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BioMed Research International 2022Sickle cell disease (SCD) is a hemoglobinopathy with increasing global prevalence resulting in pain episodes and multiorgan complications. Complications of SCD have been... (Review)
Review
BACKGROUND
Sickle cell disease (SCD) is a hemoglobinopathy with increasing global prevalence resulting in pain episodes and multiorgan complications. Complications of SCD have been shown to adversely impact health-related quality of life (HRQOL) comprised of physical, social, and emotional domains; hence, HRQOL measures can serve as an effective evaluator of disease burden. Hydroxyurea (HU) and other disease-modifying therapies have demonstrated to significantly improve clinical outcomes in patients with SCD. Medication adherence is an essential mediator of the clinical benefits of these therapies; low adherence has been shown to increase disease burden and healthcare utilization. This systematic literature review intends to determine the association between adherence to disease-modifying therapies and HRQOL in patients with SCD.
METHODS
We found a total of 12 articles involving 788 participants, which included both patients with SCD and caregivers/parents. Adherence was measured using self-report instruments, laboratory markers, such as fetal hemoglobin and mean corpuscular volume, and mHealth medication trackers. HRQOL was measured using self-report instruments.
RESULTS
All studies demonstrated a correlation between higher HU adherence and better HRQOL scores. Higher HU adherence was associated with lower pain impact, less frequent pain episodes, less fatigue, and improved physical function and mobility, reflecting better physical HRQOL outcomes. Higher adherence was also associated with improved emotional response, decreased anxiety and depressive symptoms, and better social functioning and peer relationships. In addition, our findings indicated that having less frequent barriers to HU adherence was associated with better HRQOL scores. No studies evaluated HRQOL outcomes in relation to adherence to l-glutamine, voxelotor, or crizanlizumab.
CONCLUSIONS
Optimizing HU adherence has the potential to improve HRQOL in patients with SCD in addition to reducing healthcare utilization and improving treatment satisfaction. Addressing barriers to HU adherence can positively strengthen the relationship between adherence and HRQOL to potentially improve patient outcomes.
Topics: Anemia, Sickle Cell; Humans; Hydroxyurea; Medication Adherence; Pain; Quality of Life
PubMed: 35898672
DOI: 10.1155/2022/2122056 -
American Journal of Hematology Sep 2023This systematic literature review assessed the global prevalence and birth prevalence of clinically significant forms of alpha- and beta-thalassemia. Embase, MEDLINE,...
This systematic literature review assessed the global prevalence and birth prevalence of clinically significant forms of alpha- and beta-thalassemia. Embase, MEDLINE, and the Cochrane Library were searched for observational studies published January 1, 2000, to September 21, 2021. Of 2093 unique records identified, 69 studies reported across 70 publications met eligibility criteria, including 6 records identified from bibliography searches. Thalassemia prevalence estimates varied across countries and even within countries. Across 23 population-based studies reporting clinically significant alpha-thalassemia (e.g., hemoglobin H disease and hemoglobin Bart's hydrops fetalis) and/or beta-thalassemia (beta-thalassemia intermedia, major, and/or hemoglobin E/beta-thalassemia), prevalence estimates per 100 000 people ranged from 0.2 in Spain (over 2014-2017) to 27.2 in Greece (2010-2015) for combined beta- plus alpha-thalassemia; from 0.03 in Spain (2014-2017) to 4.5 in Malaysia (2007-2018) for alpha-thalassemia; and from 0.2 in Spain (2014-2017) to 35.7 to 49.6 in Iraq (2003-2018) for beta-thalassemia. Overall, the estimated prevalence of thalassemia followed the predicted pattern of being higher in the Middle East, Asia, and Mediterranean than in Europe or North America. However, population-based prevalence estimates were not found for many countries, and there was heterogeneity in case definitions, diagnostic methodology, type of thalassemia reported, and details on transfusion requirements. Limited population-based birth prevalence data were found. Twenty-seven studies reported thalassemia prevalence from non-population-based samples. Results from such studies likely do not have countrywide generalizability as they tended to be from highly specific groups. To fully understand the global prevalence of thalassemia, up-to-date, population-based epidemiological data are needed for many countries.
Topics: Pregnancy; Female; Humans; alpha-Thalassemia; beta-Thalassemia; Prenatal Diagnosis; Hydrops Fetalis; Asia; Hemoglobins, Abnormal
PubMed: 37357829
DOI: 10.1002/ajh.27006 -
Human Genetics Dec 2021ATR-X, an acronym for alpha thalassemia and mental retardation X-linked, syndrome is a congenital condition predominantly affecting males, characterized by mild to...
ATR-X, an acronym for alpha thalassemia and mental retardation X-linked, syndrome is a congenital condition predominantly affecting males, characterized by mild to severe intellectual disability, facial, skeletal, urogenital, and hematopoietic anomalies. Less common are heart defects, eye anomalies, renal abnormalities, and gastrointestinal dysfunction. ATR-X syndrome is caused by germline variants in the ATRX gene. Until recently, the diagnosis of the ATR-X syndrome had been guided by the classical clinical manifestations and confirmed by molecular techniques. However, our new systematic analysis shows that the only clinical sign shared by all affected individuals is intellectual disability, with the other manifestations varying even within the same family. More than 190 different germline ATRX mutations in some 200 patients have been analyzed. With improved and more frequent analysis by molecular technologies, more subtle deletions and insertions have been detected recently. Moreover, emerging technologies reveal non-classic phenotypes of ATR-X syndrome as well as the description of a new clinical feature, the development of osteosarcoma which suggests an increased cancer risk in ATR-X syndrome. This review will focus on the different types of inherited ATRX mutations and their relation to clinical features in the ATR-X syndrome. We will provide an update of the frequency of clinical manifestations, the affected organs, and the genotype-phenotype correlations. Finally, we propose a shift in the diagnosis of ATR-X patients, from a clinical diagnosis to a molecular-based approach. This may assist clinicians in patient management, risk assessment and genetic counseling.
Topics: Animals; Humans; Intellectual Disability; Mental Retardation, X-Linked; Molecular Diagnostic Techniques; Mutation; alpha-Thalassemia
PubMed: 34524523
DOI: 10.1007/s00439-021-02361-5 -
The Cochrane Database of Systematic... Dec 2022Sickle cell disease (SCD) includes a group of inherited haemoglobinopathies affecting multiple organs including the eyes. Some people with SCD develop ocular... (Review)
Review
BACKGROUND
Sickle cell disease (SCD) includes a group of inherited haemoglobinopathies affecting multiple organs including the eyes. Some people with SCD develop ocular manifestations. Vision-threatening complications are mainly due to proliferative sickle retinopathy, which is characterised by proliferation of new blood vessels. Laser photocoagulation is widely applicable in proliferative retinopathies. It is important to evaluate the efficacy and safety of laser photocoagulation in the treatment of proliferative sickle retinopathy (PSR) to prevent sight-threatening complications.
OBJECTIVES
To evaluate the effectiveness of various techniques of laser photocoagulation therapy in SCD-related proliferative retinopathy.
SEARCH METHODS
We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. Date of last search: 4 July 2022. We also searched the following resources (26 June 2022): Latin American and Caribbean Health Science Literature Database (LILACS); WHO International Clinical Trials Registry Platforms (ICTRP); and ClinicalTrials.gov.
SELECTION CRITERIA
Randomised controlled trials comparing laser photocoagulation to no treatment in children and adults with SCD.
DATA COLLECTION AND ANALYSIS
Two review authors independently assessed eligibility and risk of bias of the included trials; we extracted and analysed data, contacting trial authors for additional information. We assessed the certainty of the evidence using the GRADE criteria.
MAIN RESULTS
We included three trials (414 eyes of 339 children and adults) comparing the efficacy and safety of laser photocoagulation to no therapy in people with PSR. There were 160 males and 179 females ranging in age from 13 to 67 years. The trials used different laser photocoagulation techniques; one single-centre trial employed sectoral scatter laser photocoagulation using an argon laser; a two-centre trial employed feeder vessel coagulation using argon laser in one centre and xenon arc in the second centre; while a third trial employed focal scatter laser photocoagulation using argon laser. The mean follow-up periods were 21 to 32 months in one trial, 42 to 47 months in a second, and 48 months in the third. Two trials had a high risk of allocation bias due to the randomisation method for participants with bilateral disease; the third trial had an unclear risk of selection bias. One trial was at risk of reporting bias. Given the unit of analysis is the eye rather than the individual, we chose to report the data narratively. Using sectoral scatter laser photocoagulation, one trial (174 eyes) reported no difference between groups for complete regression of PSR: 30.2% in the laser group and 22.4% in the control group. The same trial also reported no difference between groups in the development of new PSR: 34.3% of lasered eyes and 41.3% of control eyes (very low-certainty evidence). The two-centre trial using feeder vessel coagulation, only presented data at follow-up for one centre (mean period of nine years) and reported the development of new sea fan in 48.0% in the treated and 45.0% in the control group; no statistical significance (P = 0.64). A third trial reported regression in 55% of the laser group versus 28.6% of controls and progression of PSR in 10.5% of treated versus 25.7% of control eyes. We graded the evidence for these two primary outcomes as very low-certainty evidence. The sectoral scatter laser photocoagulation trial reported visual loss in 3.0% of treated eyes (mean follow-up 47 months) versus 12.0% of controlled eyes (mean follow-up 42 months) (P = 0.019). The feeder vessel coagulation trial reported visual loss in 1.14% of the laser group and 7.5% of the control group (mean follow-up 26 months at one site and 32 months in another) (P = 0.07). The focal scatter laser photocoagulation trial (mean follow-up of four years) reported that 72/73 eyes had the same visual acuity, while visual loss was seen in only one eye from the control group. We graded the certainty of the evidence as very low. The sectoral scatter laser trial detected vitreous haemorrhage in 12.0% of the laser group and 25.3% of control with a mean follow-up of 42 (control) to 47 months (treated) (P ≤ 0.5). The two-centre feeder vessel coagulation trial observed vitreous haemorrhage in 3.4% treated eyes (mean follow-up 26 months) versus 27.5% control eyes (mean follow-up 32 months); one centre (mean follow-up nine years) reported vitreous haemorrhage in 1/25 eyes (4.0%) in the treatment group and 9/20 eyes (45.0%) in the control group (P = 0.002). The scatter laser photocoagulation trial reported that vitreous haemorrhage was not seen in the treated group compared to 6/35 (17.1%) eyes in the control group and appeared only in the grades B and (PSR) stage III) (P < 0.05). We graded evidence for this outcome as low-certainty. Regarding adverse effects, only one occurrence of retinal tear was reported. All three trials reported on retinal detachment, with no significance across the treatment and control groups (low-certainty evidence). One trial reported on choroidal neovascularization, with treatment with xenon arc found to be associated with a significantly higher risk, but visual loss related to this complication is uncommon with long-term follow-up of three years or more. The included trials did not report on other adverse effects or quality of life.
AUTHORS' CONCLUSIONS
Our conclusions are based on the data from three trials (two of which were conducted over 30 years ago). Given the limited evidence available, which we assessed to be of low- or very low-certainty, we are uncertain whether laser therapy for sickle cell retinopathy improves the outcomes measured in this review. This treatment does not appear to have an effect on clinical outcomes such as regression of PSR and development of new incidences. No evidence is available assessing efficacy in relation to patient-important outcomes (such as quality of life or the loss of a driving licence). Further research is needed to examine the safety of laser treatment compared to other interventions such as intravitreal injection of anti-vascular endothelial growth factors (VEGFs) . Patient-important outcomes as well as cost-effectiveness should be addressed.
Topics: Male; Adult; Child; Female; Humans; Adolescent; Young Adult; Middle Aged; Aged; Quality of Life; Choroidal Neovascularization; Laser Therapy; Intravitreal Injections; Vision Disorders; Anemia, Sickle Cell
PubMed: 36508693
DOI: 10.1002/14651858.CD010790.pub3 -
Leukemia Research Jun 2024Acute myeloid leukemia (AML) is a complex disease with diverse mutations, including prevalent mutations in the FMS-like receptor tyrosine kinase 3 (FLT3) gene that lead... (Review)
Review
BACKGROUND
Acute myeloid leukemia (AML) is a complex disease with diverse mutations, including prevalent mutations in the FMS-like receptor tyrosine kinase 3 (FLT3) gene that lead to poor prognosis. Recent advancements have introduced FLT3 inhibitors that have improved outcomes for FLT3-mutated AML patients, however, questions remain on their application in complex conditions such as relapsed/refractory (R/R) disease. Therefore, we aimed to evaluate the clinical effectiveness of second-generation FLT3 inhibitors in treating patients with R/R AML.
METHODS
A systematic literature search of PubMed, MEDLINE, SCOPUS and Google Scholar databases was made to identify relevant studies up to January 30, 2024. This study was conducted following the guidelines of the PRISMA.
RESULTS
The ADMIRAL trial revealed significantly improved overall survival and complete remission rates with gilteritinib compared to salvage chemotherapy, with manageable adverse effects. Ongoing research explores its potential in combination therapies, showing synergistic effects with venetoclax and promising outcomes in various clinical trials. The QuANTUM-R trial suggested longer overall survival with quizartinib compared to standard chemotherapy, although concerns were raised regarding trial design and cardiotoxicity. Ongoing research explores combination therapies involving quizartinib, such as doublet or triplet regimens with venetoclax, showing promising outcomes in FLT3-mutated AML patients.
CONCLUSION
These targeted therapies offer promise for managing this subgroup of AML patients, but further research is needed to optimize their use. This study underscores the importance of personalized treatment based on genetic mutations in AML, paving the way for more effective and tailored approaches to combat the disease.
Topics: Humans; fms-Like Tyrosine Kinase 3; Leukemia, Myeloid, Acute; Protein Kinase Inhibitors; Drug Resistance, Neoplasm; Mutation; Aniline Compounds; Phenylurea Compounds; Neoplasm Recurrence, Local; Pyrazines; Benzothiazoles
PubMed: 38692232
DOI: 10.1016/j.leukres.2024.107505 -
International Journal of Molecular... Nov 2022We evaluated the relevance of plasma homocysteine (HC) and the TT genotype of the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism (rs1801133) in sickle... (Meta-Analysis)
Meta-Analysis Review
We evaluated the relevance of plasma homocysteine (HC) and the TT genotype of the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism (rs1801133) in sickle cell disease (SCD) and associated vaso-occlusive crisis (VOC) and ischemic stroke (IS). We identified in Embase and Medline 22 studies on plasma HC and 22 on MTHFR genotypes. Due to age-related HC differences, adult and paediatric SCD were separated: 879 adult SCD and 834 controls (CTR) yielded a neutral effect size; 427 paediatric SCD and 625 CTR favoured SCD (p = 0.001) with wide heterogeneity (I2 = 95.5%) and were sub-grouped by country: six studies (Dutch Antilles n = 1, USA n = 5) yielded a neutral effect size, four (India n = 1, Arab countries n = 3) favoured SCD (p < 0.0001). Moreover, 249 SCD in VOC and 419 out of VOC yielded a neutral effect size. The pooled prevalence of the MTHFR TT genotype in 267 SCD equalled that of 1199 CTR (4.26% vs. 2.86%, p = 0.45), and in 84 SCD with IS equalled that of 86 without IS (5.9% vs. 3.7%, p = 0.47); removal of one paediatric study yielded a significant effect size (p = 0.006). Plasma HC in paediatric SCD from Middle East and India was higher, possibly due to vitamin deficiencies. Despite its low prevalence in SCD, the MTHFR TT genotype relates to adult IS.
Topics: Adult; Child; Humans; Anemia, Sickle Cell; Genotype; Homocysteine; Methylenetetrahydrofolate Reductase (NADPH2); Polymorphism, Genetic
PubMed: 36498990
DOI: 10.3390/ijms232314641 -
The Cochrane Database of Systematic... Nov 2019Malaria is the most common precipitating cause of crises in sickle cell disease in malaria-endemic countries. Health professionals often recommend life-long malaria... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Malaria is the most common precipitating cause of crises in sickle cell disease in malaria-endemic countries. Health professionals often recommend life-long malaria chemoprophylaxis for people with sickle cell disease living in these areas. It is therefore important we have good evidence of benefit.
OBJECTIVES
To assess the effects of routine malaria chemoprophylaxis in people with sickle cell disease.
SEARCH METHODS
We searched the Cochrane Infectious Diseases Group Specialized Register (January 2006), Cochrane Cystic Fibrosis and Genetic Disorders Group Specialized Register (July 2006), CENTRAL (The Cochrane Library 2006, Issue 1), MEDLINE (1966 to January 2006), EMBASE (1974 to January 2006), LILACS (1982 to January 2006), and reference lists. We also contacted organizations and pharmaceutical companies.
SELECTION CRITERIA
Randomized and quasi-randomized controlled trials comparing chemoprophylaxis with any antimalarial drug given for a minimum of three months compared with a placebo or no intervention.
DATA COLLECTION AND ANALYSIS
Two authors independently applied the inclusion criteria, assessed the risk of bias in the trials, and extracted data. Dichotomous data were analysed using risk ratios (RR) and presented with 95% confidence intervals (CI).
MAIN RESULTS
Two trials with a total of 223 children with homozygous sickle cell disease met the inclusion criteria. A randomized controlled trial in Nigeria compared two different antimalarial drugs with a placebo, and reported that chemoprophylaxis reduced sickle cell crises (RR 0.17, 95% CI 0.04 to 0.83; 97 children), hospital admissions (RR 0.27, 95% CI 0.12 to 0.63; 97 participants), and blood transfusions (RR 0.16, 95% CI 0.05 to 0.56; 97 participants). A quasi-randomized controlled trial of 126 children in Uganda compared an antimalarial drug plus antibiotics with no antimalarial plus placebo. Chemoprophylaxis reduced the number of episodes of malaria and dactylitis, and increased mean haemoglobin values in this trial.
AUTHORS' CONCLUSIONS
It is beneficial to give routine malaria chemoprophylaxis in sickle cell disease in areas where malaria is endemic. 4 November 2019 Update pending New contributors needed The CIDG Editors are looking for contributors to update and maintain this Cochrane Review. Contact the CIDG Managing Editor for further information.
Topics: Anemia, Sickle Cell; Antimalarials; Chemoprevention; Child; Humans; Malaria; Randomized Controlled Trials as Topic
PubMed: 31681984
DOI: 10.1002/14651858.CD003489.pub2 -
HPB : the Official Journal of the... Jul 2021Sickle cell disease is a group of autosomal recessive disorders characterised by haemolytic anaemia. Liver is one of the most affected organs, ranging from liver tests... (Review)
Review
BACKGROUND
Sickle cell disease is a group of autosomal recessive disorders characterised by haemolytic anaemia. Liver is one of the most affected organs, ranging from liver tests alterations to acute liver failure for which liver transplantation is the only life-saving treatment.
METHODS
This study aims to make a systematic review of the current literature to evaluate indications, timing, and results of liver transplantation for patients affected by SCD.
RESULTS
Twenty-nine patients in total were reported worldwide until 2018, the average patient age is 28.7 (0.42-56), all patients have a pre-transplant diagnosis of SCD. Cirrhosis at transplantation was present in six-teen (n = 16, 55.1%) patients. In ten patients (n = 10, 34.5%), acute liver failure arises from healthy liver and presented sickle cell intrahepatic cholestasis. Eleven patients (n = 11, 39.2%) died, three (n = 3, 10.7%) in the first postoperative month, and seven (n = 7, 25%) in the first year. Mean follow-up was 27 months (range: 7-96), one-year overall survival was 48.7%.
DISCUSSION
Liver transplantation for SCD has been increasingly reported with encouraging results. Indications are presently reserved for acute liver failure arising both in healthy liver and end-stage liver disease.
Topics: Anemia, Sickle Cell; End Stage Liver Disease; Humans; Liver Cirrhosis; Liver Transplantation
PubMed: 33431265
DOI: 10.1016/j.hpb.2020.12.007 -
Ethiopian Journal of Health Sciences Jul 2022Pregnancy is a major concern among women with the sickle cell disease (SCD), and it is associated with increased adverse outcomes. The aim of the present meta-analysis... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Pregnancy is a major concern among women with the sickle cell disease (SCD), and it is associated with increased adverse outcomes. The aim of the present meta-analysis is to report the fetomaternal outcomes in different sickle cell genotypes.
METHODS
In this systematic review and meta-analysis, a comprehensive search of databases and search engines such as PubMed, Scopus, Web of Science, ProQuest, Cochrane Library, Science Direct and Google Scholar were performed. Any observational studies that had compared at least one outcome such as maternal outcomes, fetal outcomes, and morbidity between two groups of pregnant women with different types of sickle cell genotypes and pregnant women without SCD were evaluated.
RESULTS
A total number of 9,827 pregnant women with SCD were examined. The results showed that pregnancy in SCD increased the risk of adverse outcomes for the mothers (including postpartum hemorrhage, prematurity, pregnancy-induced hypertension, pre-eclampsia, eclampsia, cesarean section, lower segment cesareansection, maternal death), fetus (including live births, low birth weight, intrauterine growth restriction, APGAR score at 5 min <7, stillbirth, neonatal death, perinatal mortality, acute fetal distress, intrauterine fetal death) and morbidity among the SCD(severe anemia, urinary tract infection, blood transfusion, painful crisis, acute chest syndrome, vaso-occlusive crises).
CONCLUSION
According to the results of this meta-analysis, pregnancy in the SCD is associated with an increased risk of maternal outcomes, fetal outcomes, and morbidity among SCD patients with different genotypes. Pregnancy in sickle cell hemoglobinopathies needs careful multidisciplinary management and cautious caring so as to decrease maternal and fetal morbidity and mortality.
Topics: Anemia, Sickle Cell; Cesarean Section; Female; Genotype; Humans; Infant, Newborn; Pregnancy; Pregnancy Complications, Hematologic; Pregnancy Outcome
PubMed: 35950054
DOI: 10.4314/ejhs.v32i4.23 -
The Cochrane Database of Systematic... Apr 2021Thalassaemia is an autosomal recessive blood disorder, caused by mutations in globin genes or their regulatory regions, resulting in a reduced rate of synthesis of one...
BACKGROUND
Thalassaemia is an autosomal recessive blood disorder, caused by mutations in globin genes or their regulatory regions, resulting in a reduced rate of synthesis of one of the globin chains that make up haemoglobin. In β-thalassaemia there is an underproduction of β-globin chains combined with excess of free α-globin chains. The excess free α-globin chains precipitate in red blood cells, leading to their increased destruction (haemolysis) and ineffective erythropoiesis. The conventional treatment is based on the correction of haemoglobin through regular red blood cell transfusions and treating the iron overload that develops subsequently with iron chelation therapy. Although, early detection and initiations of such supportive treatment has improved the quality of life for people with transfusion-dependent thalassaemia, allogeneic hematopoietic stem cell transplantation is the only widely available therapy with a curative potential. Gene therapy for β-thalassaemia has recently received conditional authorisation for marketing in Europe, and may soon become widely available as another alternative therapy with curative potential for people with transfusion-dependent thalassaemia. This is an update of a previously published Cochrane Review.
OBJECTIVES
To evaluate the effectiveness and safety of different types of hematopoietic stem cell transplantation, in people with transfusion-dependent β-thalassaemia.
SEARCH METHODS
We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. We also searched online trial registries. Date of the most recent search: 07 April 2021.
SELECTION CRITERIA
Randomised controlled trials and quasi-randomised controlled trials comparing hematopoietic stem cell transplantation with each other or with standard therapy (regular transfusion and chelation regimen).
DATA COLLECTION AND ANALYSIS
Two review authors independently screened trials and had planned to extract data and assess risk of bias using standard Cochrane methodologies and assess the quality using GRADE approach, but no trials were identified for inclusion in the current review.
MAIN RESULTS
No relevant trials were retrieved after a comprehensive search of the literature.
AUTHORS' CONCLUSIONS
We were unable to identify any randomised controlled trials or quasi-randomised controlled trials on the effectiveness and safety of different types of hematopoietic stem cell transplantation in people with transfusion-dependent β-thalassaemia. The absence of high-level evidence for the effectiveness of these interventions emphasises the need for well-designed, adequately-powered, randomised controlled clinical trials.
Topics: Hematopoietic Stem Cell Transplantation; Humans; beta-Thalassemia
PubMed: 33880750
DOI: 10.1002/14651858.CD008708.pub5