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Lancet (London, England) Aug 2022Patients with non-transfusion-dependent thalassaemia (NTDT), although they do not require regular blood transfusions for survival, can still accrue a heavy burden of...
Safety and efficacy of mitapivat, an oral pyruvate kinase activator, in adults with non-transfusion dependent α-thalassaemia or β-thalassaemia: an open-label, multicentre, phase 2 study.
BACKGROUND
Patients with non-transfusion-dependent thalassaemia (NTDT), although they do not require regular blood transfusions for survival, can still accrue a heavy burden of comorbidities. No approved disease-modifying therapies exist for these patients. We aimed to investigate the safety and efficacy of mitapivat (Agios Pharmaceuticals, Cambridge, MA, USA), a pyruvate kinase activator, in adults with non-transfusion-dependent (NTD) α-thalassaemia or NTD β-thalassaemia.
METHODS
In this open-label, multicentre, phase 2 study, patients were recruited from four academic clinical study sites in Oakland, CA, and Boston, MA, USA; Toronto, ON, Canada; and London, UK. Patients were eligible if they were aged 18 years or older, with NTDT (including β-thalassaemia with or without α-globin gene mutations, haemoglobin E β-thalassaemia, or α-thalassaemia), and a baseline haemoglobin concentration of 10·0 g/dL or lower. During a 24-week core period, mitapivat was administered orally at 50 mg twice daily for the first 6 weeks followed by an escalation to 100 mg twice daily for 18 weeks thereafter. The primary endpoint was haemoglobin response (a ≥1·0 g/dL increase in haemoglobin concentration from baseline at one or more assessments between weeks 4 and 12). Efficacy and safety were assessed in the full analysis set (ie, all patients who received at least one dose of study drug). This study is registered with ClinicalTrials.gov, NCT03692052, and is closed to accrual.
FINDINGS
Between Dec 28, 2018, and Feb 6, 2020, 27 patients were screened, of whom 20 were enrolled (15 [75%] with β-thalassaemia and five [25%] with α-thalassaemia) and received mitapivat. The median age of patients was 44 years (IQR 35-56), 15 (75%) of 20 patients were female, five (25%) were male, and ten (50%) identified as Asian. 16 (80% [90% CI 60-93]) of 20 patients had a haemoglobin response (p<0·0001), five (100%) of five with α-thalassaemia and 11 (73%) of 15 with β-thalassaemia. 17 (85%) patients had a treatment-emergent adverse event, and 13 had a treatment-emergent event that was considered to be treatment related. One serious treatment-emergent adverse event occurred (grade 3 renal impairment), which was considered unrelated to study drug, resulting in discontinuation of treatment. The most commonly reported treatment-emergent adverse events were initial insomnia (ten [50%] patients), dizziness (six [30%]), and headache (five [25%]). No patients died during the 24-week core period.
INTERPRETATION
These efficacy and safety results support the continued investigation of mitapivat for the treatment of both α-thalassaemia and β-thalassaemia.
FUNDING
Agios Pharmaceuticals.
Topics: Adult; Female; Hemoglobins; Humans; Male; Middle Aged; Piperazines; Pyruvate Kinase; Quinolines; alpha-Thalassemia; beta-Thalassemia
PubMed: 35964609
DOI: 10.1016/S0140-6736(22)01337-X -
Hemoglobin Sep 2022Thalassemia is one of southern China's most common inherited disorders. Little is known about the genotypes of thalassemia in children in Jiangxi Province, the People's...
Thalassemia is one of southern China's most common inherited disorders. Little is known about the genotypes of thalassemia in children in Jiangxi Province, the People's Republic of China (PRC). Two thousand, nine hundred and fifty-two children with suspected thalassemia were recruited from August 2016 to December 2020 at the Jiangxi Provincial Children's Hospital, Nanchang, PRC. Reverse dot-blot hybridization was used to detect α- and β-thalassemia (α- and β-thal) genotypes. A rare mutation was detected using gap-polymerase chain reaction (gap-PCR) and gene sequencing. The overall distribution of thalassemia (1534 cases) was 51.96%, and the detection rate of α-thal (616 cases), β-thal (888 cases) and concurrent α- and β-thalassemias (30 cases) was 20.86, 30.08, and 1.02%, respectively. A rare α-thal genotype, -α/- - (Southeast Asian), was identified. Seventy-eight cases of severe β-thal were detected, accounting for 8.78% of the cases, including 56 double heterozygous cases and 22 cases that were homozygous. Both α- and β-thalassemias are widely distributed in the children of Jiangxi Province. Thalassemia genetic testing is essential to establish a comprehensive thalassemia prevention program and improve public education.
Topics: Child; Humans; Thalassemia; beta-Thalassemia; Mutation; Genotype; China; alpha-Thalassemia
PubMed: 36317662
DOI: 10.1080/03630269.2022.2138429 -
Blood Cells, Molecules & Diseases May 2017α-thalassemia carriers are common in Mediterranean regions, particularly in the Sardinian population. Their haematological phenotype is characterized by reduced MCV...
α-thalassemia carriers are common in Mediterranean regions, particularly in the Sardinian population. Their haematological phenotype is characterized by reduced MCV and/or MCH with normal or slightly reduced HbA2 levels and normal HbF. Krüppel-like factor 1 (KLF1) is a pleiotropic erythroid transcription factor that is essential for haematopoiesis. Mutations in the KLF1 gene trigger a series of benign human red blood phenotypes, such as an increase in HbA2 and HBF. Recently, it has been found that KLF1 mutations were a frequent cause of borderline HbA2 levels in a group of Sardinian subjects. Here, we found that KLF1 mutations modulate the phenotype in a cohort of α-thalassemia carriers.
Topics: Adolescent; Adult; Female; Fetal Hemoglobin; Hemoglobin A2; Heterozygote; Humans; Kruppel-Like Transcription Factors; Male; Middle Aged; Mutation; alpha-Thalassemia
PubMed: 28342932
DOI: 10.1016/j.bcmd.2017.03.007 -
Analytical Chemistry Jun 2023Identification of α-thalassemia silent carriers is challenging with conventional phenotype-based screening methods. A liquid chromatography tandem mass spectrometry...
Identification of α-thalassemia silent carriers is challenging with conventional phenotype-based screening methods. A liquid chromatography tandem mass spectrometry (LC-MS/MS)-based approach may offer novel biomarkers to address this conundrum. In this study, we collected dried blood spot samples from individuals with three α-thalassemia subtypes for biomarker discovery and validation. We observed differential expression patterns of hemoglobin subunits among various α-thalassemia subtypes and normal controls through proteomic profiling of 51 samples in the discovery phase. Then, we developed and optimized a multiple reaction monitoring (MRM) assay to measure all detectable hemoglobin subunits. The validation phase was conducted in a cohort of 462 samples. Among the measured hemoglobin subunits, subunit μ was significantly upregulated in all the α-thalassemia groups with distinct fold changes. The hemoglobin subunit μ exhibits great potential as a novel biomarker for α-thalassemia, especially for silent α-thalassemia. We constructed predictive models based on the concentrations of hemoglobin subunits and their ratios to classify the various subtypes of α-thalassemia. In the binary classification problems of silent α-thalassemia vs normal, non-deletional α-thalassemia vs normal, and deletional α-thalassemia vs normal, the best performance of the models achieved average ROCAUCs of 0.9505, 0.9430, and 0.9976 in the cross-validation, respectively. In the multiclass model, the best performance achieved an average ROCAUC of 0.9290 in cross-validation. The performance of our MRM assay and models demonstrated that the hemoglobin subunit μ would play a vital role in screening silent α-thalassemia in clinical practice.
Topics: Humans; Chromatography, Liquid; Hemoglobin Subunits; Tandem Mass Spectrometry; alpha-Thalassemia; Proteomics; Biomarkers
PubMed: 37285171
DOI: 10.1021/acs.analchem.3c00895 -
International Journal of Hematology Sep 2023This study reviewed and analyzed the prenatal diagnosis experience of thalassemia in our center over the past decade and the abnormal ultrasonic characteristics of...
OBJECTIVE
This study reviewed and analyzed the prenatal diagnosis experience of thalassemia in our center over the past decade and the abnormal ultrasonic characteristics of fetuses with hemoglobin (Hb) Bart's hydrops fetalis.
METHODS
Pregnant women and their partners who tested positive for α-thalassemia or were diagnosed with thalassemia intermedia (HbH diseases) underwent genetic counseling, and a prenatal diagnostic procedure for α-thalassemia was recommended. Ultrasonography was performed before prenatal diagnosis.
RESULTS
Invasive prenatal α-thalassemia diagnosis and ultrasonography were performed in 1049 patients at risk for Hb Bart's hydrops fetalis syndrome at our hospital from 2012 to 2021. Chorionic villus sampling (CVS) was performed in 58 cases (5.5%), amniocentesis in 902 cases (86%), and cordocentesis in 89 cases (8.5%). Hb Bart's hydrops fetalis syndrome was diagnosed in 280 fetuses. The most common body cavity effusion was pericardial effusion, ascites, and fetal systemic edema.
CONCLUSIONS
The extensive experience at our center shows that carrier screening, molecular diagnostics, genetic counseling, and prenatal diagnosis are effective measures to prevent Hb Bart's hydrops fetalis syndrome. The ultrasonographic abnormalities in fetuses with Hb Bart's hydrops are mainly caused by an increase in cardiac output, which leads to the body cavity effusion from various organs.
Topics: Humans; Pregnancy; Female; alpha-Thalassemia; Hydrops Fetalis; Retrospective Studies; Ultrasonics; Hospitals, Municipal; Prenatal Diagnosis; Hemoglobins, Abnormal
PubMed: 37477864
DOI: 10.1007/s12185-023-03643-6 -
Hemoglobin Jan 2020The aim of this study was to identify the rare thalassemia genotype in a family and perform prenatal diagnosis (PND) on the proband's unborn child. Peripheral blood was...
The aim of this study was to identify the rare thalassemia genotype in a family and perform prenatal diagnosis (PND) on the proband's unborn child. Peripheral blood was collected from the family members for hematology analysis and capillary electrophoresis (CE) analysis. Peripheral blood and cord blood were analyzed by gap-polymerase chain reaction (gap-PCR), reverse dot-blot and Sanger sequencing for genotypes of α-thalassemia (α-thal). A heterozygous mutation, : c.1A>G, was identified in the proband and his father. Two compound heterozygous variants, : c.1A>G and the - - (Southeast Asian) deletion, were revealed in the proband's unborn child. The hemoglobin (Hb) CE result of the fetal cord blood indicated the fetus had Hb H disease. We have identified a rare thalassemia mutation (: c.1A>G) in a Chinese family and enriched the rare α-thal gene pool in the Chinese population. When the patient's phenotype does not match the genotype detected by thalassemia gene detection kits, further investigation of rare genotypes should be conducted to avoid missed diagnosis or misdiagnosis, which can help guide clinical diagnosis, population screening and genetic counseling.
Topics: Adult; Asian People; Base Sequence; Female; Fetus; Gene Expression; Genetic Counseling; Genotype; Hemoglobin A2; Hemoglobin H; Heterozygote; Humans; Male; Mutation; Pedigree; Phenotype; Prenatal Diagnosis; Sequence Analysis, DNA; alpha-Globins; alpha-Thalassemia
PubMed: 31933393
DOI: 10.1080/03630269.2020.1711771 -
Scientific Reports Jun 2023α-thalassemia is an inherited blood disorder that is most frequently found in Southeast Asian populations. In Thailand, molecular characterization can diagnose most...
α-thalassemia is an inherited blood disorder that is most frequently found in Southeast Asian populations. In Thailand, molecular characterization can diagnose most patients with α-thalassemia; however, several atypical patients are also observed in routine analyses. Here, we characterized α-thalassemia mutations among 137 Hemoglobin H (Hb H) disease patients and three fetuses of Hb Bart's hydrops, a fatal clinical phenotype of α-thalassemia. Specifically, we performed multiplex ligation-dependent probe amplification (MLPA) followed by direct DNA sequencing. We noticed common genotypes in 129 patients and eight patients had rare Hb H disease caused by compound heterozygous α-thalassemia (-- or -- deletion) with α-thalassemia (-α/-α/αα). Furthermore, two affected fetuses had the --/-- and one had the --/-- genotypes. Next, we developed and validated a new multiplex gap-PCR and applied this method to 844 subjects with microcytic red blood cells (RBCs) from various parts of Thailand. The frequency of heterozygous α-thalassemia was dominated by -- 363/844 (43%), followed by -- 3/844 (0.4%), -- 2/844 (0.2%), and -- 2/844 (0.2%) mutations. These findings suggest that aforementioned four mutations should be routinely applied to increase the effectiveness of diagnosis and genetic counseling in this region.
Topics: Pregnancy; Female; Humans; alpha-Thalassemia; Thailand; Prenatal Diagnosis; Multiplex Polymerase Chain Reaction; Molecular Epidemiology; Sequence Deletion; Mutation; Genotype
PubMed: 37330590
DOI: 10.1038/s41598-023-36840-8 -
Hematology. American Society of... Dec 2021α-Thalassemia major (ATM) is a severe disease resulting from deletions in all 4 copies of the α-globin gene. Although it is usually fatal before birth, the advent of... (Review)
Review
α-Thalassemia major (ATM) is a severe disease resulting from deletions in all 4 copies of the α-globin gene. Although it is usually fatal before birth, the advent of in utero transfusions has enabled survival of a growing number of children. Postnatal therapy consists of chronic transfusions or stem cell transplantation, similar to patients with β-thalassemia major. In this review, we discuss the experience with postnatal stem cell transplantation in patients with ATM, as well as the ongoing phase 1 clinical trial of in utero stem cell transplantation for this condition.
Topics: Blood Transfusion; Blood Transfusion, Intrauterine; Disease Management; Hematopoietic Stem Cell Transplantation; Humans; Prenatal Diagnosis; alpha-Thalassemia
PubMed: 34889445
DOI: 10.1182/hematology.2021000295 -
Hemoglobin Jul 2022Vietnam has a high thalassemia burden. We collected blood samples from 5880 pregnant Vietnamese women during prenatal health checks to assess thalassemia carrier...
Vietnam has a high thalassemia burden. We collected blood samples from 5880 pregnant Vietnamese women during prenatal health checks to assess thalassemia carrier frequency using combined gap-polymerase chain reaction (gap-PCR) and targeted next-generation sequencing (NGS). Thalassemia carriers were identified with prevalence of 13.13% (772), including 7.82% (460) carriers of α-thalassemia (α-thal), 5.31% (312) carriers of β-thalassemia (β-thal), and 0.63% (37) concurrent α-/β-thal carriers. Deletional mutations (368) accounted for 80.0% of α-thal carriers, of which, -- (Southeast Asian) ( = 254; 55.0%) was most prevalent, followed by the -α (rightward) ( = 66; 14.0%) and -α (leftward) ( = 45; 9.8%) deletions. Hb Westmead (: c.369C>G) ( = 53) and Hb Constant Spring (Hb CS or : c.427T>C) (in 28) are the two most common nondeletional α-globin variants, accounting for 11.5 and 6.0% of α-thal carriers. We detected 11 different β-thal genotypes. Hb E (: c.79G>A) (in 211) accounted for 67.6% of β-thal carriers. The most common β-thal genotypes were associated with mutations at codon 17 (A>T) (: c.52A>T), codons 41/42 (-TTCT) (: c.126_129delCTTT), and codon 71/72 (+A) (: c.217_218insA) (prevalence 0.70%, 0.68%, and 0.2%, respectively). Based on mutation frequencies calculated in this study, estimates of 5021 babies in Vietnam are affected with clinically severe thalassemia annually. Our data suggest a higher thalassemia carrier frequency in Vietnam than previously reported. We established that combining NGS with gap-PCR creates an effective large-scale thalassemia screening method that can detect a broad range of mutations.
Topics: Female; Humans; Pregnancy; beta-Thalassemia; beta-Globins; Pregnant Women; Vietnam; Gene Frequency; alpha-Thalassemia; Polymerase Chain Reaction; Mutation; Codon; Genotype; High-Throughput Nucleotide Sequencing
PubMed: 35993587
DOI: 10.1080/03630269.2022.2096461 -
Annals of Medicine 2023An increasing number of α-hemoglobin (Hb) variants is causing various clinical symptoms; therefore, accurate identification of these Hb variants is important.
Hemoglobin profile and molecular characteristics of the complex interaction of hemoglobin Doi-Saket [α9(A7) asn > lys, HBA2:c.30C > a], a novel α2α1 hybrid globin variant, with hemoglobin E [β26(B8) Glu > lys, HBB:c.79G > A] and deletional α-thalassemia in a Thai family.
BACKGROUND
An increasing number of α-hemoglobin (Hb) variants is causing various clinical symptoms; therefore, accurate identification of these Hb variants is important.
OBJECTIVE
This study aimed to describe the molecular and hematological characteristics of novel Hb Doi-Saket that gives rise to a typical α-thalassemia phenotype in carriers with and without other hemoglobinopathies.
MATERIALS AND METHODS
Biological samples from a proband and his family members were analyzed. Hematological profiles were analyzed using a standard automated cell counter. Hb was analyzed by capillary electrophoresis and high-performance liquid chromatography. Mutations and globin haplotype were identified by DNA analysis. Novel diagnostic tools based on allele-specific polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism were developed.
RESULTS
Hb analysis showed a major abnormal Hb fraction, moving slower than HbA, and a minor Hb fraction alongside HbA in the proband, his father, and son. DNA analysis of the α-globin gene identified the -α deletion and in the C > A mutation on codon 9 of the α2α1 gene, corresponding to Hb Doi-Saket [α9(A7) Asn > Lys]. This mutation could be identified using newly developed allele-specific PCR-based assays. The Hb Doi-Saket al.lele was significantly associated with haplotype [- + M + + 0 -]. Interaction of α with β globin chains led to a new Hb variant (HbE Doi-Saket). Phenotypic expression was clinically silent in heterozygotes and might present slight microcytosis.
CONCLUSIONS
Hb Doi-Saket emphasizes a great diversity present in α-globin gene. The mutation in this family from Thailand was linked to -α and caused mild microcytosis in the carriers. The combination of this variant with deletions in α genes might cause a severe clinical phenotype. Different methods of separation can provide useful information in diagnosis, and a complete molecular approach is needed for confirmation before considering patient management.
Topics: Humans; Hemoglobin E; Thailand; Southeast Asian People; alpha-Thalassemia; Hemoglobins, Abnormal; Mutation; DNA; alpha-Globins
PubMed: 37796611
DOI: 10.1080/07853890.2023.2264174