Thalassaemia is a diverse group of genetic disorders with a worldwide distribution affecting globin chain synthesis. The pathogenesis of thalassaemia lies in the unbalanced globin chain production, ...leading to ineffective erythropoiesis, increased haemolysis, and deranged iron homoeostasis. The clinical phenotype shows heterogeneity, ranging from close to normal without complications to severe requiring lifelong transfusion support. Conservative treatment with transfusion and iron chelation has transformed the natural history of thalassaemia major into a chronic disease with a prolonged life expectancy, albeit with co-morbidities and substantial disease burden. Curative therapy with allogeneic haematopoietic stem cell transplantation is advocated for suitable patients. The understanding of the pathogenesis of the disease is guiding therapeutic advances. Novel agents have shown efficacy in improving anaemia and transfusion burden, and initial results from gene therapy approaches are promising. Despite scientific developments, worldwide inequality in the access of health resources is a major concern, because most patients live in underserved areas.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
2.
Gene addition for beta thalassemia Kwiatkowski, Janet L.
Annals of the New York Academy of Sciences,
December 2023, 2023-12-00, 20231201, Volume:
1530, Issue:
1
Journal Article
Peer reviewed
Individuals with transfusion‐dependent beta thalassemia require a high burden of care and experience significant morbidity from the underlying disease and its treatment, which negatively impact the ...quality of life. Allogeneic hematopoietic stem cell transplantation offers the chance for a cure, but donor availability and transplant‐related risks, especially in older patients, limit its use. Gene addition utilizing autologous CD34+ cells is an alternative, potentially curative, treatment option. Several clinical trials have investigated the use of lentiviral vectors containing a functional beta globin gene, including Lentiglobin BB305, GLOBE, and TNS9.3.55. The efficacy and safety data from these ongoing trials are discussed in this review.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Conventional therapy for severe thalassemia includes regular red cell transfusions and iron chelation therapy to prevent and treat complications of iron overload. Iron chelation is very effective ...when appropriately used, but inadequate iron chelation therapy continues to contribute to preventable morbidity and mortality in transfusion-dependent thalassemia. Factors that contribute to suboptimal iron chelation include poor adherence, variable pharmacokinetics, chelator adverse effects, and difficulties with precise monitoring of response. The regular assessment of adherence, adverse effects, and iron burden with appropriate treatment adjustments is necessary to optimize patient outcomes.
An unprespecified interim analysis of results from a phase 1–2 study of gene therapy for sickle cell disease shows resolution of severe vaso-occlusive events in 25 patients who could be evaluated. In ...the 24 months before enrollment, these patients had a median of 3.5 severe vaso-occlusive events per year.
Regular red cell transfusions used to treat thalassemia cause iron loading that must be treated with chelation therapy. Morbidity and mortality in thalassemia major are closely linked to the adequacy ...of chelation. Chelation therapy removes accumulated iron and detoxifies iron, which can prevent and reverse much of the iron‐mediated organ injury. Currently, three chelators are commercially available––deferoxamine, deferasirox, and deferiprone––and each can be used as monotherapy or in combination. Close monitoring of hepatic and cardiac iron burden is central to tailoring chelation. Other factors, including properties of the individual chelators, ongoing transfusional iron burden, and patient preference, must be considered. Monotherapy generally is utilized if the iron burden is in an acceptable or near‐acceptable range and the dose is adjusted accordingly. Combination chelation often is employed for patients with high iron burden, iron‐related organ injury, or where adverse effects of chelators preclude administration of an appropriate chelator dose. The combination of deferoxamine and deferiprone is the best studied, but increasing data are available on the safety and efficacy of newer chelator combinations, including deferasirox with deferoxamine and the oral‐only combination of deferasirox with deferiprone. The expanding chelation repertoire should enable better control of iron burden and improved outcomes.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Abstract
Recently, gene therapy clinical trials have been successfully applied to hemoglobinopathies, such as sickle cell disease (SCD) and β-thalassemia. Among the great discoveries that led to the ...design of genetic approaches to cure these disorders is the discovery of the β-globin locus control region and several associated transcription factors, which determine hemoglobin switching as well as high-level, erythroid-specific expression of genes at the ß-globin locus. Moreover, increasing evidence shows that lentiviral vectors are efficient tools to insert large DNA elements into nondividing hematopoietic stem cells, showing reassuring safe integration profiles. Alternatively, genome editing could restore expression of fetal hemoglobin or target specific mutations to restore expression of the wild-type β-globin gene. The most recent clinical trials for β-thalassemia and SCD are showing promising outcomes: patients were able to discontinue transfusions or had reduced transfusion requirements. However, toxic myeloablation and the high cost of current ex vivo hematopoietic stem cell gene therapy platforms represent a barrier to a widespread application of these approaches. In this review, we summarize these gene therapy strategies and ongoing clinical trials. Finally, we discuss possible strategies to improve outcomes, reduce myeloablative regimens and future challenges to reduce the cost of gene therapy platform.
Stroke is one of the most devastating complications of sickle cell anemia (SCA), and risk of stroke starts very early in life. Before screening techniques were available, 11% of children with ...homozygous SCA had ischemic stroke by their 20th birthday. Although most children with SCA will have neurologic recovery after stroke, approximately one-third will have long-term neurologic sequelae, including motor impairment. Moreover, children with SCA who have had a stroke often have neurocognitive impairment and difficulties with academic performance.
Beta thalassemias are a significant global health problem. Globin chain imbalance leads to a complex physiologic cascade of hemolytic anemia, ineffective erythropoiesis, and iron overload. Management ...of the broad spectrum of phenotypes requires the careful use of red blood transfusions, supportive care, monitoring, and management of iron overload. In this article, the authors discuss recommendations for monitoring of individuals with thalassemia, as well as ongoing preclinical and clinical trials of therapies targeting different aspects of thalassemia pathophysiology.
Of 23 patients with transfusion-dependent β-thalassemia who received gene-transfected autologous hematopoietic cells, 91% became transfusion independent; the remaining 2 patients had a low level of ...engraftment of vector-expressing cells. With a median of 29.5 months of follow-up, the average hemoglobin level was 11.7 g per deciliter.
Summary Background For children with sickle cell anaemia and high transcranial doppler (TCD) flow velocities, regular blood transfusions can effectively prevent primary stroke, but must be continued ...indefinitely. The efficacy of hydroxycarbamide (hydroxyurea) in this setting is unknown; we performed the TWiTCH trial to compare hydroxyurea with standard transfusions. Methods TWiTCH was a multicentre, phase 3, randomised, open-label, non-inferiority trial done at 26 paediatric hospitals and health centres in the USA and Canada. We enrolled children with sickle cell anaemia who were aged 4–16 years and had abnormal TCD flow velocities (≥200 cm/s) but no severe vasculopathy. After screening, eligible participants were randomly assigned 1:1 to continue standard transfusions (standard group) or hydroxycarbamide (alternative group). Randomisation was done at a central site, stratified by site with a block size of four, and an adaptive randomisation scheme was used to balance the covariates of baseline age and TCD velocity. The study was open-label, but TCD examinations were read centrally by observers masked to treatment assignment and previous TCD results. Participants assigned to standard treatment continued to receive monthly transfusions to maintain 30% sickle haemoglobin or lower, while those assigned to the alternative treatment started oral hydroxycarbamide at 20 mg/kg per day, which was escalated to each participant's maximum tolerated dose. The treatment period lasted 24 months from randomisation. The primary study endpoint was the 24 month TCD velocity calculated from a general linear mixed model, with the non-inferiority margin set at 15 cm/s. The primary analysis was done in the intention-to-treat population and safety was assessed in all patients who received at least one dose of assigned treatment. This study is registered with ClinicalTrials.gov , number NCT01425307. Findings Between Sept 20, 2011, and April 17, 2013, 159 patients consented and enrolled in TWiTCH. 121 participants passed screening and were then randomly assigned to treatment (61 to transfusions and 60 to hydroxycarbamide). At the first scheduled interim analysis, non-inferiority was shown and the sponsor terminated the study. Final model-based TCD velocities were 143 cm/s (95% CI 140–146) in children who received standard transfusions and 138 cm/s (135–142) in those who received hydroxycarbamide, with a difference of 4·54 (0·10–8·98). Non-inferiority (p=8·82 × 10−16 ) and post-hoc superiority (p=0·023) were met. Of 29 new neurological events adjudicated centrally by masked reviewers, no strokes were identified, but three transient ischaemic attacks occurred in each group. Magnetic resonance brain imaging and angiography (MRI and MRA) at exit showed no new cerebral infarcts in either treatment group, but worsened vasculopathy in one participant who received standard transfusions. 23 severe adverse events in nine (15%) patients were reported for hydroxycarbamide and ten serious adverse events in six (10%) patients were reported for standard transfusions. The most common serious adverse event in both groups was vaso-occlusive pain (11 events in five 8% patients with hydroxycarbamide and three events in one 2% patient for transfusions). Interpretation For high-risk children with sickle cell anaemia and abnormal TCD velocities who have received at least 1 year of transfusions, and have no MRA-defined severe vasculopathy, hydroxycarbamide treatment can substitute for chronic transfusions to maintain TCD velocities and help to prevent primary stroke. Funding National Heart, Lung, and Blood Institute, National Institutes of Health.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
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