Nondrug and supportive care
Main therapy is transfusion of packed RBCs r60c114
- Required routinely (eg, monthly, bimonthly, weekly) for patients with β-thalassemia major
- Monitor patients with less severe forms of β- and α-thalassemia by CBC and transfuse when needed
- Patients with the trait rarely or never require transfusion
More advanced procedures are hematopoietic stem cell transplantr50 and gene therapyr61c115c116
Calcium and vitamin D supplementation recommendations for all patients r5c117c118c119
Patients with anemia: folic acid supplementation recommended for these patients; can be considered for all patients r5
Patients with zinc deficiency: zinc supplementation recommended for these patients; can be considered in all patients r5r62
Avoid iron-containing supplements unless patient has documented iron deficiency; dietary iron restriction may be necessary for some patients at risk of iron overload r5c120
Diet rich in vitamin E is recommended r5
Vitamin C supplementation is recommended with deferoxamine infusions or if deficiency is proven r5
Counsel to avoid alcohol and tobacco use r5c121c122
- Alcohol exacerbates the oxidative damage of iron; in conjunction with the hepatitis viruses, it significantly increases the risk of cirrhosis and hepatocarcinoma r5
- Tobacco use affects bone remodeling and increases the risk of osteoporosis r5
Psychological support may improve overall well-being and adherence to treatment r5
Genetic counseling r13r17c123
- Offer preconception genetic counseling and testing to people of childbearing age
Procedures
General explanation- Lifelong regular blood transfusions are recommended for patients with transfusion-dependent thalassemia r5
- Regular transfusion therapy is usually initiated in first 2 years of life for severe thalassemia genotypes; some patients with milder forms may need regular transfusions later in life r5
- Transfusion promotes normal growth, facilitates normal functioning, and suppresses excessive bone marrow activity r5
- Patients are given leuko-depleted packed RBCs that are matched appropriately with the patient's RBC antigen phenotype r11
- Extended phenotype-matched RBCs should be used for patients who develop alloimmunization r63
- Before a first transfusion, perform extended RBC antigen typing of at least ABO, C, c, D, E, e, and Kell, although preferably perform a full RBC phenotype/genotype panel
- At each transfusion, give blood compatible for ABO, C, c, E, e, and Kell antigens
- Obtain serum immunoglobulin determination to identify patients with IgA deficiency who may benefit from washed RBCs
- Volume of packed RBCs required is calculated for children as follows: required increase in hemoglobin (g/L) × child's weight (kg) × 0.3 r5
- Normal transfusion rate is 5 mL/kg/hour for children, completing transfusion within 4 hours r18
- In adults, 1 unit of packed RBCs will typically raise the hemoglobin concentration by 1 g/dL and the hematocrit by 3% r64
- Transfusion must be completed within 4 hours
Indication- Criteria required to initiate transfusion therapy include confirmed thalassemia diagnosis and either or both of the following: r5
- Hemoglobin less than 7 g/dL on 2 occasions spaced at least 2 weeks apart
- Symptomatic anemia, poor growth/failure to thrive, complications from excessive intramedullary hematopoiesis, or clinically significant extramedullary hematopoiesis
- Goals of therapy: r5
- β-Thalassemia major
- Goal of regular scheduled transfusion therapy is to maintain a pretransfusion target hemoglobin range of 9.5 to 10.5 g/dL
- Consider higher pretransfusion target hemoglobin level (10-12 g/dL) in the setting of cardiac insufficiency or other cardiac complications
- Typical posttransfusion target hemoglobin range is 13 to 15 g/dL
- Transfusion approach aims to promote normal growth and activity, suppress ineffective erythropoiesis, and minimize iron overload
- Suppressing erythropoiesis helps to prevent cardiac and endocrine complications and reduces splenomegaly and its consequences r65
- Patients with α- and β-thalassemia intermedia are typically treated with sporadic transfusions, using the same approach as is taken with β-thalassemia major; some patients will become transfusion dependent r11
Complications r66- Alloimmunization
- Iron overload
- Blood-borne infection
- Transfusion reactions
Interpretation of results- Treatment is successful if posttransfusion hemoglobin level is greater than 10.5 g/dL but not higher than 13 to 15 g/dL r4r5
General explanation- Surgical removal of spleen
- Decision to remove spleen must be balanced with increased risk of thrombosis and bacterial infection leading to sepsis
- 1 month or more before splenectomy, immunize the patient with the pneumococcal polysaccharide vaccine and vaccines against Haemophilus influenza and Neisseria meningitidisr5
- Also give pneumococcal conjugate vaccine series to children
- Patients who have undergone splenectomy should receive influenza immunization annually r5
- Give antibiotic prophylaxis to all patients who have had a splenectomy for at least 2 to 5 years postoperatively, lifelong for high-risk patients r5
- Lifelong prophylaxis is indicated after an episode of postsplenectomy sepsis
Indication- Increased transfusion requirement that prevents adequate iron control with chelation therapy r8
- Symptomatic splenomegaly r5
- Hypersplenism r5
Contraindications- Inability to tolerate general anesthesia
- Uncontrollable coagulopathy
Complications- Major long-term postsurgical risk is sepsis
- Thromboembolism, particularly in postoperative period
- Pulmonary hypertension
Hematopoietic stem cell transplantation r50r67c126
General explanation- Patient is implanted with hematopoietic stem cells obtained from any of the following:
- Bone marrow from a matched sibling or other well-matched donor
- Embryonic source
- HLA-identical sibling umbilical cord cells
- The transplanted stem cells have normal globin genes, so the patient begins making normal RBCs
- Usually before transplant, the patient's own bone marrow is myeloablated (the bone marrow is suppressed with chemotherapy), but new methods allow for hematopoietic stem cell transplant without myeloablation
- No controlled trials have compared effectiveness/safety of different types of hematopoietic stem cell transplantation r68
- Potentially curative treatment option for transfusion-dependent thalassemia r5
- Health-related quality of life is good in transfusion-dependent thalassemia patients undergoing hematopoietic stem cell transplantation r69
Indication- Thalassemia major with dependency on transfusion
- Ideally offered at early age before complications from iron overload have developed r5
- Patients aged 15 years or younger are the best candidates for hematopoietic stem cell transplantation methods that use myeloablation, but nonablative approaches allow more adults with thalassemia major to qualify as candidates r50
Contraindications- No available matched donor
Complications r70r71- Toxicity secondary to myeloablative regimen
- Infection secondary to immunosuppression
- Acute or chronic graft-versus-host disease
- Late endocrine complications such as thyroid dysfunction, diabetes, and hypogonadism
Interpretation of results- Development of normal CBC results indicates a successful procedure
Gene therapy c127
General explanation- Any or all of the following genetic modification approaches: r72
- Gene for the deficient/absent globin is added to the genome of the patient's hematopoietic stem cells
- Gene for alternate globin that can substitute for deficient chain is turned on or its expression is amplified
- For β-thalassemia, this means turning on γ-globin expression to replace deficient β globin
- Expression of the other globin (α in the case of β-thalassemia) is decreased to prevent tetramer formation
- Betibeglogene autotemcel was the first gene therapy product approved by FDA for β-thalassemia r61
- Production of the patient's hematopoietic stem cells is chemically stimulated; stem cells are then harvested via apheresis r61
- A modified β-globin gene is added to the stem cells' genome ex vivo using lentiviral transduction r61
- Chemotherapeutic agents are used to deplete the patient's hematopoietic stem and progenitor cells to facilitate engraftment (myeloablative bone marrow conditioning) r73
- Genetically modified stem cells are infused back into the patient in a manner similar to hematopoietic stem cell transplant
- Exagamglogene autotemcel was approved by the FDA in 2024 r6r7
- Uses ex vivo clustered regularly interspaced short palindromic repeats (CRISPR)-Cas 9 gene editing technology to edit the erythroid-specific enhancer region of the gene BCL11A in hematopoietic stem cells; reactivates fetal hemoglobin expression r6r7
- CD34+ hematopoietic stem cells from the patient are mobilized using granulocyte-colony stimulating factor and plerixafor; stem cells are then collected using apheresis r7
- Patient's hematopoietic stem cells are modified using CRISPR-Cas 9 gene editing r7
- Patient is treated with myeloablative chemotherapy regimen using busulfan as the conditioning regimen r7
- Modified CD34+ hematopoietic stem cells are infused through a central line r7
- Eliminates the need for a donor and the risks associated with allogenic hematopoietic stem cell transplant (graft rejection, graft-versus-host disease, infertility, and other treatment-related toxic effects) r74
- Results in normal or near-normal hemoglobin levels in 91% of patients followed up for up to 4 years after transplant r75
- Cost may limit use; distribution in Europe was halted following failed negotiations over price r76
Indication- Thalassemia major with dependency on transfusion
Complications- Potential toxicities of hematopoietic stem cell gene therapy can result from the myeloablative conditioning and unintended effects of genetic manipulation; improved conditioning regimens are an active area of research r73
Interpretation of results- Development of normal CBC results indicates a successful procedure