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Hematology/oncology Clinics of North... Apr 2023Clinical manifestations of α-thalassemia range from no symptoms to severe transfusion-dependent anemia. Alpha thalassemia trait is deletion of 1 to 2 α-globin genes,... (Review)
Review
Clinical manifestations of α-thalassemia range from no symptoms to severe transfusion-dependent anemia. Alpha thalassemia trait is deletion of 1 to 2 α-globin genes, whereas α-thalassemia major (ATM; Barts hydrops fetalis) is the deletion all 4 α genes. All other genotypes of intermediate severity are categorized as HbH disease, a vastly heterogenous group. Clinical spectrum is classified as mild, moderate, and severe by symptoms and need for intervention. Anemia in prenatal period may be fatal without intrauterine transfusions. New therapies to modify HbH disease or provide cure for ATM are under development.
Topics: Pregnancy; Female; Humans; alpha-Thalassemia; Hydrops Fetalis; Phenotype; Genotype; Anemia
PubMed: 36907606
DOI: 10.1016/j.hoc.2022.12.004 -
The New England Journal of Medicine Aug 2019Deoxygenated sickle hemoglobin (HbS) polymerization drives the pathophysiology of sickle cell disease. Therefore, direct inhibition of HbS polymerization has potential... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
Deoxygenated sickle hemoglobin (HbS) polymerization drives the pathophysiology of sickle cell disease. Therefore, direct inhibition of HbS polymerization has potential to favorably modify disease outcomes. Voxelotor is an HbS polymerization inhibitor.
METHODS
In a multicenter, phase 3, double-blind, randomized, placebo-controlled trial, we compared the efficacy and safety of two dose levels of voxelotor (1500 mg and 900 mg, administered orally once daily) with placebo in persons with sickle cell disease. The primary end point was the percentage of participants who had a hemoglobin response, which was defined as an increase of more than 1.0 g per deciliter from baseline at week 24 in the intention-to-treat analysis.
RESULTS
A total of 274 participants were randomly assigned in a 1:1:1 ratio to receive a once-daily oral dose of 1500 mg of voxelotor, 900 mg of voxelotor, or placebo. Most participants had sickle cell anemia (homozygous hemoglobin S or hemoglobin Sβ-thalassemia), and approximately two thirds were receiving hydroxyurea at baseline. In the intention-to-treat analysis, a significantly higher percentage of participants had a hemoglobin response in the 1500-mg voxelotor group (51%; 95% confidence interval [CI], 41 to 61) than in the placebo group (7%; 95% CI, 1 to 12). Anemia worsened between baseline and week 24 in fewer participants in each voxelotor dose group than in those receiving placebo. At week 24, the 1500-mg voxelotor group had significantly greater reductions from baseline in the indirect bilirubin level and percentage of reticulocytes than the placebo group. The percentage of participants with an adverse event that occurred or worsened during the treatment period was similar across the trial groups. Adverse events of at least grade 3 occurred in 26% of the participants in the 1500-mg voxelotor group, 23% in the 900-mg voxelotor group, and 26% in the placebo group. Most adverse events were not related to the trial drug or placebo, as determined by the investigators.
CONCLUSIONS
In this phase 3 randomized, placebo-controlled trial involving participants with sickle cell disease, voxelotor significantly increased hemoglobin levels and reduced markers of hemolysis. These findings are consistent with inhibition of HbS polymerization and indicate a disease-modifying potential. (Funded by Global Blood Therapeutics; HOPE ClinicalTrials.gov number, NCT03036813.).
Topics: Adolescent; Adult; Anemia, Sickle Cell; Antisickling Agents; Benzaldehydes; Biomarkers; Child; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Female; Hemoglobin, Sickle; Hemoglobins; Hemolysis; Humans; Hydroxyurea; Intention to Treat Analysis; Male; Middle Aged; Polymerization; Pyrazines; Pyrazoles; Young Adult
PubMed: 31199090
DOI: 10.1056/NEJMoa1903212 -
The New England Journal of Medicine May 2024Exagamglogene autotemcel (exa-cel) is a nonviral cell therapy designed to reactivate fetal hemoglobin synthesis by means of ex vivo clustered regularly interspaced short...
BACKGROUND
Exagamglogene autotemcel (exa-cel) is a nonviral cell therapy designed to reactivate fetal hemoglobin synthesis by means of ex vivo clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 gene editing of autologous CD34+ hematopoietic stem and progenitor cells (HSPCs) at the erythroid-specific enhancer region of .
METHODS
We conducted a phase 3, single-group, open-label study of exa-cel in patients 12 to 35 years of age with sickle cell disease who had had at least two severe vaso-occlusive crises in each of the 2 years before screening. CD34+ HSPCs were edited with the use of CRISPR-Cas9. Before the exa-cel infusion, patients underwent myeloablative conditioning with pharmacokinetically dose-adjusted busulfan. The primary end point was freedom from severe vaso-occlusive crises for at least 12 consecutive months. A key secondary end point was freedom from inpatient hospitalization for severe vaso-occlusive crises for at least 12 consecutive months. The safety of exa-cel was also assessed.
RESULTS
A total of 44 patients received exa-cel, and the median follow-up was 19.3 months (range, 0.8 to 48.1). Neutrophils and platelets engrafted in each patient. Of the 30 patients who had sufficient follow-up to be evaluated, 29 (97%; 95% confidence interval [CI], 83 to 100) were free from vaso-occlusive crises for at least 12 consecutive months, and all 30 (100%; 95% CI, 88 to 100) were free from hospitalizations for vaso-occlusive crises for at least 12 consecutive months (P<0.001 for both comparisons against the null hypothesis of a 50% response). The safety profile of exa-cel was generally consistent with that of myeloablative busulfan conditioning and autologous HSPC transplantation. No cancers occurred.
CONCLUSIONS
Treatment with exa-cel eliminated vaso-occlusive crises in 97% of patients with sickle cell disease for a period of 12 months or more. (CLIMB SCD-121; ClinicalTrials.gov number, NCT03745287.).
Topics: Adolescent; Adult; Child; Female; Humans; Male; Young Adult; Anemia, Sickle Cell; Antigens, CD34; Busulfan; CRISPR-Cas Systems; Fetal Hemoglobin; Gene Editing; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Repressor Proteins; Transplantation Conditioning; Cell- and Tissue-Based Therapy; Myeloablative Agonists; Europe; North America
PubMed: 38661449
DOI: 10.1056/NEJMoa2309676 -
Internal Medicine Journal May 2020
Topics: Edema; Hemoglobins, Abnormal; Humans; Hydrops Fetalis; alpha-Thalassemia
PubMed: 32431038
DOI: 10.1111/imj.14823 -
Annals of the New York Academy of... 2005alpha-Thalassemia mutations are one of the most common mutations of man, and they cause Hb H disease and Hb Barts hydrops fetalis. Hb H disease is not necessarily a... (Review)
Review
alpha-Thalassemia mutations are one of the most common mutations of man, and they cause Hb H disease and Hb Barts hydrops fetalis. Hb H disease is not necessarily a benign disorder as has been generally thought. Furthermore, in southern China and in Southeast Asia, there are 2-3 times more fetuses afflicted with the invariably fatal Hb Barts hydrops fetalis than with the beta-thalassemia major or intermedia. These findings underscore the public health importance of these hereditary disorders, and they call for better education, diagnosis, treatment, prevention, and research for these diseases.
Topics: Asia, Southeastern; China; Female; Fetal Death; Fetal Diseases; Forecasting; Gene Frequency; Genotype; Globins; Health Education; Hemoglobins, Abnormal; Humans; Hydrops Fetalis; Infant, Newborn; International Cooperation; Male; Mutation; Pregnancy; Pregnancy Complications, Hematologic; Pregnancy Outcome; Prenatal Diagnosis; Research; Risk; Sequence Deletion; Stillbirth; alpha-Thalassemia
PubMed: 16339648
DOI: 10.1196/annals.1345.004 -
Current Opinion in Obstetrics &... Dec 2019The implementation of palliative care at birth has led to a significant rise in the number of couples who choose to continue with pregnancies complicated by... (Review)
Review
PURPOSE OF REVIEW
The implementation of palliative care at birth has led to a significant rise in the number of couples who choose to continue with pregnancies complicated by life-limiting malformations (LLMs). Prenatal counselling and appropriate antenatal/perinatal management in these cases are poorly studied and may pose significant challenges. The purpose of this review is to outline specific obstetric risks and to suggest management for mothers who choose to continue with pregnancies with the most common LLMs.
RECENT FINDINGS
In pregnancies complicated by LLMs where parents opt for expectant management, clinicians should respect parental wishes, whilst openly sharing potential serious maternal medical risks specific for the identified abnormalities. The focus of both antenatal and perinatal care should be maternal wellbeing rather than foetal survival. Follow-up ultrasound examinations and maternal surveillance should be aimed at achieving timely diagnosis and effective management of obstetric complications. A clear perinatal plan, agreed with the couples by a multi-disciplinary team including a foetal medicine specialist, a neonatologist and a geneticist, is crucial to reduce maternal morbidity.
SUMMARY
This review provides a useful framework for clinicians who face the challenges of counselling and managing cases complicated by LLMs where parents opt for pregnancy continuation.
Topics: Anencephaly; Congenital Abnormalities; Female; Genetic Counseling; Holoprosencephaly; Humans; Hydrops Fetalis; Neonatology; Obstetrics; Palliative Care; Patient Care Team; Pregnancy; Pregnancy Complications; Prenatal Care; Risk; Triploidy; Trisomy 13 Syndrome; Trisomy 18 Syndrome; Turner Syndrome; Ultrasonography
PubMed: 31693566
DOI: 10.1097/GCO.0000000000000583 -
Hematology. American Society of... 2004New developments in the epidemiology, treatment and prognosis of thalassemia have dramatically altered the approach to the care of affected patients, and these... (Review)
Review
New developments in the epidemiology, treatment and prognosis of thalassemia have dramatically altered the approach to the care of affected patients, and these developments are likely to have an even greater impact in the next few years. Demographic changes have required an awareness and understanding of the unique features of thalassemia disorders that were previously uncommon in North America but are now seen more frequently in children and recognized more consistently in adults. New methods for measuring tissue iron accumulation and new drugs to remove excessive iron are advancing two of the most challenging areas in the management of thalassemia as well as other transfusion-dependent disorders. Improved survival of patients with thalassemia has given new importance to adult complications such as endocrinopathies and hepatitis that have a major impact on the quality of life. This chapter describes how these changes are redefining the clinical management of thalassemia. In Section I, Dr. Renzo Galanello describes recent advances in iron chelation therapy. Several new chelators are either licensed in some countries, are in clinical trials or are in the late stages of preclinical development. Some of these iron chelators, such as deferiprone (DFP) and ICL670, are orally active. Others, such as hydroxybenzyl-ethylenediamine-diacetic acid (HBED) and starch deferoxamine, require parenteral administration but may be effective with less frequent administration than is currently required for deferoxamine. Chelation therapy employing two chelators offers the possibility of more effective removal of iron without compromising safety or compliance. Other strategies for chelation therapy may take advantage of the ability of particular chelators to remove iron from specific target organs such as the heart and the liver. In Section II, Dr. Dudley Pennell addresses cardiac iron overload, the most frequent cause of death from chronic transfusion therapy. The cardiac complications related to excessive iron may result from long-term iron deposition in vulnerable areas or may be due to the more immediate effects of nontransferrin-bound iron. Cardiac disease is reversible in some patients with intensive iron chelation therapy, but identification of cardiac problems prior to the onset of serious arrhythmias or congestive heart failure has proven difficult. New methods using magnetic resonance imaging (MRI) have recently been developed to assess cardiac iron loading, and studies suggest a clinically useful relationship between the results using these techniques and critical measures of cardiac function. Measurements such as T2* may help guide chelation therapy in individual patients and may also enhance the assessment of new chelators in clinical trials. The use of MRI-based technology also holds promise for wider application of non-invasive assessment of cardiac iron in the management of patients with thalassemia. In Section III, Dr. Melody Cunningham describes some of the important complications of thalassemia that are emerging as patients survive into adulthood. Hepatitis C infection is present in the majority of patients older than 25 years. However, antiviral therapy in patients with thalassemia has been held back by the absence of large clinical trials and concern about ribavirin-induced hemolysis. More aggressive approaches to the treatment of hepatitis C may be particularly valuable because of the additive risks for cirrhosis and hepatocellular carcinoma that are posed by infection and iron overload. Thrombosis is recognized with increasing frequency as a significant complication of thalassemia major and thalassemia intermedia, and pulmonary hypertension is now the focus of intense study. Risk factors for thrombosis such as splenectomy are being identified and new approaches to anticoagulation are being initiated. Pregnancies in women with thalassemia are increasingly common with and without hormonal therapy, and require a better understanding of the risks of iron overload and cardiac disease in the mother and exposure of the fetus to iron chelators. In Section IV, Dr. Elliott Vichinsky describes the dramatic changes in the epidemiology of thalassemia in North America. Hemoglobin E-beta thalassemia is seen with increasing frequency and poses a particular challenge because of the wide variability in clinical severity. Some affected patients may require little or no intervention, while others need chronic transfusion therapy and may be appropriate candidates for hematopoietic stem cell transplantation. Enhancers of fetal hemoglobin production may have a unique role in Hb E-beta thalassemia since a modest increase in hemoglobin level may confer substantial clinical benefits. Alpha thalassemia is also being recognized with increasing frequency in North America, and newborn screening for Hemoglobin Barts in some states is leading to early detection of Hb H disease and Hb H Constant Spring. New data clarify the importance of distinguishing these two disorders because of the increased severity associated with Hb H Constant Spring. The use of intrauterine transfusions to sustain the viability of fetuses with homozygous alpha thalassemia has created a new population of patients with severe thalassemia and has raised new and complex issues in genetic counseling for parents with alpha thalassemia trait.
Topics: Heart; Humans; Iron; Iron Chelating Agents; Liver; Thalassemia
PubMed: 15561674
DOI: 10.1182/asheducation-2004.1.14 -
Nature Communications Apr 2023Haemoglobin E (HbE) β-thalassaemia causes approximately 50% of all severe thalassaemia worldwide; equating to around 30,000 births per year. HbE β-thalassaemia is due...
Haemoglobin E (HbE) β-thalassaemia causes approximately 50% of all severe thalassaemia worldwide; equating to around 30,000 births per year. HbE β-thalassaemia is due to a point mutation in codon 26 of the human HBB gene on one allele (GAG; glutamatic acid → AAG; lysine, E26K), and any mutation causing severe β-thalassaemia on the other. When inherited together in compound heterozygosity these mutations can cause a severe thalassaemic phenotype. However, if only one allele is mutated individuals are carriers for the respective mutation and have an asymptomatic phenotype (β-thalassaemia trait). Here we describe a base editing strategy which corrects the HbE mutation either to wildtype (WT) or a normal variant haemoglobin (E26G) known as Hb Aubenas and thereby recreates the asymptomatic trait phenotype. We have achieved editing efficiencies in excess of 90% in primary human CD34 + cells. We demonstrate editing of long-term repopulating haematopoietic stem cells (LT-HSCs) using serial xenotransplantation in NSG mice. We have profiled the off-target effects using a combination of circularization for in vitro reporting of cleavage effects by sequencing (CIRCLE-seq) and deep targeted capture and have developed machine-learning based methods to predict functional effects of candidate off-target mutations.
Topics: Humans; Animals; Mice; beta-Thalassemia; Hemoglobin E; Thalassemia; Mutation; Point Mutation
PubMed: 37076455
DOI: 10.1038/s41467-023-37604-8 -
American Journal of Clinical Pathology Apr 2006High-performance liquid chromatography (HPLC) is replacing electrophoresis for identification of hemoglobin variants. Our objective was to identify unknown tall peaks...
High-performance liquid chromatography (HPLC) is replacing electrophoresis for identification of hemoglobin variants. Our objective was to identify unknown tall peaks with elution times and shapes of hemoglobin Barts found on hemoglobin chromatograms that could not be confirmed by alkaline and acid gel electrophoresis. Of 90 specimens identified with this peak, 86 were from patients with hemoglobin SS. Regression of the height of the unknown peaks to serum bilirubin concentrations, diminution of the unknown peaks by washing the specimens, and chromatographic similarity of a total bilirubin serum calibrator, a bilirubin proficiency testing specimen, and 3 patients' serum samples with markedly elevated bilirubin to hemoglobin Barts provide evidence the peak was bilirubin. We suggest exclusion of bilirubin before HPLC results are reported as consistent with hemoglobin Barts.
Topics: Adolescent; Adult; Bilirubin; Child; Child, Preschool; Chromatography, High Pressure Liquid; Electrophoresis; Hemoglobinopathies; Hemoglobins; Hemoglobins, Abnormal; Humans; Middle Aged; Phenotype
PubMed: 16627270
DOI: 10.1309/73WJ-V2E0-RTVQ-H0BB -
Clinics in Laboratory Medicine Jun 2003This review summarizes state-of-the-art and emerging techniques in the antenatal diagnosis of fetal anemia and hemoglobinopathies. Fetal anemia may result from hemolytic... (Review)
Review
This review summarizes state-of-the-art and emerging techniques in the antenatal diagnosis of fetal anemia and hemoglobinopathies. Fetal anemia may result from hemolytic disease, hemorrhage, suppression of erythropoiesis, infection (eg, parvovirus B19), or trauma. The clinical laboratory plays an essential role in the evaluation of these disorders by way of the use of various hematologic, biochemical, serologic, cytometric, and molecular genetics methods. Hemoglobinopathies are the most common class of single gene disorders worldwide. The authors have used the example of homozygous alpha-thalassemia major (Hb Barts disease) as a paradigmatic case for antenatal hemoglobinopathy screening. Perhaps the most familiar indication for hematologic screening in pregnancy is HDFN, most commonly in pregnancies previously sensitized to the RhD antigen. All pregnant women, regardless of their past medical or obstetric history or previous antibody screens, should have ABO/Rh blood typing and a red cell antibody screen performed at the first prenatal visit. Long-established methods for assaying FMH (KB method), microcytosis (hemogram with red cell indices), and blood group incompatibility (direct antigen test, serologies) remain critical for rapid, sensitive diagnosis. Analysis of fetal free DNA in maternal plasma holds the promise for rapid, ultrasensitive, and noninvasive detection of many fetal hematologic disorders.
Topics: Adult; Female; Fetal Blood; Fetal Diseases; Hematologic Diseases; Humans; Pregnancy; Prenatal Diagnosis
PubMed: 12848447
DOI: 10.1016/s0272-2712(03)00031-3