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Efficacy and safety of treatments in newly diagnosed adult primary immune thrombocytopenia: A systematic review and network meta-analysis
Wang Y, Sheng L, Han F, Guo Q, Zhang Z, Hou Y, Feng Q, Zhou H, Ji X, Peng J, et al
EClinicalMedicine. 2023;56:101777
Abstract
BACKGROUND Immune thrombocytopenia is an autoimmune disease characterised by decreased platelet count. In recent years, novel therapeutic regimens have been investigated in randomised controlled trials (RCTs). We aimed to compare the efficacy and safety of different treatments in newly diagnosed adult primary immune thrombocytopenia. METHODS We did a systematic review and network meta-analysis of RCTs involving treatments for newly diagnosed primary immune thrombocytopenia. PubMed, Embase, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov databases were searched up to April 31, 2022. The primary outcomes were 6-month sustained response and early response. Secondary outcome was grade 3 or higher adverse events. This study is registered with PROSPERO (CRD42022296179). FINDINGS Eighteen RCTs (n = 1944) were included in this study. Pairwise meta-analysis showed that the percentage of patients achieving early response was higher in the dexamethasone-containing doublet group than in the dexamethasone group (79.7% vs 68.7%, odds ratio [OR] 1.82, 95% CI 1.10-3.02). The difference was more profound for sustained response (60.5% vs 37.4%, OR 2.57, 95% CI 1.95-3.40). Network meta-analysis showed that dexamethasone plus recombinant human thrombopoietin ranked first for early response, followed by dexamethasone plus oseltamivir or tacrolimus. Rituximab plus prednisolone achieved highest sustained response, followed by dexamethasone plus all-trans retinoic acid or rituximab. Rituximab plus dexamethasone showed 15.3% of grade 3 or higher adverse events, followed by prednis(ol)one (4.8%) and all-trans retinoic acid plus dexamethasone (4.7%). INTERPRETATION Our findings suggested that compared with monotherapy dexamethasone or prednis(ol)one, the combined regimens had better early and sustained responses. rhTPO plus dexamethasone ranked top in early response, while rituximab plus corticosteroids obtained the best sustained response, but with more adverse events. Adding oseltamivir, all-trans retinoic acid or tacrolimus to dexamethasone reached equally encouraging sustained response, without compromising safety profile. Although this network meta-analysis compared all the therapeutic regimens up to date, more head-to-head RCTs with larger sample size are warranted to make direct comparison among these strategies. FUNDING National Natural Science Foundation of China, Major Research Plan of National Natural Science Foundation of China, Shandong Provincial Natural Science Foundation and Young Taishan Scholar Foundation of Shandong Province.
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All-trans retinoic acid plus high-dose dexamethasone as first-line treatment for patients with newly diagnosed immune thrombocytopenia: a multicentre, open-label, randomised, controlled, phase 2 trial
Huang QS, Liu Y, Wang JB, Peng J, Hou M, Liu H, Feng R, Wang JW, Xu LP, Wang Y, et al
The Lancet. Haematology. 2021;8(10):e688-e699
Abstract
BACKGROUND High-dose dexamethasone is the standard initial treatment for patients with immune thrombocytopenia, but many patients still relapse and require further treatments. All-trans retinoic acid has been shown to exert immunomodulatory effects and promote thrombopoiesis, and so we aimed to assess the activity and safety of all-trans retinoic acid plus high-dose dexamethasone as a first-line treatment for newly diagnosed patients with immune thrombocytopenia. METHODS This multicentre, open-label, randomised, controlled, phase 2 trial was done at six different tertiary medical centres in China. Eligible participants were adults (aged >18 years) with treatment-naive, newly diagnosed, primary immune thrombocytopenia who had either a platelet count of less than 30 × 10(9) platelets per L or a platelet count of less than 50 × 10(9) platelets per L and clinically significant bleeding. We randomly assigned (1:1) participants to receive either all-trans retinoic acid (10 mg orally twice daily for 12 weeks) plus high-dose dexamethasone (40 mg/day intravenously for 4 consecutive days) or high-dose dexamethasone alone using a central, web-based randomisation system. If patients did not respond by day 14, the 4-day course of dexamethasone was repeated. The primary endpoint was 6-month sustained response, defined as the maintenance of a platelet count of at least 30 × 10(9) platelets per L and at least 2-times higher than the baseline count and the absence of bleeding, with no need for rescue medication at this time. The primary endpoint was analysed by intention-to-treat and safety was assessed in all participants who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov, NCT04217148, and is now completed. FINDINGS Between Jan 1, 2020, and June 30, 2020, 132 patients were randomly assigned to either all-trans retinoic acid plus high-dose dexamethasone (n=66) or high-dose dexamethasone alone (n=66). Three patients did not receive their allocated treatment, leaving 129 in the safety analysis set. At 6 months, a significantly higher proportion of participants in the all-trans retinoic acid plus high-dose dexamethasone group (45 [68%] of 66) than in the high-dose dexamethasone monotherapy group (27 [41%] of 66) had a sustained response (OR 3·095, 95% CI 1·516-6·318; p=0·0017). The most common adverse events were dry skin (31 [48%] of 64 patients), headaches (12 [19%]), and insomnia (12 [19%]) in the combination group, and insomnia (ten [15%] of 65 patients) and anxiety or mood disorders (eight [12%]) in the monotherapy group. Both treatments were well tolerated and no grade 4 or worse adverse events occurred. There were no treatment-related deaths. INTERPRETATION The combination of all-trans retinoic acid and high-dose dexamethasone was safe and active in newly diagnosed patients with primary immune thrombocytopenia, providing a sustained response. This regimen represents a potential first-line treatment in this setting, but further studies are needed to validate its efficacy and safety. FUNDING The Beijing Municipal Science and Technology Commission, the National Natural Science Foundation of China, the Beijing Natural Science Foundation, the National Key Research and Development Program of China, and the Foundation for Innovative Research Groups of the National Natural Science Foundation of China.
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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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High-dose dexamethasone plus recombinant human thrombopoietin versus high-dose dexamethasone alone as frontline treatment for newly diagnosed adult primary immune thrombocytopenia:a prospective, multicenter, randomized trial
Yu Y, Wang M, Hou Y, Qin P, Zeng Q, Yu W, Guo X, Wang J, Wang X, Liu G, et al
American journal of hematology. 2020
Abstract
We conducted a prospective, multicenter, randomized, controlled clinical trial to compare the efficacy and safety of high-dose dexamethasone (HD-DXM) plus recombinant human thrombopoietin (rhTPO) versus HD-DXM alone in newly diagnosed adult immune thrombocytopenia (ITP) patients. Enrolled patients were randomly assigned to receive DXM plus rhTPO or DXM monotherapy. Another 4-day course of DXM was repeated if response was not achieved by day 10 in both arms. One hundred patients in the HD-DXM plus rhTPO arm and 96 patients in the HD-DXM monotherapy arm were included in the full analysis set. HD-DXM plus rhTPO resulted in a higher incidence of initial response (89.0% vs. 66.7%, P < 0.001) and complete response (CR, 75.0% vs. 42.7%, P < 0.001) compared with HD-DXM monotherapy. Response rate at 6 months was also higher in the HD-DXM plus rhTPO arm than that in the HD-DXM monotherapy arm (51.0% vs. 36.5%, P = 0.02; sustained CR: 46.0% vs. 32.3%, P = 0.043). Throughout the follow-up period, the overall duration of response was greater in the HD-DXM plus rhTPO arm compared to the HD-DXM monotherapy arm (P = 0.04), as estimated by the Kaplan-Meier analysis. The study drugs were generally well tolerated. In conclusion, the combination of HD-DXM with rhTPO significantly improved the initial response and yielded favorable SR in newly diagnosed ITP patients, thus could be further validated as a frontline treatment for ITP. This study is registered as clinicaltrials.gov identifier: NCT01734044. This article is protected by copyright. All rights reserved.
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Matching-adjusted indirect comparisons of annualized bleeding rate and utilization of BAY 94-9027 versus three recombinant factor VIII agents for prophylaxis in patients with severe hemophilia A
Batt K, Gao W, Ayyagari R, Deschaseaux C, Vashi PB, Yao Z, Wang Y, Kessabi S, Klamroth R
Journal of blood medicine. 2019;10:147-159
Abstract
Background: BAY 94-9027 is an extended half-life recombinant factor VIII (rFVIII) that prevents bleeding in persons with hemophilia A at twice-weekly, 5-day, and 7-day dosing intervals. In rare diseases such as hemophilia, where small populations preclude head-to-head comparisons in randomized controlled trials, outcomes from different studies can be compared by matching-adjusted indirect treatment comparisons (MAICs) via matched summary statistics of individual patient data. This study compared MAIC-adjusted outcomes of BAY 94-9027 with other FVIII agents for prophylaxis of hemophilia. Methods: Weighted patient data from the BAY 94-9027 PROTECT VIII trial were used to compare annualized bleeding rates (ABRs), percentage of patients with zero bleeds, and factor utilization against published data on rFVIII-Fc fusion protein (rFVIIIFc), BAX 855, and recombinant antihemophilic factor/plasma/albumin-free method (rAHF-PFM). Results: After matching BAY 94-9027 and comparators, the mean BAY 94-9027 utilization was significantly lower than rFVIIIFc pre- and post-matching (66.2 vs 82.2 IU/kg/week; 66.5 vs 82.2 IU/kg/week; both P<0.001). Median BAY 94-9027 utilization (IU/kg/week) trended lower than BAX 855 (64.3 vs 87.4) and rAHF-PFM (2004 study: 64.0 vs 107.5; 2012 study: 63.6 vs 109.9). Mean ABRs and percentages of patients with zero bleeds were similar post-matching between BAY 94-9027 and comparators. Conclusion: BAY 94-9027 demonstrated similar MAIC-adjusted ABR with lower utilization than rFVIIIFc, BAX 855, and rAHF-PFM.
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Efficacy of recombinant human thrombopoietin combined with high-dose dexamethasone in the treatment of refractory immune thrombocytopenia in children
Lu YY, Guan N, Meng QH, Li ML, Liu YY, Wang Y
Zhongguo Dang Dai Er Ke Za Zhi = Chinese Journal of Contemporary Pediatrics. 2018;20((7)):534-537.
Abstract
OBJECTIVE To explore the efficacy and safety of recombinant human thrombopoietin (rhTPO) combined with high-dose dexamethasone (DXM) in the treatment of children with refractory immune thrombocytopenic purpura (ITP). METHODS Fifty-eight ITP children who had failed first-line therapy were randomly divided into two groups: DXM treatment (n=27) and rhTPO + DXM treatment (n=31). The DXM treatment group received two continuous cycles of DXM treatment; in each cycle, patients received high-dose DXM (0.6 mg/kg daily) by intravenous drip for 4 days every 28 days. The rhTPO group received subcutaneous injection of rhTPO (300 U/kg daily) for 14 days additional to DXM treatment. The overall response rate (marked response rate + slight response rate) and adverse reactions were evaluated after 3, 7, and 14 days and 1, 2, and 3 months of treatment. RESULTS After 7 and 14 days and 1 month of treatment, the rhTPO + DXM treatment group had a significantly higher marked response rate and a significantly higher overall response rate than the DXM treatment group (P<0.05). After 2 months of treatment, the rhTPO + DXM treatment group had a significantly higher overall response rate than the DXM group (P<0.05). One patient in the DXM treatment group had liver damage during the first week of treatment. There was no hypertension, fever, rash, allergy, or weakness in the two groups. CONCLUSIONS rhTPO combined with high-dose DXM is an effective and safe approach for treating refractory ITP.