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Safety of non‑peptide thrombopoietin receptor agonists in patients with immune thrombocytopenia: A systematic review and meta‑analysis of short‑term double‑blind randomized clinical trials
Shen, N., Qiao, J., Jiang, Y., Yin, H., Li, M., Zhu, S., Li, J.
Experimental and therapeutic medicine. 2023;26(2):393
Abstract
The aim of the present study was to analyze the safety of non-peptide thrombopoietin receptor agonists (TPO-RAs) for immune thrombocytopenia (ITP) treatment. All studies reporting adverse events (AEs) in relation to ITP treatment with eltrombopag, avatrombopag, and hetrombopag were retrieved from PubMed, Web of Science, and Embase databases. RevMan 5.4.1 was used for meta-analysis, heterogeneity and bias analyses. A total of 1,078 patients from seven eligible studies were enrolled. In the enrolled clinical trials, the double-blind period was between 6 weeks and 6 months. The results revealed that the chances of any AEs [relative risk (RR)=1.16; 95% confidence interval (CI), 0.90-1.51; I(2)=78%; P=0.26], grade 3/4 AEs (RR=1.07; 95% CI, 0.63-1.80; I(2)=0%; P=0.81), elevated transaminase levels (RR=1.09; 95% CI, 0.68-1.74; I(2)=0%; P=0.72), thrombosis (RR=1.92; 95% CI, 0.55-6.66; I(2)=0%; P=0.31) and cataracts (RR=0.83; 95% CI, 0.38-1.83; I(2)=0%; P=0.65) were not significantly higher in patients with ITP that received non-peptide TPO-RAs compared with patients with ITP treated with a placebo. The present study indicated that non-peptide TPO-RAs were relatively safe for patients with ITP, at least within 6 months of administration.
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A Phase 2 Randomized Controlled Trial of Single-Agent Hydroxyurea Versus Thalidomide Among Adult Transfusion Dependent β Thalassemia Patients
Bhattacharjee U, Khadwal A, Shafiq N, Lad D, Sharma P, Das R, Shukla P, Jain A, Prakash G, Malhotra P
Indian journal of hematology & blood transfusion : an official journal of Indian Society of Hematology and Blood Transfusion. 2023;:1-10
Abstract
Hydroxyurea and low dose thalidomide are low-cost, easily accessible Hb F inducing agents that have been found to decrease transfusion dependency among transfusion-dependent thalassemia patients. However, these drugs have not much been explored in a randomized controlled setting. The objective of this study was to determine the efficacy and safety of hydroxyurea and low dose thalidomide in adult transfusion dependent β thalassemia. A total of 39 transfusion dependent β thalassemia patients were randomized into three arms: Arm A (Hydroxyurea 500 mg/day), Arm B (thalidomide 50 mg/day), and Control Arm. The primary outcome was rise in haemoglobin at 24-weeks from the baseline levels. The mean age of the cohort was 26.9 ± 4.7 years. Total 13 patients (33.3%) were splenectomised. The mean rise of haemoglobin at the end of 24 weeks was 0.18 ± 0.645 g/dl, 0.56 ± 1.343 g/dl, and - 0.31 ± 0.942 g/dl in Arm A, Arm B and control arm, respectively, p = 0.127. The mean volume of blood transfused per unit body weight in 24 weeks was significantly less in the thalidomide arm compared with the control arm (p = 0.035). Abdominal pain (Grade 1-2, 23.1%) and pruritus (Grade 1, 15.4%) were the main adverse events in hydroxyurea arm, whereas somnolence was the main side effect noted in the thalidomide arm (Grade 1-2, 78.3%). Single agent hydroxyurea or thalidomide is ineffective in increasing haemoglobin and decreasing transfusion burden among majority of the adult transfusion dependent thalassemia patients. SUPPLEMENTARY INFORMATION The online version contains supplementary material available at 10.1007/s12288-022-01620-3.
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Desmopressin as a Treatment in Patients With Von Willebrand Disease: A Systematic Review
Beltran, A., Jaramillo, A. P., Vallejo, M. P., Acosta, L., Barberan Parraga, G. C., Guanín Cabrera, C. L., Gaibor, V. G., Cueva, M. G.
Cureus. 2023;15(8):e44310
Abstract
Von Willebrand disease (VWD) and hemophilia A are the most common inherited bleeding disorders. Quantitative or qualitative von Willebrand factor (VWF) anomalies cause this disorder in men and women. VWF, a plasma glycoprotein, relies on platelets for primary hemostasis. It also carries and stabilizes factor VIII in the blood. VWD has several categories. Types 1 and 3 have partial or total VWF quantitative deficiencies. However, type 2 and its subtypes have VWF quality issues. The major treatment is desmopressin (DDAVP), which replaces endogenous VWF and factor VIII (FVIII). Plasma-derived VWF/FVIII products may also be substituted exogenously. Treatment with plasma-derived or recombinant VWF concentrates without FVIII is also possible. The purpose of this retrospective, single-center research was to evaluate DDAVP's efficacy in treating VWD based on many criteria established in the current literature. We looked at the results on Google Scholar, the Cochrane Library, and PubMed/Medline. There were a total of 10 papers found, evaluated, and accepted for inclusion in this study. A comprehensive analysis of DDVAP's role in VWD was compiled from the aforementioned papers. Various aspects of DDVAP were captured by including an analysis of complementary treatments used in surgical and clinical settings. We also describe the treatment's intended impact on the different variations of the disease. Given these results, further investigation is required to determine the most effective method for managing VWD so that it may be included in standard clinical practice.
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Efficacy and safety of caffeic acid tablets in the treatment of thrombocytopenia: A systematic review and meta-analysis
Yu, H., Chen, R., Zhou, Z., Liu, R., Wen, J.
Medicine. 2023;102(40):e35353
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Abstract
BACKGROUND Caffeic acid tablets (CFA) are a proprietary Chinese medicine in treating thrombocytopenia. The efficacy and safety of CFA compared with other platelet-raising drugs for the treatment of thrombocytopenia have been widely reported in the literature, but there is no systematic evaluation. Therefore, we designed this meta-analysis to further establish the efficacy and safety of CFA in treating thrombocytopenia. METHODS A computerized search was conducted in the Chinese biomedical database (CBM), Chinese National Knowledge Infrastructure (CNKI), Wanfang database, Chinese Scientific Journal Database (VIP), PubMed, and Web of Science databases using the keywords "caffeic acid tablets" and "thrombocytopenia." All randomized controlled trials were selected for the timeframe of build to 02/2023 and then screened and analyzed using RevMan 5.4 and stata17.0 software. RESULTS A total of 35 publications with an overall 2533 patients were included in the study. The results of the meta-analysis showed that CFA were effective in the treatment of thrombocytopenia with a statistically significant difference [relative risk ratio (RR) = 1.24, 95% CI (1.17, 1.31), P < .00001] and in increasing platelet counts [standardized mean difference (SMD) = 1.50, 95% CI (1.09, 1.91), P < .00001], white blood cell count [SMD = 1.08, 95% CI (0.77, 1.39), P < .00001], and neutrophil count [SMD = 0.73, 95% CI (0.19, 1.28), P = .009], and CFA reduced myelosuppression [RR = 0.19, 95% CI (0.1, 0.37), P < .00001] and adverse effects [RR = 0.75, 95% CI (0.58, 0.96), P = .02]. CONCLUSION CFA can effectively improve the clinical outcome of patients with thrombocytopenia with a good safety profile and are worth promoting. However, due to the low quality and small sample size of the included literature, a larger sample size and more standardized, high-quality studies are needed to validate these results.
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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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Intravenous Iron Therapy to Treat Anemia in Oncology: A Mapping Review of Randomized Controlled Trials
Lim, J., Auerbach, M., MacLean, B., Al-Sharea, A., Richards, T.
Current oncology (Toronto, Ont.). 2023;30(9):7836-7851
Abstract
Anemia is a common problem when patients present with cancer, and it can worsen during treatment. Anemia can directly impact the cognitive and physical quality of life and may impair fitness for oncological therapy. The most common cause of anemia is iron deficiency. Newer intravenous (IV) iron formulations offer a safe and rapidly effective treatment option. We performed a systematic mapping review of randomized controlled trials (RCTs) evaluating intravenous iron therapy in patients with cancer and anemia and their outcomes. A total of 23 RCTs were identified. The median number of patients enrolled was 104 (IQR: 60-134). A total of 5 were focused on surgical outcomes (4 preoperative, 1 postoperative), and 15 were in adjuvant therapies for a variety of tumor types (breast, colorectal, lung, gynecological, myeloid, and lymphomas), 10 of which were in combination with erythropoietin-stimulating agents (ESAs) therapy, 2 in radiotherapy, and 1 in palliative care. Overall, the studies reported that the use of IV iron increased hemoglobin concentration and decreased transfusion rates during different cancer treatment regimes. IV iron can be administered safely throughout the cancer treatment pathway from primary surgery to the palliative setting. More studies are needed to demonstrate net clinical outcomes.
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Safety and Efficacy of Tyrosine Kinase Inhibitors in Immune Thrombocytopenic Purpura: A Systematic Review of Clinical Trials
Ali MA, Anwar MY, Aiman W, Dhanesar G, Omar Z, Hamza M, Zafar M, Rengarajan HK, Maroules M
Journal of xenobiotics. 2023;13(1):29-41
Abstract
Immune thrombocytopenic purpura (ITP) is an acquired antibody or cell-mediated platelet damage or decreased platelet production. Steroids, IV immunoglobulins (IVIG), and Rho-anti-D antibodies are the commonly used initial treatments for ITP. However, many ITP patients either do not respond or do not maintain a response to initial therapy. Splenectomy, rituximab, and thrombomimetics are the commonly used second-line treatment. More treatment options include tyrosine kinases inhibitors (TKI), including spleen tyrosine kinase (Syk) and Bruton's tyrosine kinase (BTK) inhibitors. This review aims to assess the safety and efficacy of TKIs. Methods: Literature was searched on PubMed, Embase, WOS, and clinicaltrials.gov using keywords, "tyrosine kinase" and "idiopathic thrombocytopenic purpura". PRISMA guidelines were followed. Results: In total, 4 clinical trials were included with 255 adult patients with relapsed/refractory ITP. In all, 101 (39.6%) patients were treated with fostamatinib, 60 (23%) patients with rilzabrutinib, and 34 (13%) with HMPL-523. Patients treated with fostamatinib achieved a stable response (SR) and overall response (OR) in 18/101 (17.8%) and 43/101 (42.5%) of the patients, respectively, while SR and OR were achieved in 1/49 (2%) and 7/49 (14%) of the patients, respectively, in the placebo group. Patients treated with HMPL-523 (300 mg dose expansion) achieved an SR and OR in 5/20 (25%) and 11/20 (55%) of the patients, respectively, while SR and OR were achieved in 1/11 (9%) of the patients treated with the placebo. Patients treated with rilzabrutinib achieved an SR in 17/60 (28%) patients. Dizziness (1%), hypertension (2%), diarrhea (1%), and neutropenia (1%) were serious adverse events in fostamatinib patients. Rilzabrutinib or HMPL-523 patients did not require a dose reduction due to drug-related adverse effects. Conclusions: Rilzabrutinib, fostamatinib, and HMPL-523 were safe and effective in the treatment of relapsed/refractory ITP.
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Eltrombopag for Low-Risk Myelodysplastic Syndromes With Thrombocytopenia: Interim Results of a Phase-II, Randomized, Placebo-Controlled Clinical Trial (EQOL-MDS)
Oliva, E. N., Riva, M., Niscola, P., Santini, V., Breccia, M., Giai, V., Poloni, A., Patriarca, A., Crisà, E., Capodanno, I., et al
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2023;:Jco2202699
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Editor's Choice
Abstract
PURPOSE In myelodysplastic syndromes (MDS), severe thrombocytopenia is associated with poor prognosis. This multicenter trial presents the second-part long-term efficacy and safety results of eltrombopag in patients with low-risk MDS and severe thrombocytopenia. METHODS In this single-blind, randomized, placebo-controlled, phase-II trial of adult patients with International Prognostic Scoring System low- or intermediate-1-risk MDS, patients with a stable platelet (PLT) count (<30 × 10(3)/mm(3)) received eltrombopag or placebo until disease progression. Primary end points were duration of PLT response (PLT-R; calculated from the time of PLT-R to date of loss of PLT-R, defined as bleeding/PLT count <30 × 10(3)/mm(3) or last date in observation) and long-term safety and tolerability. Secondary end points included incidence and severity of bleeding, PLT transfusions, quality of life, leukemia-free survival, progression-free survival, overall survival and pharmacokinetics. RESULTS From 2011 to 2021, of 325 patients screened, 169 patients were randomly assigned oral eltrombopag (N = 112) or placebo (N = 57) at a starting dose of 50 mg once daily to maximum of 300 mg. PLT-R, with 25-week follow-up (IQR, 14-68) occurred in 47/111 (42.3%) eltrombopag patients versus 6/54 (11.1%) in placebo (odds ratio, 5.9; 95% CI, 2.3 to 14.9; P < .001). In eltrombopag patients, 12/47 (25.5%) lost the PLT-R, with cumulative thrombocytopenia relapse-free survival at 60 months of 63.6% (95% CI, 46.0 to 81.2). Clinically significant bleeding (WHO bleeding score ≥ 2) occurred less frequently in the eltrombopag arm than in the placebo group (incidence rate ratio, 0.54; 95% CI, 0.38 to 0.75; P = .0002). Although no difference in the frequency of grade 1-2 adverse events (AEs) was observed, a higher proportion of eltrombopag patients experienced grade 3-4 AEs (χ(2) = 9.5, P = .002). AML evolution and/or disease progression occurred in 17% (for both) of eltrombopag and placebo patients with no difference in survival times. CONCLUSION Eltrombopag was effective and relatively safe in low-risk MDS with severe thrombocytopenia. This trial is registered with ClinicalTrials.gov identifier: NCT02912208 and EU Clinical Trials Register: EudraCT No. 2010-022890-33.
PICO Summary
Population
Adult patients with low-risk myelodysplastic syndromes and severe thrombocytopenia (n= 169).
Intervention
Oral eltrombopag (n= 112).
Comparison
Placebo (n= 57).
Outcome
Primary end points were duration of platelets response (PLT-R) and long-term safety and tolerability. PLT-R, with 25-week follow-up (IQR, 14-68) occurred in 47/111 (42.3%) eltrombopag patients vs. 6/54 (11.1%) in placebo (odds ratio, 5.9; 95% CI [2.3, 14.9]. In eltrombopag patients, 12/47 (25.5%) lost the PLT-R, with cumulative thrombocytopenia relapse-free survival at 60 months of 63.6%; 95% CI [46.0, 81.2]. Clinically significant bleeding occurred less frequently in the eltrombopag arm than in the placebo group (incidence rate ratio, 0.54; 95% CI [0.38, 0.75]. Although no difference in the frequency of grade 1-2 adverse events (AEs) was observed, a higher proportion of eltrombopag patients experienced grade 3-4 AEs (χ2= 9.5). AML evolution and/or disease progression occurred in 17% (for both) of eltrombopag and placebo patients with no difference in survival times.
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Rilzabrutinib versus placebo in adults and adolescents with persistent or chronic immune thrombocytopenia: LUNA 3 phase III study
Kuter, D. J., Bussel, J. B., Ghanima, W., Cooper, N., Gernsheimer, T., Lambert, M. P., Liebman, H. A., Tarantino, M. D., Lee, M., Guo, H., et al
Therapeutic advances in hematology. 2023;14:20406207231205431
Abstract
BACKGROUND Immune thrombocytopenia (ITP) is characterized by primarily autoantibody-mediated platelet destruction and impaired platelet production resulting in thrombocytopenia and an increased risk of bleeding. Other manifestations include increased risk of thrombosis and diminished quality of life. Current treatment approaches are directed toward lowering the rate of platelet destruction or stimulating platelet production to prevent bleeding. Rilzabrutinib is an oral, reversible, potent Bruton tyrosine kinase inhibitor that was specifically designed to treat immune-mediated diseases and mediates its therapeutic effect through a dual mechanism of action: (1) inhibiting B-cell activation and (2) interrupting antibody-coated cell phagocytosis by Fc gamma receptor in spleen and liver. A 24-week dose-finding phase I/II study of rilzabrutinib in patients with ITP showed a 40% platelet response (⩾2 consecutive platelet counts of ⩾50 × 10(9)/L and increase from baseline ⩾20 × 10(9)/L without rescue medication use) and a well-tolerated safety profile with only grade 1/2 transient adverse events across dose levels. OBJECTIVES Assess the efficacy and safety of oral rilzabrutinib in adult and adolescent patients with persistent or chronic ITP. DESIGN Rilzabrutinib 400 mg BID is being evaluated in the ongoing LUNA 3 multicenter, double-blind, placebo-controlled phase III study. METHODS AND ANALYSIS The primary endpoint is durable platelet response, defined as achieving platelet counts of ⩾50 × 10(9)/L for at least two-thirds of ⩾8 available weekly scheduled platelet measurements during the last 12 weeks (including ⩾2 available measurements within the last 6 weeks) of the 24-week blinded treatment period in the absence of rescue therapy. ETHICS Ethical guidelines and informed consent are followed. DISCUSSION The LUNA 3 trial will further investigate rilzabrutinib's safety and efficacy in adult and adolescent patients, with the primary goal of addressing a major objective in treating patients with ITP: durability of platelet response. TRAIL REGISTRATION ClinicalTrials.gov NCT04562766: https://clinicaltrials.gov/ct2/show/NCT04562766; EU Clinical Trials Register EudraCT 2020-002063-60: https://www.clinicaltrialsregister.eu/ctr-search/search?query=2020-002063-60.
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Improved benefit of continuing luspatercept therapy: sub-analysis of patients with lower-risk MDS in the MEDALIST study
Germing, U., Fenaux, P., Platzbecker, U., Buckstein, R., Santini, V., Díez-Campelo, M., Yucel, A., Tang, D., Fabre, S., Zhang, G., et al
Annals of Hematology. 2023;102(2):311-321
Abstract
Red blood cell transfusion independence (RBC-TI) is an important goal in treating lower-risk myelodysplastic syndromes with ring sideroblasts. In the phase 3 MEDALIST study, RBC-TI of ≥ 8 weeks was achieved by significantly more luspatercept- versus placebo-treated patients in the first 24 weeks of treatment. In this post hoc analysis, we evaluated RBC transfusion units and visits based on patients' baseline transfusion burden level and the clinical benefit of luspatercept treatment beyond week 25 in initial luspatercept nonresponders (patients who did not achieve RBC-TI ≥ 8 weeks by week 25) but continued luspatercept up to 144 weeks. RBC transfusion burden, erythroid response, serum ferritin levels, and hemoglobin levels relative to baseline were evaluated. Through week 25, fewer RBC transfusion units and visits were observed in luspatercept-treated patients versus placebo, regardless of baseline transfusion burden. This continued through 144 weeks of luspatercept treatment, particularly in patients with low baseline transfusion burden. Sixty-eight patients were initial nonresponders at week 25 but continued treatment; most (81%) received the maximum dose of luspatercept (1.75 mg/kg). Sixteen percent achieved RBC-TI for ≥ 8 weeks during weeks 25-48, 26% had reduced RBC transfusion burden, 10% achieved an erythroid response, 44% had reduced serum ferritin, and hemoglobin levels increased an average of 1.3 g/dL from baseline. These data have implications for clinical practice, as transfusion units and visits are less in luspatercept-treated patients through week 25 regardless of baseline transfusion burden, and continuing luspatercept beyond week 25 can potentially provide additional clinical benefits for initial nonresponders. Trial registration: NCT02631070.