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Amustaline-glutathione pathogen-reduced red blood cell concentrates for transfusion-dependent thalassaemia.

ABSTRACT: Transfusion-dependent thalassaemia (TDT) requires red blood cell concentrates (RBCC) to prevent complications of anaemia, but carries risk of infection. Pathogen reduction of RBCC offers potential to reduce infectious risk. We evaluated the efficacy and safety of pathogen-reduced (PR) Amustaline-Glutathione (A-GSH) RBCC for TDT. Patients were randomized to a blinded 2-period crossover treatment sequence for six transfusions over 8-10 months with Control and A-GSH-RBCC. The efficacy outcome utilized non-inferiority analysis with 90% power to detect a 15% difference in transfused haemoglobin (Hb), and the safety outcome was the incidence of antibodies to A-GSH-PR-RBCC. By intent to treat (80 patients), 12·5 ± 1·9 RBCC were transfused in each period. Storage durations of A-GSH and C-RBCC were similar (8·9 days). Mean A-GSH-RBCC transfused Hb (g/kg/day) was not inferior to Control (0·113 ± 0·04 vs. 0·111 ± 0·04, P = 0·373, paired t-test). The upper bound of the one-sided 95% confidence interval for the treatment difference from the mixed effects model was 0·005 g/kg/day, within a non-inferiority margin of 0·017 g/kg/day. A-GSH-RBCC mean pre-transfusion Hb levels declined by 6·0 g/l. No antibodies to A-GSH-RBCC were detected, and there were no differences in adverse events. A-GSH-RBCCs offer potential to reduce infectious risk in TDT with a tolerable safety profile.

SUBMITTER: Aydinok Y

PROVIDER: S-EPMC6771954 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Amustaline-glutathione pathogen-reduced red blood cell concentrates for transfusion-dependent thalassaemia.

Aydinok Yesim Y Piga Antonio A Origa Raffaella R Mufti Nina N Erickson Anna A North Anne A Waldhaus Katie K Ernst Christine C Lin Jin-Sying JS Huang Norman N Benjamin Richard J RJ Corash Laurence L

British journal of haematology 20190530 4

Transfusion-dependent thalassaemia (TDT) requires red blood cell concentrates (RBCC) to prevent complications of anaemia, but carries risk of infection. Pathogen reduction of RBCC offers potential to reduce infectious risk. We evaluated the efficacy and safety of pathogen-reduced (PR) Amustaline-Glutathione (A-GSH) RBCC for TDT. Patients were randomized to a blinded 2-period crossover treatment sequence for six transfusions over 8-10 months with Control and A-GSH-RBCC. The efficacy outcome utili ...[more]

PMID: 31148155

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Project description:BackgroundRed blood cell (RBC) transfusion is a critical supportive therapy in cardiovascular surgery (CVS). Donor selection and testing have reduced the risk of transfusion-transmitted infections; however, risks remain from bacteria, emerging viruses, pathogens for which testing is not performed and from residual donor leukocytes. Amustaline (S-303)/glutathione (GSH) treatment pathogen reduction technology is designed to inactivate a broad spectrum of infectious agents and leukocytes in RBC concentrates. The ReCePI study is a Phase 3 clinical trial designed to evaluate the efficacy and safety of pathogen-reduced RBCs transfused for acute anemia in CVS compared to conventional RBCs, and to assess the clinical significance of treatment-emergent RBC antibodies.MethodsReCePI is a prospective, multicenter, randomized, double-blinded, active-controlled, parallel-design, non-inferiority study. Eligible subjects will be randomized up to 7 days before surgery to receive either leukoreduced Test (pathogen reduced) or Control (conventional) RBCs from surgery up to day 7 post-surgery. The primary efficacy endpoint is the proportion of patients transfused with at least one study transfusion with an acute kidney injury (AKI) diagnosis defined as any increased serum creatinine (sCr) level ≥ 0.3 mg/dL (or 26.5 µmol/L) from pre-surgery baseline within 48 ± 4 h of the end of surgery. The primary safety endpoints are the proportion of patients with any treatment-emergent adverse events (TEAEs) related to study RBC transfusion through 28 days, and the proportion of patients with treatment-emergent antibodies with confirmed specificity to pathogen-reduced RBCs through 75 days after the last study transfusion. With ≥ 292 evaluable, transfused patients (> 146 per arm), the study has 80% power to demonstrate non-inferiority, defined as a Test group AKI incidence increase of no more than 50% of the Control group rate, assuming a Control incidence of 30%.DiscussionRBCs are transfused to prevent tissue hypoxia caused by surgery-induced bleeding and anemia. AKI is a sensitive indicator of renal hypoxia and a novel endpoint for assessing RBC efficacy. The ReCePI study is intended to demonstrate the non-inferiority of pathogen-reduced RBCs to conventional RBCs in the support of renal tissue oxygenation due to acute anemia and to characterize the incidence of treatment-related antibodies to RBCs.

Project description:BackgroundHydroxyurea (hydroxycarbamide) promotes the production of foetal haemoglobin (HbF) by reactivating gamma-genes. Evidence has shown clinical benefits of hydroxyurea in people with sickle cell anemia; however, only a few studies have assessed this treatment in people with beta (β)-thalassaemia.ObjectivesThe primary objective is to review the efficacy of hydroxyurea in reducing or ameliorating the requirement of blood transfusions in people with transfusion-dependent β-thalassaemia. The second objective is to review the safety of hydroxyurea with regards to severe adverse effects in this population.Search methodsWe searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register, compiled from electronic database searches and hand searching of journals and conference abstract books. We also searched electronic databases and trial registries, including ClinicalTrials.gov, the WHO ICTRP and PubMed (09 October 2018).Date of last search of the Group's haemoglobinopathies trials register: 04 March 2019.Selection criteriaRandomised controlled trials of hydroxyurea in people with transfusion-dependent β-thalassaemia, compared with placebo or standard treatment or comparing different doses of hydroxyurea.Data collection and analysisTwo authors independently assessed trials for inclusion in the review, which was verified by a third author.Main resultsNo trials were eligible for inclusion in this review.Authors' conclusionsCurrently, there is no high-quality evidence to support or challenge the continued use of hydroxyurea for managing people with transfusion-dependent β-thalassaemia. Multicentre, randomised controlled trials (compared to placebo or other available treatment, i.e. blood transfusion and iron chelation) are needed in order to assess the efficacy and safety of hydroxyurea for reducing the need for blood transfusion, for maintaining or improving mean haemoglobin levels, as well as for determining its cost-effectiveness.

Project description:IntroductionAround 5% of the world's population is expected to have some degree and type of thalassaemia. Beta thalassaemia (BT) occurs due to a deficient production of the beta-globin chain of haemoglobin. Extramedullary haematopoiesis (EMH) is one of the complications of BT, mainly observed in minor/intermedia subtypes. EMH is the production of blood cells outside the marrow as a compensatory response to longstanding hypoxia. Due to chronic transfusions, it is not expected in patients with beta-thalassaemia major (BTM). However, there are increasingly reported cases of EMH in BTM. The incidence of EMH in BTM is thought to be <1%. We aim to pool the available data and provide cumulative evidence on the occurrence of EMH in BTM patients.MethodsThis is a systematic review of case reports, series, and retrospective studies that presented data on the occurrence of EMH in BTM patients. Data were recorded and analyzed in Microsoft Excel 2016 and SPSS 26. The protocol has been registered in PROSPERO: CRD42021242943.ResultsData from 253 cases of EMH in BTM patients were extracted with a mean age of 35.3 years. Mean haemoglobin at presentation with EMH was 8.2 mg/dL. Lower limb weakness was the most common presenting feature (N = 23) (paraspinal EMH). Magnetic resonance imaging (MRI) was the most widely used diagnostic modality (226). Overall, blood transfusion was the commonest reported treatment (30), followed by radiotherapy (20), surgery (15), hydroxyurea (12), steroids (6), and exchange transfusion (2). An outcome was reported in 20% of patients, all recovered, except one who died as a result of nosocomial infection.ConclusionEMH is rare in BTM and can occur in any organ system with varied clinical features. MRI can effectively diagnose EMH, and conservative management has similar results compared to invasive treatments. Larger studies, focussing on outcomes may enhance guidelines on preventive and therapeutic strategies for managing EMH in BTM.KEY MESSAGESExtramedullary haematopoiesis is a rare complication in beta thalassaemia. Although it is more common in non-transfusion dependent thalassaemia, increasingly reported cases suggest a higher prevalence of EMH in TDT than what is known before.There are no clear guidelines on the management of EMH in TDT, with reported patients showing similar outcomes with conservative invasive treatment modalities.More extensive and preferably prospectively designed studies are required focussing on the management of EMH and its outcomes in patients with TDT to formulate evidence-based guidelines.

Project description:Objective: Unexpectedly wide distribution (<10 to >90%) of hemoglobin oxygen saturation (sO2) within red cell concentrates (RCCs) has recently been observed. Causes of such variability are not yet completely explained whereas the roles of oxygen and oxidative lesions during the storage of RCCs are known. The objectives of the present study are to characterize sO2 distribution in RCCs produced in a Swiss blood center and to investigate the influence of processing and donors' characteristics. Methods: The level of sO2 was measured in 1701 leukocyte-depleted RCCs derived from whole blood donations in both top-bottom (TB; component filtered, SAGM) and top-top (TT; whole blood filtration, PAGGSM) RCCs. The sO2 value was measured non-invasively through the PVC bag prior to storage by resonance Raman spectroscopy. Gender, age, blood type, hemoglobin level, and living altitude of donors, as well as process method and time-to-process were recorded. Results: Overall, the sO2 exhibited a wide non-Gaussian distribution with a mean of 51.2 ± 18.5%. Use of top-top kits resulted in a 16% higher sO2 (P < 0.0001) than with top-bottom ones. Waiting time before processing only had a modest impact, but the blood processing itself reduced the sO2 by almost 12% (P < 0.0001). sO2 was also significantly affected by some donors' characteristics. RCCs from men exhibited 25% higher sO2 (P < 0.0001) than those donated by women. Multivariate analysis revealed that the apparent correlation observed with hemoglobin level and age was actually due to multicollinearity with the sex variable. Finally, we noticed no significant differences across blood type but found that altitude of residence was associated with the sO2 (i.e., higher in higher living place). Conclusion: These data confirm wide sO2 distribution in RCCs reported recently. The sO2 was impacted by the processing and also by donors' characteristics such as the gender and the living altitude, but not by the hemoglobin level, blood group and donor age. This study provides new hints on the factors influencing red blood cells storage lesions, since they are known to be related to O2 content within the bags, giving clues to better process and to better store RCCs and therefore potentially improve the efficacy of transfusion.

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Amustaline-glutathione pathogen-reduced red blood cell concentrates for transfusion-dependent thalassaemia.

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Amustaline-glutathione pathogen-reduced red blood cell concentrates for transfusion-dependent thalassaemia.

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