Emerging therapies in β-thalassemia: toward a new era in management

Bou‐Fakhredin, Rayan; Tabbikha, Rami; Daadaa, Hisham; Taher, Ali T.

doi:10.1080/14728214.2020.1752180

Cited by 17 publications

(28 citation statements)

References 80 publications

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“…9,10 There are currently no approved agents for the management of anemia in NTDT. 11 Transfusions are used in settings of expected drop in Hb such as pregnancy, infection or surgery; and some physicians also elect to use short courses of regular transfusions to promote growth in childhood or prevent/treat morbidity in adulthood in view of evidence of benefit from observational studies. [12][13][14] Even in the absence of transfusions, NTDT Khaled M. Musallam and Rayan Bou-Fakhredin contributed equally as first authors.…”

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confidence: 99%

2021 update on clinical trials in β‐thalassemia

Musallam¹,

Bou‐Fakhredin

Cappellini

et al. 2021

American J Hematol

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The treatment landscape for patients with β-thalassemia is witnessing a swift evolution, yet several unmet needs continue to persist. Patients with transfusiondependent β-thalassemia (TDT) primarily rely on regular transfusion and iron chelation therapy, which can be associated with considerable treatment burden and cost.Patients with non-transfusion-dependent β-thalassemia (NTDT) are also at risk of significant morbidity due to the underlying anemia and iron overload, but treatment options in this patient subgroup are limited. In this review, we provide updates on clinical trials of novel therapies targeting the underlying pathology in β-thalassemia, including the α/non-α-globin chain imbalance, ineffective erythropoiesis, and iron dysregulation. | INTRODUCTIONThe β-thalassemias are a group of inherited disorders of hemoglobin (Hb) synthesis characterized by chronic anemia of varying severity.The degree of anemia relies on several genetic and environmental factors and determines the need for regular transfusion therapy. It is now common practice to classify patients as having transfusion-The TDT patients (β-thalassemia major and severe forms of HbE/β-thalassemia) are those who commonly present in early childhood with severe anemia and require lifelong transfusion therapy for survival. 1 Although the introduction of transfusions improved survival in TDT patients, it did not come without its own side-effect, systemic iron overload leading to end-organ damage and increased mortality from cardiac or hepatic disease. [2][3][4] Advances in iron chelation therapy and the introduction of MRI techniques to detect organ-specific iron overload have led to improved management and patient outcomes. 5,6 Still, TDT comes with considerable burden to the patient, clinician, and overall healthcare system owing to persistent morbidity and high healthcare utilization, poor access to optimal care and high treatment cost especially in resource-limited countries, and several unmet needs in terms of efficacy, safety and adherence to conventional therapies. 7 Allogeneic hematopoietic stem-cell transplantation (HSCT) has been used successfully for the past few decades to offer curative therapy for patients with TDT, but is only available to a minority of patients with compatible donors. 1 Patients with NTDT (β-thalassemia intermedia and mildmoderate forms of HbE/β-thalassemia) usually present later in childhood or even in adolescence with mild-moderate anemia that does not require immediate placement on a regular transfusion program. 1,8 Progress made over the past few decades has indicated that the diagnosis of NTDT carries greater morbidity than previously recognized.Ineffective erythropoiesis and anemia have been linked to an array of morbidities stemming from chronic hypoxia and an established hypercoagulable state. 1 Patients with Hb levels < 10 g/dl are at an increased risk of morbidity development, and variations of 1 g/dl can change a patient's morbidity risk. 9,10 There are currently no approved agents for the management of anem...

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confidence: 99%

2021 update on clinical trials in β‐thalassemia

Musallam¹,

Bou‐Fakhredin

Cappellini

et al. 2021

American J Hematol

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“…Several treatment modalities like drugs that act by increasing hemoglobin (Hb) F (like hydroxyurea, azacytidine, thalidomide, and butyrates) or stimulate erythropoiesis (recombinant erythropoietin) have been tried in thalassemia with some success [3][4][5][6]. Among these drugs, thalidomide and hydroxyurea have been known to cause severe adverse effects, thus limiting their routine use in thalassemia treatment.…”

Section: Review Classification Of Newer Pharmacological Agentsmentioning

confidence: 99%

“…Due to the limited availability of both these curative treatments, clinical studies have explored non-curative pharmacological treatment options such as erythropoiesis-stimulating agents that may prevent the complications associated with anemia, hemolysis, and iron overload [3][4][5][6]. Herein, we provide an insight into the recent advances in the drugs targeting ineffective erythropoiesis in beta-thalassemia.…”

Section: Introductionmentioning

confidence: 99%

Improving Ineffective Erythropoiesis in Thalassemia: A Hope on the Horizon

Madan¹,

Bhasin²,

Dewan³

et al. 2021

Cureus

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Beta-thalassemia is an inherited hemoglobinopathy characterized by the impaired synthesis of beta-globin chains of hemoglobin leading to chronic hemolytic anemia. The mainstay of treatment for most patients remains regular blood transfusions and iron chelation. This conventional therapy has many limitations and challenges. Allogeneic hematopoietic stem cell transplant (HSCT) is the only available curative treatment but the availability of a suitable donor, financial constraints, and a need for specialist physicians can be limiting factors. Gene therapy is an upcoming curative therapeutic modality. An increased understanding of the underlying pathophysiology and molecular mechanisms of thalassemia has paved the way for novel pharmacological agents targeting ineffective erythropoiesis. These drugs act by decreasing transfusion requirements and hence decrease transfusion-related complications. The present review intends to provide an insight into the recent advances in pharmacological agents targeting ineffective erythropoiesis. Literature was searched and relevant articles evaluating newer drugs in thalassemia were collected from databases, including Pubmed, Scopus, Prospero, Clinicaltrials.gov, Google Scholar, and the Google search engine. We used the following keywords: thalassemia, novel, treatment, drugs, and ineffective erythropoiesis during the initial search. Relevant titles and abstracts were screened to choose relevant articles. Further, the full-text articles were retrieved and relevant cross-references were scanned to collect information for the present review.

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“…Conventional treatments for patients with transfusiondependent (TD) β-thalassemia are regular RBC transfusions plus iron chelation therapy (ICT) to correct anemia and reduce iron accumulation (Figure 1). Hematopoietic stem cell transplantation (HSCT), the only curative option, is only available for a very limited subgroup of patients with a suitable matched donor (Figure 1) [8,11,12]. Patients with more clinically severe disease, known as TD β-thalassemia, often present with symptoms very early in life (before the age of 2 years), require lifelong disease management, and are dependent on regular RBC transfusions in order to prevent organ damage or early death [8,9].…”

Section: Introductionmentioning

confidence: 99%

“…activin ligand traps, JAK2 inhibitors), and those that reduce iron accumulation (e.g. hepcidin-like molecules, transmembrane protease serine 6 inhibitors) [11,18]. This review will focus on the potential to improve QoL for patients with TD β-thalassemia by summarizing current management recommendations and focusing on clinical use of two novel treatments that have recently been approved (gene therapy and the activin ligand trap, luspatercept; Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Improving outcomes and quality of life for patients with transfusion-dependent β-thalassemia: recommendations for best clinical practice and the use of novel treatment strategies

Taher

Bou‐Fakhredin

Kattamis

et al. 2021

Expert Review of Hematology

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Introduction: β-thalassemia is one of the most common inherited monogenic diseases. Many patients are dependent on a lifetime of red blood cell (RBC) transfusions and iron chelation therapy. Although treatments have a significant impact on quality of life (QoL), life expectancy, and long-term health outcomes have improved in recent decades through safer RBC transfusion practices and better iron chelation strategies. Advances in the understanding of the pathology of β-thalassemia have led to the development of new treatment options that have the potential to reduce the RBC transfusion burden in patients with transfusion-dependent (TD) β-thalassemia and improve QoL.Areas covered: This review provides an overview of currently available treatments for patients with TD βthalassemia, highlighting QoL issues, and providing an update on current clinical experience plus important practical points for two new treatments available for TD β-thalassemia: betibeglogene autotemcel (beti-cel) gene therapy and the erythroid maturation agent luspatercept, an activin ligand trap. Expert opinion: Approved therapies, including curative gene therapies and supportive treatments such as luspatercept, have the potential to reduce RBC transfusion burden, and improve clinical outcomes and QoL in patients with TD β-thalassemia. Cost of treatment is, however, likely to be a significant barrier for payors and patients.

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Emerging therapies in β-thalassemia: toward a new era in management

Cited by 17 publications

References 80 publications

2021 update on clinical trials in β‐thalassemia

2021 update on clinical trials in β‐thalassemia

Improving Ineffective Erythropoiesis in Thalassemia: A Hope on the Horizon

Improving outcomes and quality of life for patients with transfusion-dependent β-thalassemia: recommendations for best clinical practice and the use of novel treatment strategies

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