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Red Blood Cell Alloimmunizations in Thalassaemia Patients With Regular Transfusion in China: a Systematic Review and Meta-Analysis
Zhang X, Li Y, Yan B, Li X, Gui S, Sun A
Transfusion clinique et biologique : journal de la Societe francaise de transfusion sanguine. 2023
Abstract
OBJECTIVE The development of red blood cell alloimmunization intensifies transfusion complication in thalassaemia patients. The purpose of this paper is to evaluate the existing evidence on the prevalence of erythrocyte alloimmunization in China by meta-analysis. We systematically searched cross-sectional studies regarding the alloimmunization of thalassaemia patients with regular blood transfusion in China from year 2000 to May 2021 in the Cochrane library, PubMed, EMBASE, Web of Science, and Chinese databases including CNKI, Wanfang Data, Vip and CBM. Data extraction and quality evaluation of the included studies were performed. Meta-analysis was performed using the DerSimonian and Laird random-effects models with inverse variance weighting. The presence of publication bias was tested by Egger's test, and the methodological quality of each included article was evaluated by the criteria specific to prevalence studies. RESULTS A total of 1874 patients and 263 alloantibodies from 11 studies were identified and included in the meta-analysis. The proportion of alloantibodies against antigens belonging to the Rh, MNSs and Kidd systems were as high as 70.3%, 17.9%, and 6.5%, respectively. Meta-analysis showed that the overall prevalence of alloimmunization among transfusion-dependent thalassaemia patients in China is 11.4% (95%CI: 7.2%∼16.3%). CONCLUSIONS The characteristics of red blood cell alloimmunization among thalassaemia patients with regular transfusion in China differ greatly from those in other countries. Therefore, transfusion strategies shall be actively adapted in line with thalassaemia patients in China to minimize the risk of alloimmunization.
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2.
Sovleplenib (HMPL-523), a novel Syk inhibitor, for patients with primary immune thrombocytopenia in China: a randomised, double-blind, placebo-controlled, phase 1b/2 study
Liu X, Zhou H, Hu Y, Yin J, Li J, Chen W, Huang R, Gong Y, Luo C, Mei H, et al
The Lancet. Haematology. 2023
Abstract
BACKGROUND Spleen tyrosine kinase (Syk) inhibitor is a treatment option for primary immune thrombocytopenia. We aimed to evaluate the safety, tolerability, pharmacokinetics, preliminary activity, and recommended phase 2 dose of sovleplenib in patients with primary immune thrombocytopenia. METHODS This randomised, double-blind, placebo-controlled, phase 1b/2 study was conducted at nine hospitals in China. Eligible patients were aged 18-75 years, had an ECOG performance score of 0-1, had primary immune thrombocytopenia for more than 6 months, and did not respond or relapsed after previous first-line treatment or had poor response or postoperative relapse after a splenectomy. Dose-escalation (100 mg, 200 mg, or 300 mg given orally once a day) and dose-expansion phases (recommended phase 2 dose) each consisted of an 8-week, double-blind, placebo-controlled period in which patients were randomly assigned (3:1) to receive sovleplenib or placebo with an interactive web response system followed by a 16-week, open-label period with sovleplenib. Patients, investigators, and the sponsor were masked to treatment allocation during the first 8 weeks. The main efficacy endpoint was the proportion of patients whose platelet count reached 30 × 10(9) platelets per L or higher and was double of the baseline at two consecutive visits during 0-8 weeks without rescue therapy. Efficacy was evaluated by intention-to-treat. This study is registered with ClinicalTrials.gov, NCT03951623. FINDINGS Between May 30, 2019, and April 22, 2021, 62 patients were assessed for eligibility and 45 (73%) were randomly assigned. Patients received at least one dose of the study drug during the 8-week double-blind period (placebo [n=11] and sovleplenib 100 mg [n=6], 200 mg [n=6], 300 mg [n=16], and 400 mg [n=6]; this group was added following the observation of no protocol-specified safety events at the previous doses). All participants were Asian; 18 (40%) of 45 were male and 27 (60%) were female. The median age was 40·0 years (IQR 33·0-50·0). Ten (29%) of 34 patients in sovleplenib groups versus five (45%) of 11 in the placebo group received concomitant anti-primary immune thrombocytopenia therapy. The recommended phase 2 dose was determined as 300 mg once a day. The proportion of patients who met the main efficacy endpoint were three (50%; 95% CI 12-88) in the 100 mg group, three (50%; 12-88) in the 200 mg group, ten (63%; 35-85) in the 300 mg group, and two (33%; 4-78) in the 400 mg group compared with one (9%; 0-41) in the placebo group. The overall response rate in the 300 mg group was 80% (16 of 20 who received continuous sovleplenib plus those who crossed over from placebo) and the durable response rate was 31% (11-59; five of 16) in the continuous sovleplenib 300 mg and 75% (19-99; three of four) crossed from placebo to sovleplenib during 0-24 weeks. During the 28-day safety evaluation period, two grade 2 or worse treatment-related treatment-emergent adverse events occurred in the sovleplenib groups (hypertriglyceridaemia and anaemia). During 0-8 weeks, the most frequent treatment-emergent adverse events were an increase in blood lactate dehydrogenase, haematuria, and urinary tract infection (seven [21%] of 34 in sovleplenib groups vs one [9%] of 11 in the placebo group); and occult blood-positive and hyperuricaemia (four [12%] vs three [27%] for each). No fatal treatment-emergent adverse events were recorded. INTERPRETATION Sovleplenib was well tolerated, and the recommended phase 2 dose showed a promising durable response in patients with primary immune thrombocytopenia, which provides evidence for future investigations. A phase 3 trial is ongoing (NCT05029635) to confirm the efficacy and safety of sovleplenib in patients with primary immune thrombocytopenia. FUNDING HUTCHMED.
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3.
A multicenter, randomized phase III trial of hetrombopag: a novel thrombopoietin receptor agonist for the treatment of immune thrombocytopenia
Mei H, Liu X, Li Y, Zhou H, Feng Y, Gao G, Cheng P, Huang R, Yang L, Hu J, et al
Journal of hematology & oncology. 2021;14(1):37
Abstract
BACKGROUND Hetrombopag, a novel thrombopoietin receptor agonist, has been found in phase I studies to increase platelet counts and reduce bleeding risks in adults with immune thrombocytopenia (ITP). This phase III study aimed to evaluate the efficacy and safety of hetrombopag in ITP patients. METHODS Patients who had not responded to or had relapsed after previous treatment were treated with an initial dosage of once-daily 2.5 or 5 mg hetrombopag (defined as the HETROM-2.5 or HETROM-5 group) or with matching placebo in a randomized, double-blind, 10-week treatment period. Patients who received placebo and completed 10 weeks of treatment switched to receive eltrombopag, and patients treated with hetrombopag in the double-blind period continued hetrombopag during the following open-label 14-week treatment. The primary endpoint was the proportion of responders (defined as those achieving a platelet count of ≥ 50 × 10(9)/L) after 8 weeks of treatment. RESULTS The primary endpoint was achieved by significantly more patients in the HETROM-2.5 (58.9%; odds ratio [OR] 25.97, 95% confidence interval [CI] 9.83-68.63; p < 0.0001) and HETROM-5 (64.3%; OR 32.81, 95% CI 12.39-86.87; p < 0.0001) group than in the Placebo group (5.9%). Hetrombopag was also superior to placebo in achieving a platelet response and in reducing the bleeding risk and use of rescue therapy throughout 8 weeks of treatment. The durable platelet response to hetrombopag was maintained throughout 24 weeks. The most common adverse events were upper respiratory tract infection (42.2%), urinary tract infection (17.1%), immune thrombocytopenic purpura (17.1%) and hematuria (15%) with 24-week hetrombopag treatment. CONCLUSIONS In ITP patients, hetrombopag is efficacious and well tolerated with a manageable safety profile. Trial registration Clinical trials.gov NCT03222843 , registered July 19, 2017, retrospectively registered.
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4.
Eltrombopag versus romiplostim in treatment of children with persistent or chronic immune thrombocytopenia: a systematic review incorporating an indirect-comparison meta-analysis
Zhang J, Liang Y, Ai Y, Li X, Xie J, Li Y, Zheng W, He R.
Scientific Reports. 2018;8((1)):576.
Abstract
In absence of direct comparison, we conducted an indirect-comparison meta-analysis to evaluate the efficacy and safety of thrombopoietin-receptor agonists(TPO-RAs) in treatment of pediatric persistent or chronic immune thrombocytopenia(ITP). PubMed, Embase, Cochrane Library, Clinical Trials.gov, China National Knowledge Infrastructure, and Chinese Biomedical Literature Database were searched from their earliest records to May 2017. Randomized controlled trials comparing the TPO-RAs with placebo in pediatric ITP were included. Outcomes included overall response rate(primary), durable response, overall or clinically significant bleeding, the proportion of patients receiving rescue medication, and safety. Five randomized placebo-controlled studies(N = 261) were analyzed. The overall response[Risk Ratio(RR) 0.57, 95% confidence interval(CI) 0.21-1.56], the incidence of adverse events (RR 0.96, 95%CI 0.66-1.39), durable response(RR 2.48, 95%CI 0.31-19.97), and the proportion of patients receiving rescue treatment(RR 0.73, 95%CI 0.20-2.73) were similar between eltrombopag and romiplostim group. Nevertheless, eltrombopag might have lower risk of overall bleeding(RR 0.43, 95%CI 0.23-0.80) and clinically significant bleeding(RR 0.33, 95%CI 0.12-0.89) than romiplostim. This meta-analysis suggests that eltrombopag might be similar to romiplostim in efficacy and safety, but seems to reduce the risk of bleeding compared to romiplostim. Furthermore, cost of the treatment, comorbidity of patients and drug compliance should also be considered in clinical decision making.
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5.
Eltrombopag versus romiplostim in treatment of adult patients with immune thrombocytopenia: A systematic review incorporating an indirect-comparison meta-analysis
Zhang J, Liang Y, Ai Y, Li X, Xie J, Li Y, Zheng W, He R
Plos One. 2018;13((6)):e0198504.
Abstract
PURPOSE In absence of direct comparison randomized controlled trials (RCTs), indirect comparison was conducted to evaluate the efficacy and safety of thrombopoietin-receptor agonists (TPO-RAs) in treatment of adult immune thrombocytopenia (ITP). METHODS We searched PubMed, Embase and Cochrane Library, Clinical Trials.gov, China National Knowledge Infrastructure, and Chinese Biomedical Literature Database from their earliest records to May 2017. RCTs comparing the TPO-RAs with placebo in adult ITP were included. Primary outcomes were the overall response rate. Secondary outcomes included safety, durable response, overall or clinically significant bleeding, and the proportion of patients receiving rescue medication. RESULTS Nine randomized placebo-controlled trials (786 participants) were included in this systematic review. Overall response [Risk Ratio(RR) = 0.59, 95%Confidence Interval(CI): 0.24-1.45], the incidence of adverse events (RR = 0.98, 95%CI: 0.79-1.21), durable response (RR = 0.47, 95%CI: 0.08-2.81), the incidence of overall bleeding (RR = 1.15, 95%CI: 0.52-2.57) and clinically significant bleeding (RR = 1.09, 95%CI: 0.37-3.24), and the proportion of patients receiving rescue treatment (RR = 0.95, 95%CI: 0.47-1.90) were similar between eltrombopag and romiplostim. CONCLUSIONS Eltrombopag and romiplostim might be equivalent in efficacy and safety for adult ITP, however, physicians should still take into account drug cost and comorbidities of the specific patient while making decisions on the treatment of ITP with TPO-RAs. REGISTRATION PROSPERO International Prospective Register of Systematic Review (PROSPERO 2017: CRD42017068661).
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6.
Efficacy and Safety of the Combination Treatment of Rituximab and Dexamethasone for Adults with Primary Immune Thrombocytopenia (ITP): A Meta-Analysis
Wang J, Li Y, Wang C, Zhang Y, Gao C, Lang H, Chen X
BioMed research international. 2018;2018:1316096
Abstract
Objective. To conduct a meta-analysis, assessing the efficacy and safety of the combination treatment of dexamethasone and rituximab for adults with ITP (primary immune thrombocytopenia). Methods. Randomized controlled trials that compared rituximab and dexamethasone combination treatment to dexamethasone monotherapy in the treatment of adults with ITP were collected by searching Pubmed, Embase, Cochrane, China National Knowledge (CNKI), Wanfang database, and Sino Med. We conducted pooled analyses on OR (overall response) rate, CR (complete response) rate, PR (partial response) rate, SR (sustained response) rate, R (relapse) rate, change in Treg cell count (mean [SD]), and AE (adverse event). GRADE pro scale was used to assess the quality of the evidence. Publication bias was assessed with Egger's test method. Results. A total of 11 randomized controlled trials were eligible for inclusion. The overall efficacy estimates favored combination arm in terms of OR rate at month 3, CR rate at week 4 and month 3, SR rate, and Treg cell count at week 2. Subgroup analysis showed that females obtained a higher OR rate than males did at week 4. No significant difference was found in pooled analysis of relapse rate between combination arm and monotherapy arm. The comparison of serious AE and other AEs showed no significant difference either. A total of 19 outcomes were assessed by GRADE pro software, of which 79% (15/19) was scaled as moderate-to-high level. Publication bias existed in studies on OR at week 4 (P=0.025), CR at week 4 (P=0.017), infection (P=0.006), and rash (P=0.028) of the AEs. Conclusion. Dexamethasone combined with rituximab can provide a better long-term response in the treatment of adults with ITP and will not increase the risk of adverse effects.
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7.
Thrombopoietin-receptor agonists for children with immune thrombocytopenia: a systematic review
Li Y, Zhang J, Liang Y, Ai Y, Xie J, Zheng W
Expert Opinion on Pharmacotherapy. 2017;18((15):):1543-1551
Abstract
OBJECTIVE We conducted a systematic review to assess the efficacy and safety of Thrombopoietin-receptor agonists(TPOras) for pediatric immune thrombocytopenia(ITP). METHODS We searched PubMed, Embase and Cochrane Library from their earliest records to January 2017. Randomized controlled trials(RCTs) evaluating the efficacy and safety of TPOras in children were included. Primary outcomes were durable response and clinically significant bleeding. Secondary outcomes were overall response, overall bleeding events, the proportion of patients receiving rescue medication and adverse events(AEs). RESULTS Five randomized RCTs(261participants) were included in this systematic review. Compared with placebo group, the proportion of patients achieving durable platelet response was significantly higher in Eltrombopag(92 participants, P=0.0004) or Romiplostim(62 participants, P=0.002) group, so was the overall response in Eltrombopag[RR=2.64, 95%CI(1.58, 4.44)] or Romiplostim[RR=5.05, 95%CI(2.21, 11.53)] group. Both clinically significant bleeding(159 participants, P=0.04) and total bleeding(183 participants, P=0.01) in Eltrombopag group were significantly less frequent than those in placebo group, while no significant difference between Romiplostim and placebo group. The proportion of patients receiving rescue medication, the incidence of overall AEs and serious AEs between TPO-receptor agonists and placebo group were not significantly different. CONCLUSION TPOras might improve both durable and overall platelet response in pediatric ITP, compared with placebo.