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1.
Efficacy and safety of intravenous bevacizumab on severe bleeding associated with hemorrhagic hereditary telangiectasia: A national, randomized multicenter trial
Dupuis-Girod, S., Rivière, S., Lavigne, C., Fargeton, A. E., Gilbert-Dussardier, B., Grobost, V., Leguy-Seguin, V., Maillard, H., Mohamed, S., Decullier, E., et al
Journal of internal medicine. 2023
Abstract
BACKGROUND Bevacizumab-a humanized monoclonal antibody-has been widely used to treat patients with hereditary hemorrhagic telangiectasia, but no randomized trial has yet been conducted. METHODS This study is a double-blind multi-center randomized phase 2 trial with a 1:1 active-treatment-to-placebo ratio. We included patients over the age of 18 with a confirmed diagnosis and the need for at least four red blood cell units transfused in the three months before study enrollment. Bevacizumab was administered at a dose of 5 mg/kg every 14 days with a total of six injections. The primary efficacy criterion was a decrease of at least 50% in the cumulative number of red blood cell units transfused in a three-month period before and after treatment. RESULTS 24 patients (12 in each group) were included and randomized at four different centers. In intention-to-treat analysis, 63.6% of patients (7/11) in the bevacizumab group versus 33.3% of patients (4/12) in the placebo group decreased the number of blood transfusions by at least 50% (p = 0.22). Hemoglobin levels significantly improved at six months in the bevacizumab versus placebo group (p = 0.02). The pharmacokinetics study revealed that patients with high exposure to bevacizumab had a significant decrease in red blood cell transfusions (p = 0.03). Fifty-nine adverse events were observed, 34 in the placebo arm versus 25 in the bevacizumab arm. CONCLUSION Though the present trial was underpowered, patients with HHT receiving bevacizumab required numerically fewer red blood cell transfusions than those receiving placebo, particularly those with high exposure. This article is protected by copyright. All rights reserved.
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2.
Effectiveness of Pharmacokinetic-Guided Hydroxyurea Dose Individualization in Patients with Sickle Cell Anemia: A Mini-Review
Dos Santos Neres, J. S., Yahouédéhou, Scma, Goncalves, M. S.
Pharmaceuticals (Basel, Switzerland). 2023;16(6)
Abstract
Inconsistent therapeutic responses have been observed among patients with sickle cell anemia (SCA) undergoing hydroxyurea (HU) following the adoption of the standardized protocol. Moreover, this treatment regimen necessitates a prolonged period to reach the maximum tolerated dose in which beneficial therapeutic effects are observed in most SCA patients. To overcome this limitation, several studies have performed HU dose adjustments in SCA patients based on individualized pharmacokinetic profiles. The present systematic mini-review aims to select and analyze published data to present an overview of HU pharmacokinetics studies performed in SCA patients, as well as evaluate the effectiveness of the dose adjustment strategy. A systematic search was performed in the Embase, Pubmed, Scopus, Web of Science, Scielo, Google Scholar, and the Virtual Library of Health databases from December 2020 to August 2022, with a total of five studies included. Inclusion criteria consisted of studies in which the dose adjustment was performed in SCA patients based on pharmacokinetic parameters. Quality analyzes were performed using QAT, while data synthesis was performed according to the Cochrane Manual of Systematic Reviews of Interventions. Analysis of the selected studies revealed improved HU treatment effectiveness using personalized dosages in SCA patients. Moreover, several laboratory parameters were utilized as biomarkers of the HU response, and methods designed to simplify the adoption of this practice were presented. Despite the scarcity of studies on this topic, HU-personalized treatment based on individualized pharmacokinetic profiles represents a viable alternative for SCA patients who are candidates for HU therapy, especially for pediatric patients. Registration number: PROSPERO CRD42022344512.
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3.
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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4.
Efficacy and safety of pharmacological interventions for managing sickle cell disease in children and adolescents: protocol for a systematic review with network meta-analysis
Tonin, F. S., Ginete, C., Fernandez-Llimos, F., Ferreira, J., Delgadinho, M., Brito, M.
BMJ open. 2023;13(2):e064872
Abstract
INTRODUCTION Sickle cell disease (SCD), an inherited haemoglobinopathy, has important impact on morbidity and mortality, especially in paediatrics. Previous systematic reviews are limited to adult patients or focused only on few therapies. We aim to synthesise the evidence on efficacy and safety of pharmacological interventions for managing SCD in children and adolescents. METHODS AND ANALYSIS This systematic review protocol is available at Open Science Framework (doi:10.17605/OSF.IO/CWAE9). We will follow international recommendations on conduction and report of systematic reviews and meta-analyses. Searches will be conducted in PubMed, Scopus and Web of Science (no language nor time restrictions) (first pilot searches performed in May 2022). We will include randomised controlled trials comparing the effects of disease-modifying agents in patients with SCD under 18 years old. Outcomes of interest will include: vaso-occlusive crisis, haemoglobin levels, chest syndrome, stroke, overall survival and adverse events. We will provide a narrative synthesis of the findings, and whenever possible, results will be pooled by means of pairwise or Bayesian network meta-analyses with surface under the cumulative ranking curve analyses. Different statistical methods and models will be tested. Dichotomous outcomes will be reported as OR, risk ratio or HR, while continuous data will be reported as standard mean differences, both with 95% CI/credibility interval. The methodological quality of the trials will be evaluated using the Risk of Bias 2.0 tool, and the certainty of the evidence will be assessed with the Grading of Recommendations Assessment, Development and Evaluation approach. ETHICS AND DISSEMINATION This study refers to a systematic review, so no ethics approval is necessary. We intent to publish our findings in international, peer-reviewed journal. Data will also be presented to peers in scientific events. Additionally, the results obtained in this study may contribute towards the update of therapeutic guidelines and for the development of health policies for SCD. PROSPERO REGISTRATION NUMBER CRD42022328471.
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5.
All-trans retinoic acid added to treatment of primary immune thrombocytopenia: a systematic review and meta-analysis
Yang J, Zhao L, Wang W, Wu Y
Annals of hematology. 2023
Abstract
All-trans retinoic acid (ATRA) application is a novel treatment approach for primary immune thrombocytopenia (ITP). This study aimed to evaluate the efficacy and safety of ATRA in the treatment of ITP. The databases of PubMed (MEDLINE), EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), and China National Knowledge Internet were searched on August 5, 2022, to find randomized controlled trials (RCTs) and observational studies. Five observational studies and four RCTs from China were included, and 760 Chinese patients were analyzed. In the five observational studies, the pooled overall response rate (ORR) and complete response rate (CRR) were 59.5% (95% confidence interval [CI], 52.4-66.4%) and 20.6% (95% CI, 14.3-27.6%), respectively. In the selected four RCTs, the pooled odds ratios for sustained response rate, ORR, and CRR were 3.00 (95% CI, 1.97-4.57; P < 0.01), 3.21 (95% CI, 2.15-4.78; P < 0.01), and 2.12 (95% CI, 1.17-3.86; P = 0.01), respectively. ATRA was associated with a reduction in relapse rate and salvage treatment rate (odds ratio, 0.30; 95% CI, 0.18-0.50; P < 0.01; 0.36; 95% CI, 0.23-0.56; P < 0.01, respectively). The pooled odds ratios for grade 1-2 dry skin, headache (or dizziness), and rash acneiform were 49.99 (95% CI, 16.05-155.67; P < 0.01), 1.75 (95% CI, 0.98-3.12; P = 0.06), and 0.37 (95% CI, 0.10-1.34; P = 0.13), respectively. This study suggests that ATRA may significantly improve the initial and long-term response of patients with ITP.
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6.
Efficacy of Hydroxyurea in Transfusion-Dependent Major β-Thalassemia Patients: A Meta-Analysis
Hatamleh, M. I., Chenna, V. S. H., Contractor, H., Krishna Mohan, G. V., Tirumandyam, G., Dammas, N., Khan, M. W., Hirani, S.
Cureus. 2023;15(4):e38135
Abstract
The present meta-analysis was conducted to determine the efficacy of hydroxyurea in patients with transfusion dependent major β-thalassemia. The present meta-analysis was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Meta-analyses of Observational Studies in Epidemiology (MOOSE) guidelines. A systematic search was carried out to evaluate the efficacy of hydroxyurea in patients with transfusion-dependent B-thalassaemia using electronic databases, including MEDLINE, Cochrane Central Register of Controlled Trials, and EMBASE. The keywords used to search for relevant studies included "hydroxyurea", "thalassemia", "transfusion-dependent", and "efficacy". Outcomes assessed in the present meta-analysis included transfusion in one year and intervals between transfusions (in days). Other outcomes assessed in the present meta-analysis were fetal hemoglobin (%), hemoglobin (%), and ferritin levels (ng/dl). Total of five studies were included in the analysis enrolling 294 patients with major B-thalassemia. The pooled analysis reported that the mean interval between transfusions was significantly higher in patients receiving hydroxyurea compared to those not receiving hydroxyurea (mean deviation {MD}: 10.07, 95% CI: 2.16, 17.99). Hemoglobin was significantly higher in patients receiving hydroxyurea compared to its counterparts (MD: 1.71, 95% CI: 0.84, 2.57). Patients receiving hydroxyurea had significantly lower ferritin levels compared to those not receiving hydroxyurea (MD: -299.65, 95% CI: -518.35, -80.96). These findings suggest that hydroxyurea may be a promising and cost-effective alternative to blood transfusions and iron chelation therapies for beta-thalassemia patients. However, the authors noted that further randomized controlled trials are needed to validate these findings and to determine the optimal dosages and treatment regimens for hydroxyurea in this patient population.
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7.
Efficacy and safety of fitusiran prophylaxis in people with haemophilia A or haemophilia B with inhibitors (ATLAS-INH): a multicentre, open-label, randomised phase 3 trial
Young G, Srivastava A, Kavakli K, Ross C, Sathar J, You CW, Tran H, Sun J, Wu R, Poloskey S, et al
Lancet (London, England). 2023
Abstract
BACKGROUND Fitusiran, a subcutaneous investigational small interfering RNA therapeutic, targets antithrombin to rebalance haemostasis in people with haemophilia A or haemophilia B, irrespective of inhibitor status. We evaluated the efficacy and safety of fitusiran prophylaxis in people with haemophilia A or haemophilia B with inhibitors. METHODS This multicentre, randomised, open-label phase 3 study was done at 26 sites (primarily secondary or tertiary centres) in 12 countries. Men, boys, and young adults aged 12 years or older with severe haemophilia A or haemophilia B with inhibitors previously treated with on-demand bypassing agents were randomly assigned (2:1) to receive once-a-month 80 mg subcutaneous fitusiran prophylaxis (fitusiran prophylaxis group) or to continue with bypassing agents on-demand (bypassing agents on-demand group) for 9 months. The primary endpoint was mean annualised bleeding rate during the efficacy period in the intention-to-treat population estimated by negative binomial model. Safety was assessed as a secondary endpoint in the safety population. This trial is complete and is registered with ClinicalTrials.gov, NCT03417102. FINDINGS Between Feb 14, 2018, and June 23, 2021, 85 participants were screened for inclusion, of whom 57 (67%; 57 [100%] men; median age 27·0 years [IQR 19·5-33·5]) were randomly assigned: 19 (33%) participants to the bypassing agent on-demand group and 38 (67%) participants to the fitusiran prophylaxis. Negative binomial model-based mean annualised bleeding rate was significantly lower in the fitusiran prophylaxis group (1·7 [95% CI 1·0-2·7]) than in the bypassing agents on-demand group (18·1 [10·6-30·8]), corresponding to a 90·8% (95% CI 80·8-95·6) reduction in annualised bleeding rate in favour of fitusiran prophylaxis (p<0·0001). 25 (66%) participants had zero treated bleeds in the fitusiran prophylaxis group versus one (5%) in the bypassing agents on-demand group. The most frequent treatment-emergent adverse event in the fitusiran prophylaxis group was increased alanine aminotransferase in 13 (32%) of 41 participants in the safety population; there were no increased alanine aminotransferase treatment-emergent adverse events in the bypassing agents on-demand group. Suspected or confirmed thromboembolic events were reported in two (5%) participants in the fitusiran prophylaxis group. No deaths were reported. INTERPRETATION Subcutaneous fitusiran prophylaxis resulted in statistically significant reductions in annualised bleeding rate in participants with haemophilia A or haemophilia B with inhibitors, with two-thirds of participants having zero bleeds. Fitusiran prophylaxis might show haemostatic efficacy in participants with haemophilia A or haemophilia B with inhibitors; therefore, the therapeutic might have the potential to improve the management of people with haemophilia. FUNDING Sanofi.
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8.
Targeting an elevated FVIII level using personalized rurioctocog alfa pegol prophylaxis in specific patient populations with hemophilia A: post hoc subanalysis of the randomized, phase 3 PROPEL study
Escuriola-Ettingshausen, C., Klamroth, R., Escobar, M., Stasyshyn, O., Tangada, S., Engl, W., Honauer, I., Lee, H. Y., Chowdary, P., Windyga, J.
Therapeutic advances in hematology. 2023;14:20406207231178596
Abstract
BACKGROUND The phase 3, prospective PROPEL study demonstrated that pharmacokinetic (PK)-guided prophylaxis targeting elevated factor VIII (FVIII) troughs in patients with hemophilia A resulted in lower annualized bleeding rates (ABRs) and a higher proportion of patients experiencing zero bleeds in the second 6 months of treatment when targeting a FVIII trough of 8-12% versus 1-3%. OBJECTIVE To investigate the benefit of PK-guided prophylaxis with rurioctocog alfa pegol targeting two FVIII trough levels in specific patient subgroups in a post hoc analysis using data from PROPEL. DESIGN This is a post hoc analysis of data from the PROPEL study. The design and primary outcomes of the prospective, randomized PROPEL study (NCT02585960) have been reported previously. METHODS This post hoc analysis reports data stratified by FVIII half-life (t(1/2)), hemophilic arthropathy status, number of target joints at screening, previous treatment regimen, and ABR range in the 12 months before study entry. RESULTS Targeting an elevated FVIII trough of 8-12% was associated with higher average FVIII levels over time, regardless of FVIII t(1/2) at baseline. The decrease in total ABR between the 8-12% and 1-3% arms was greatest in patients with a FVIII t(1/2) of 6 to <12 h (0.7 versus 3.5); a higher number of target joints, that is, at least four target joints, at baseline (0.2 versus 1.6); the presence of arthropathy (0.1 versus 1.7); and those previously treated on-demand (0.3 versus 1.8). CONCLUSION These results support the feasibility of targeting elevated FVIII levels using personalized rurioctocog alfa pegol prophylaxis. These benefits may be especially important in patients with a short FVIII t(1/2) and those receiving standard prophylaxis with frequent breakthrough bleeds, arthropathy, and target joints. REGISTRATION ClinicalTrials.gov Identifier: NCT02585960; https://clinicaltrials.gov/ct2/show/NCT02585960.
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9.
Hydroxyurea for Secondary Stroke Prevention in Children with Sickle Cell Anemia in Nigeria:a Randomized Controlled Trial
Abdullahi S, Sunusi SM, Abba MS, Sani S, Inuwa HA, Gambo S, Gambo A, Musa BS, Covert Greene BV, Kassim A, et al
Blood. 2022
Abstract
We tested the hypothesis that fixed oral moderate-dose hydroxyurea (20 mg/kg/day) for initial treatment of secondary stroke prevention results in an 80% relative risk reduction of stroke or death when compared to fixed oral low-dose hydroxyurea (10 mg/kg/day) in a phase III, double-blind, parallel-group, randomized controlled trial in children with sickle cell anemia (SCA) living in Nigeria. The median participant follow-up was 1.6 years (interquartile range 1.0-2.3) with a planned minimum follow-up of 3.0 years. A total of 6 recurrent strokes and 2 deaths versus 5 recurrent strokes and 3 deaths occurred in the low- and moderate-dose groups, respectively. The incidence rate ratio (IRR) of the primary outcome measure of stroke or death in the low- and moderate-dose hydroxyurea treatment groups was 0.98 (95% CI 0.32 - 3.00), P=0.97. The trial was stopped early due to no clinical difference in the incidence rates of the primary outcome measure. The incidence rates of recurrent strokes were 7.1 and 6.0 per 100 person-years in the low- and moderate-dose groups, respectively, IRR= 1.18 (95% CI: 0.30-4.88); P=0.74. As a measure of adherence to the oral hydroxyurea therapy, the median percent of returned pills were 3.0% and 2.6% in the low- and moderate-dose groups, respectively. No participant had hydroxyurea therapy stopped for myelosuppression. For children with SCA in low-income settings, without access to regular blood transfusion therapy, initial low-dose hydroxyurea is a minimum known efficacious dose for secondary stroke prevention. The ID number assigned to the study is NCT02675790.
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10.
Hydroxyurea for primary stroke prevention in children with sickle cell anaemia in Nigeria (SPRING): a double-blind, multicentre, randomised, phase 3 trial
Abdullahi, S. U., Jibir, B. W., Bello-Manga, H., Gambo, S., Inuwa, H., Tijjani, A. G., Idris, N., Galadanci, A., Hikima, M. S., Galadanci, N., et al
The Lancet. Haematology. 2022;9(1):e26-e37
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Abstract
BACKGROUND In high-income countries, standard care for primary stroke prevention in children with sickle cell anaemia and abnormal transcranial Doppler velocities results in a 92% relative risk reduction of strokes but mandates initial monthly blood transfusion. In Africa, where regular blood transfusion is not feasible for most children, we tested the hypothesis that initial moderate-dose compared with low-dose hydroxyurea decreases the incidence of strokes for children with abnormal transcranial Doppler velocities. METHODS SPRING is a double-blind, parallel-group, randomised, controlled, phase 3 trial of children aged 5-12 years with sickle cell anaemia with abnormal transcranial Doppler velocities conducted at three teaching hospitals in Nigeria. For randomisation, we used a permuted block allocation scheme with block sizes of four, stratified by sex and site. Allocation was concealed from all but the pharmacists and statisticians. Participants were assigned in a 1:1 ratio to low-dose (10 mg/kg per day) or moderate-dose (20 mg/kg per day) oral hydroxyurea taken once daily with monthly clinical evaluation and laboratory monitoring. The primary outcome was initial stroke or transient ischaemic attack, centrally adjudicated. The secondary outcome was all-cause hospitalisation. We used the intention-to-treat population for data analysis. The trial was stopped early for futility after a planned minimum follow-up of 3·0 years to follow-up for participants. This trial was registered with ClinicalTrials.gov, number NCT02560935. FINDINGS Between Aug 2, 2016, and June 14, 2018, 220 participants (median age 7·2 years [IQR 5·5-8·9]; 114 [52%] female) were randomly allocated and followed for a median of 2·4 years (IQR 2·0-2·8). All participants were Nigerian and were from the following ethnic groups: 179 (82%) people were Hausa, 25 (11%) were Fulani, and 16 (7%) identified as another ethnicity. In the low-dose hydroxyurea group, three (3%) of 109 participants had strokes, with an incidence rate of 1·19 per 100 person-years and in the moderate-dose hydroxyurea group five (5%) of 111 had strokes with an incidence rate of 1·92 per 100 person-years (incidence rate ratio 0·62 [95% CI 0·10-3·20], p=0·77). The incidence rate ratio of hospitalisation for any reason was 1·71 (95% CI 1·15-2·57, p=0·0071), with higher incidence rates per 100 person-years in the low-dose group versus the moderate-dose group (27·43 vs 16·08). No participant had hydroxyurea treatment stopped for myelosuppression. INTERPRETATION Compared with low-dose hydroxyurea therapy, participants treated with moderate-dose hydroxyurea had no difference in the stroke incidence rate. However, secondary analyses suggest that the moderate-dose group could lower incidence rates for all-cause hospitalisations. These findings provide an evidence-based guideline for the use of low-dose hydroxyurea therapy for children with sickle cell anaemia at risk of stroke. FUNDING National Institute of Neurological Disorders and Stroke.
