David Green
George Honig
George Dunea
Chicago, Illinois, United States

The thalassemias comprise a large and diverse group of genetic disorders which share as a common feature a deficiency, or in the most severe forms a total absence, of one or more of the globin chains of hemoglobin. It was first recognized as a clinical entity distinct from other childhood anemias by Dr. Thomas Benton Cooley, an American physician specializing in pediatrics and hematology. Cooley, the chief of pediatrics at the Children’s Hospital of Michigan, initiated an investigation into a form of childhood anemia affecting four children of Italian and Greek heritage who had similar changes in the skull, vertebrae, ribs, and long bones. Cooley presented his findings to the American Pediatric Society in 1925, referring to this disorder as erythroblastic anemia. However, in a 1932 publication by Whipple and Bradford,¹ it was called thalassemia (the sea anemia) because the authors wished to associate the disease with the Mediterranean area.² Thalassemia is also known to occur in those of Middle Eastern, Sub-Saharan African, South Asian, and Southeast Asian descent, and recent migration patterns have often brought affected individuals to temperate zones.

The prevalence and persistence of thalassemia is attributed to its association with malaria resistance, a characteristic it shares with sickle cell trait, red cell enzymopathies, and certain mutant erythrocyte membrane proteins. Mechanisms that might account for this resistance are enhanced antibody binding and subsequent clearance of infected variant red cells, and increased phagocytosis of infected variant red cells by monocytes.³ Protection against severe malaria is variable and mainly observed in those who carry one or more of these traits.

The human genome includes a pair of β-globin genes, and consequently β-thalassemia can exist as a heterozygous trait, usually regarded as a genetic carrier state, or in the homozygous form, which usually is expressed as a clinically severe form of the disease. As for α-globin, two corresponding gene pairs are normally present, thereby allowing for four degrees of severity of α- thalassemia (the “silent carrier” state; α-thalassemia trait; hemoglobin H disease; and the hydrops fetalis form of α-thalassemia. Genetic counseling is essential for individuals with a family history of the disorder, as it can help them understand the risk of passing the condition on to their children.

A definitive diagnosis of thalassemia requires a study of the synthesis of the individuals’ globin chains, a type of analysis that is costly and not easily available, and more conventional laboratory testing will usually suffice. Patients with heterozygous β-thalassemia most often present with mild, microcytic anemia (MCV 55-70 ml; Hb 8.5-10.5 g/dl), have an elevated level of Hb A2 in their blood, and are usually symptom-free. Those with homozygous β-thalassemia often have severe anemia (4.0-7.5 g/dl) beginning in the first months of life; they frequently also have high levels of Hb F (>20%). Typical findings associated with α-thalassemia are 1) normal blood counts and normal hemoglobin composition in their red cells in individuals with the silent-carrier form (although infants less than two months of age may have significant amounts of Hb Barts (γ4) a homotetramer of γ-globin chains); 2) mild anemia and microcytosis in those with α-thalassemia trait; 3) moderate to severe anemia and the presence of 5 to 30% of Hb H (a homotetramer of β-globin chains) in their red cells; and 4) infants born with the most severe, hydrops fetalis form of α-thalassemia cannot produce α-globin chains, and therefore have no Hb F or Hb A in their erythrocytes. They are extremely anemic at birth and require immediate red cell transfusions if they are to survive.

Treatment for thalassemia depends on the type and severity of the condition. Individuals with α- thalassemia trait and those with β-thalassemia trait usually have no or mild anemia and do not require treatment. Individuals with homozygous β-thalassemia (Cooley’s anemia) frequently require periodic red cell transfusions in order to maintain their hemoglobin levels; treatment regimens for these patients are often include “hypertransfusion” regimens whereby their hemoglobin levels are maintained at a high level in order to suppress the ineffective erythropoiesis that typically accompanies this syndrome. Repeated transfusions have multiple adverse effects such as red cell immunization, iron overload, and transmission of infection.

Iron accumulation occurs in thalassemic patients because their ineffective erythropoiesis stimulates the release of erythroferrone from erythroid precursors. Erythroferrone inhibits hepcidin, an inhibitor of iron absorption, enhancing the uptake of iron by the gastrointestinal tract.⁴ In addition, transfusions add 1 mg of iron for every milliliter of red cells infused. The iron accumulates in the liver and other organs, including the heart, where it can induce cardiomyopathy, heart failure, and death. Management includes regular assessment of the volume of red cells transfused, serum ferritin, and measurements of hepatic and cardiac iron by MRI. Therapy with the oral drug, deferasirox, or other chelators, is given to remove as much of the excess iron as possible. In some patients, the frequency of transfusions is decreased by the administration of the recombinant fusion protein, luspatercept, an agent that ameliorates anemia by boosting late-stage erythropoiesis.⁵

Curative therapy includes stem cell transplantation and gene therapy. The general health of 109 thalassemic patients was greatly improved in the 20 years after stem cell transplantation from HLA-identical sibling donors.⁶ However, there are many limitations to this approach, including patient eligibility, availability of suitable donors, access to Centers with appropriate expertise, and the considerable financial resources required. Furthermore, patients might experience severe graft versus host disease and other morbidities associated with the transplant regimens. A new alternative is gene therapy. Various strategies are being used to restore hemoglobin production in persons with transfusion-dependent β-thalassemia.⁷ One method transduces the patients’ CD34 stem cells with a lentivirus vector whose RNA carries the code for a functional globin chain. The RNA is converted to DNA and becomes integrated into the host genome. The degree of correction of the anemia is dependent on the vector copy number and percentage of transduced CD34 cells. Another approach uses gene editing to restore production of fetal γ-globin chains, which can combine with α-chains to substitute for the lack of β-chains.⁸ Transfusion independence has been reported with either method, but the second approach avoids exposure to a viral vector and the risk of insertional mutagenesis.

Since the time of Cooley and Whipple, an enormous amount of progress has occurred in elucidating the genetics and pathophysiology of the thalassemias. Although transfusions are still the bedrock of management for severe disease, their adverse effects have been reduced by advances in immunology, infection control, and iron elimination. Other treatments, such as stem cell transplantation and gene therapy, have shown that long-term disease remission is possible. Further improvements in treatment are likely, and if thalassemic individuals are given access to the requisite health and financial resources, they will greatly benefit from the scientific advances currently underway.

References

1. Whipple GH, Bradford WL. Mediterranean disease-thalassemia (erythroblastic anemia of Cooley); associated pigment abnormalities simulating hemochromatosis. J Pediatr 1936; 9:279-311.
2. Weatherall DJ. Toward an understanding of the molecular biology of some common inherited anemias: the storyof thalassemia. In Blood, Pure and Eloquent, edited by MM Wintrobe, McGraw-Hill, New York, 1980, pp.373-414.
3. Kariuki SN, Williams TN. Human genetics and malaria resistance. Hum Genet 2020; 139:801-11.
4. Kautz L, Jung G, Du X, et al. Erythroferrone contributes to hepcidin suppression and iron overload in a mouse model of β-thalassemia. Blood 2015; 126:2011-17.
5. Cappelli MD, Viprakasit V, Taher AT, et al. A phase 3 trial of luspatercept in patients with transfusion-dependent β-thalassemia. N Engl J Med 2020; 382:1219-31.
6. La Nasa G, Caocci G, Efficace F, et al. Long-term health-related quality of life evaluated more than 20 years after hematopoietic stem cell transplantation for thalassemia. Blood 2013; 122:2262-70.
7. Locatelli F, Cavazzana M, Frangoul H, de la Fuente J, Algeri M, Meisel R. Autologous gene therapy for hemoglobinopathies: from bench to patient’s bedside. Mol Ther. 2024; 32:1202-18.
8. Locatelli F, Lang P, Wall D, et al. Exagamglogene autotemcel for transfusion-dependent β-thalassemia. N Engl J Med 2024; 390:1663-76).