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A safety analysis of pooled data from clinical studies of romiplostim, a thrombopoietin (TPO) receptor agonist, in which patients with immune thrombocytopaenia (ITP) received romiplostim, placebo, or medical standard of care (SOC) Rodeghiero et al. (Eur J Haematol 91:423–436, 2013 ), has been updated. Included are data from 14 trials spanning 2002–2011; placebo- and SOC-arm data are pooled. Most patients ( n  = 1059) were female (61 %) and Caucasian (85 %); 38 % had undergone splenectomy; 23 were children. Mean (SD) baseline platelet count was 20.6 (16.5) × 10 9 /L. Mean (SD) weekly dose of romiplostim was 4.2 (2.8) µg/kg; total exposure was 1520 patient-years. Overall, 921 patients received romiplostim only, 65 received placebo/SOC only, and 73 received placebo/SOC followed by romiplostim. Rates of haemorrhage (romiplostim, 205/100 patient-years; placebo/SOC, 263/100), thrombosis (both, 5.5/100 patient-years), haematological malignancy/myelodysplastic syndrome (romiplostim, 0.5/100 patient-years; placebo/SOC, 2.7/100), and non-haematological tumours (romiplostim, 2.2/100 patient-years; placebo/SOC, 3.6/100) were comparable among groups. Bone marrow reticulin was reported in 17 patients and collagen in one patient receiving romiplostim; one patient receiving placebo/SOC had reticulin reported. Three patients developed neutralizing antibodies to romiplostim, but not to endogenous TPO. This integrated analysis of the safety profile of romiplostim in patients with ITP is consistent with previously reported studies; no new safety concerns emerged.

Thrombopoietin (TPO) and the TPO-receptor (TPO-R, or c-MPL) are essential for hematopoietic stem cell (HSC) maintenance and megakaryocyte differentiation. Agents that can modulate TPO-R signaling are highly desirable for both basic research and clinical utility. We developed a series of surrogate protein ligands for TPO-R, in the form of diabodies (DBs), that homodimerize TPO-R on the cell surface in geometries that are dictated by the DB receptor binding epitope, in effect “tuning” downstream signaling responses. These surrogate ligands exhibit diverse pharmacological properties, inducing graded signaling outputs, from full to partial TPO agonism, thus decoupling the dual functions of TPO/TPO-R. Using single-cell RNA sequencing and HSC self-renewal assays we find that partial agonistic diabodies preserved the stem-like properties of cultured HSCs, but also blocked oncogenic colony formation in essential thrombocythemia (ET) through inverse agonism. Our data suggest that dampening downstream TPO signaling is a powerful approach not only for HSC preservation in culture, but also for inhibiting oncogenic signaling through the TPO-R.

The thrombopoietin receptor agonist romiplostim could be an effective treatment in symptomatic children with persistent or chronic immune thrombocytopenia. We aimed to assess whether romiplostim is safe and effective in children with immune thrombocytopenia of more than 6 months' duration. In this phase 3 double-blind study, eligible participants were children with immune thrombocytopenia aged 1 year to 17 years and mean platelet counts 30 × 109/L or less (mean of two measurements during the screening period) with no single count greater than 35 × 109/L, and were recruited from 27 sites in the USA, Canada, and Australia. Participants were randomly assigned (2:1) through the interactive voice response system to receive weekly romiplostim or placebo for 24 weeks stratified by age (1 year to <6 years, 6 years to <12 years, 12 years to <18 years), adjusting the dose weekly from 1 μg/kg to 10 μg/kg to target platelet counts of 50–200 × 109/L. Patients and investigators were blinded to the treatment assignment. The primary analysis included all randomised patients and the safety analysis included all randomised patients who received at least one dose of investigational product. The primary endpoint, durable platelet response, was defined as achievement of weekly platelet responses (platelet counts ≥50 × 109/L without rescue drug use in the preceding 4 weeks) in 6 or more of the final 8 weeks (weeks 18–25). This study is registered with ClinicalTrials.gov, NCT 01444417. Between Jan 24, 2012, and Sept 3, 2014, 62 patients were randomly assigned; 42 to romiplostim and 20 to placebo. Durable platelet response was seen in 22 (52%) patients in the romiplostim group and two (10%) in the placebo group (p=0·002, odds ratio 9·1 [95% CI 1·9–43·2]). Durable platelet response rates with romiplostim by age were 38% (3/8) for 1 year to younger than 6 years, 56% (10/18) for 6 years to younger than 12 years, and 56% (9/16) for 12 years to younger than 18 years. One (5%) of 19 patients in the placebo group had serious adverse events compared with 10 (24%) of 42 patients in the romiplostim group. Of these serious adverse events, headache and thrombocytosis, in one (2%) of 42 patients in the romiplostim group, were considered treatment related. No patients withdrew due to adverse events. In children with chronic immune thrombocytopenia, romiplostim induced a high rate of platelet response with no new safety signals. Ongoing romiplostim studies will provide further information as to long-term efficacy, safety, and remission in children with immune thrombocytopenia. Amgen Inc.

The platelet-stimulating agent romiplostim was compared with standard interventions for chronic immune thrombocytopenic purpura. Patients given romiplostim had higher platelet counts, less treatment failure, fewer bleeding episodes, and better quality of life. Immune thrombocytopenia is an autoimmune disease characterized by low platelet counts due to both increased platelet destruction and suboptimal platelet production. 1 After initial treatment with glucocorticoids or intravenous immune globulin or anti-D immune globulin, most adult patients require second-line medical therapy (e.g., azathioprine or rituximab) or surgical therapy (i.e., splenectomy). 2 However, most first- and second-line medical treatments are short-acting, have severe side effects, or are potentially toxic. 2 – 4 These problems can adversely affect the health and quality of life of patients. Splenectomy is used to remove the major site of platelet destruction and increase the platelet count. 5 In approximately two . . .

Immune thrombocytopenia (ITP) is a disease which sees one-third of patients failing first and subsequent therapeutic approaches, including splenectomy. Thrombopoietin-receptor agonists (TPO-RAs) are recommended for adults who relapse after splenectomy or who have contraindications for splenectomy. In this multicenter study, a total of 124 patients were retrospectively evaluated: 55 (44.3 %) were treated by romiplostim and 69 (55.6 %) by eltrombopag. Mean age, number of young patients (<60 years), time from primary diagnosis of ITP to TPO-RA treatment, and previous lines of therapy were similar in both groups. The overall response rate was 80 % (44/55) for romiplostim and 94.2 % (65/69) for eltrombopag; the duration of response and the time to response were similar ( p  = NS). The response rate to both drugs in non-splenectomized patients was higher than that of splenectomized patients ( p  < 0.05). The mean duration of response was 30 months for romiplostim and 15 months for eltrombopag, due to later commercialization of eltrombopag. Failure was the most frequent cause of discontinuation. Thrombotic events were the most consistent adverse events and were recorded in 2 and 3 % of patients treated by romiplostim and eltrombopag, respectively. In conclusion, romiplostim and eltrombopag are effective in the majority of patients with chronic ITP who failed several lines of therapy; whether TPO-RAs could substitute splenectomy is under discussion and studies are warranted.

In this trial involving patients with cirrhosis and thrombocytopenia, treatment with eltrombopag before invasive procedures reduced the need for platelet transfusions. More thrombotic events of the portal venous system were observed with eltrombopag than with placebo. Thrombocytopenia is frequently observed in patients with chronic liver disease, with studies suggesting that it occurs in up to 76% of patients with cirrhosis. 1 – 3 The degree of thrombocytopenia is proportional to the severity of the liver disease. 4 , 5 Thrombocytopenia increases the risk of bleeding during and after invasive procedures and may result in the cancellation or postponement of elective procedures. 6 Platelet transfusions are commonly used to reduce the risk of bleeding during a procedure, but their short duration of efficacy and the risk of transfusion reactions limit their use. 7 , 8 Furthermore, the development of antiplatelet antibodies (alloimmunization) can cause . . .

This trial tested the efficacy of eltrombopag, a small nonpeptide agonist of the thrombopoietin receptor, in patients with immune thrombocytopenia who had not had a response to at least one previous treatment for the disorder. At a dose of 50 or 75 mg, the agonist, which had been shown to increase platelet production in normal volunteers, increased platelet counts to a clinically safe level (≥50,000 per cubic millimeter) in most patients. Eltrombopag, a small nonpeptide agonist of the thrombopoietin receptor, increased platelet counts to a clinically safe level (≥5;50,000 per cubic millimeter) in most patients. Idiopathic thrombocytopenic purpura (ITP) is an autoimmune disease in which antiplatelet antibodies accelerate the destruction of platelets. In addition, platelet production can be impaired 1 because the antiplatelet antibodies can also damage megakaryocytes. 2 – 4 Although the thrombocytopenia of ITP can be severe, signs of bleeding are usually only minor. Persistently low platelet counts (<20,000 per cubic millimeter), however, are associated with an increased risk of serious bleeding, such as intracranial hemorrhage. 5 , 6 The goal of managing chronic ITP is to maintain platelet counts, with the least possible intervention, at levels that prevent bleeding, thereby reducing treatment-related toxicity. 7 Glucocorticoids and intravenous immunoglobulins . . .

Delayed platelet engraftment (DPE) is a prevalent complication following umbilical cord blood transplantation (UCBT), accompanied by increased transplant-related mortality. This study aims to evaluate the efficacy, safety, and tolerability of romiplostim and recombinant human thrombopoietin (rhTPO) in enhancing platelet engraftment after UCBT. A total of 19 patients scheduled to receive UCBT were randomly assigned to the romiplostim group (250 µg once weekly from day 5 to platelet engraftment after UCBT, n  = 7) or rhTPO group (300 U/kg once daily from days 5 to 18 after UCBT, n  = 12). The median time of PLT engraftment was no statistical difference between rhTPO and romiplostim group: 29.5 days (range: 13–43 days) compared to 31 days (range: 23–40 days; P  =.269). The median dose of romiplostim was 4 (range: 2–5 doses). Furthermore, the consumption of PLT was equivalent between the Ro group and the rhTPO group: 10 units (range: 7–26 units) and 10 units (range: 3–24 units; P  =.694). All patients survived for one year and remained relapse-free. Romiplostim group had a lower incidence of acute graft versus host disease (aGvHD). No severe adverse effects were observed in any of the patients. This study demonstrated that romiplostim and rhTPO are both effective in promoting platelet engraftment after UCBT. Romiplostim was more practical and tolerable due to its cost and labor-saving benefits.

Primary immune thrombocytopenia is an autoimmune disorder marked by accelerated platelet destruction and reduced production, posing risks of severe bleeding and mortality. Thrombopoietin (TPO) mimetic peptide (TMP) stimulates platelet generation via TPO receptor activation but is hindered by rapid clearance and short half-life. The primary objective of this study is to optimize TMP fusion proteins with the albumin-binding domain (ABD) for enhanced expression in Escherichia coli ( E. coli ), extended half-life via indirect FcRn-mediated recycling, and improved thrombopoietic activity in cellular assays and murine models. TMP dimers were fused to the C-terminus of ABD. GS peptides with either Cys or Ala were fused to the N-terminus of ABD (yielding C-ABD-2TMP and A-ABD-2TMP fusion proteins). The fusion proteins were expressed in E. coli BL21 (DE3) with Trx-tags for solubility, purified by Ni–NTA and ion exchange chromatography, and dimerized via disulfide bonds (2C-ABD-2TMP). Thermal stability was assessed by circular dichroism; HSA affinity by ELISA; bioactivity by MO7e cell proliferation assay; and in vivo pharmacokinetics and platelet stimulation in C57BL/6 mice. The fusion proteins were successfully expressed in E. coli . Following purification via Ni 2+ –NTA, tag cleavage, ion-exchange chromatography, and disulfide bond formation, high-purity fusion proteins were obtained: disulfide-bonded 2C-ABD-2TMP and A-ABD-TMP lacking disulfide bonds. Fusion proteins displayed highly stability up to 70 °C. 2C-ABD-2TMP exhibited an apparent EC 50 for HSA of 2.1 ± 0.6 nM (vs. 5.5 ± 1.1 nM for A-ABD-2TMP). In MO7e cells, 2C-ABD-2TMP promoted dose-dependent proliferation, exceeding 2TMP at 25 nM ( p  < 0.01) and A-ABD-2TMP ( p  < 0.05). In mice, 150 nmol/kg 2C-ABD-2TMP increased platelets to 3.1 × 10 9 /mL by day 12, sustained exceeding 2.4 × 10 9 /mL at day 18 (AUC p  < 0.01 vs. controls). The 2C-ABD-2TMP fusion protein displayed a half-life of 17.6 ± 2.9 h, while the A-ABD-2TMP exhibited a half-life of 13.2 ± 1.6 h. significantly longer than 2TMP alone (~ 1 h). ABD fusion enhanced the pharmacokinetics and thrombopoietic activity of 2TMP by enabling binding to HSA while retaining the ability to activate the TPO receptor.

This multicenter, randomized trial assessed the efficacy and safety of a recombinant human thrombopoietin (rhTPO) in patients with persistent primary immune thrombocytopenia (ITP) who had failed glucocorticosteroid treatment. A total of 140 eligible patients were randomized to receive rhTPO + danazol (rhTPO group, 73 patients) or danazol (control group, 67 patients) alone. During the first phase, the increase in the mean maximal platelet counts (101.2 × 10 9 /L) and the area under curve (749.6) in the rhTPO group were significantly higher compared to control (33.3 × 10 9 /L and 316.2; P  = 0.0060 and 0.0000, respectively). The major response rate (MRR) and total response rate (TRR) in the rhTPO group were 38.4 and 60.3 %, respectively, significantly higher than in control (MRR 7.9 %, P  = 0.0003; TRR 36.5 %, P  = 0.0104). In the control group, 45 patients with platelet counts <20 × 10 9 /L were given rhTPO during the second phase and achieved MRR 31.1 % and TRR 66.7 %. The mean platelet counts in the rhTPO group were still approximately 50 × 10 9 /L on day 28 of the study. The overall incidence of rhTPO-related adverse events was 13.6 %. All the adverse events were generally mild. This study demonstrated that rhTPO was well tolerated, and it markedly increased platelet counts in chronic ITP patients. Stimulation of platelet production by rhTPO may provide a new therapeutic option for patients with ITP.