Rare anemias are primarily hereditary disorders caused by defects in erythropoiesis or red blood cell (RBC) components.1 Examples include thalassemias, sickle cell disease (SCD), congenital hemolytic anemias, and hemoglobinopathies.2 In addition to recently approved treatment options, various novel agents are under investigation.3

In a review published in Hemasphere, Maria Domenica Cappellini, MD, of the department of clinical sciences and community health at the University of Milan in Italy, summarized current literature surrounding the treatment of rare anemias.3 Dr Cappellini and her coauthors also reviewed several emerging therapies, which are currently being studied in clinical trials.

Treatment of Beta-Thalassemias

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Conventional management of beta-thalassemias includes RBC transfusions, and in certain cases, splenectomy. Emerging therapies target genetic defects, ineffective erythropoiesis, as well as iron overload and dysregulation.

There are 2 novel agents, luspatercept and sotatercept, that act as activin receptor (ACVR) ligand traps by binding the transforming growth factor (TGF)-beta-like molecules through the extracellular domain of the ACVR type 2A (ACVR2A) or 2B (ACVR2B). They aim to correct ineffective erythropoiesis and increase hemoglobin values.

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

Treatment of SCD

Over 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 effectiveness; 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 raises the nicotinamide adenine dinucleotide redox ratio within sickle cells and is associated with patient-reported clinical improvement. Voxelotor improves hemoglobin levels, resulting in reduced hemolysis markers through inhibition of hemoglobin S polymerization. Crizanlizumab improves vaso-occlusion rate, thereby extending median time to first vaso-occlusive crises.

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

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

Among symptomatic, severely anemic patients with congenital hemolytic anemias, transfusions and splenectomy have remained the only available treatment options for decades. Novel treatment strategies are under active investigation, 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 challenging to diagnose, and until recently, with limited treatment options. A new era of innovative treatments has begun, and their use will most likely result in combinatorial strategies tailored to patients’ genotypic and phenotypic characteristics.

“In the future, the cost of these new therapies may impact adoption in some countries, especially in the developing world,” Dr Cappellini said in an interview. “However, after the initial marketing phase, there will most likely be a decline in cost and a global positive impact on quality of life.”

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


1. GBD 2015 Disease and Injury Incidence and Prevalence Collaborators. 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 iron metabolism defects. 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