Approach Considerations
The therapeutic approach to thalassemia varies between thalassemia minor and thalassemia major.
Thalassemia minor
Patients with thalassemia minor usually do not require any specific treatment. Inform patients that their condition is hereditary and that physicians sometimes mistake the disorder for iron deficiency. Some pregnant patients with the beta thalassemia trait may develop concurrent iron deficiency and severe anemia; they may require transfusional support if they are not responsive to iron repletion modalities.
Thalassemia major
Treatment for patients with thalassemia major includes the following:
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Long-term transfusion therapy
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Erythroid maturation agents (eg, luspatercept)
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Iron chelation
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Splenectomy
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Allogeneic hematopoietic transplantation
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Supportive measures
Supportive measures include folic acid replacement and monitoring for the development of complications such as pulmonary hypertension, osteoporosis, and bone fractures, poor dentition, heart failure, and aplastic crisis with parvovirus B-19 infection.
Long-term transfusion therapy
The goal of long-term hypertransfusional support is to maintain the patient's hemoglobin level at 9-10 g/dL, thus improving his or her sense of well being while simultaneously suppressing enhanced erythropoiesis. This strategy treats the anemia and suppresses endogenous erythropoiesis so that extramedullary hematopoiesis and skeletal changes are suppressed. Patients receiving long-term transfusion therapy also require iron chelation. (See Medication.)
Blood banking considerations for these patients include completely typing their erythrocytes for Rh and ABO antigens prior to the first transfusion. This procedure helps future cross-matching processes and minimizes the chances of alloimmunization. Transfusion of washed, leukocyte-poor red blood cells (RBCs) at approximately 8-15 mL RBCs per kilogram (kg) of body weight over 1-2 hours is recommended. [12]
Hapgood et al suggest that current recommendations lead to undertransfusion in males. As a result, males may be more likely to have extramedullary hematopoiesis and thus more likely to require splenectomy or to develop spinal cord compression, an uncommon but serious complication of paraspinal extramedullary hematopoiesis. [13]
In their study of 116 patients (51 males and 65 females) with thalassemia major, males were receiving more units of RBCs per transfusion and had a higher annual transfusion volume, but with correction for weight, females were receiving a higher transfused volume per kg: 225 versus 202 mL/kg in males (P=0.028). Erythropoietin (EPO) levels were higher in males: 72 versus 52 mIU/mL (P=0.006). The incidence of splenectomy was higher in males (61%, vs 40% in females; P=0.031). [13]
Hematopoietic stem cell transplantation
Allogeneic hematopoietic transplantation may be curative in some patients with thalassemia major. [14] The first successful allogeneic stem cell transplant from an HLA-identical sibling donor was reported in 1982. [15] An Italian group led by Lucarelli has the most experience with this procedure. [16] This group's research documented a 90% long-term survival rate in patients with favorable characteristics (young age, HLA match, no organ dysfunction).
Transplantation-related issues such as graft versus host disease, graft failure, chronic immunosuppressive therapy, and transplantation-related mortality should be carefully considered prior to proceeding with this approach.
Diet and activity
Drinking tea may help to reduce iron absorption through the intestinal tract. Vitamin C may improve iron excretion in patients receiving iron chelation, especially with deferoxamine. [17] However, anecdotal reports suggest that large doses of vitamin C can cause fatal arrhythmias when administered without concomitant infusion of deferoxamine.
Patient activity may be limited secondary to severe anemia.
Gene therapy
Since the first successful gene therapy for thalassemia major, in 2007, researchers have worked to improve the efficacy and safety of the procedure. [14, 18, 19] In this process, autologous hematopoietic stem cells (HSCs) are harvested from the patient and then genetically modified with a lentiviral vector expressing a normal globin gene. After the patient has undergone appropriate conditioning therapy to destroy existing HSCs, the modified HSCTs are reinfused into the patient.
A newer approach employs genome editing techniques, such as zinc finger nucleases (ZFN), transcription activator–like effectors with Fokl nuclease (TALEN), or the clustered regularly interspaced short palindromic repeats (CRISPR) with Cas9 nuclease system. These can specifically target single-mutation sites and replace them with the normal sequence, restoring the wild-type functional configuration of the gene. Producing a sufficiently large number of corrected genes is the major challenge with this approach. [14, 20]
In 2019, the European Union conditionally approved the use of betibeglogene autotemcel (Zynteglo), the first gene therapy for the treatment of transfusion-dependent beta thalassemia. However, the expense of such therapy is likely to restrict its application. The US Food and Drug Administration (FDA) approved betibeglogene autotemcel in August 2022.
The autologous, one-time IV infusion adds functional copies of a modified beta-globin gene into the patients’ HSCs through transduction of autologous CD34+ cells using a lentiviral vector. Providing the functional gene addresses the underlying genetic cause of β-thalassemia.
The single-arm, open-label, 24-month phase 3 studies of betibeglogene autotemcel included 41 patients aged 4 to 34 years with both non-β0/β0 and β0/β0 genotypes, with longest follow up out to 4 years. Among evaluable patients across ages and genotypes, 89% (32/36) achieved transfusion independence, defined as no longer needing RBC transfusions for at least 12 months while maintaining a weighted average total hemoglobin of at least 9 g/dL. [21, 22]
Surgical Treatment
Splenectomy
Physicians often use splenectomy to decrease transfusion requirements in patients with thalassemia major. (Patients with thalassemia minor only rarely require splenectomy.) Splenectomy is recommended when the calculated annual transfusion requirement is greater than 200-220 mL RBCs/kg/y with a hematocrit value of 70%. [12] In addition to reducing transfusion requirements and the resultant iron overload, splenectomy also prevents extramedullary hematopoiesis.
Because postsplenectomy sepsis is possible, defer this procedure until the patient is older than 6-7 years. In addition, to minimize the risk of postsplenectomy sepsis, vaccinate the patient against Pneumococcus species, Meningococcus species, and Haemophilus influenzae. Administer penicillin prophylaxis to children after splenectomy. Postsplenectomy thrombocytosis can increase the risk of thrombotic events. The risk-to-benefit ratio for this procedure should be cautiously evaluated.
Cholecystectomy
Patients with thalassemia minor may have bilirubin stones in their gallbladder and, if symptomatic, may require treatment. Perform a cholecystectomy using a laparoscope or carry out the procedure at the same time as the splenectomy.
Investigational Therapy
Emerging therapies include pharmacologic agents that induce fetal hemoglobin, Jak2 inhibitors to reverse splenomegaly, hepcidin-related compounds to improve iron metabolism, and gene therapy aimed at delivering the beta globin gene into cells by a viral vector. [23]
Because fetal globin gene expression is associated with a milder phenotype, approaches to enhance intracellular Hb F levels (through drugs that activate gamma-globin gene expression) are under investigation. The two most widely studied drugs in this area are butyrates and hydroxyurea. [24] More recently, new therapeutic targets have been reported, such as BCL11A, which regulates fetal hemoglobin expression. [25, 26]
Other therapeutic approaches currently being investigated include the following [27, 28] :
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Demethylating agents (eg, decitabine, 5-azacytidine)
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Histone deacetylase (HDAC) inhibitors (eg, vorinostat, panobinostat)
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Immunomodulating agents (eg, pomalidomide)
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Short-chain fatty acid derivatives (eg, arginine butyrate, sodium phenylbutyrate)
Sotatercept (ACE-011) is a promising activin type IIA receptor fusion protein that has been recently reported to improve anemia in patients with non–transfusion-dependent thalassemia intermedia. [29]
Improvement in anemia has been reported with administration of erythropoietin in several studies; however, well-controlled clinical trials have not been performed. The postulated mechanism of action of erythropoietin is that increasing the erythroid mass (pathologic and less pathologic RBCs) and, thus hemoglobin, stimulates fetal hemoglobin, increases iron use, and reduces oxidative stress. [30]
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Peripheral smear in beta-zero thalassemia minor showing microcytes (M), target cells (T), and poikilocytes.
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Peripheral smear from a patient with beta-zero thalassemia major showing more marked microcytosis (M) and anisopoikilocytosis (P) than in thalassemia minor. Target cells (T) and hypochromia are prominent.
