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.
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.
Lenalidomide-Epoetin Alfa Versus Lenalidomide Monotherapy in Myelodysplastic Syndromes Refractory to Recombinant Erythropoietin
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2021;:Jco2001691
PURPOSE Impaired response to erythropoietin underlies ineffective erythropoiesis and anemia in myelodysplastic syndromes (MDS). We investigated whether treatment with lenalidomide (LEN), which augments erythropoietin receptor signaling in vitro, can restore and improve hemoglobin response to epoetin (EPO) alfa in patients with lower-risk, non-del(5q) MDS who have anemia that is refractory to or have low probability of benefit from treatment with recombinant erythropoietin. METHODS In a phase III, US intergroup trial, we randomly assigned patients to receive either LEN and EPO alfa or LEN alone following stratification by serum erythropoietin concentration and prior erythropoietin treatment. RESULTS A total of 195 evaluable patients were randomly assigned: 99 patients to the LEN-EPO alfa cohort and 96 to LEN alone. After four cycles of treatment, the primary end point of major erythroid response (MER) was significantly higher (28.3%) with the combination compared with LEN alone (11.5%) (P = .004). Among 136 patients who completed 16 weeks of study treatment, 38.9% and 15.6% achieved MER, respectively (P = .004). Additionally, minor erythroid response was achieved in 18.2% and 20.8% of patients, for an overall erythroid response rate of 46.5% versus 32.3%. Among LEN nonresponders, 38 crossed over to the addition of EPO alfa with 10 patients (26.3%) achieving a MER. Responses to the combined treatment were highly durable with a median MER duration of 23.8 months compared with 13 months with LEN alone. CONCLUSION LEN restores sensitivity to recombinant erythropoietin in growth factor-insensitive, lower-risk, non-del(5q) MDS, to yield a significantly higher rate and duration of MER compared with LEN alone (funded by the National Cancer Institute; E2905 ClinicalTrials.gov identifier: NCT02048813).
Metabolomics-Based Clinical Efficacy of Compound Shenlu Granule, a Chinese Patent Medicine, in the Supportive Management of Aplastic Anemia Patients: A Randomized Controlled Pilot Trial
Evidence-based complementary and alternative medicine : eCAM. 2021;2021:6655848
OBJECTIVE To explore the clinical efficacy and mechanism of compound Shenlu granule (SLG) treatment in patients with aplastic anemia (AA). METHODS A total of 89 AA patients were randomly divided into an SLG supportive group (group A, n = 44) and a control group (group B, n = 45) while continuing Western medical management. After 6 months, hemograms, traditional Chinese medicine (TCM) syndrome scores, and overall clinical efficacy rate were assessed. Serum metabolomics characteristics were observed using ultraperformance liquid chromatography-mass spectrometry after SLG intervention. RESULTS The levels of red blood cell (RBC), hemoglobin (Hb), and platelet (PLT) were increased in both groups after treatment for 6 months (P < 0.05), and in group A, the elevation of PLT became much more significant (P < 0.01). The TCM syndrome score was lower in group A than in group B after treatment (P < 0.05). Metabolomics data showed a significant difference in the patients using SLG after 6 months, and 14 biomarkers were identified. CONCLUSION SLG supportive treatment showed positive results in patients with AA, and metabolomics data indicated that SLG influenced aminoacyl-tRNA biosynthesis and glycerophospholipid metabolism to gradually return to normal.
Orthopedic surgery in hemophilic patients with musculoskeletal disorders: A systematic review
Experimental and therapeutic medicine. 2021;22(3):995
Hemophilia is a hereditary coagulopathy caused by factor VIII (hemophilia type A) or by coagulation factor IX (hemophilia type B) dysfunction, characterized by an increased bleeding predisposition, which is either spontaneous or secondary to minimal trauma. Currently, hemophilia may also be considered an 'orthopedic' condition, due to the fact that it affects the musculoskeletal system of most hemophilic patients. In recent years, constant prophylaxis using coagulation factors has led to a significant improvement in the hemophilic patient's quality of life, by reducing both life-threatening hemorrhagic phenomena, as well as the occurrence of chronic complications. Nevertheless, progressive joint bleeding remains unavoidable in this category of patients, and the onset of chronic arthropathy with secondary motor deficiency remains the main complication with an invalidating character. In such cases, orthopedic management is imperative; osteoarticular complications being managed most often with the help of conservative or surgical techniques. The purpose of this review is to provide an overview of modern orthopedic practices which are useful in the management of hemophilic patients suffering from osteoarticular disorders.
Deferiprone vs deferoxamine for transfusional iron overload in SCD and other anemias: a randomized, open-label, noninferiority study
Blood advances. 2021
Many people with sickle cell disease (SCD) or other anemias require chronic blood transfusions, which often causes iron overload and requires chelation therapy. The iron chelator deferiprone is often used in individuals with thalassemia syndromes, but data in patients with SCD are limited. This open-label study (NCT02041299) assessed the efficacy and safety of deferiprone in patients with SCD or other anemias receiving chronic transfusion therapy. A total of 228 patients (mean age: 16.9 [range 3-59] years; 46.9% female) were randomized to receive either oral deferiprone (n = 152) or subcutaneous deferoxamine (n = 76). The primary endpoint was change from baseline at 12 months in liver iron concentration (LIC), assessed by R2* magnetic resonance imaging (MRI). The least squares mean (standard error) change in LIC was -4.04 (0.48) mg/g dry weight for deferiprone vs -4.45 (0.57) mg/g dry weight for deferoxamine, with noninferiority of deferiprone to deferoxamine demonstrated by analysis of covariance (least squares mean difference 0.40 [0.56]; 96.01% confidence interval, -0.76, 1.57). Noninferiority of deferiprone was also shown for both cardiac T2* MRI and serum ferritin. Rates of overall adverse events (AEs), treatment-related AEs, serious AEs, and AEs leading to withdrawal did not differ significantly between the groups. AEs related to deferiprone treatment included abdominal pain (17.1% of patients), vomiting (14.5%), pyrexia (9.2%), increased alanine transferase (9.2%) and aspartate transferase levels (9.2%), neutropenia (2.6%), and agranulocytosis (0.7%). The efficacy and safety profiles of deferiprone were acceptable and consistent with those seen in patients with transfusion-dependent thalassemia.
Patients with sickle cell disease or other anaemias receiving chronic transfusion therapy (n= 228).
Oral deferiprone (n= 152).
Subcutaneous deferoxamine (n= 76).
The least squares mean (standard error) change in liver iron concentration was -4.04 (0.48) mg/g dry weight for deferiprone vs. -4.45 (0.57) mg/g dry weight for deferoxamine, with noninferiority of deferiprone to deferoxamine demonstrated by analysis of covariance. Non-inferiority of deferiprone was also shown for both cardiac T2* MRI and serum ferritin. Treatment-related adverse events (AEs), serious AEs, and AEs leading to withdrawal did not differ significantly between the groups.
Safety and efficacy of thalidomide in patients with transfusion-dependent β-thalassemia: a randomized clinical trial
Signal transduction and targeted therapy. 2021;6(1):405
Thalidomide induces γ-globin expression in erythroid progenitor cells, but its efficacy on patients with transfusion-dependent β-thalassemia (TDT) remains unclear. In this phase 2, multi-center, randomized, double-blind clinical trial, we aimed to determine the safety and efficacy of thalidomide in TDT patients. A hundred patients of 14 years or older were randomly assigned to receive placebo or thalidomide for 12 weeks, followed by an extension phase of at least 36 weeks. The primary endpoint was the change of hemoglobin (Hb) level in the patients. The secondary endpoints included the red blood cell (RBC) units transfused and adverse effects. In the placebo-controlled period, Hb concentrations in patients treated with thalidomide achieved a median elevation of 14.0 (range, 2.5 to 37.5) g/L, whereas Hb in patients treated with placebo did not significantly change. Within the 12 weeks, the mean RBC transfusion volume for patients treated with thalidomide and placebo was 5.4 ± 5.0 U and 10.3 ± 6.4 U, respectively (P < 0.001). Adverse events of drowsiness, dizziness, fatigue, pyrexia, sore throat, and rash were more common with thalidomide than placebo. In the extension phase, treatment with thalidomide for 24 weeks resulted in a sustainable increase in Hb concentrations which reached 104.9 ± 19.0 g/L, without blood transfusion. Significant increase in Hb concentration and reduction in RBC transfusions were associated with non β0/β0 and HBS1L-MYB (rs9399137 C/T, C/C; rs4895441 A/G, G/G) genotypes. These results demonstrated that thalidomide is effective in patients with TDT.
Caplacizumab prevents refractoriness and mortality in acquired thrombotic thrombocytopenic purpura: integrated analysis
Blood advances. 2021;5(8):2137-2141
The efficacy and safety of caplacizumab in individuals with acquired thrombotic thrombocytopenic purpura (aTTP) have been established in the phase 2 TITAN and phase 3 HERCULES trials. Integrated analysis of data from both trials was conducted to increase statistical power for assessing treatment differences in efficacy and safety outcomes. Caplacizumab was associated with a significant reduction in the number of deaths (0 vs 4; P < .05) and a significantly lower incidence of refractory TTP (0 vs 8; P < .05) vs placebo during the treatment period. Consistent with the individual trials, treatment with caplacizumab resulted in a faster time to platelet count response (hazard ratio, 1.65; P < .001), a 72.6% reduction in the proportion of patients with the composite end point of TTP-related death, TTP exacerbation, or occurrence of at least 1 treatment-emergent major thromboembolic event during the treatment period (13.0% vs 47.3%; P < .001), and a 33.3% reduction in the median number of therapeutic plasma exchange days (5.0 vs 7.5 days) vs placebo. No new safety signals were identified; mild mucocutaneous bleeding was the main safety finding. This integrated analysis provided new evidence that caplacizumab prevents mortality and refractory disease in acquired TTP and strengthened individual trial findings, with a confirmed favorable safety and tolerability profile. These trials were registered at www.clinicaltrials.gov as #NCT01151423 and #NCT02553317.
Biological stratification of clinical disease courses in childhood immune thrombocytopenia
Journal of thrombosis and haemostasis : JTH. 2021
BACKGROUND In childhood immune thrombocytopenia (ITP), an autoimmune bleeding disorder, there is a need for better prediction of individual disease courses and treatment outcomes. OBJECTIVE To predict the response to intravenous Immunoglobulins (IVIg) and ITP disease course using genetic and immune markers. METHODS Children aged below seven years with newly diagnosed ITP (N = 147) from the TIKI study were included, which randomized children to an IVIg or observation group. A total of 46 variables were available: clinical characteristics, targeted genotyping, lymphocyte immune phenotyping, and platelet autoantibodies. RESULTS In the treatment arm, 48/80 children (60%) showed a complete response (platelets ≥100 x 10(9) /L) that lasted for at least one month (complete sustained response; CSR) and 32 exhibited no or a temporary response (absence of a sustained response; ASR). For a biological risk score, five variables were selected by regularized logistic regression that predicted ASR vs CSR: 1) hemoglobin; 2) platelet count; 3) genetic polymorphisms of FcγRIIc; 4) the presence of IgG anti-platelet antibodies; and 5) preceding vaccination. The ASR sensitivity was 0.91 (95% CI, 0.80 - 1.00) and specificity was 0.67 (95% CI, 0.53 - 0.80). In the 67 patients of the observation arm, this biological score was also associated with recovery during one-year follow-up. The addition of the biological score to a predefined clinical score further improved the discrimination of favorable ITP disease courses. CONCLUSIONS The prediction of disease courses and IVIg treatment responses in ITP is improved by using both clinical and biological stratification.
Risk factors for and effects of persistent and severe hypophosphatemia following ferric carboxymaltose
The Journal of clinical endocrinology and metabolism. 2021
CONTEXT Hypophosphatemia, osteomalacia and fractures are complications of certain intravenous iron formulations. OBJECTIVE To investigate risk factors for incident, severe and persistent hypophosphatemia, and associated alterations in bone and mineral biomarkers following intravenous iron treatment. DESIGN Secondary analysis of the PHOPHARE-IDA randomized clinical trials. SETTING Thirty outpatient clinics in the United States. PATIENTS 245 patients aged 18 years or older with iron deficiency anemia. INTERVENTIONS Intravenous ferric carboxymaltose (FCM) versus ferric derisomaltose (FDI). MAIN OUTCOME MEASURES Serum phosphate, intact fibroblast growth factor-23 (iFGF23), 1,25-dihydroxyvitamin D (1,25(OH)2D), ionized calcium, parathyroid hormone (PTH), and alkaline phosphatase. RESULTS FCM was the only consistent risk factor for incident hypophosphatemia (<2.0 mg/dl; odds ratio versus FDI: 38.37; 95% confidence interval [CI]: 16.62, 88.56; p<0.001). Only FCM-treated patients developed severe hypophosphatemia (<1.0 mg/dl; 11.3%; 13/115) or persistent hypophosphatemia (<2.0 mg/dl at study end; 40.0%; 46/115). More severe hypophosphatemia associated with significantly greater increases in iFGF23, PTH, and alkaline phosphatase, and more severe decreases in 1,25(OH)2D and ionized calcium (all p<0.05). Patients with persistent versus resolved hypophosphatemia demonstrated significantly greater changes in iFGF23, PTH, 1,25(OH)2D and N-terminal procollagen-1 peptide levels (all p<0.01), but alkaline phosphatase increased similarly in both groups. CONCLUSIONS Treatment with FCM was the only consistent risk factor for hypophosphatemia. Patients who developed severe or persistent hypophosphatemia after FCM treatment manifested more severe derangements in bone and mineral metabolism. Changes in bone biomarkers continued beyond resolution of hypophosphatemia, suggesting ongoing effects on bone that may help explain the association of FCM with osteomalacia and fractures.