% in CsA cohort (OR: 0.2; 95% CI: 0.0 ~ 0.8; p = 0.018). Treatment-related hepatic or renal injury occurred in 7 patients (29%) in hetrombopag plus CsA cohort with only one ≥ Grade 3; all gained remission after dose reduction or discontinuation. Multivariate analysis of clinical parameters of all patients from both cohorts revealed that adding hetrombopag to therapy was strongly correlated with response (OR: 43; 95% CI: 4 ~ 528; p = 0.003), as was lower lymphocyte count (OR: 0.5; 95% CI: 0.3 ~ 0.8; p = 0.011). Conclusion: The combination of hetrombopag with CsA improved the rate, rapidity, and strength of hematologic response among patients with TD-NSAA, and lowered their risks of transforming to SAA. Disclosure: This study is supported by National Natural Science Foundation of China (81900109). The authors declare that there is no conflict of interest.

Cost-per-responder analysis for eltrombopag and rituximab in the treatment of primary immune thrombocytopenia in Spain

ObjectiveSplenectomy, thrombopoietin receptor agonists and rituximab are the second-line treatments for steroid-resistant adult primary immune thrombocytopenia. The last two are becoming the most widely used treatments to avoid splenectomy adverse effects and inconveniences. However, the choice between rituximab and thrombopoietin receptor agonists is unclear. Therefore, the treatment cost may be of particular interest to prioritize the therapy option. Our aim is to determine the cost per responding-patient after 6 months of use of rituximab compared to thrombopoietin receptor agonists eltrombopag in the treatment of chronic primary immune thrombocytopenia in the Spanish National Health Service. MethodA 26-week decision tree model was developed to assess the cost of treatment response of adult patients with chronic-refractory primary immune thrombocytopenia to eltrombopag and rituximab from the perspective of the Spanish National Health System. Effectiveness was obtained from the literature, and cost was obtained from the official rates. Costs were expressed in € (2018). Due to the short period of assessment, no discount rate was applied. ResultsThe average cost per patient after 6 months of treatment was slightly higher for eltrombopag (€13,089.40) than for rituximab (€11,852.60). However, the greater response rate of eltrombopag decreases the bleeding costs, resulting in a 29% higher cost per responding-patient with rituximab (€18,964.15) than for eltrombopag (€14,732.65). This result is consistent with the results of the 15 sensitivity analyses carried out where eltrombopag always represents a lower cost per responding patient, except in the sensitivity analysis in which treatment with eltrombopag is performed at its maximum dose (75mg). Only in this case, the cost per responder of eltrombopag is €48 more expensive than that of rituximab. Likewise, the greatest difference in favor of eltrombopag occurs in the scenario that uses the minimum dose of this drug —25mg— (eltrombopag €7,622.14 compared to €18,964.15 for rituximab). Thus, the cost per responding patient is lower in eltrombopag even if a second cycle of retreatment with rituximab is not performed (€14,732.65 versus €15,298.61). ConclusionsThe treatment cost of rituximab, including monitoring and bleeding costs, is higher than eltrombopag, favoring the latter over rituximab treatment.

Severe Thrombocytopenia Due to Bone Marrow Failure in Children With Dyskeratosis Congenita Does Not Respond to Eltrombopag Treatment: Case Series.

Dyskeratosis congenita is a rare inherited disease with classic cutaneous symptoms, sometimes accompanied with more severe extracutaneous manifestations such as bone marrow failure, which can be lethal. Eltrombopag is an orally available thrombopoietin receptor agonist in clinical use for increasing platelet levels in patients with immune thrombocytopenia and aplastic anemia. Here, 3 pediatric patients with dyskeratosis congenita are presented with varying disease severity, in which off-label eltrombopag treatment had no clinical effect on bone marrow failure. This, in addition to the negative results in a previous case report, supports the preclusion of eltrombopag use in dyskeratosis congenita.

Patient preferences and experiences regarding thrombopoietin-receptor agonists for immune thrombocytopenia in The Netherlands (TRAPeze Netherlands study)

ABSTRACT Objective: Identify patient experience and preference towards thrombopoietin-receptor agonists (TPO-RAs) in treatment of immune thrombocytopenia (ITP) in the Netherlands. Methods: The Thrombopoietin-Receptor Agonist Patient experience (TRAPeze) survey used a discrete choice experiment (DCE) to elicit patient preferences and a patient burden survey (PBS) to evaluate the clinical and social impact of ITP. TRAPeze collected responses from 6th October to 19th November 2021. Results: Seventy-six respondents completed the DCE: treatment preference appeared to be driven by method of administration (odds ratio [OR] 4.33; 95% confidence interval [CI] 2.88–6.52), frequency of dosing (OR 2.33; 95% CI 1.86–2.92) and drug–food interactions (OR 1.91; 95% CI 1.54–2.37). Respondents preferred therapies delivered orally over subcutaneous injection (OR 4.22; 95% CI 2.76–6.46), dosed once weekly over once daily (OR 2.37; 95% CI 1.58–3.54) and without food restrictions over with restrictions (OR 1.90; 95% CI 1.52–2.38). Sixty-nine respondents completed the DCE and PBS (mean [range] age 53 [19–83] years, 65% female). Seven incomplete PBS responses were excluded from analysis. Respondents were currently, or most recently, receiving eltrombopag (n = 43) or romiplostim (n = 26), of which 30% (n = 21/69) had previously received another TPO-RA. Loss (29%, n = 6/21) and lack (29%, n = 6/21) of response were the most common reasons for switching TPO-RA. Only 28% (n = 18/65) of respondents felt their TPO-RA increased energy levels. Conclusion: Patients preferred therapies delivered orally, dosed less frequently and without food restrictions. QoL of ITP patients on TPO-RAs can be improved; the burden analyses presented can inform future efforts towards this.

Thrombocytopenia Induced by Clopidogrel: A Rare Adverse Effect.

Immune thrombocytopenic purpura (ITP) can be induced by several drugs but there are few case reports of ITP induced by clopidogrel. Second-line treatment with thrombopoietin receptor agonists (TPO-RA) presents solid evidence and should be considered in patients in need of elective surgery who are poor responders to steroids. We report the case of a 79-year-old male who developed severe immune thrombocytopenic purpura after initiating treatment with clopidogrel. Because he needed elective orthopaedic surgery and he did not respond to corticotherapy and immunoglobulin, second-line treatment with romiplostim was initiated with a significant increase in platelet count. Clopidogrel can induce ITP and this diagnosis should be considered in patients who present with isolated thrombocytopenia. First-line therapy of ITP is not always successful; second-line treatment with TPO-RA has a high response rate and should be considered in patients in need of elective surgery who have failed to respond to first-line therapy. Clopidogrel can cause immune thrombocytopenic purpura (ITP); although there are some published cases in literature, it is a rare adverse effect.ITP induced by clopidogrel should be considered in the differential diagnosis of patients experiencing isolated thrombocytopenia.Second-line treatment of ITP with thrombopoietin receptor agonists (TPO-RA) presents solid evidence and should be considered in patients in need of elective surgery who are poor responders to steroids.

DEVELOPMENT AND VALIDATION OF VISIBLE SPECTROPHOTOMETRIC METHOD FOR ESTIMATION OF ELTROMBOPAG OLAMINE IN BULK AND TABLET DOSAGE FORM

A simple and sensitive visible spectrophotometric method has been developed for the quantitative estimation of Eltrombopag Olamine in its bulk and tablet dosage form. It is an orally active ethanolamine salt of Eltrombopag, a smallmolecule, nonpeptide thrombopoietin receptor agonist with megakaryopoiesis-stimulating activity. The maximum absorbance of drug was found at 425nm. Eltrombopag Olamine was found to be dissolved in Methanol so it was used as solvent for the conduction of work. Linearity range for the method was finalized as 3-18 μg/ml with R2 value of 0.9995. % RSD less than 2 which is well within indicates the method is precise and robust. The % recovery rate was found to be 100-101% indicating the method’s accuracy. The method was validated as per ICH guidelines provided and the results were found to be satisfactory. LOD & LOQ values were obtained as 0.150 & 0.456 respectively. Stability studies shows that the drug is unstable in various stress conditions like acid, base, water and oxidation.

Aplastic Anemia with Thrombopoietin Gene Mutation Successfully Treated with Romiplostim Monotherapy

Background: Eltrombopag and romiplostim are thrombopoietin-receptor agonists (TPO-RA), which are approved globally for the treatment of immune thrombocytopenia. However, thrombopoietin (TPO) is not just a regulator of megakaryocyte expansion but is also a vital cytokine for hematopoietic stem cell maintenance, supporting all cell lines. While the role of eltrombopag has already been established in aplastic anemia (AA) and is recommended in guidelines, evidence regarding romiplostim in AA is gradually emerging. Here, we narrate the successful treatment of AA with romiplostim. Clinical Description: A 6-year-old girl born out of third-degree consanguineous marriage, presented with pancytopenia without hepatosplenomegaly nor lymphadenopathy. Management and Outcome: Bone marrow was hypocellular. Etiological workup for bone marrow failure syndrome was unremarkable, confirming primary AA. She received blood products and intravenous immunoglobulin. Clinical exome sequencing showed homozygous mutation of the TPO gene, following which a trial of romiplostim, a TPO-RA, was given. Her cell lines improved dramatically, so she was continued on romiplostim maintenance therapy. The child soon became transfusion free and is asymptomatic currently after 2½ years, since diagnosis. Conclusion: Romiplostim, a TPO-RA, can be a potential therapeutic option, as monotherapy, in children with AA associated with TPO loss-of-function mutation. The treatment seems to be promising as it is well tolerated and economical.

Hetrombopag plus recombinant human thrombopoietin for chemotherapy-induced thrombocytopenia in patients with solid tumors

BackgroundChemotherapy-induced thrombocytopenia (CIT) is a common hematological complication in patients with cancer. Hetrombopag is a novel thrombopoietin receptor agonist that has shown an additive effect in stimulating platelet production when combined with recombinant human thrombopoietin (rhTPO). ObjectivesThis multicenter retrospective cohort study aimed to evaluate the efficacy and safety of hetrombopag plus rhTPO compared with rhTPO alone for CIT. MethodsA total of 294 patients with solid tumors and CIT (platelet count, <50 × 109/L) who received either rhTPO plus hetrombopag (146 patients) or rhTPO alone (148 patients) at 3 centers from January to December 2022 were included in the study. The primary outcome was a platelet count at least 50 × 109/L higher than the baseline value within 14 days. Chemotherapy dose reductions/delays, bleeding, and adverse events were reported. ResultsOne hundred twenty patients (82.2%) in the rhTPO-hetrombopag group vs 100 patients (67.6%) in the rhTPO group achieved the primary outcome (P = .005). This significant difference persisted in adjusted analysis (odds ratio, 2.01; 95% CI, 1.12-3.60). A total of 115 patients (78.8%) in the rhTPO-hetrombopag group and 101 patients (68.2%) in the rhTPO group avoided chemotherapy dose reductions/delays (P = .041). There was no significant difference in bleeding rates, and adverse events were mild and similar between the 2 groups. No deaths occurred. ConclusionCompared to rhTPO alone, our findings suggest that the combination of hetrombopag and rhTPO is safe and more effective in patients with CIT.

674P Response of thrombopoietin receptor agonists in MDM2 inhibitor induced thrombocytopenia

674P Response of thrombopoietin receptor agonists in MDM2 inhibitor induced thrombocytopenia

Thrombocytopenia Associated with Elemental Mercury Poisoning in Two Siblings - Connecticut, July 2022.

Two siblings aged 5 and 15 years from Connecticut were hospitalized with petechial rash, oral mucositis, and severe thrombocytopenia approximately 10 days after they played with a jar of elemental mercury they found in their home. Before the mercury exposure was disclosed, the siblings were treated with platelet transfusions, intravenous immune globulin (IVIG) for possible immune thrombocytopenic purpura, and antibiotics for possible infectious causes. When their conditions did not improve after 6 days, poison control facilitated further questioning about toxic exposures including mercury, testing for mercury, and chelation with dimercaptosuccinic acid. The older sibling soon recovered, but the younger child required a prolonged hospitalization for severe thrombocytopenia, ultimately receiving repeated doses of IVIG, steroids, and romiplostim, a thrombopoietin receptor agonist. Close collaboration among multiple agencies was required to identify the extent of mercury contamination, evaluate and treat the other family members, and decontaminate the home. These cases demonstrate the importance of ongoing public health outreach to promote early detection of elemental mercury toxicity, and the need to evaluate for environmental exposures when multiple close contacts experience similar signs and symptoms.

Is splenectomy a good strategy for refractory immune thrombocytopenia in adults?

Rituximab and thrombopoietin receptor agonists (TPO-RAs) have profoundly changed the management of immune thrombocytopenia (ITP) over the last 20 years. Even if most current guidelines put splenectomy, rituximab and TPO-RAs on the same treatment level, most clinicians and patients clearly prefer to postpone splenectomy and to multiply the lines of medical treatment before considering surgery. The management of ITP refractory to rituximab and TPO-RAs is challenging. Splenectomy is currently performed much less frequently because of a better knowledge of its complications, particularly severe late infections and deep vein thrombosis, and the inability to reliably predict its effectiveness. Furthermore, there is a reluctance to propose splenectomy when other treatments have been ineffective, based on the not well-documented risk that splenectomy could not be effective in such a case. The objective of this update was to review the most recent published data on the long-term tolerability and side effects of splenectomy and the predictors of response and efficacy, especially for patients exposed to multiple medical lines. This update can help physicians and patients with failure of multiple lines of therapy make an informed decision on the indication for splenectomy with the help of up-to-date data.

Early immunomodulation in immune thrombocytopenia-A report of the ICIS meeting in Lenzerheide, Switzerland 2022.

The only way to prevent immune thrombocytopenia (ITP) from becoming refractory would be to restore tolerance to platelets at an early phase of the disease. Numerous immune alterations probably accumulate in chronic ITP; thus, the chances of cure decrease significantly with time. Currently, sustained remission off treatment (SROT) is a clinical definition describing patients who can discontinue their ITP treatment without risk and maintain a state of remission. Different treatment strategies are presently being evaluated with the goal of attaining SROT, mostly combining drugs targeting the innate and/or the adaptive immune system, the inflammation state, so as increasing the platelet load. In this sense, thrombopoietin receptor agonists (TPO-RAs) have shown promising results if used as upfront treatment. TPO-RAs seem to exhibit immunomodulation and immune tolerance properties, increasing not only the platelet antigen mass but also increasing the transforming growth factor-β concentration, and stimulating regulatory T and B lymphocytes. However, more immunological studies are needed to establish accurate molecular alterations in ITP that are potentially reversed with treatments.

Immunomodulation with romiplostim as a second-line strategy in primary immune thrombocytopenia: The iROM study.

Thrombopoietin receptor agonists (TPO-RAs) stimulate platelet production, which might restore immunological tolerance in primary immune thrombocytopenia (ITP). The iROM study investigated romiplostim's immunomodulatory effects. Thirteen patients (median age, 31 years) who previously received first-line treatment received romiplostim for 22 weeks, followed by monitoring until week 52. In addition to immunological data, secondary end-points included the sustained remission off-treatment (SROT) rate at 1 year, romiplostim dose, platelet count and bleedings. Scheduled discontinuation of romiplostim and SROT were achieved in six patients with newly diagnosed ITP, whereas the remaining seven patients relapsed. Romiplostim dose titration was lower and platelet count response was stronger in patients with SROT than in relapsed patients. In all patients, regulatory T lymphocyte (Treg) counts increased until study completion and the counts were higher in patients with SROT. Interleukin (IL)-4, IL-9 and IL-17F levels decreased significantly in all patients. FOXP3 (Treg), GATA3 (Th2) mRNA expression and transforming growth factor-β levels increased in patients with SROT. Treatment with romiplostim modulates the immune system and possibly influences ITP prognosis. A rapid increase in platelet counts is likely important for inducing immune tolerance. Better outcomes might be achieved at an early stage of autoimmunity, but clinical studies are needed for confirmation.

Novel therapeutics and future directions for refractory immune thrombocytopenia.

Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder affecting approximately 1 in 20 000 people. While most patients with ITP are successfully managed with the current set of standard and approved therapeutics, patients who cannot be adequately managed with these therapies, considered to have refractory ITP, are not uncommon. Therefore, there remains an ongoing need for novel therapeutics and drug development in ITP. Several agents exploiting novel targets and mechanisms in ITP are presently under clinical development, with trials primarily recruiting heavily pretreated patients and those with otherwise refractory disease. Such agents include the neonatal Fc receptor antagonist efgartigimod, the Bruton tyrosine kinase inhibitor rilzabrutinib, the complement inhibitors sutimlimab and iptacopan and anti-CD38 monoclonal antibodies such as daratumumab and mezagitamab, among others. Each of these agents exploits therapeutic targets or other aspects of ITP pathophysiology currently not targeted by the existing approved agents (thrombopoietin receptor agonists and fostamatinib). This manuscript offers an in-depth review of the current available data for novel therapeutics in ITP presently undergoing phase 2 or 3 studies in patients with heavily pretreated or refractory ITP. It additionally highlights the future directions for drug development in refractory ITP, including discussion of innovative clinical trial designs, health-related quality of life as an indispensable clinical trial end-point and balancing potential toxicities of drugs with their potential benefits in a bleeding disorder in which few patients suffer life-threatening bleeding.

Experience of 2&lt;sup&gt;nd&lt;/sup&gt; line therapy with eltrombopag in patients with immune thrombocytopenia

Background. Immune thrombocytopenia (ITP), or idiopathic thrombocytopenic purpura, is a hematological autoimmune disease characterized by bleeding and an isolated decrease in platelet count &lt;100 × 109 / l. The decision to start treatment for ITP depends on several factors. The ITP treatment strategy is based on the clinical symptoms, with a focus on reducing the risk of severe bleeding and increasing platelet counts. Aim. To evaluate the efficacy of 2nd line therapy with the thrombopoietin receptor agonist eltrombopag in patients with ITP. Materials and methods. 490 patients with ITP are under observation at the center for orphan diseases of M. F. Vladimirskiy Moscow Regional Research Clinical Institute. The present study included 186 patients with primary ITP after 1st line glucocorticosteroid therapy. eltrombopag, a thrombopoietin receptor agonist, was prescribed as the 2nd line of therapy. Results. The median platelet count prior to eltrombopag therapy in all patients was 27.5 × 109 / l. after eltrombopag therapy, a significant (by 490 %) increase in platelet levels (median 135 × 109 / l) and a complete response according to clinical recommendations were noted. Conclusion. Glucocorticosteroids (prednisolone, dexamethasone) remain the drugs of choice for the 1st line of therapy. Treatment with drugs of this group in most cases allows achieving an optimal platelet level and preventing bleeding. In case of inefficiency, intolerance, occurrence of side effects, the appointment of thrombopoietin receptor agonists eltrombopag or romiplostim is recommended. therapy with eltrombopag at a dose of 50 mg daily for several weeks has been able to achieve an increase in platelet levels, correct hemorrhagic syndrome, reduce the number of side effects during first-line glucocorticosteroid therapy, and improve the patient’s quality of life.