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Pegcetacoplan controls hemolysis in complement inhibitor-naive patients with paroxysmal nocturnal hemoglobinuria
Wong RSM, Navarro-Cabrera JR, Comia NS, Goh YT, Idrobo H, Kongkabpan D, Gómez-Almaguer D, Al-Adhami M, Ajayi T, Alvarenga P, et al
Blood advances. 2023
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Abstract
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disease characterized by complement-mediated hemolysis. Pegcetacoplan is the first C3-targeted therapy approved for adults with PNH (United States), adults with PNH with inadequate response to or intolerance of a C5 inhibitor (Australia), and adults with anemia despite C5-targeted therapy for 3 months (European Union). PRINCE was a phase 3, randomized, multicenter, open-label, controlled study to evaluate efficacy and safety of pegcetacoplan versus control (supportive care only; eg, blood transfusions, corticosteroids, and supplements) in complement inhibitor-naive patients with PNH. Eligible adults receiving supportive care only for PNH were randomized and stratified based on their number of transfusions (<4, ≥4) 12 months before screening. Patients received pegcetacoplan 1080 mg subcutaneously twice weekly or continued supportive care (control) for 26 weeks. Coprimary endpoints were hemoglobin stabilization (avoidance of >1-g/dL decrease in hemoglobin levels without transfusions) from baseline through week 26 and lactate dehydrogenase (LDH) change at week 26. Overall, 53 patients received pegcetacoplan (n=35) or control (n=18). Pegcetacoplan was superior to control for hemoglobin stabilization (pegcetacoplan, 85.7%; control, 0; difference, 73.1% [95% CI: 57.2, 89.0]; P <0.0001) and change from baseline in LDH (least-square mean change: pegcetacoplan, -1870.5 U/L; control -400.1 U/L; difference, -1470.4 U/L [95% CI: -2113.4, -827.3]; P <0.0001). Pegcetacoplan was well tolerated. No pegcetacoplan-related adverse events were serious, and no new safety signals observed. Pegcetacoplan rapidly and significantly stabilized hemoglobin and reduced LDH in complement inhibitor-naive patients and had a favorable safety profile. This trial was registered at www.clinicaltrials.gov as #NCT04085601.
PICO Summary
Population
Adult patients with paroxysmal nocturnal haemoglobinuria enrolled in the PRINCE trial conducted in 22 centres in Hong Kong, Malaysia, Philippines, Singapore, Thailand, Colombia, Mexico and Peru (n= 53).
Intervention
Subcutaneous infusions of pegcetacoplan (pegcetacoplan group, n= 35).
Comparison
Supportive care including transfusions, anticoagulants, corticosteroids, and supplements (control group, n= 18).
Outcome
Pegcetacoplan was superior to control for haemoglobin stabilization (pegcetacoplan, 85.7%; control, 0; difference, 73.1%, 95% CI [57.2, 89.0]) and change from baseline in lactate dehydrogenase, (least-square mean change: pegcetacoplan, -1870.5 U/L; control -400.1 U/L; difference, -1470.4 U/L, 95% CI [-2113.4, -827.3]). Pegcetacoplan was well tolerated. No pegcetacoplan-related adverse events were serious, and no new safety signals were observed.
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A pilot randomized study for optimal red cell transfusion in acute myeloid leukemia patients with intensive chemotherapy
Byun JM, Park W, Shin DY, Koh Y, Kim I, Yoon SS, Park JH, Kim H, Hong J
Blood transfusion = Trasfusione del sangue. 2023
Abstract
BACKGROUND Although blood transfusion is fundamental throughout the course of hematologic malignancies, acute myeloid leukemia (AML) patients requiring intensive chemotherapy are left at the edges of patient blood management programs because current guidelines do not have established recommendations for red blood cell (RBC) transfusion threshold in patients treated for hematological disorders with anemia and accompanied severe thrombocytopenia. To provide answers for the trigger and doses of ideal RBC transfusion in such situation, we conducted this prospective randomized trial. MATERIALS AND METHODS Newly diagnosed non-acute promyelocytic AML patients undergoing chemotherapy were considered eligible for enrollment. Patients were randomized into 4 groups using a 2 by 2 factorial design, according to the RBC transfusion trigger (hemoglobin [Hb], 7 vs 8 g/dL) and the number of units per transfusion episode (quantity, single vs double-unit). RESULTS Initially 91 patients were randomized into 4 groups, but the protocol adherence rate was 90.1%. Hb trigger did not affect the amount of RBC transfusion required during treatment. Patients receiving RBC transfusion at Hb <7 g/dL used a median of 4 units of RBC (range 0-12), and those receiving transfusion at Hb <8 g/dL also used a median of 4 units of RBC (range 0-24) (p=0.305). The number of RBC units per transfusion did not affect the total amount of RBC transfusion required during treatment. AML treatment outcomes and bleeding events did not differ across the 4 groups. DISCUSSION This study demonstrated the feasibility for restrictive RBC transfusion (Hb <7 g/dL, RBC 1 unit) in AML patients undergoing chemotherapy, regardless of chemotherapy intensity.
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Transfusion use and effect on progression-free, overall survival, and quality of life in upfront treatment of advanced epithelial ovarian cancer: evaluation of the European Organization for Research and Treatment EORTC-55971 Cohort
Prescott LS, Vergote I, Sun CC, Bodurka DC, Coleman RL
International journal of gynecological cancer : official journal of the International Gynecological Cancer Society. 2022
Abstract
BACKGROUND The impact of blood transfusion on ovarian cancer survival is uncertain. OBJECTIVE To investigate whether peri-operative blood transfusion negatively impacted progression-free survival, overall survival, and quality of life in patients with advanced ovarian cancer. METHODS We performed an ancillary analysis of the European Organization for Research and Treatment (EORTC) 55971 phase III trial, in which patients were randomized to primary debulking surgery versus neoadjuvant chemotherapy. Patients included in the per-protocol analysis were categorized by receipt of a transfusion. RESULTS 612 of 632 (97%) of patients had adequate data for analysis. Of those, 323 (53%) received a transfusion. The transfusion cohort was more likely to have had better Word Health Organization (WHO) performance status, serous histology, undergone primary debulking surgery, and received more aggressive surgery, with higher rates of no gross residual disease. Median overall survival was 34.0 vs 35.2 months in the no transfusion and transfusion cohorts (p=0.97). The adjusted HR for death was 1.18 (95% CI 0.94 to 1.48) in favor of the transfusion cohort. Median progression-free survival was 13.6 vs 12.6 months in the no transfusion and transfusion cohorts (p=0.96). The adjusted HR for progression was 1.14 (95% CI 0.91 to 1.43). There were no significant differences in global quality of life, fatigue, dyspnea, or physical functioning between the two cohorts at baseline or at any of the four assessment times. Grade 3 and 4 surgical site infections were more common in the transfusion cohort. CONCLUSION Transfusion did not negatively impact progression-free survival or overall survival; however, it was associated with increased peri-operative morbidity without improvements in quality of life.
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Do liberal thresholds for red cell transfusion result in improved quality of life for patients undergoing intensive chemotherapy for acute myeloid leukemia? A randomized cross over feasibility study
Morton S, Sekhar M, Smethurst H, Mora A, Hodge RL, Hudson CL, Parsons J, Hopkins V, Stanworth SJ
Haematologica. 2022
Abstract
Not available.
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Impact of the preparation method of red cell concentrates on transfusion indices in thalassemia patients: A randomized crossover clinical trial
Gamberini MR, Fortini M, Stievano A, Calori E, Riontino MV, Ceccherelli G, Venturelli D, Chicchi R, Biguzzi R, Fagnoni F, et al
Transfusion. 2021
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Editor's Choice
Abstract
BACKGROUND The average hemoglobin content of red cell concentrates (RCC) varies depending on the method of preparation. Surprisingly less data are available concerning the clinical impact of those differences. STUDY DESIGN AND METHODS The effects of two types of RCC (RCC-A, RCC-B) on transfusion regime were compared in a non-blinded, prospective, randomized, two-period, and crossover clinical trial. RCC-A was obtained by whole blood leukoreduction and subsequent plasma removal, RCC-B removing plasma and buffy coat first, followed by leukoreduction. Eligible patients were adult, with transfusion-dependent thalassemia (TDT). RESULTS RCC-A contained 63.9 (60.3-67.8) grams of hemoglobin per unit (median with 1(st) and 3(rd) quartile), RCC-B 54.5 (51.0-58.2) g/unit. Fifty-one patients completed the study. With RCC-B, the average pre-transfusion hemoglobin concentration was 9.3 ± 0.5 g/dl (mean ± SD), the average transfusion interval 14.2 (13.7-16.3) days, the number of RCC units transfused per year 39.3 (35.4-47.3), and the transfusion power index (a composite index) 258 ± 49. With RCC-A, the average pre-transfusion hemoglobin concentration was 9.6 ± 0.5 g/dl (+2.7%, effect size 0.792), the average transfusion interval 14.8 (14.0-18.5) days (+4.1%, effect size 0.800), the number of RCC units transfused per year 34.8 (32.1-42.5) (-11.4%, effect size -1.609), and the transfusion power index 272 ± 61 (+14.1%, effect size 0.997). All differences were statistically highly significant (p < .00001). The frequency of transfusion reactions was 0.59% with RCC-A and 0.56% with RCC-B (p = 1.000). CONCLUSION To reduce the number of RCC units consumed per year and the number of transfusion episodes, TDT patients should receive RCC with the highest average hemoglobin content.
PICO Summary
Population
Adult patients with transfusion-dependent thalassemia (n= 51).
Intervention
Red cell concentrates obtained by whole blood leukoreduction and subsequent plasma removal (RCC-A).
Comparison
Red cell concentrates obtained by removing plasma and buffy coat first, followed by leukoreduction (RCC-B).
Outcome
With RCC-B, the average pre-transfusion haemoglobin concentration was 9.3 ± 0.5 g/dl (mean ± SD), the average transfusion interval 14.2 (13.7-16.3) days, the number of RCC units transfused per year 39.3 (35.4-47.3), and the transfusion power index (a composite index) 258 ± 49. With RCC-A, the average pre-transfusion haemoglobin concentration was 9.6 ± 0.5 g/dl (+2.7%, effect size 0.792), the average transfusion interval 14.8 (14.0-18.5) days (+4.1%, effect size 0.800), the number of RCC units transfused per year 34.8 (32.1-42.5) (-11.4%, effect size -1.609), and the transfusion power index 272 ± 61 (+14.1%, effect size 0.997). All differences were statistically highly significant. The frequency of transfusion reactions was 0.59% with RCC-A and 0.56% with RCC-B.
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Red cell transfusion in outpatients with myelodysplastic syndromes: a feasibility and exploratory randomised trial
Stanworth SJ, Killick S, McQuilten ZK, Karakantza M, Weinkove R, Smethurst H, Pankhurst LA, Hodge RL, Hopkins V, Thomas HL, et al
British journal of haematology. 2020
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Abstract
Optimal red cell transfusion support in myelodysplastic syndromes (MDS) has not been tested and established. The aim of this study was to demonstrate feasibility of recruitment and follow-up in an outpatient setting with an exploratory assessment of quality of life (QoL) outcomes (EORTC QLQ-C30 and EQ-5D-5L). We randomised MDS patients to standardised transfusion algorithms comparing current restrictive transfusion thresholds (80 g/l, to maintain haemoglobin 85-100 g/l) with liberal thresholds (105 g/l, maintaining 110-125 g/l). The primary outcomes were measures of compliance to transfusion thresholds. Altogether 38 patients were randomised (n = 20 restrictive; n = 18 liberal) from 12 participating sites in UK, Australia and New Zealand. The compliance proportion for the intention-to-treat population was 86% (95% confidence interval 75-94%) and 99% (95-100%) for restrictive and liberal arms respectively. Mean pre-transfusion haemoglobin concentrations for restrictive and liberal arms were 80 g/l (SD6) and 97 g/l (SD7). The total number of red cell units transfused on study was 82 in the restrictive and 192 in the liberal arm. In an exploratory analysis, the five main QoL domains were improved for participants in the liberal compared to restrictive arm. Our findings support the feasibility and need for a definitive trial to evaluate the effect of different red cell transfusion thresholds on patient-centred outcomes.
PICO Summary
Population
Patients with myelodysplastic syndrome, (n=38).
Intervention
Restrictive transfusion threshold (80 g/l, to maintain haemoglobin 85-100 g/l), (n=20).
Comparison
Liberal transfusion threshold (105 g/l, to maintain haemoglobin 110-125 g/l), (n=18).
Outcome
The compliance proportion for the intention-to-treat population was 86% and 99% for restrictive and liberal arms respectively. Mean pre-transfusion haemoglobin concentrations for restrictive and liberal arms were 80 g/l (SD6) and 97 g/l (SD7). The total number of red cell units transfused on study was 82 in the restrictive and 192 in the liberal arm. In an exploratory analysis, the five main QoL domains were improved for participants in the liberal compared to restrictive arm.
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Comparative Effectiveness of a Web-Based Patient Decision Aid for Therapeutic Options for Sickle Cell Disease: Randomized Controlled Trial
Krishnamurti L, Ross D, Sinha C, Leong T, Bakshi N, Mittal N, Veludhandi D, Pham AP, Taneja A, Gupta K, et al
Journal of medical Internet research. 2019;21(12):e14462
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Editor's Choice
Abstract
BACKGROUND Hydroxyurea, chronic blood transfusions, and bone marrow transplantation are efficacious, disease-modifying therapies for sickle cell disease but involve complex risk-benefit trade-offs and decisional dilemma compounded by the lack of comparative studies. A patient decision aid can inform patients about their treatment options, the associated risks and benefits, help them clarify their values, and allow them to participate in medical decision making. OBJECTIVE The objective of this study was to develop a literacy-sensitive Web-based patient decision aid based on the Ottawa decision support framework, and through a randomized clinical trial estimate the effectiveness of the patient decision aid in improving patient knowledge and their involvement in decision making. METHODS We conducted population decisional needs assessments in a nationwide sample of patients, caregivers, community advocates, policy makers, and health care providers using qualitative interviews to identify decisional conflict, knowledge and expectations, values, support and resources, decision types, timing, stages and learning, and personal clinical characteristics. Interview transcripts were coded using QSR NVivo 10. Alpha testing of the patient decision aid prototype was done to establish usability and the accuracy of the information it conveyed, and then was followed by iterative cycles of beta testing. We conducted a randomized clinical trial of adults and of caregivers of pediatric patients to evaluate the efficacy of the patient decision aid. RESULTS In a decisional needs assessment, 223 stakeholders described their preferences, helping to guide the development of the patient decision aid, which then underwent alpha testing by 30 patients and 38 health care providers and iterative cycles of beta testing by 87 stakeholders. In a randomized clinical trial, 120 participants were assigned to either the patient decision aid or standard care (SC) arm. Qualitative interviews revealed high levels of usability, acceptability, and utility of the patient decision aid in education, values clarification, and preparation for decision making. On the acceptability survey, 72% (86/120) of participants rated the patient decision aid as good or excellent. Participants on the patient decision aid arm compared to the SC arm demonstrated a statistically significant improvement in decisional self-efficacy (P=.05) and a reduction in the informed sub-score of decisional conflict (P=.003) at 3 months, with an improvement in preparation for decision making (P<.001) at 6 months. However, there was no improvement in terms of the change in knowledge, the total or other domain scores of decisional conflicts, or decisional self-efficacies at 6 months. The large amount of missing data from survey completion limited our ability to draw conclusions about the effectiveness of the patient decision aid. The patient decision aid met 61 of 62 benchmarks of the international patient decision aid collaboration standards for content, development process, and efficacy. CONCLUSIONS We have developed a patient decision aid for sickle cell disease with extensive input from stakeholders and in a randomized clinical trial demonstrated its acceptability and utility in education and decision making. We were unable to demonstrate its effectiveness in improving patient knowledge and involvement in decision making. TRIAL REGISTRATION ClinicalTrials.gov NCT03224429; https://clinicaltrials.gov/ct2/show/NCT03224429 and ClinicalTrials.gov NCT02326597; https://clinicaltrials.gov/ct2/show/NCT02326597.
PICO Summary
Population
Adult patients and caregivers of pediatric patients with sickle cell disease (n=120).
Intervention
Web-based patient decision aid for sickle cell disease.
Comparison
Standard care (SC).
Outcome
Participants on the patient decision aid arm compared to the SC arm demonstrated a statistically significant improvement in decisional self-efficacy and a reduction in the informed sub-score of decisional conflict at 3 months, with an improvement in preparation for decision making at 6 months. However, there was no improvement in terms of the change in knowledge, the total or other domain scores of decisional conflicts, or decisional self-efficacies at 6 months.
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Amustaline-glutathione pathogen-reduced red blood cell concentrates for transfusion-dependent thalassaemia
Aydinok Y, Piga A, Origa R, Mufti N, Erickson A, North A, Waldhaus K, Ernst C, Lin JS, Huang N, et al
British journal of haematology. 2019
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.
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Efficacy and safety of wheat grass in thalassemic children on regular blood transfusion
Mutha A S, Shah K U, Kinikar A A, Ghongane B B
Cureus. 2018;10((3)):e2306.
Abstract
BACKGROUND In thalassemia, mutations either in alpha or beta chain synthesis results in low hemoglobin (Hb). Wheatgrass has been used for many years for health purposes. Some reports suggest the beneficial effect of wheatgrass on transfusion requirements. Folic acid is also known to play an important role in several biochemical reactions. In some patients with thalassemia, the supplementation of folic acid is useful. OBJECTIVE To evaluate the efficacy and safety of wheatgrass in children with thalassemia receiving chronic blood transfusions. MATERIAL AND METHODS In this randomized prospective study, 69 children with thalassemia were divided into the wheatgrass group and the control group (no wheatgrass). Both groups received a regular blood transfusion and folic acid. The treatment duration was 18 months. Anthropometric parameters, number of transfusions, and amount of blood transfused were compared within and between the groups at the end of the therapy. Clinical examinations, laboratory investigations, and ultrasounds for liver and spleen span were performed at the baseline and then every six months till 18 months. Adverse effects (if any) were noted on every visit. Quality of life (QOL) was evaluated before and at the end of the study using a questionnaire. RESULTS Sixty-nine (study group (n=45; mean age 6.35 +/- 2.65 yrs); control group (n=24; 4.86 +/- 2.77 yrs)) patients were enrolled, of which 12 from the study group and three from the control group did not complete the study. The difference in liver size within the wheatgrass group was significant (P <0.021) only at 18 months but not in the control group at any time point. The difference in spleen size was significant within the wheatgrass group (P<0.005) as well as the control group (P<0.001) at 18 months only. The difference in serum ferritin levels was not significant between the two groups. The increase in serum ferritin levels at the end of the study was significant in the control group when compared to the baseline (P<0.01). There was no difference in the average number of transfusions or in the blood transfusion requirement between the two groups. The difference in the QOL at the start and end was significant in the wheatgrass group (P<0.05). CONCLUSION Wheatgrass appears to play a promising role in children with thalassemia receiving chronic blood transfusions.
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Effect of allogeneic blood transfusion on levels of IL-6 and sIL-R2 in peripheral blood of children with acute lymphocytic leukemia
Zhao H, Zhou H, Cao Q, Wang C, Bai J, Lv P, Zhao F
Oncology Letters. 2018;16((1)):849-852.
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Abstract
Effect of allogeneic blood transfusion on the expression of interleukin-6 (IL-6) and soluble interleukin-2 receptor (sIL-2R) in peripheral blood of children with acute lymphoblastic leukemia (ALL) was investigated. A total of 91 ALL children admitted to Nanfang Hospital from June 2014 to January 2017 were selected as the study group. Patients were randomly divided into allogeneic blood transfusion group (n=38) and non-transfusion group (n=53). In addition, a total of 64 healthy children were also selected from June 2014 to January 2017 as the control group. Patients in allogeneic blood transfusion group were transfused with red blood cell suspension and machine-collected platelets, while patients in non-transfusion group were not treated with blood transfusion. Peripheral venous blood was collected before and at 4, 8 and 12 weeks after blood transfusion to prepare serum. Serum IL-6 and sIL-2R levels were measured by enzyme-linked immunosorbent assay (ELISA). Before transfusion, serum levels of IL-6 and sIL-2R were significantly lower in the study group than those in control group (p<0.05), and no significant differences in serum levels of IL-6 and sIL-2R were found between the allogeneic blood transfusion and non-transfusion group. After transfusion, serum levels of IL-6 and sIL-2R were stable for 12 weeks in the non-transfusion group, while IL-6 and sIL-2R levels were significantly increased in the allogeneic blood transfusion group. The results showed that serum level of IL-6 and sIL-2R was increased in ALL patients with allogeneic blood transfusion, which resulted in reduced antibody production and decreased cellular immunity. The patients had low immunity, and attention should be paid on the pathogen infection prevention.