Voxelotor in adolescents and adults with sickle cell disease (HOPE): long-term follow-up results of an international, randomised, double-blind, placebo-controlled, phase 3 trial
The Lancet. Haematology. 2021
BACKGROUND For decades, patients with sickle cell disease have had only a limited number of therapies available. In 2019, voxelotor (1500 mg), an oral once-daily sickle haemoglobin polymerisation inhibitor, was approved in the USA for the treatment of sickle cell disease in patients aged 12 years and older on the basis of HOPE trial data. To further describe the applicability of voxelotor as a treatment for this chronic illness, we report the long-term efficacy and safety of this drug at 72 weeks of treatment; the conclusion of the placebo-controlled HOPE trial. METHODS HOPE is an international, randomised, double-blind, placebo-controlled, phase 3 trial done at 60 clinical sites in Canada, Egypt, France, Italy, Jamaica, Kenya, Lebanon, Netherlands, Oman, Turkey, the USA, and the UK. Patients (aged 12-65 years) with confirmed sickle cell disease, a haemoglobin concentration of 5·5-10·5 g/dL at enrolment, and who had between one and ten vaso-occlusive crisis events in the previous 12 months were enrolled. Patients receiving regularly scheduled transfusion therapy, who had received a transfusion in the previous 60 days, or who had been admitted to hospital for a vaso-occlusive crisis in the previous 14 days were excluded. Patients were randomly assigned (1:1:1) to receive either once-daily oral voxelotor 1500 mg, voxelotor 900 mg, or placebo for 72 weeks. Randomisation was done centrally by use of an interactive web response system, stratified by baseline hydroxyurea use (yes vs no), age group (adolescents [12 to <18 years] vs adults [18 to 65 years]), and geographic region (North America vs Europe vs other). The primary endpoint (already reported) was the proportion of patients who achieved a haemoglobin response at week 24. In this final analysis, we report prespecified long-term efficacy assessments by intention to treat, including changes in haemoglobin concentrations from baseline to week 72, changes in the concentration of haemolysis markers (absolute and percentage reticulocytes, indirect bilirubin concentrations, and lactate dehydrogenase concentrations) from baseline to week 72, the annualised incidence of vaso-occlusive crises, and patient functioning, as assessed with the Clinical Global Impression of Change (CGI-C) scale. Safety was assessed in patients who received at least one dose of treatment (modified intention-to-treat population). This trial is registered with ClinicalTrials.gov, NCT03036813. FINDINGS Between Dec 5, 2016, and May 3, 2018, 449 patients were screened, of whom 274 were randomly assigned to the voxelotor 1500 mg group (n=90), the voxelotor 900 mg group (n=92), or the placebo group (n=92). At week 72, the adjusted mean change in haemoglobin concentration from baseline was 1·0 g/dL (95% CI 0·7 to -1·3) in the voxelotor 1500 mg group, 0·5 g/dL (0·3 to -0·8) in the voxelotor 900 mg group, and 0·0 g/dL (-0·3 to 0·3) in the placebo group, with a significant difference observed between the voxelotor 1500 mg group and the placebo group (p<0·0001), and between the voxelotor 900 mg group and the placebo group (p=0·014). Significant improvements in markers of haemolysis, as assessed by the difference in adjusted mean percentage change from baseline at week 72 versus placebo, were observed in the voxelotor 1500 mg group in indirect bilirubin concentrations (-26·6% [95% CI -40·2 to -12·9]) and percentage of reticulocytes (-18·6% [-33·9 to -3·3]). The proportion of patients in the voxelotor 1500 mg group who were rated as "moderately improved" or "very much improved" at week 72 with the CGI-C was significantly greater than in the placebo group (39 [74%] of 53 vs 24 [47%] of 51; p=0·0057). Serious adverse events unrelated to sickle cell disease were reported in 25 (28%) of 88 patients in the voxelotor 1500 mg group, 20 (22%) of 92 patients in the voxelotor 900 mg group, and 23 (25%) of 91 patients in the placebo group. Grade 3 or 4 adverse events were infrequent (ie, occurred in <10% of patients); anaemia occurred in five or more patients (two [2%] patients in the voxelotor 1500 mg group, seven [8%] patients in the voxelotor 900 mg group, and three [3%] patients in the placebo group). Of all 274 patients, six (2%) deaths occurred during the study (two deaths in each treatment group), all of which were judged as unrelated to treatment. INTERPRETATION Voxelotor 1500 mg resulted in rapid and durable improvements in haemoglobin concentrations maintained over 72 weeks and has potential to address the substantial morbidity associated with haemolytic anaemia in sickle cell disease. FUNDING Global Blood Therapeutics.
Neonatal Uterine Bleedings: An Ignored Sign but a Possible Cause of Early-Onset Endometriosis - A Systematic Review
Biomedicine hub. 2021;6(1):6-16
OBJECTIVE Based on the hypothesis that neonatal uterine bleedings (NUB), occurring mostly in the first week after birth, could represent a pathogenetic mechanism for early-onset endometriosis, this systematic review (SR) was undertaken to evaluate the prevalence and screening strategies used to assess and quantify NUB. DESIGN Both a SR and a sample literature search in PubMed and Embase were conducted to gather information on NUB prevalence and screening techniques. This was performed by an information specialist. Only full-text articles regarding the assessment of NUB in neonates in the first 2 weeks after birth were included. No limit on language or publication data was used. MATERIALS AND METHODS The SR was registered in PROSPERO (CRD42019138121). Data was first assessed for eligibility on title and abstract by 2 blinded review authors. Any disagreements were discussed with a third reviewer if necessary. Subsequently, full-text articles were read and assessed for quality using the Cochrane Collaboration Handbook. RESULTS Out of 1,988 articles in the systematic search, 10 relevant articles were selected, of which 8 were identified through the systematic search and 2 were found through other sources. The sample search of 4,445 articles did not bring up relevant articles. Results were not comparable due to the heterogeneity of screening techniques, although data showed consensus. The prevalence of visible bleeding ranged from 3.3 to 53.8% and the prevalence of occult bleeding from 25.4 to 96.7%. The occurrence was the highest between the 3rd and 7th day postpartum (PP) and the bleeding lasted for 3-4 days on average. Various screening techniques for detecting NUB were found in the literature, including the use of hemoglobin detection devices (such as Hemastix) in the vaginal vestibulum, comparison of diapers with stains of known volume, colposcopy, and ultrasonography. CONCLUSION The reported prevalence of NUB varies considerably, with a consistent occurrence between the 3rd and the 7th day PP. Literature to assess NUB is dated. The techniques are poorly described and heterogeneous. Future research should focus on prospective cohort studies in order to attempt to correlate NUB cases to (early-onset) endometriosis.
Transfusion management of severe anaemia in African children: a consensus algorithm
British journal of haematology. 2021
The phase III Transfusion and Treatment of severe anaemia in African Children Trial (TRACT) found that conservative management of uncomplicated severe anaemia [haemoglobin (Hb) 40-60 g/l] was safe, and that transfusion volume (20 vs. 30 ml/kg whole blood equivalent) for children with severe anaemia (Hb <60 g/l) had strong but opposing effects on mortality, depending on fever status (>37·5°C). In 2020 a stakeholder meeting of paediatric and blood transfusion groups from Africa reviewed the results and additional analyses. Among all 3196 children receiving an initial transfusion there was no evidence that nutritional status, presence of shock, malaria parasite burden or sickle cell disease status influenced outcomes or modified the interaction with fever status on volume required. Fever status at the time of ordering blood was a reliable determinant of volume required for optimal outcome. Elevated heart and respiratory rates normalised irrespective of transfusion volume and without diuretics. By consensus, a transfusion management algorithm was developed, incorporating three additional measurements of Hb post-admission, alongside clinical monitoring. The proposed algorithm should help clinicians safely implement findings from TRACT. Further research should assess its implementation in routine clinical practice.
Children presenting to hospital with both uncomplicated and complicated severe anaemia enrolled in the TRACT trial (n= 3,196).
Large volume of whole blood transfusion: 30 ml/kg, (n= 1,598).
Recommended blood volume transfusion by current WHO guidelines: 20 ml/kg (n= 1,598).
Transfusion volume (20 vs. 30 ml/kg whole blood equivalent) for children with severe anaemia had strong but opposing effects on mortality, depending on fever status. There was no evidence that nutritional status, presence of shock, malaria parasite burden or sickle cell disease status influenced outcomes or modified the interaction with fever status on volume required. Fever status at the time of ordering blood was a reliable determinant of volume required for optimal outcome. Elevated heart and respiratory rates normalised irrespective of transfusion volume and without diuretics. By consensus, a transfusion management algorithm was developed, incorporating three additional measurements of Hb post-admission, alongside clinical monitoring.
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.
A scoping review of transition interventions for young adults with sickle cell disease
Pediatric blood & cancer. 2021;:e29135
Standardized programming for individuals with sickle cell disease (SCD) transitioning from pediatric to adult-centered care does not currently exist, resulting in high rates of mortality and morbidity. This scoping review examines and evaluates the current literature on SCD transition programs and interventions. Eligible studies described an existing program for individuals with SCD aged 12-29 years preparing to transition. The Evidence Project risk-of-bias tool was used to assess article quality. We identified 30 eligible articles, of which, only two were randomized controlled trials. Many studies have incomplete reports of feasibility information, such as completion rates, patient characteristics, and attrition; all studies were limited to a single institution; and most studies were rated high for risk of bias. Progress has been made in designing and gathering initial evaluation data for SCD transition programs; however, there is a need for higher quality studies, consistent assessment, and better dissemination of programs.
Recent insight on improving the iron chelation efficacy of deferasirox by adjuvant therapy in transfusion dependent beta thalassemia children with sluggish response
Expert opinion on drug metabolism & toxicology. 2020
Background: Deferasirox is the first line of treatment in iron overload. In spite of the many studies concerning the efficacy of deferasirox, some patients remain unresponsive to deferasirox.Methods: One hundred and sixty patients were enrolled in stratified randomized controlled study. Patients were randomly divided into four regimens, group I (n=40) received 30 mg/kg deferasirox, group II (n=40) received 20 mg omeprazole and 30 mg/kg deferasirox, group III (n=40) received 400 mg vitamin E and 30 mg/kg deferasirox and group IV (n=40) received 420 mg silymarin and 30 mg/kg deferasirox. Blood specimens were collected from each patient for up to 24 h, and then plasma deferasirox concentrations were inspected.Results: Silymarin, Vitamin E and omeprazole significantly increased the peak plasma concentration of deferasirox (P<0.001) by 27.9, 14.9 and 2.4 fold respectively as compared to deferasirox alone. The bioavailability of deferasirox was improved up to 3.03, 3.57 and 4.98-fold, respectively, following administration of omeprazole, vitamin E and silymarin compared to deferasirox alone.Conclusion: Silymarin, vitamin E and omeprazole represent promising adjuvant therapy to improve the chelation efficacy of deferasirox that might also be further applied to enhance the pharmacokinetics of deferasirox to overcome the lack of response.
Transfusion dependent beta thalassemia children with sluggish response (n=160).
Group I 30 mg/kg deferasirox. (n=40).
Group II 20 mg omeprazole and 30 mg/kg deferasirox (n=40); group III 400 mg vitamin E and 30 mg/kg deferasirox (n=40); group IV 420 mg silymarin and 30 mg/kg deferasirox (n=40).
Silymarin, Vitamin E and omeprazole significantly increased the peak plasma concentration of deferasirox by 27.9, 14.9 and 2.4 fold respectively as compared to deferasirox alone. The bioavailability of deferasirox was improved up to 3.03, 3.57 and 4.98-fold, respectively, following administration of omeprazole, vitamin E and silymarin compared to deferasirox alone.
Clinical value of different anti-D immunoglobulin strategies for preventing Rh hemolytic disease of the fetus and newborn: A network meta-analysis
PLoS One. 2020;15(3):e0230073
BACKGROUND Several anti-D immunoglobulin strategies exist for preventing Rh hemolytic disease of the fetus and newborn. This study systematically assessed the clinical value of those therapeutic strategies. METHODS The Web of Science, PubMed, EMBASE, China National Knowledge Infrastructure (CNKI) and Wanfang databases were searched for eligible studies that evaluated the value of different anti-D immunoglobulin strategies in preventing maternal anti-D antibody sensitization. Combined odds ratios (ORs) and their 95% confidence intervals (CIs) were calculated. The network meta-analysis was conducted using Stata 14.2 and WinBUGS 1.4.3 software. RESULTS Twenty-four original studies involving 64860 patients were included. Among all therapeutic measures, injecting 300 mug anti-D immunoglobulin at 28 and 34 gestational weeks (antenatal 5/E) appeared to be the most effective measure for preventing maternal antibody sensitization (surface under the cumulative ranking curve [SUCRA] = 96.8%), while a single injection at 28 gestational weeks (SUCRA = 89.2%) was the second most effective. Administering no injection or a placebo (SUCRA = 0.0%) was the least effective intervention measure. CONCLUSION Among the therapeutic measures, antenatal 5/E appeared to be the best method for reducing the positive incidence of anti-D antibodies in the maternal serum; thus, it may be the most effective treatment for preventing fetal hemolytic disease.
Etiology and therapeutic management of neonatal jaundice in Iran: a systematic review and meta-analysis
World journal of pediatrics : WJP. 2020
BACKGROUND Jaundice is a life-threatening disorder in the neonates. In the present study, we aimed to assess systematically available evidence on causes and management of jaundice in Iranian newborn patients. METHODS We searched the databases of PubMed, Web of Sciences, Scopus and Google Scholar for English articles published since inception until May 2019. A search was also done for Persian articles in Magiran and Scientific Information Database. Studies were evaluated based on predefined criteria by two reviewers. Data analysis was performed by STATA software. RESULTS A total of 33 articles were finally included. The overall pooled prevalence of causes of jaundice among Iranian neonates was as follows: ABO blood groups incompatibility, 16.9% [95% confidence interval (CI) 10.9-22.8]; Rh blood group incompatibility, 4% (95% CI 2.5-5.5); ABO and Rh blood groups incompatibility, 3.6% (95% CI 0-7.7); glucose-6-phosphate dehydrogenase (G6PD) deficiency, 6.3% (95% CI 5.1-7.5); infection, 6.6% (95% CI 5.2-8.1); hypothyroidism, 4.2% (95% CI 0.1-8.3); infant of diabetic mother: 2.3% (95% CI 0.1-4.5); unknown, 50.7% (95% CI 33.4-68); cephalohematoma, 0.6% (95% CI 0.3-0.9). Regarding treatment of icterus, seven and eight articles were found on phototherapy and exchange transfusion, respectively. In five studies, all patients underwent phototherapy, but rate of exchange transfusion use was between 6.6% and 50.9%. CONCLUSIONS According to the results, unknown factors were the most common causes of icterus in Iranian neonates, followed by ABO blood groups incompatibility, infections and G6PD deficiency. By the way, phototherapy and exchange transfusion were found as therapeutic choices of neonatal jaundice.
Randomized controlled trial of effect of N-acetylcysteine as an antioxidant on iron overload in children with thalassemia major
Clinical and experimental pediatrics. 2020
BACKGROUND β-Thalassemias are characterized by the presence of mutations in the globin gene that result in the absence or reduced synthesis of β-globin chains of the hemoglobin tetramer. Several studies have reported increased oxidative stress in β-thalassemia major (β-TM) patients. N-acetylcysteine (NAC), a derivative of L-cysteine amino acid, is commonly used as a mucolytic drug. Numerous studies have reported efficient antioxidant activity of NAC. PURPOSE To evaluate the effects of NAC on oxidative stress status and hemoglobin levels in children with β-TM. METHODS This study was conducted between June and December 2019. One hundred β-TM patients were divided into two groups: 50 received NAC 10 mg/kg orally for 3 months (treatment group), while the other 50 received no treatment (non-treatment group). Total oxidant status (TOS), total antioxidant capacity (TAC), oxidative stress index (OSI), and hemoglobin (Hb) and ferritin levels were measured and compared between groups. RESULTS At the end of the study period, Hb and TAC levels were significantly higher in the treatment group than in the non-treatment group (P < .001 and .01, respectively). On the other hand, serum ferritin levels, TOS, and OSI were significantly lower (P = .004, .01, and .001, respectively) in the treatment group. CONCLUSION NAC can effectively reduce the oxidative status and increase the pre-transfusion Hb levels in children with β-TM. Furthermore, NAC could reduce iron overload in these patients.
Prevalence of neonatal hyperbilirubinaemia and its association with glucose-6-phosphate dehydrogenase deficiency and blood-type incompatibility in sub-Saharan Africa: a systematic review and meta-analysis
BMJ paediatrics open. 2020;4(1):e000750
BACKGROUND Hyperbilirubinaemia is a silent cause of newborn disease and death worldwide. However, studies of the disease in sub-Saharan Africa are highly variable with respect to its prevalence. Hence, this study aimed to estimate the overall magnitude of neonatal hyperbilirubinaemia and its association with glucose-6-phosphate dehydrogenase (G6PD) deficiency and blood-type incompatibility in sub-Saharan Africa. METHODS PubMed, Scopus, Google Scholar and the Cochrane Review were systematically searched online to retrieve hyperbilirubinaemia-related articles. All observational studies reported the prevalence of hyperbilirubinaemia in sub-Saharan Africa were included for analysis and excluded if the study failed to determine the desired outcome. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. Heterogeneity across the included studies was evaluated using the inconsistency index (I(2)). Subgroup and meta- regression analysis were also done. Publication bias was examined by funnel plot and the Egger's regression test. The random-effect model was fitted to estimate the pooled prevalence of neonatal hyperbilirubinaemia. The meta-analysis was performed using the STATA V.14 software. RESULTS A total of 30 486 studies were collected from the different databases and 10 articles were included for the final analysis. The overall magnitude of neonatal hyperbilirubinaemia was 28.08% (95% CI20.23 to 35.94, I(2)=83.2) in sub-Saharan Africa. Neonates with G6PD deficiency (OR 2.42, 95% CI 1.64 to 3.56, I(2)=37%) and neonates that had a blood type that was incompatible with their mother's (OR 3.3, (95% CI 1.96 to 5.72, I(2)=84%) were more likely to develop hyperbilirubinaemia. CONCLUSION The failure to prevent and screen G6PD deficiency and blood-type incompatibility with their mother's results in high burden of neonatal hyperbilirubinaemia in sub-Saharan Africa. Therefore, early identification and care strategies should be developed to the affected neonates with G6PD deficiency and blood-type incompatibility with their mother's to address long-term medical and scholastic damages among those exposed to hyperbilirubinaemia.