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1.
Efficacy and safety of deferoxamine, deferasirox and deferiprone triple iron chelator combination therapy for transfusion-dependent β-thalassaemia with very high iron overload: a protocol for randomised controlled clinical trial
Premawardhena, A., Perera, C., Wijethilaka, M. N., Wanasinghe, S. K., Rajakaruna, Rhmg, Samarasinghe, Rankk, Williams, S., Mettananda, S.
BMJ open. 2024;14(2):e077342
Abstract
INTRODUCTION Despite the improvement in medical management, many patients with transfusion-dependent β-thalassaemia die prematurely due to transfusion-related iron overload. As per the current guidelines, the optimal chelation of iron cannot be achieved in many patients, even with two iron chelators at their maximum therapeutic doses. Here, we evaluate the efficacy and safety of triple combination treatment with deferoxamine, deferasirox and deferiprone over dual combination of deferoxamine and deferasirox on iron chelation in patients with transfusion-dependent β-thalassaemia with very high iron overload. METHODS AND ANALYSIS This is a single-centre, open-label, randomised, controlled clinical trial conducted at the Adult and Adolescent Thalassaemia Centre of Colombo North Teaching Hospital, Ragama, Sri Lanka. Patients with haematologically and genetically confirmed transfusion-dependent β-thalassaemia are enrolled and randomised into intervention or control groups. The intervention arm will receive a combination of oral deferasirox, oral deferiprone and subcutaneous deferoxamine for 6 months. The control arm will receive the combination of oral deferasirox and subcutaneous deferoxamine for 6 months. Reduction in iron overload, as measured by a reduction in the serum ferritin after completion of the treatment, will be the primary outcome measure. Reduction in liver and cardiac iron content as measured by T2* MRI and the side effect profile of trial medications are the secondary outcome measures. ETHICS AND DISSEMINATION Ethical approval for the study has been obtained from the Ethics Committee of the Faculty of Medicine, University of Kelaniya (Ref. P/06/02/2023). The trial results will be disseminated in scientific publications in reputed journals. TRIAL REGISTRATION NUMBER The trial is registered in the Sri Lanka Clinical Trials Registry (Ref: SLCTR/2023/010).
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2.
Compliance and clinical benefit of deferasirox granule and dispersible tablet formulation in pediatric patients with transfusional iron overload: in a randomized, open-label, multicenter, phase II study
Taher, A. T., Wali, Y., Cruz, M. C., Charoenkwan, P., Aydinok, Y., Werner, O., Govindaraju, S., Romen, F., Viprakasit, V.
Haematologica. 2023
Abstract
CALYPSO (NCT02435212), a randomized, open-label, multicenter, phase 2 study evaluated the compliance, clinical benefits, and safety of deferasirox granules and dispersible tablets in pediatric patients with iron overload. Iron chelation therapy-naive and iron chelation therapy-pre-treated patients aged 2 to 0.5 mg/mg; 24.5% and 34.2%), upper respiratory tract infection (28.2% and 29.7%), and pyrexia (26.4% and 23.4%). In iron chelation therapy-naive patients, mean compliance and change from baseline in serum ferritin with both deferasirox formulations were not significantly different. The safety profile was comparable between granule and dispersible tablets formulations, and was consistent with the general safety profile of deferasirox.
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3.
The incidence of transfusion-related acute lung injury using active surveillance: A systematic review and meta-analysis
White, S. K., Walker, B. S., Schmidt, R. L., Metcalf, R. A.
Transfusion. 2023
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Editor's Choice
Abstract
BACKGROUND Transfusion-related acute lung injury (TRALI) is a leading cause of transfusion-related mortality. A concern with passive surveillance to detect transfusion reactions is underreporting. Our aim was to obtain evidence-based estimates of TRALI incidence using meta-analysis of active surveillance studies and to compare these estimates with passive surveillance. STUDY DESIGN AND METHODS We performed a systematic review and meta-analysis of studies reporting TRALI rates. A search of Medline and Embase by a research librarian identified studies published between January 1, 1991 and January 20, 2023. Prospective and retrospective observational studies reporting TRALI by blood component (red blood cells [RBCs], platelets, or plasma) were identified and all inpatient and outpatient settings were eligible. Adult and pediatric, as well as general and specific clinical populations, were included. Platelets and plasma must have used at least one modern TRALI donor risk mitigation strategy. A random effects model estimated TRALI incidence by blood component for active and passive surveillance studies and heterogeneity was examined using meta-regression. RESULTS Eighty studies were included with approximately 176-million blood components transfused. RBCs had the highest number of studies (n = 66) included, followed by platelets (n = 35) and plasma (n = 34). Pooled TRALI estimates for active surveillance studies were 0.17/10,000 (95% confidence intervals [CI]: 0.03-0.43; I(2) = 79%) for RBCs, 0.31/10,000 (95% CI: 0.22-0.42; I(2) = <1%) for platelets, and 3.19/10,000 (95% CI: 0.09-10.66; I(2) = 86%) for plasma. Studies using passive surveillance ranged from 0.02 to 0.10/10,000 among the various blood components. DISCUSSION In summary, these estimates may improve a quantitative understanding of TRALI risk, which is important for clinical decision-making weighing the risks and benefits of transfusion.
PICO Summary
Population
Adult and paediatric patients, as well as general and specific clinical populations (80 studies).
Intervention
Systematic review and meta-analysis to estimate the incidence of transfusion-related acute lung injury (TRALI) by blood component, using active surveillance and modern donor risk mitigation strategies implemented for plasma and platelets.
Comparison
Outcome
The included studies reported approximately 176-million blood components transfused. Red blood cells (RBCs) had the highest number of studies (n= 66) included, followed by platelets (n= 35) and plasma (n= 34). Pooled TRALI estimates for active surveillance studies were 0.17/10,000; 95% confidence intervals (CI) [0.03, 0.43]; I(2)= 79%) for RBCs, 0.31/10,000; 95% CI [0.22, 0.42]; I(2)= <1%) for platelets, and 3.19/10,000; 95% CI [0.09, 10.66]; I(2)= 86% for plasma. Studies using passive surveillance ranged from 0.02 to 0.10/10,000 among the various blood components.
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4.
Association between red blood cell transfusion and bronchopulmonary dysplasia: a systematic review and meta-analysis
Tang, L., Zhu, T. T., Zhao, J.
Frontiers in pediatrics. 2023;11:1095889
Abstract
BACKGROUND We aimed to determine the association between red blood cell transfusions (RBCT) and bronchopulmonary dysplasia (BPD) in neonates. METHODS A systematic review and meta-analysis were conducted using data obtained from literature search of PubMed, Embase, and Web of Science from their inception till May 1, 2022. Two reviewers independently selected potentially relevant studies, and after data extraction, they assessed the methodological quality of the included studies using the Newcastle-Ottawa scale. Data were pooled using random-effects models in Review Manager 5.3. Subgroup-analysis was performed based on the number of transfusions and adjusted results. RESULTS Of the 1,011 identified records, 21 total case-control, cross-sectional, and cohort studies were selected, which included a total of 6,567 healthy controls and 1,476 patients with BPD. The pooled unadjusted odds ratio ([OR], 4.01; 95% confidence interval [CI] 2.31-6.97) and adjusted OR (5.11; 95% CI 3.11-8.4) showed significant association between RBCT and BPD. A substantial heterogeneity was noted, which could be due to different variables controlled for in each study. The subgroup analysis showed that heterogeneity may be partially explained by the extent of transfusion. CONCLUSION The association between BPD and RBCT remains unclear based on the current data due to the substantial heterogeneity among the results. Well-designed studies are still needed in the future.
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Efficacy and safety of early-start deferiprone in infants and young children with transfusion-dependent beta thalassemia: Evidence for iron shuttling to transferrin in a randomized, double-blind, placebo-controlled, clinical trial (START)
Elalfy, M. S., Hamdy, M., Adly, A., Ebeid, F. S. E., Temin, N. T., Rozova, A., Lee, D., Fradette, C., Tricta, F.
American journal of hematology. 2023
Abstract
Children with transfusion-dependent thalassemia (TDT) require regular blood transfusions that, without iron-chelation therapy, lead to iron-overload toxicities. Current practice delays chelation therapy (late-start) until reaching iron overload (serum ferritin ≥1000 μg/L) to minimize risks of iron-depletion. Deferiprone's distinct pharmacological properties, including iron-shuttling to transferrin, may reduce risks of iron depletion during mild-to-moderate iron loads and iron overload/toxicity in children with TDT. The early-start deferiprone (START) study evaluated the efficacy/safety of early-start deferiprone in infants/young children with TDT. Sixty-four infants/children recently diagnosed with beta-thalassemia and serum ferritin (SF) between 200 and 600 μg/L were randomly assigned 1:1 to receive deferiprone or placebo for 12 months or until reaching SF-threshold (≥1000 μg/L at two consecutive visits). Deferiprone was initiated at 25 mg/kg/day and increased to 50 mg/kg/day; some recipients' dosages increased to 75 mg/kg/day based on iron levels. The primary endpoint was the proportion of patients ≥SF-threshold by month 12. Monthly transferrin saturation (TSAT) assessment evaluated iron-shuttling. At baseline, there was no significant difference in mean age (deferiprone: 3.03 years, placebo: 2.63 years), SF (deferiprone: 513.8 μg/L, placebo: 451.7 μg/L), or TSAT (deferiprone: 47.98%, placebo: 43.43%) between groups. At month 12, there was no significant difference in growth or adverse event (AE) rates between groups. No deferiprone-treated patients were iron-depleted. At month 12, 66% of patients receiving deferiprone remained below SF threshold versus 39% of placebo (p = .045). Deferiprone-treated patients showed higher TSAT levels and reached ≥60% TSAT threshold faster. Early-start deferiprone was well-tolerated, not associated with iron depletion, and efficacious in reducing iron overload in infants/children with TDT. TSAT results provide the first clinical evidence of deferiprone shuttling iron to transferrin.
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6.
Deferiprone versus deferoxamine for transfusional iron overload in sickle cell disease and other anemias: Pediatric subgroup analysis of the randomized, open-label FIRST study
Hamdy, M., El-Beshlawy, A., Veríssimo, M. P. A., Kanter, J., Inusa, B., Williams, S., Lee, D., Temin, N. T., Fradette, C., Tricta, F., et al
Pediatric blood & cancer. 2023;:e30711
Abstract
BACKGROUND Children with sickle cell disease (SCD) who are chronically transfused often, require iron chelation therapy. There are limited data that allow for comparison of the efficacy and safety of the iron chelator deferiprone versus deferoxamine in children with SCD. METHODS This post hoc analysis of the phase 3b/4, randomized, open-label FIRST (Ferriprox in Patients with IRon Overload in Sickle Cell Disease Trial) study (NCT02041299) included patients 17 years and younger with SCD or other anemias receiving deferiprone or deferoxamine. RESULTS Overall, 142 patients were evaluated; mean ages were 10.5 and 11.7 years in the deferiprone and deferoxamine groups, respectively. At 12 months: mean change from baseline in liver iron concentration was -3.3 mg/g dry weight (dw) with deferiprone and -3.4 mg/g dw with deferoxamine (p = .8216); relative mean change (coefficient of variation %) in log cardiac T2* magnetic resonance imaging was 1.02 (21.8%) with deferiprone and 0.95 (19.5%) with deferoxamine (p = .0717); and the mean (standard error) change in serum ferritin levels was -133.0 (200.3) μg/L with deferiprone and -467.1 (244.1) μg/L with deferoxamine (p = .2924). The most common deferiprone-related adverse events (AEs) were upper abdominal pain (20.2%), vomiting (13.8%), pyrexia (9.6%), decreased neutrophil count (9.6%), increased alanine aminotransferase (ALT; 9.6%), and increased aspartate aminotransferase (AST; 9.6%). All cases of increased ALT, increased AST, and neutropenia resolved, most without intervention. CONCLUSIONS This post hoc analysis of pediatric patients from FIRST corroborated previous findings in adults that deferiprone is comparable to deferoxamine in reducing iron overload. No new safety concerns were observed. Deferiprone is an oral chelation option that could improve adherence and outcomes in children.
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No difference in myocardial iron concentration and serum ferritin with deferasirox and deferiprone in pediatric patients with hemoglobinopathies: A systematic review and meta-analysis
Saleem A, Waqar E, Shuja SH, Naeem U, Moeed A, Rais H, Ahmed J
Transfusion clinique et biologique : journal de la Societe francaise de transfusion sanguine. 2022
Abstract
OBJECTIVES Iron overload is a common complication experienced by transfusion-dependent children with hemoglobin disorders. Chelators such as deferasirox (DFX) and deferiprone (DFP) are effective in overcoming this problem. We conducted this systematic review and meta-analysis to evaluate the effectiveness of DFX compared to DFP in treating iron overload amongst pediatric patients with hemoglobin disorders. MATERIAL AND METHODS PubMed and Cochrane Central were searched from their inception until Dec 21 2021, for randomized clinical trials (RCTs) and observational studies, which assessed the efficacy of DFX compared to DFP in the treatment of inherited hemoglobin disorders. The outcomes of interest included myocardial iron concentration (MRI T2*) at the end of the trial and change in mean serum ferritin (SF) levels at the 6 and 12 months mark. Weighted mean differences (WMDs) with their corresponding 95% confidence intervals (CIs) were calculated for continuous outcomes using random effects model. RESULTS A total of 5 studies comprising 607 children were included. The results of our analysis revealed no significant difference between DFX and DFP in MRI T2* at the end of treatment (WMD: -0.92;95% CI[-3.35,1.52]; p=0.46; I(2)=0). Moreover, there has been no significant difference noted in SF levels at both 6 months (WMD: 97.31; 95% CI[-236.16,430.77]; p=0.57; I(2)=0) and 12 months (WMD: 46.99; 95% CI[-191.42,285.40]; p=0.70; I(2)=0) respectively. CONCLUSION Our analysis shows no significant difference between the efficacy of DFX and DFP in the management of iron overload in children with inherited blood disorders. Future large-scale clinical trials are required to further validate our results.
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A systematic review of adherence to iron chelation therapy among children and adolescents with thalassemia
Reddy PS, Locke M, Badawy SM
Annals of medicine. 2022;54(1):326-342
Abstract
INTRODUCTION Iron chelation therapy (ICT) is essential to prevent complications of iron overload in patients with transfusion-dependent thalassaemia. However, there is currently no standard for how to best measure adherence to ICT, nor what level of adherence necessitates concern for poor outcomes, especially in paediatric patients. The objectives of this review are to identify rates of adherence to ICT, predictors of adherence, methods of measurement, and adherence-related health outcomes in children and adolescents. METHODS This review covers the literature published between 1980 and 2020 on ICT in thalassaemia that assessed adherence or compliance. Included studies reflect original research. The preferred reporting items of systematic reviews and meta-analyses (PRISMA) guidelines were followed for reporting results, and the findings were critically appraised with the Oxford Centre for Evidence-based Medicine criteria. RESULTS Of the 543 articles, 37 met the inclusion criteria. The most common methods of assessing adherence included patient self-report (n = 15/36, 41.7%), and pill count (n = 15/36, 41.7%), followed by subcutaneous medication monitoring (5/36, 13.8%) and prescription refills (n = 4/36, 11.1%). Study sizes ranged from 7 to 1115 participants. Studies reported adherence either in "categories" with different levels of adherence (n = 29) or "quantitatively" as a percentage of medication taken out of those prescribed (n = 7). Quantitatively, the percentage of adherence varied from 57% to 98.4% with a median of 89.5%. Five studies focussed on interventions, four of which were designed to improve adherence. Studies varied in sample size and methods of assessment, which prohibited performing a meta-analysis. CONCLUSIONS Due to a lack of clinical consensus on how adherence is defined, it is difficult to compare adherence to ICT in different studies. Future studies should be aimed at creating guidelines for assessing adherence and identifying suboptimal adherence. These future efforts will be crucial in informing evidence-based interventions to improve adherence and health outcomes in thalassaemia patients.Key messagesPredictive factors associated with ICT adherence in the paediatric population include age, social perception of ICT, social support, and side effects/discomfort.Increased adherence in the paediatric population is associated with decreased serum ferritin and improved cardiac, hepatic, and endocrine outcomes.Inadequate adherence to ICT is associated with increased lifetime health costs.There are few studies that focussed on interventions to increase adherence in the paediatric population, and the studies that do exist all focussed on different types of interventions; successful interventions focussed on consistent, long-term engagement with patients.
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Hyperkalaemia Following Blood Transfusion-a Systematic Review Assessing Evidence and Risks
Wolf J, Geneen LJ, Meli A, Doree C, Cardigan R, New HV
Transfusion medicine reviews. 2022
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Full text
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Editor's Choice
Abstract
Hyperkalaemia following transfusion is widely reported in the literature. Our objective was to critically review recent evidence on hyperkalaemia in association with transfusion and to assess whether specific aspects of transfusion practice can affect the likelihood of developing hyperkalaemia. We searched 9 electronic databases (including MEDLINE, Embase, and Transfusion Evidence Library) using a predefined search strategy, from 2010 to April 8, 2021. Three reviewers performed dual screening, extraction, and risk of bias assessment. We used Cochrane risk of bias (ROB) 2 for assessment of RCTs, ROBINS-I for non-RCTs, and GRADE to assess the certainty of the evidence. We report 7 comparisons of interest in n = 3729 patients from 28 studies (11 RCTs, 4 prospective cohort studies, and 13 retrospective cohort studies): (1) age of blood, (2) washing, (3) filtration, (4) irradiation, (5) fluid type, (6) transfusion vs no transfusion, (7) blood volume/rate. Of the 28 studies included, 25 reported outcomes of potassium (K+) concentration, 17 the number developing hyperkalaemia, 13 mortality, 10 cardiac arrest, and 10 cardiac arrhythmia. Only 16 studies provided analysable data suitable for quantitative analysis. Evidence addressing our outcomes was of very low certainty (downgraded for incomplete outcome data, baseline imbalance, imprecision around the estimate, and small sample size). While 5 studies showed a difference in K+ concentration up to 6 hours posttransfusion for 3 comparisons (age of blood, washing, and transfusion volume/rate), and 3 studies showed a difference in the diagnosis of hyperkalaemia for 2 comparisons (age of blood, and transfusion volume/rate), the evidence was inconsistent across all included studies. There was no difference in any reported outcomes for 4 comparisons (filtration, irradiation, fluid type, or transfusion vs no transfusion). Overall, the reported evidence was too weak to support identification of groups most at risk of hyperkalaemia or to support recommendations on use of short-storage RBC. For other commonly used risk mitigations for hyperkalaemia in transfusion medicine, the (low certainty) evidence was either conflicting or not supportive.
PICO Summary
Population
Neonates, children, and adults receiving red blood cell transfusions (28 studies, n= 3,729).
Intervention
To systematically review hyperkalaemia in association with transfusion and to assess whether specific aspects of transfusion practice can affect the likelihood of developing hyperkalaemia.
Comparison
Outcome
25 studies reported outcomes of potassium (K+) concentration, 17 the number developing hyperkalaemia, 13 mortality, 10 cardiac arrest, and 10 cardiac arrhythmia. While 5 studies showed a difference in K+ concentration up to 6 hours post-transfusion for age of blood, washing, and transfusion volume/rate, and 3 studies showed a difference in the diagnosis of hyperkalaemia for age of blood, and transfusion volume/rate, the evidence was inconsistent across all included studies. There was no difference in any reported outcomes for filtration, irradiation, fluid type, or transfusion vs. no transfusion. Overall, the reported evidence was too weak to support identification of groups most at risk of hyperkalaemia or to support recommendations on use of short-storage red blood cells.
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Comparison of transfusion reactions in children and adults: A systematic review and meta-analysis
Wang Y, Sun W, Wang X, Ren X, Gao A, Li M, Wang X
Pediatric blood & cancer. 2022;:e29842
Abstract
BACKGROUND There are no international standards or normalizations for diagnosing and treating complications from blood transfusions. We comprehensively compared the incidence of adverse blood transfusions in children and adults. METHODS Available literature on blood transfusion adverse reactions in children and adults prior to November 27, 2021 was collected from several electronic databases. This meta-analysis was performed using Revman 5.2 and Stata 15.1. RESULTS The incidence of transfusion reactions is higher in children than in adults. Children transfused with red blood cells and platelets exhibited a higher incidence of transfusion reaction than that of adults. Moreover, the incidence of allergic and febrile non-hemolytic transfusion reactions was significantly higher in children than in adults. The incidence of some rare transfusion reactions was also significantly higher in children than in adults. CONCLUSION The incidence of transfusion reactions in children and adults is varied. Guidelines for children are necessary.