Current and future landscape of treatment options for rare anemias


Rare anemias are mostly inherited disorders caused by abnormalities in erythropoiesis or red blood cell (RBC) components.1 Examples include thalassemias, sickle cell anemia (SCD), congenital hemolytic anemias and hemoglobinopathies.2 In addition to recently approved treatment options, various new agents are being investigated.3

In a review published in HemasphereMaria Domenica Cappellini, MD, from the Department of Clinical Sciences and Community Health, University of Milan in Italy, summarized the current literature regarding the treatment of rare anemias.3 Dr. Cappellini and his co-authors also reviewed several emerging therapies currently being studied in clinical trials.

Treatment of beta-thalassemias

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Conventional management of beta-thalassemia includes red blood cell transfusions and, in some cases, splenectomy. Emerging therapies target genetic defects, ineffective erythropoiesis, as well as iron overload and dysregulation.

There are 2 new agents, luspatercept and sotatercept, which act as activin receptor ligand traps (ACVR) by binding to transforming growth factor (TGF) beta-like molecules via the extracellular domain of the ‘ACVR type 2A (ACVR2A) or 2B (ACVR2B). They are aimed at correcting ineffective erythropoiesis and increasing hemoglobin values.

Luspatercept was approved by the United States Food and Drug Administration (FDA) in 2019 and by the European Medicines Agency (EMA) in 2020 for the treatment of anemia in adult patients with beta-thalassemia who require regular transfusions of red blood cells. With regard to safety, no contraindications are reported in the product descriptions of the FDA and EMA, except for hypersensitivity to the active substance or to any of the excipients and the pregnancy.

Treatment of SCD

For the past 2 decades, hydroxyurea has been the only FDA-approved pharmacological option for patients with SCD. Several studies have shown that hydroxyurea improves SCD morbidity by reducing the risk of vaso-occlusive events, acute chest syndrome, chronic kidney disease, and stroke. Despite these benefits, some clinicians are hesitant to prescribe hydroxyurea due to concerns of teratogenicity, carcinogenicity, and efficacy; thus, new treatment strategies have emerged.

Over the past 5 years, the FDA has approved 3 drugs for SCD: L-glutamine, voxelotor, and crizanlizumab. L-glutamine increases the redox ratio of nicotinamide adenine dinucleotide in sickle cells and is associated with patient-reported clinical improvement. Voxelotor improves hemoglobin levels, leading to reduction of hemolysis markers through inhibition of hemoglobin S polymerization. Crizanlizumab improves rate of vaso-occlusion, thereby prolonging median time to first vaso-occlusive crises .

Other investigational agents target different pathophysiological mechanisms, including inflammation, adhesion, and oxidative stress.

Treatment of beta-hemoglobinopathies and congenital hemolytic anemias

Until recently, allogeneic hematopoietic stem cell transplantation (allo-HSCT) was the only curative option for hemoglobinopathies. In June 2019, the betibeglogene autotemcel gene addition product was approved by the EMA for patients with transfusion-dependent beta-thalassemia aged 12 years or older who do not have a beta0/beta0 genotype and for whom HSCT is appropriate but a human leukocyte antigen HLA-compatible related hematopoietic stem cell donor is not available.

Various other clinical trials are investigating the feasibility of addition and gene editing therapies in beta-thalassemia and sickle cell disease.3

In symptomatic and severely anemic patients with congenital hemolytic anemia, transfusions and splenectomy remained the only treatment options available for decades. New treatment strategies are being explored, including mitapivat, an oral small-molecule allosteric activator of pyruvate kinase in red blood cells.

Future directions

Rare anemias are a heterogeneous group of blood disorders, often difficult to diagnose and, until recently, with limited treatment options. A new era of innovative treatments is opening up and their use will most likely lead to combinatorial strategies adapted to the genotypic and phenotypic characteristics of patients.

“Going forward, the cost of these new therapies could impact adoption in some countries, especially in developing countries,” Dr. Cappellini said in an interview. “However, after the initial commercialization phase, there will most likely be lower costs and an overall positive impact on quality of life.”

Disclosure: Some guideline authors have claimed to be affiliated with or have received funding from the pharmaceutical industry. Please refer to the original study for a full list of disclosures.


1. GBD 2015 Collaborators on Incidence and Prevalence of Diseases and Injuries. Global, regional and national incidence, prevalence and years lived with disability for 310 diseases and injuries, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet. 2016;388(10053):1545-1602. doi:10.1016/S0140-6736(16)31678-6

2. Brissot P, Bernard DG, Brissot E, Loréal O, Troadec MB. Rare anemias due to genetic defects in iron metabolism. Mutat Res Rev Mutat Res. 2018;777:52-63. doi:10.1016/j.mrrev.2018.06.003

3. Cappellini MD, Marcon A, Fattizzo B, Motta I. Innovative treatments for rare anemias. Hemasphere. 2021;5(6):e576. doi:10.1097/HS9.0000000000000576


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