Disease modifying therapies

Different pharmacological agents that may improve anaemia in α-thalassaemia by acting in different stages of the thalassaemia pathogenesis are being evaluated. These agents are not expected to have any benefit in patients with haemoglobin Bart’s hydrops foetalis who do not have the ability to produce functional haemoglobin. The patients that will benefit the most from these agents are patients with moderate to severe forms of haemoglobin H (HbH) disease, who require red blood cell transfusions and/or exhibit thalassaemia-related morbidities. These patients exhibit a high degree of haemolysis and/or ineffective erythropoiesis, and they usually carry non-deletional α-thalassaemia mutations.

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Luspatercept, a recombinant fusion protein consisting of a modified form of the extracellular domain of the activin receptor type IIB (ActRIIB) linked to the human immunoglobin G1 Fc domain, is the first-in-class erythroid maturation agent that has been (more...)

Thalassaemic red blood cells have substantially increased metabolic oxidative stress, leading to increased haemolysis and early cell death. Increasing the erythrocytic ATP levels will counterbalance the augmented intracellular energy demands and decrease the vulnerability of the thalassaemic erythrocytes. Allosteric activators of pyruvate kinase have been shown to increase ATP concentrations and ameliorate haemolysis in different chronic haemolytic anaemias. The first-in-class of these medications, mitapivat, has been shown to increase haemoglobin levels in a few patients with haemoglobin H disease in a phase 2 study [2]. Mitapivat is currently studied in phase 3 clinical trials for either α-TDT (NCT04770779) or α-NTDT (NCT04770753). A phase 2 clinical trial with the use a second pyruvate kinase activator, Etavopivat, is also currently ongoing (NCT04987489). Based on their mode of action, which targets mainly to the increased haemolysis, the allosteric activators of pyruvate kinase may be shown to have a more robust and homogeneous efficacy in individuals with α-thalassaemia compared to luspatercept.

Iron chelation medications

Iron homeostasis is deranged in thalassaemia both secondary to red blood cell transfusions and to increased gastrointestinal iron absorption. Agents that increase hepcidin levels or block ferroportin may improve erythropoiesis and anaemia and enhance the efficacy of iron chelation. Different agents are being studied in this setting. So far, despite initial encouraging preclinical observations, results have not been positive.

Gene therapy

The use of autologous gene therapy using lentiviral vectors carrying β-globin gene has been successfully validated for β-thalassaemia treatment [3]. Similarly, ex-vivo lentiviral gene therapy to introduce α-globin gene is a potential strategy to cure α-thalassaemia. However, no gene therapy clinical trial is currently available for patients with α-thalassaemia.

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Clinical trials evaluating gene editing approaches for the treatment of β-thalassaemia are currently ongoing. The most advanced studies have been using CRISPR/Cas9 methods to reactivate γ-globin expression [4]. These strategies are based (more...)

Brief summary and recommendations

References

1.

Kattamis A, Kwiatkowski JL, Aydinok Y. Thalassaemia. Lancet. 2022;399(10343):2310–24. [PubMed: 35691301] [CrossRef]

2.

Kuo KHM, Layton MD, Lal A, et al. Safety and efficacy of mitapivat, an oral pyruvate kinase activator, in adults with non-transfusion dependent α- or β-thalassaemia: results from a phase 2, open-label, multicentre study. Lancet. 2022 Aug 13;400(10351):493–501. [PubMed: 35964609] [CrossRef]

3.

Thompson AA, Walters MC, Kwiatkowski J, et al. Gene therapy in patients with transfusion-dependent beta-thalassaemia. N Engl J Med. 2018;378(16):1479–93. [PubMed: 29669226] [CrossRef]

4.

Frangoul H, Altshuler D, Cappellini MD, et al. CRISPR-Cas9 gene editing for sickle cell disease and beta-thalassaemia. N Engl J Med. 2021;384:252–60. [PubMed: 33283989] [CrossRef]

5.

Horvei P, MacKenzie T, Kharbanda S. Advances in the management of α-thalassaemia major: reasons to be optimistic. Haematology Am Soc Hematol Educ Program. 2021 Dec 10;2021(1):592–9. [PMC free article: PMC8791144] [PubMed: 34889445] [CrossRef]