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Thrombopoietin receptor agonists use and risk of thrombotic events in patients with immune thrombocytopenic purpura: A systematic review and meta‑analysis of randomized controlled trials
Shen, N., Qiao, J., Jiang, Y., Yan, J., Wu, R., Yin, H., Zhu, S., Li, J.
Biomedical reports. 2024;20(3):44
Abstract
Thrombopoietin receptor agonists (TPO-RAs) have a role in second-line immune thrombocytopenic purpura (ITP) treatment, binding to and activating thrombopoietin receptors on megakaryocyte membranes in the bone marrow. This promotes megakaryocyte maturation and increases platelet production. Despite a 2-6% incidence of thrombotic events during TPO-RA treatment, it remains uncertain whether TPO-RAs elevate thrombosis rates. A comprehensive search of electronic databases was conducted using the relevant search criteria. To assess the risk of bias, the included studies were assessed using the revised Cochrane Risk of Bias Assessment Tool 2.0, and a meta-analysis was performed using RevMan 5.4.1. A total of 1,698 patients with ITP were included from randomized controlled trials (RCTs). There were 26 thromboembolic events in the TPO-RAs group and 4 in the control group. However, there was no significant difference in the incidence of thrombotic events between the two groups [odds ratio (OR)=1.76, 95% confidence interval (CI): 0.78-4.00, P=0.18], even if the duration of treatment was >12 weeks (OR=2.46, 95% CI: 0.81-7.43, P=0.11). Subgroup analysis showed that none of the four drugs significantly increased the incidence of thrombotic events (romiplostim: OR=0.92, 95% CI: 0.14-6.13, P=0.93; eltrombopag: OR=2.32, 95% CI: 0.64-8.47, P=0.20; avatrombopag: OR=4.15, 95% CI: 0.20-85.23, P=0.36; and hetrombopag: OR=0.76, 95% CI: 0.03-18.76, P=0.87). There was also no significant difference in the results of the double-blinded placebo-controlled RCTs (OR=1.21, 95% CI: 0.41-3.58, P=0.73). Compared to patients with ITP who did not receive TPO-RA treatment, those receiving TPO-RA treatment did not exhibit a significantly increased risk of thrombotic events.
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Efficacy and Safety of Biosimilar Romiplostim Versus Innovator Romiplostim in Patients with Chronic Immune Thrombocytopenia
Chandrakala, S., Toshniwal, M., Halvawala, M., Padwal, N., Sidharthan, N., Malhotra, P., Prashantha, B., Ballikar, R., Shah, S., Apte, S., et al
Indian journal of hematology & blood transfusion : an official journal of Indian Society of Hematology and Blood Transfusion. 2023;39(3):435-441
Abstract
Romiplostim is a Food and Drug Administration (FDA)-approved therapy for immune thrombocytopenia (ITP). Biosimilar is a biological product that has no clinical meaningful difference from an existing FDA-approved reference product. It has a potential of lowering health-care-related cost. Biosimilar of romiplostim can be made available to patients with ITP at a low cost and can be beneficial in providing the best therapy. Thus, the efficacy and safety of biosimilar romiplostim (ENZ110) was compared with innovator romiplostim (Nplate) with respect to platelet response in patients with chronic ITP. This was a prospective, multicenter, randomized, and double-blind clinical trial. Patients with chronic ITP, aged 18-65 years, were enrolled in a study and were randomized to receive either ENZ110 or Nplate in a 3:1 ratio for a treatment period of 12 weeks, respectively. After completion of the treatment period, the patients were followed-up for one week to evaluate the platelet response and to monitor the adverse events (AEs). Over the duration of 12 weeks, platelet response of > 50 × 10(9)/L was achieved in 85.3% patients treated with ENZ110 and in 75.0% patients treated with Nplate in per protocol population. In intent-to-treat population, 83.8% patients with ENZ110 and 76.9% patients with Nplate achieved a platelet response of > 50 × 10(9)/L. In the ENZ110 group, 111 AEs were recorded in 66.7% patients, while 18 AEs were reported in 61.5% patients in the Nplate group. The study demonstrated non-inferiority with comparable efficacy and safety between biosimilar romiplostim and innovator romiplostim in patients with chronic ITP. Trial registration number and date of registration: CTRI/2019/04/018614.
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Efficacy of Eltrombopag with Immunosuppressive Therapy Versus Immunosuppressive Therapy Alone on Severe Aplastic Anaemia: A Systematic Review and Meta-analysis
Zhang S, Wang Q, Cui K, Cheng B, Fan J, Hu S
Clinical drug investigation. 2023
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Abstract
BACKGROUND AND OBJECTIVE Severe aplastic anaemia (SAA) is a syndrome of bone marrow failure caused by T cell-mediated destruction of haematopoietic stem cells and progenitor cells. Whether patients with SAA should be treated with eltrombopag (EPAG) and immunosuppressive therapy (IST) or IST alone remains debatable. Therefore, we conducted this meta-analysis to compare the efficacy of eltrombopag + IST with that of IST alone in patients with SAA and to assess the difference in the efficacy of eltrombopag in adults and children. METHODS We performed this meta-analysis by retrieving studies that met the inclusion and exclusion criteria from PubMed, EMBASE, and the Cochrane Library up to 1 January 2023. We used a random-effects model to calculate odds ratios (ORs) with 95% confidence intervals (CIs) for primary and secondary outcomes. I(2) statistics were used to evaluate the heterogeneity of the included studies. RESULTS Six studies involving a total of 699 patients were included. In terms of the primary outcomes, our pooled results indicated that patients treated with EPAG + IST had a higher 6-month overall response rate (OR = 2.25; 95% CI, 1.60-3.16; p < 0.00001), a higher 6-month complete response rate (OR = 2.61; 95% CI, 1.82-3.74; p < 0.00001), and a lower 6-month nonresponse rate (OR = 0.32; 95% CI, 0.19-0.52; p < 0.00001). However, there was no significant difference in the rate of 6-month partial response (OR = 0.94; 95% CI, 0.49-1.81; p = 0.85). CONCLUSION This meta-analysis indicated that patients treated with additional eltrombopag for IST may have a higher rate of haematological response.
PICO Summary
Population
Children and adults with severe aplastic anaemia (6 studies, n= 699).
Intervention
Eltrombopag (EPAG) and immunosuppressive therapy (IST), (n= 364).
Comparison
IST alone (n= 335).
Outcome
Patients treated with EPAG + IST had a higher 6-month overall response rate (odds ratio (OR), 2.25; 95% confidence interval (CI), [1.60, 3.16]), a higher 6-month complete response rate (OR, 2.61; 95% CI [1.82, 3.74]), and a lower 6-month non-response rate (OR, 0.32; 95% CI [0.19, 0.52]). There was no significant difference in the rate of 6-month partial response (OR, 0.94; 95% CI [0.49, 1.81]).
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Romiplostim in primary immune thrombocytopenia that is persistent or chronic: phase III multicenter, randomized, placebo-controlled clinical trial in China
Zhou, H., Zhou, J., Wu, D., Ma, L., Du, X., Niu, T., Yang, R., Liu, J., Zhang, F., Shi, Q., et al
Research and practice in thrombosis and haemostasis. 2023;7(5):100192
Abstract
BACKGROUND Multiple trials have confirmed that romiplostim could increase platelet count in individuals with primary immune thrombocytopenia (ITP), but no related study has assessed Chinese patients. OBJECTIVES To assess the effectiveness of romiplostim as a second-line treatment of persistent or chronic ITP in Chinese adults. METHODS This phase III multicenter, randomized, placebo-controlled, double-blind, then open-label clinical trial (NCT02868099, CTR20150395) was conducted at 28 investigational sites in China. The patients were randomly assigned (3:1) to romiplostim (starting and maximum doses of 1 and 10 μg/kg, respectively) or placebo for 9 weeks (double-blind period), followed by the open-label period (both groups administered romiplostim) to week 22. The primary endpoint was the time (in weeks) during which platelet counts were ≥50 × 10(9)/L in the double-blind period. RESULTS In this study, 202 patients (romiplostim, n = 151; placebo, n = 51) started the treatment. The median (range) numbers of weeks with platelet response after 6 weeks of treatment were 2 (0-6) and 0 (0-2) in patients administered romiplostim and placebo, respectively (P < .001). During the double-blind period, the proportions of patients with treatment-emergent adverse events were comparable between the romiplostim and placebo groups (82.8% vs 82.4%). The treatment-emergent adverse event with ≥10% difference in incidence between these 2 groups was injection site bleeding (1.3% vs 11.8%). CONCLUSION Romiplostim significantly increased the time with maintained platelet response in patients with persistent or chronic ITP in comparison with placebo. No new safety signal was observed. TRIAL REGISTRATION ClinicalTrials.gov, NCT02868099. www.chinadrugtrials.org.cn/clinicaltrials.searchlist.dhtml, CTR20150395.
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Efficacy and safety of QL0911 in adult patients with chronic primary immune thrombocytopenia: A multicenter, randomized, double-blind, placebo-controlled, phase III trial
Zhou, H., Han, S., Jin, J., Huang, R., Guo, X., Shen, X., Wang, B., Wang, X., Yao, H., Du, X., et al
Journal of translational internal medicine. 2023;11(4):423-432
Abstract
OBJECTIVE QL0911, a recombinant human thrombopoietin mimetic peptide-Fc fusion protein, is a romiplostim (Nplate(®)) biosimilar used to treat primary immune thrombocytopenia (ITP). This phase III study aimed to assess the efficacy and safety of QL0911 in adult patients with chronic primary ITP over a 24-week treatment period. METHODS We conducted a double-blind, placebo-controlled, phase III study in patients diagnosed with primary ITP for at least 12 months who had received at least one first-line ITP treatment with no response or recurrence after treatment, or who relapsed after splenectomy at 44 sites in China. Patients were randomly allocated (2:1 ratio) to QL0911 or placebo injection subcutaneously once weekly at an initial dose of 1 μg/kg for 24 weeks. The doses were adjusted to maintain the target platelet counts from 50 × 109/L to 200 × 109/L. Patients and investigators were blinded to the assignment. The primary endpoints were the proportion of patients who achieved a durable platelet response at week 24 (platelet count, ≥ 50 × 109/L during 6 of the last 8 weeks of treatment) and safety. The study was registered at ClinicalTrials.gov (NCT05621330). RESULTS Between October 2019 and December 2021, 216 patients were randomly assigned (QL0911,144; placebo,72). A durable platelet response was achieved by significantly more patients in the QL0911 group (61.8%, 95% CI: 53.3-69.8; P < 0.0001) than in the placebo group (0%). The mean duration of platelet responses was 15.9 (SE: 0.43) weeks with QL0911, and 1.9 (SE:0.26) week with placebo. Consistent results were achieved in subgroup analyses categorized by baseline splenectomy status (yes/no), concomitant ITP treatment (yes/no), and baseline platelet count (≤ 10 × 109/L, > 10 × 109/L, ≤ 20 × 109/L, > 20 × 109/L, and < 30 × 109/L). The incidence of TEAEs was comparable between the QL0911 and the placebo groups (91.7% and 88.9%, respectively). The most common adverse events overall were ecchymosis (28.5% for QL0911 vs. 37.5% for placebo), upper respiratory tract infections respiratory tract infections (31.9% for QL0911 vs. 27.8% for placebo), and gingival bleeding (17.4% for QL0911 vs. 26.4% for placebo). CONCLUSION QL0911 was well-tolerated and increased and maintained platelet counts in adults with ITP. QL0911, a biosimilar to romiplostim (Nplate®), may be a novel treatment option for patients with ITP who have failed or relapsed from first-line treatment in China. Ongoing studies will provide further data on long-term efficacy and safety in such patient populations.
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Effect of recombinant human thrombopoietin on IL-2, IL-4 and platelet parameters in thrombocytopenic purpura
Zhao, M., Liang, X., Chen, C., Du, X., Dang, X.
Cellular and molecular biology (Noisy-le-Grand, France). 2023;69(5):119-125
Abstract
The objective of this study was to observe the effect of recombinant human thrombopoietin on IL-2, IL-4 and platelet parameters in thrombocytopenic purpura. For this purpose, a convenient sampling method was used to select 84 patients with thrombocytopenic purpura who visited the hospital from January 2018 to December 2022. The patients were divided into the norm group and rhTPO group with 42 cases each by random number table. The norm group was treated with routine treatment, while the rhTPO group was treated with recombinant thrombopoietin based on routine treatment. The changes in IL-2, IL-4, platelet parameters, immune recovery and treatment efficiency of the two groups were compared before and after treatment. Findings suggested that the levels of IL-2 and IL-4 in both groups decreased after treatment compared with those before treatment. However, the level of IL-2 in the rhTPO group after treatment was lower than that in the norm group, and the level of IL-4 in the rhTPO group after treatment was higher than that in the norm group (P<0.05). The levels of platelet parameters PLT and PCT in the two groups after treatment were higher than those before treatment, but the levels of PLT and PCT in the rhTPO group after treatment were higher than those in the norm group (P<0.05). The PLT of the rhTPO group was (69.57±6.73)×109/L after 7 days of treatment, which was higher than that in the norm group (62.05 ± 8.52)×109/L (P<0.05). The levels of PDW and MPV in the two groups after treatment decreased compared with those before treatment, but the levels of PDW and MPV in the rhTPO group after treatment were lower than those in the norm group (P<0.05). The overall immune recovery and treatment effectiveness of the rhTPO group were significantly better than those of the norm group. In summary, recombinant human thrombopoietin used in patients with thrombocytopenic purpura can maintain the balance between T cell activation and inhibition homeostasis, and promote faster recovery of platelet parameters.
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Recombinant human thrombopoietin (rhTPO) of different dosing regimens for refractory/relapsed primary immune thrombocytopenia: a multicenter, randomized controlled trial and pharmacokinetics study
Liu, X., Bai, Y., Wang, T., Song, Y., Sun, F., Xia, R., Zhu, F., Ma, J., Lu, Q., Ye, X., et al
Platelets. 2023;34(1):2157806
Abstract
Recombinant human TPO (rhTPO) is effective for refractory/relapsed primary immune thrombocytopenia (ITP), but optimal dosing regimen remains elusive. In this multicenter, randomized, controlled trial, a total of 282 adult ITP patients (mean age 47.3 years; 82 men) with a platelet count ≤30 × 10(9)/L or >30 × 10(9)/L with active bleeding randomly received a once daily (QD) subcutaneous injection of 7500 U (n = 64) or 15000 U rhTPO for 14 injections, or 15000 U or 30000 U rhTPO once every other day (QOD) for 7 injections. The primary outcomes included change from baseline in platelet count and total response rate (TRR) on day 14. On day 14, the median increase of platelet count from baseline was the highest in the 15000-U QD group (167.5 × 10(9)/L, interquartile range [IQR] 23.0-295.0 × 10(9)/L), followed by the 30000-U QOD group (57.5 × 10(9)/L, IQR 9.0-190.0 × 10(9)/L) (ANCOVA P < .001; P = .266 with baseline count as a covariate). The TRR on day 14 was also the highest in the 15000-U QD group (63.2%), followed by the 30000-U QOD group (59.7%). The rate of grade 3 and above adverse events did not differ among the four groups. There were no new safety concerns. All 4 regimens are safe and well-tolerated. The 30000-U QOD regimen is practically indistinguishable in efficacy to the 15000-U QD regimen.
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Role of thrombopoietin receptor agonists in chemotherapy-induced thrombocytopenia: A meta-analysis
Gurumurthy, G., Kisiel, F., Gurumurthy, S., Gurumurthy, J.
Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners. 2023;:10781552231219003
Abstract
INTRODUCTION Chemotherapy-induced thrombocytopenia (CIT) is a significant challenge in cancer treatment, often leading to dose reductions and reduced number of cycles. The limited effectiveness of platelet transfusions in managing CIT highlights the need for alternative treatments. Thrombopoietin receptor agonists (TPO-RA), including romiplostim, eltrombopag and avatrombopag, have shown potential in increasing platelet counts in CIT patients, necessitating a comprehensive analysis of their efficacy. METHODS This meta-analysis followed the Preferred Reporting Items for Systemic Reviews and Meta-analysis guidelines, searching Ovid databases up to 5 October 2023. The primary metric of interest was platelet count changes post-TPO-RA administration in CIT patients. RESULTS From the initial 867 studies obtained, 7 studies were selected based on the inclusion criteria. The analysis included 348 patients. A significant association was found between TPO-RA administration and platelet count increase, with a combined-effect increase of 69.52 ± 2.24 × 10(9)/l. Subgroup analysis based on Romiplostim use suggested an increase of approximately 70.11 ± 39.07 × 10(9)/l, while non-Romiplostim TPO-RAs showcased an increase of about 68.09 ± 82.58 × 10(9)/l. CONCLUSIONS The meta-analysis demonstrates the effectiveness of TPO-RAs in managing CIT. Further research comparing platelet increases across standardised TPO-RA regimens is recommended to refine treatment strategies. This analysis provides valuable insights for clinicians in tailoring CIT treatment using TPO-RAs.
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Avatrombopag for adult chronic primary immune thrombocytopenia: a randomized phase 3 trial in China
Mei, H., Zhou, H., Hou, M., Sun, J., Zhang, L., Luo, J., Jiang, Z., Ye, X., Xu, Y., Lu, J., et al
Research and practice in thrombosis and haemostasis. 2023;7(6):102158
Abstract
BACKGROUND Immune thrombocytopenia (ITP) is an autoimmune disorder with decreased platelet counts and increased bleeding risk. OBJECTIVES To evaluate the efficacy and safety of avatrombopag, a second-generation oral thrombopoietin receptor agonist, for the treatment of Chinese patients with chronic primary ITP. METHODS This multicenter, randomized, double-blind, placebo-controlled phase 3 study (CTR20210431) consisted of a 6-week double-blind core treatment phase followed by a 20-week, open-label extension phase. Chinese adults with chronic primary ITP for at least 12 months and a platelet count <30 × 10(9)/L were randomized (2:1) to receive avatrombopag (initial dose of 20 mg/day) or matched placebo. The primary endpoint was the proportion of subjects with a platelet count ≥50 × 10(9)/L at week 6 of the core treatment phase in absence of rescue therapy. RESULTS In total, 74 patients were randomized (avatrombopag: N = 48; placebo: N = 26) between March 5, 2021, and August 6, 2021; all of whom entered the extension phase (72 received avatrombopag up to 26 weeks). At week 6 of the core study, the platelet response (≥50 x 10(9)/L) rate was significantly higher in the avatrombopag group (77.1%; 95% CI, 62.7, 88.0) vs placebo (7.7%; 95% CI, 1.0, 25.1); the treatment difference was 69.4% (95% CI, 56.2, 86.3; P < .0001). During the 6-week core study, treatment-emergent adverse events were reported in 41 (85.4%) and 20 (76.9%) patients in the avatrombopag and placebo groups, respectively. The most common avatrombopag-related treatment-emergent adverse events were upper respiratory tract infection (14/48 [29.2%]), increased platelet count (13/48 [27.1%]) and headache (7/48 [14.6%]). CONCLUSION Avatrombopag was efficacious and generally well tolerated in Chinese patients with chronic primary ITP, with comparable efficacy and safety to previous reports in Western patients.
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Eltrombopag for Adults and Children with Immune-Refractory Thrombocytopenic Purpura: A Systematic Review
de Barros Torelli, D. F. H., Oliveira, C. B. S., Nai, G. A., Trindade, E. M., Prestes-Carneiro, L. E.
Journal of clinical medicine. 2023;12(12)
Abstract
Eltrombopag is an agonist that binds to the membrane-bound domain of the thrombopoietin receptor used in immune thrombocytopenic purpura (ITP). We conducted a meta-analysis of randomized controlled trials to assess the efficacy and safety of eltrombopag in adults and children with refractory ITP. Adults who received eltrombopag had a significantly better platelet response (relative risk [RR], 3.65; 95% confidence interval [CI], 2.39-5.55), but there were no differences in the incidence of bleeding (RR, 0.8; 95% CI, 0.52-1.22) and adverse effects (RR, 0.99; 95% CI, 0.55-1.78) compared with the placebo. In children, there was no difference between eltrombopag and placebo for a platelet response >50,000/mm(3) (RR, 3.93; 95% CI, 0.56-27.79) and the number of adverse events (RR, 0.99; 95% CI, 0.25-1.49); however, a lower incidence of bleeding was observed (RR, 0.47; 95% CI, 0.27-0.83). Treatment with eltrombopag protected adults and children from severe disease and death.