Efficacy of packed red blood cell transfusions based on weight versus formula in thalassemic children: An open-label randomized control trial
BACKGROUND Protocols for transfusion therapy in transfusion-dependent thalassemia (TDT) children differ among various medical centers. In India, most centers consider only the patient's weight while calculating the volume of packed red blood cells (PRBCs) to be transfused. This study aimed to compare the efficacy of PRBC transfusions of different volumes calculated either by weight or by a formula using weight and pretransfusion hemoglobin of patient and hematocrit of PRBC. STUDY DESIGN AND METHODS Sixty TDT patients in the age group of 3-9 years were enrolled and randomly allocated to two groups. Group A received PRBC transfusion volume based on the patient's weight, and Group B received PRBC volume calculated using a formula for 6 months. RESULTS Average pretransfusion hemoglobin in Group A and Group B (9 ± 0.4 vs. 8.9 ± 0.4 g/dl) was not significantly different (p = .353). Although the average number of visits in 6 months was less for Group A compared to Group B (7 ± 1 vs. 8 ± 1; p = .001); the average volume transfused per visit was more (351 ± 78 vs. 287 ± 68 ml; p = .003). The calculated average annual pure red cell requirement of the patients was 178 ml/kg/year for Group A and 154 ml/kg/year for Group B (p = .000). Total donor exposures were significantly lower in Group B than Group A (11 ± 3 vs. 14 ± 3; p = .006). CONCLUSION The number of donor exposures and annual pure red cell requirement was significantly lower in the formula-based group. Transfusions based on formula are recommended in TDT patients.
Transfusion-dependent thalassemia children (n= 60).
Packed red blood cells (PRBC) transfusion volume based on the patient’s weight (Group A, n= 30).
PRBC transfusion volume calculated according to a formula based on haematocrit of blood unit, desired rise in patient's haemoglobin, and patient's weight (Group B, n= 30).
The average number of visits in 6 months was less for Group A compared to Group B (7 ± 1 vs. 8 ± 1). The average volume transfused per visit was higher for Group A than Group B (351 ± 78 vs. 287 ± 68 ml). The calculated average annual pure red cell requirement of the patients was 178 ml/kg/year for Group A and 154 ml/kg/year for Group B. The total donor exposures were significantly lower in Group B than Group A (11 ± 3 vs. 14 ± 3).
Comparison of the effects of calcium channel blockers plus iron chelation therapy versus chelation therapy only on iron overload in children and young adults with transfusion-dependent thalassemia: A randomized double-blind placebo-controlled trial
Pediatric blood & cancer. 2022;:e29564
BACKGROUND Myocardial iron deposition is a significant cause of morbidity and mortality in patients with transfusion-dependent thalassemia (TDT). Amlodipine, L-type calcium channel blocker with regular chelation therapy may reduce myocardial iron overload. Lack of randomized trials prompted this study to assess the effect of calcium channel blocker (amlodipine) in combination with iron chelation therapy on iron overload in patients with TDT. METHODS Sixty-four eligible patients were randomized to receive either amlodipine and chelation (group A) or chelation alone (group B) in double-blind placebo-controlled trial. Myocardial iron concentration (MIC) using T2* magnetic resonance imaging (MRI), liver iron concentration (LIC), left ventricular ejection fraction (LVEF), and serum ferritin were measured at baseline and 12 months. RESULTS In the amlodipine group, mean cardiac T2* value significantly increased from 18.11 ± 8.47 to 22.15 ± 7.61 (p = .002) at 12 months, whereas in control group, there was a nonsignificant increase (p = .62) in cardiac T2* value from 19.50 ± 8.84 to 20.03 ± 9.07. There was a significant decrease in MRI-derived MIC in the amlodipine group compared to control group (1.93 ± 1.61 to 1.29 ± 0.90, p = .01). Changes in the LVEF (p = .45), MRI-derived LIC (p = .09), and serum ferritin (p = .81) were not significant between the two groups. CONCLUSION Amlodipine is safe and when combined with chelation therapy appears to be more effective in reducing cardiac iron overload than chelation only in children and young adults with TDT.
The impact of pathogen-reduced platelets in acute leukaemia treatment on the total blood product requirement: a subgroup analysis of an EFFIPAP randomised trial
Transfusion medicine (Oxford, England). 2022
OBJECTIVE To evaluate the impact of pathogen-reduced (PR) platelet transfusions on blood products requirement for clinical practice. BACKGROUND PR platelets are increasing in use as standard blood products. However, few randomised trials have evaluated their impact on bleeding control or prevention. Furthermore, PR platelets recirculate less than untreated platelets. METHODS A subgroup study of the randomised clinical trial EFFIPAP compared three arms of platelet preparations (PR: P-PRP/PAS, additive solution: P-PAS and plasma P-P arms respectively). The subgroup of acute leukaemia patients, in their chemotherapy induction phase, included 392 patients (133 P-PRP/PAS arm, 132 P-PAS arm and 130 P-P arm). Blood requirements were analysed across over periods of 7 days. RESULTS The number of platelet transfusions per week was significantly higher in the P-PRP/PAS group 2.3 [1.6-3.3] compared to the control groups 1.9 [1.3-2.8] and 2.0 [1.3-3.0] for P-P and P-PAS groups respectively (p < 0.0001). However, the total number of platelets transfused per week was not different. The number of red blood cell concentrates (RBC) transfusion per week did not differ either. CONCLUSION In a homogeneous group of patients, platelet pathogen reduction resulted in an increased number of platelet units transfused per week while having no impact on the total number of platelets transfused or the number of RBC transfusion; resulting to an average requirement of 2 RBC and 2-3 platelets transfusions per week of marrow aplasia.
Two trade names of deferasirox (Osveral® and Exjade®) in reduction of iron overload parameters in major beta-thalassemia patients: A randomized open labeled clinical trial
Caspian journal of internal medicine. 2022;13(1):61-69
BACKGROUND Beta-thalassemia major patients typically require chronic transfusion and iron-chelating agents to reduce serum iron overload. Osveral(®) is an available Iranian brand name of deferasirox used by majority of thalassemic patients. The aim of this study was to compare the efficacy of Osveral(®) vs. Exjade(®) in major beta- thalassemia patients. METHODS In this randomized clinical trial, all patients received a single daily dose of 30 mg/kg either of Osveral(®) or Exjade(®) for 6 months. Primary outcome was the mean of bimonthly changes in serum ferritin concentration and secondary outcomes included mean changes of heart and liver MRI T2* after a year. RESULTS Finally, 80 patients completed the study. The mean serum ferritin level at the end of sixth month significantly decreased in Osveral(®) and Exjade(®) groups (p<0.01). After a year, means cardiac MRI T2* in Osveral(®) group were changed from 25.9±9.6 ms to 25.4±9.7 ms and in Exjade(®) group from 24.8±9.2 ms to 26.9±5.9 ms, with no significant difference (P=0.43). Mean liver MRI T2* for Osveral(®) and Exjade(®) groups were 8.6±6.4 ms (baseline 6.3±4.7) and 6.3±4 ms (baseline 4.9±3.5), respectively and there was no significant difference between two study arms (P=0.1). CONCLUSION Osveral(®) decreased significantly the serum ferritin level and improved heart and liver iron overload as efficient as Exjade(®). It can be a suitable cost-effective alternative agent in beta-thalassemia major patients.
Sirolimus plus prednisolone vs sirolimus monotherapy for kaposiform hemangioendothelioma: a randomized clinical trial
The Kasabach-Merritt phenomenon (KMP) in kaposiform hemangioendothelioma (KHE) is characterized by life-threatening thrombocytopenia and consumptive coagulopathy. This study compared the efficacy and safety of sirolimus plus prednisolone versus sirolimus monotherapy as treatment strategies for KHE with KMP in the largest cohort to date. Participants were randomized to receive either sirolimus in combination with a short course of prednisolone or sirolimus monotherapy for at least 12 months. The primary outcome was defined as achievement of a durable platelet response (platelet count >100×109/L) at week 4. Participants completed efficacy assessments 2 years after the initial treatment. At week 4, a durable platelet response was achieved by 35 of 37 patients given sirolimus and prednisolone compared with 24 of 36 patients given sirolimus monotherapy (difference 27.9%; 95% CI, 10.0% to 44.7%). Compared with the sirolimus monotherapy group, the combination treatment group showed improvements in terms of measures of durable platelet responses at all points during the initial 3-week treatment period, median platelet counts during weeks 1 to 4, increased numbers of patients achieving fibrinogen stabilization at week 4, and objective lesion responses at month 12. Patients receiving combination therapy had fewer blood transfusions and a lower total incidence of disease sequelae than patients receiving sirolimus alone. The frequencies of total adverse events and grade 3-4 adverse events during treatment were similar in both groups. The responses seen in patients with KHE with KMP were profound and encouraging, suggesting that sirolimus plus prednisolone should be considered a valid treatment for KHE with KMP. ClinicalTrial.gov, number NCT03188068.
Eltrombopag Added to Immunosuppression in Severe Aplastic Anemia
The New England journal of medicine. 2022;386(1):11-23
BACKGROUND A single-group, phase 1-2 study indicated that eltrombopag improved the efficacy of standard immunosuppressive therapy that entailed horse antithymocyte globulin (ATG) plus cyclosporine in patients with severe aplastic anemia. METHODS In this prospective, investigator-led, open-label, multicenter, randomized, phase 3 trial, we compared the efficacy and safety of horse ATG plus cyclosporine with or without eltrombopag as front-line therapy in previously untreated patients with severe aplastic anemia. The primary end point was a hematologic complete response at 3 months. RESULTS Patients were assigned to receive immunosuppressive therapy (Group A, 101 patients) or immunosuppressive therapy plus eltrombopag (Group B, 96 patients). The percentage of patients who had a complete response at 3 months was 10% in Group A and 22% in Group B (odds ratio, 3.2; 95% confidence interval [CI], 1.3 to 7.8; P = 0.01). At 6 months, the overall response rate (the percentage of patients who had a complete or partial response) was 41% in Group A and 68% in Group B. The median times to the first response were 8.8 months (Group A) and 3.0 months (Group B). The incidence of severe adverse events was similar in the two groups. With a median follow-up of 24 months, a karyotypic abnormality that was classified as myelodysplastic syndrome developed in 1 patient (Group A) and 2 patients (Group B); event-free survival was 34% and 46%, respectively. Somatic mutations were detected in 29% (Group A) and 31% (Group Β) of the patients at baseline; these percentages increased to 66% and 55%, respectively, at 6 months, without affecting the hematologic response and 2-year outcome. CONCLUSIONS The addition of eltrombopag to standard immunosuppressive therapy improved the rate, rapidity, and strength of hematologic response among previously untreated patients with severe aplastic anemia, without additional toxic effects. (Funded by Novartis and others; RACE ClinicalTrials.gov number, NCT02099747; EudraCT number, 2014-000363-40.).
Patients with severe aplastic anaemia (n= 197).
Immunosuppressive therapy plus eltrombopag (n= 96).
Immunosuppressive therapy (n= 101).
The percentage of patients who had a complete response at 3 months was 10% for patients in the immunosuppressive therapy group, and 22% for patients in the immunosuppressive therapy plus eltrombopag group. At 6 months, the overall response rate (the percentage of patients who had a complete or partial response) was 41% for those receiving immunosuppressive therapy, and 68% for those receiving immunosuppressive therapy plus eltrombopag. The median times to the first response were 8.8 months (immunosuppressive therapy group) and 3.0 months (immunosuppressive therapy plus eltrombopag group). The incidence of severe adverse events was similar in all patients.
A randomised double-blind placebo-controlled clinical trial of oral hydroxyurea for transfusion-dependent β-thalassaemia
Scientific reports. 2022;12(1):2752
Hydroxyurea is an antimetabolite drug that induces fetal haemoglobin in sickle cell disease. However, its clinical usefulness in β-thalassaemia is unproven. We conducted a randomised, double-blind, placebo-controlled clinical trial to evaluate the efficacy and safety of hydroxyurea in transfusion-dependent β-thalassaemia. Sixty patients were assigned 1:1 to oral hydroxyurea 10-20 mg/kg/day or placebo for 6 months by stratified block randomisation. Hydroxyurea treatment did not alter the blood transfusion volume overall. However, a significantly higher proportion of patients on hydroxyurea showed increases in fetal haemoglobin percentage (89% vs. 59%; p < 0.05) and reductions in erythropoietic stress as measured by soluble transferrin receptor concentration (79% vs. 40%; p < 0.05). Based on fetal haemoglobin induction (> 1.5%), 44% of patients were identified as hydroxyurea-responders. Hydroxyurea-responders, required significantly lower blood volume (77 ± SD27ml/kg) compared to hydroxyurea-non-responders (108 ± SD24ml/kg; p < 0.01) and placebo-receivers (102 ± 28ml/kg; p < 0.05). Response to hydroxyurea was significantly higher in patients with HbE β-thalassaemia genotype (50% vs. 0%; p < 0.01) and Xmn1 polymorphism of the γ-globin gene (67% vs. 27%; p < 0.05). We conclude that oral hydroxyurea increased fetal haemoglobin percentage and reduced erythropoietic stress of ineffective erythropoiesis in patients with transfusion-dependent β-thalassaemia. Hydroxyurea reduced the transfusion burden in approximately 40% of patients. Response to hydroxyurea was higher in patients with HbE β-thalassaemia genotype and Xmn1 polymorphism of the γ-globin gene.
The safety of activated eptacog beta in the management of bleeding episodes and perioperative haemostasis in adult and paediatric haemophilia patients with inhibitors
Haemophilia : the official journal of the World Federation of Hemophilia. 2021
INTRODUCTION Haemophilia patients with inhibitors often require a bypassing agent (BPA) for bleeding episode management. Eptacog beta (EB) is a new FDA-approved recombinant activated human factor VII BPA for the treatment and control of bleeding in haemophilia A or B patients with inhibitors (≥12 years of age). We describe here the EB safety profile from the three prospective Phase 3 clinical trials performed to date. AIM: To assess EB safety, immunogenicity and thrombotic potential in children and adults who received EB for treatment of bleeding and perioperative care. METHODS Using a randomized crossover design, 27 subjects in PERSEPT 1 (12-54 years) and 25 subjects in PERSEPT 2 (1-11 years) treated bleeding episodes with 75 or 225 μg/kg EB initially followed by 75 μg/kg dosing at predefined intervals as determined by clinical response. Twelve PERSEPT 3 subjects (2-56 years) received an initial preoperative infusion of 75 μg/kg (minor procedures) or 200 μg/kg EB (major surgeries) with subsequent 75 μg/kg doses administered intraoperatively and post-operatively as indicated. Descriptive statistics were used for data analyses. RESULTS Sixty subjects who received 3388 EB doses in three trials were evaluated. EB was well tolerated, with no allergic, hypersensitivity, anaphylactic or thrombotic events reported and no neutralizing anti-EB antibodies detected. A death occurred during PERSEPT 3 and was determined to be unlikely related to EB treatment by the data monitoring committee. CONCLUSION Results from all three Phase 3 trials establish an excellent safety profile of EB in haemophilia A or B patients with inhibitors for treatment of bleeding and perioperative use.
Weekly epistaxis duration as an indicator of epistaxis severity in hereditary hemorrhagic telangiectasia-Preliminary results from a randomized controlled trial
Laryngoscope investigative otolaryngology. 2021;6(3):370-375
OBJECTIVES There is great interest in developing and studying novel therapies for epistaxis in hereditary hemorrhagic telangiectasia (HHT) given its associated morbidity and impact on patients' quality of life. Several recent randomized controlled trials (RCTs) have been negative, likely attributed to poorly characterized outcome measures. This study reported on and evaluated an epistaxis outcome measure, weekly epistaxis duration (WED) in an ongoing RCT, with the aim of better characterizing the measurement of epistaxis for clinical trials. MATERIALS AND METHODS Patients were recruited to an ongoing phase II, double-blind, cross-over RCTs of oral doxycycline for HHT-associated epistaxis. Patients were included for the epistaxis measures analysis if they had already completed the initial 3-month run-in period, and had received treatment of either study drug doxycycline or placebo for a minimum of 6 months. The primary measure of interest was patient-reported outcome (PRO)-WED, captured from prospective daily diaries. Epistaxis severity score (ESS) was collected as a secondary outcome. RESULTS Seven patients were included for analysis, with 98% completion of the daily diary. The average PRO-WED across all patients was 85.0 minutes, SD 93.2 at baseline, and 65.6 minutes, SD 59.5 during treatment/placebo. Coefficient of variance for PRO-WED at baseline and during treatment/placebo was 0.49, SD 0.1 and 0.58, SD 0.2, respectively. Statistically significant changes in the mean PRO-WED from baseline to treatment/placebo was noted in six patients (86%). Only two patients (29%) had a significant change in ESS, with both reporting decreased (improved) scores after treatment/placebo as compared to baseline. CONCLUSIONS PRO-WED was a feasible clinical trials measure, was reasonably stable during baseline measurement, and appeared to be variable with treatment state, suggesting it may provide a sensitive clinical trials PRO in HHT.
Eltrombopag for Post-Transplantation Thrombocytopenia: Results of Phase II Randomized, Double-Blind, Placebo-Controlled Trial
Transplantation and cellular therapy. 2021;27(5):430.e1-430.e7
Prolonged thrombocytopenia occurs in up to 37% of patients after hematopoietic stem cell transplantation (HSCT) and is associated with adverse prognosis and increased risk of bleeding. Eltrombopag, a thrombopoietin receptor agonist, can increase platelet counts in thrombocytopenic patients. We conducted a phase II study, adaptively randomizing patients at ≥35 days post-HSCT to receive placebo or eltrombopag at a platelet count ≤20,000/µL for 7 days or platelet transfusion-dependent and a neutrophil count ≥1500/µL. Sixty patients were randomized to eltrombopag (n = 42) or placebo (n = 18) and received at least 1 dose. Fifteen patients (36%) in the eltrombopag arm achieved a platelet count of ≥30,000/µL, compared with 5 patients (28%) in the placebo arm, with a posterior probability of 0.75. (The protocol required this probability to be >0.975 to declare a winner; thus, the results are inconclusive.) However, 9 patients (21%) in the eltrombopag arm achieved a platelet count of ≥50,000/µL, compared with no patients in the placebo arm (P = .046). The overall survival, progression-free survival, relapse rate, and nonrelapse mortality were similar in the 2 arms. In conclusion, compared with placebo, treatment with eltrombopag led to a higher percentage of patients achieving a platelet count of ≥50,000/µL in patients with persistent thrombocytopenia after HSCT.