See ((Thalassemia))
Beta thalassemia is caused by mutations resulting in a single nucleotide substitution, small deletions or insertions within the beta-globulin gene or its immediate flanking sequence, or in rare cases, gross deletions.
These mutations result in reduced production of beta-globulin chains and HbA.
More than 350 bets Thalassemia Mutations have been described.
Estimated 13 to 1500 people in US have transfusion dependent thalassemia.
The severity of anemia, need for transfusions and clinical morbidity are closely tied to the degree of imbalance between alpha-globin and beta-globin chains.
Worldwide patients with thalassemia major receive more red cell products than any other types of patients.
Red blood cell transfusion therapy decreases the complications of severe anemia and prolongs survival.
End-organ manifestations of iron overload causes cirrhosis, hepatocellular carcinoma, cardiac failure, diabetes mellitus and hypopituitarism.
Patients with transfusion-dependent β-thalassemia present in early childhood and need regular red-cell transfusions to maintain adequate hemoglobin levels.
Red-cell transfusion carries infectious and noninfectious risks.
Despite the availability of iron-chelation therapy, many patients with transfusion-dependent β-thalassemia still have complications related to secondary iron overload that may result in end-organ failure and death in early adulthood.
The lifelong need for blood transfusions and iron-chelation therapy negatively affects the quality of life of patients with transfusion dependent patients.
Allogeneic hematopoietic stem-cell transplantation and gene therapy are potentially curative but carry inherent risks and are suitable only in a limited population of patients.
Disease free survival rates succeeding 90% have been reported for hematopoietic stem cell transplantation in children with transfusion dependent beta thalassemia who have favorable risk profiles and matched sibling donors.
Gene therapy is based on the concept of correcting the defective production of beta globin chains by isolating hematopoietic stem cells from a person with beta thalassemia and transducing them with the virus to introduce exogenous beta like globin transgenes that can allow for gene expression.
Gene therapy with betibeglogene autotemcel is being utilized.
Diabetes mellitus and cardiac failure usually occur when hepatic iron concentrations exceed 268 micro mol per gram of liver, dry weight 15 mg per gram.
Patients have fewer cardiac-related complications of iron overload as well as improved survival when chelation therapy keeps serum concentrations below 2500 micro g per liter or hepatic iron concentrations below 268 micro mol per gram of liver.
Cardiac disease is the most important consequence of iron overload in thalassemia.
Hepatomegaly prominent early in the disease with progression to cirrhosis secondary to increased iron deposition.
Elevation of aminotransferase levels and cholestasis are common.
Liver function abnormalities are frequent.
Cardiac complications cause 71% of deaths.
Heart failure with iron overload associated with a poor prognosis.
A Phase 3 Trial of Luspatercept in Patients with Transfusion-Dependent β-Thalassemia: A recombinant fusion protein that binds to select transforming growth factor β superfamily ligands, may enhance late stage erythroid maturation and reduce the transfusion burden in thalassemia patients.
Adults with transfusion-dependent β-thalassemia phase 3 trial received best supportive care plus luspatercept at a dose of 1.00 to 1.25 mg per kilogram of body weight or placebo for at least 48 weeks. I Luspatercept or placebo was administered for a median of approximately 64 weeks in both groups.
The percentage of patients who had a reduction in the transfusion burden of at least 33% from baseline during weeks 13 through 24 plus a reduction of at least 2 red-cell units over this 12-week interval was significantly greater in the luspatercept group than in the placebo group, 21.4% vs. 4.5%.
Adverse events of transient bone pain, arthralgia, dizziness, hypertension, and hyperuricemia were more common with luspatercept than placebo.
The percentage of patients with transfusion-dependent β-thalassemia who had a reduction in transfusion burden was significantly greater in the luspatercept group than in the placebo group.
Allogeneic hematopoietic stem-cell transplantation and gene therapy are potentially curative but carry inherent risks and are suitable only in a limited population of patients.
Serum ferritin levels at week 48 were reduced from baseline in the luspatercept group mean change, −248±800 μg per liter and we’re increased from baseline in the placebo group mean change, 107±526 μg per liter.
A phase 3, randomized, placebo-controlled trial established the efficacy and safety of luspatercept in reducing the transfusion burden among patients with transfusion-dependent β-thalassemia.
Betibeglogene autotemcel (Zynteglo) Gene therapy that uses a patient’s own bone marrow stem cells that has been genetically modified to produce a hemoglobin component has been approved for therapy of beta thalassemia major.