Deciphering Effects of Thalidomide on Red Blood Cells in Transfusion Dependents Beta Thalassemia Patients
Condition: Transfusion-dependent Beta-Thalassemia
MeSH terms: Thalassemia; beta-Thalassemia
Study type: Interventional
Phase: Phase 3

Summary: 
      The goal of this Non-Randomized Clinical Trial is to determine the effects of thalidomide on
      red blood cells in transfusion dependent beta thalassemia patients. The main aims of this
      study are:

        -  To determine the therapeutic effect of Thalidomide on hemoglobin.

        -  To analyze association of different β- globin mutations with response to thalidomide in
           β-thalassemia patients.

        -  To analyze association of Single Nucleotide Polymorphisms (SNPS) of HBG2, BCL11A and
           HBS1L-MYB with response to thalidomide in β-thalassemia patients.

        -  To correlate GATA1 and KLF1 gene expression with response to thalidomide in
           β-thalassemia patients.

      Patients will be grouped into thalidomide and non-thalidomide groups on the basis of their
      willingness to receive thalidomide therapy. Thalidomide will be given at an average dose of
      1.5mg/kg/day (range 1-2mg/kg/day). Patients will be followed up for 12 months and data will
      be collected at different visits. After 12 months of thalidomide therapy patients will be
      divided into responders and non-responders for comparative analyses on the basis of increase
      in hemoglobin level.
    

Detailed description: 
      Thalassemias are a group of genetic disorder of hemoglobin synthesis characterized by a
      decreased synthesis of globin chain. Thalassemias are classified as α-,β-, γ-,or
      δ-thalassemias depending upon the chain whose synthesis is reduced. Among these,
      β-thalassemia is more common. In β-thalassemia there is a decreased or absent hemoglobin A
      (HbA). Normal adult hemoglobin is primarily HbA, which represents approximately 98% of
      circulating hemoglobin. HbA is formed from 2 α and 2 β chains (α2β2). Combination of 2 α and
      2 δ (α2δ2) form hemoglobin A2 (HbA2). Combination of 2 α and 2 γ (α2γ2) form hemoglobin F
      (HbF) which is a major form of hemoglobin in fetal life but comprises less than 1% of adult
      hemoglobin. Human beta-globin protein is encoded by HBB gene on chromosome 11, which
      contributes two β polypeptide chains. Therefore, one chain is inherited from the mother and
      one inherited from the father. In normal (homozygote) both genes are normal and produce
      normal β polypeptide chains to normal quantity. In heterozygote one gene is normal and other
      is abnormal which does not produce β polypeptide chain. Such condition is called
      β-thalassemia minor. In such a person normal gene produces enough β chain to maintain
      hemoglobin level. In abnormal homozygote both beta chain genes are abnormal and do not
      produce β polypeptide chain. Such condition is called β-thalassemia major. Reduced or absent
      production of β-globin chains with relative excess of α-chains cause imbalance and free α
      chains precipitate within the red blood cells. This result in extensive premature destruction
      of red cell precursors in the bone marrow, referred to as "ineffective erythropoiesis". The
      imbalance causes peripheral hemolysis as well. The two phenomena culminate in clinically
      significant anemia.

      Severity of anemia due to β-thalassemia depends upon the type of mutations in β-globin gene.
      Mostly point mutations and frame shift mutations, in intronic as well exonic region, are
      reported in Pakistani β-thalassemia patients. Some mutations completely block the β-gene and
      thus no β globin chain is produced (βo) while in other mutations there is production of some
      β globin chains (β+). In β-thalassemia major both β globin alleles undergo mutations (βo/βo)
      and disease is severe. In β-thalassemia minor only one of β globin alleles are mutated (β+/β
      or βo/β) and patient is asymptomatic. β-thalassemia intermedia (β+/β+ or βo/β+) is the form
      of disease which is milder than thalassemia major but more severe than thalassemia minor.
      Besides less severe β+ mutations, inheritance of HbF inducing genetic variations and
      co-inheritance of alpha globin mutations can also ameliorate the clinical severity of the
      disease. In regards to HbF induction, genetic association studies have shown that there are
      at least three major loci that play a major role in increasing HbF and are associated with
      severity of β-thalassemia. These include -158 C > T in the promoter gene Gamma 2 (locus
      XmnI), intergenic regions HBS1L-MYB in the 6q23.3 chromosomal region, and the BCL11A gene on
      chromosome 2p16.1.

      Annually about 60000 babies are born with thalassemia all over the world. Global annual
      incidence of β-thalassemia is estimated at a rate of 1/100,000 . Carrier rate for
      β-thalassemia in Pakistan ranges between 5-8%, and around 5000 children are diagnosed each
      year with the disease .

      Severe anemia in β-thalassemia patients necessitates frequent transfusions, which lead to
      iron overload. Chronic anemia and iron overload lead to several complications including
      skeletal deformities, splenomegaly, osteoporosis, endocrinopathies, growth retardation and
      cardiac complications. Iron overload is treated with iron chelating agents. Definitive
      treatment is bone marrow transplantation (9).Thalassemia patients who do not respond well to
      blood transfusions can take hydroxyurea or thalidomide, and sometimes a combination of both.

      Thalidomide, an immuno-modulatory drug is currently approved by FDA for the treatment of
      multiple myeloma and Leprosy. Thalidomide is used off-label for the treatment of
      β-thalassemia patients worldwide. Thalidomide has been reported to reduce or even eliminate
      the need for red blood cell transfusions in patients with transfusion dependent β-thalassemia
      . Although association of β globin gene mutations and genetic modifiers with severity of
      β-thalassemia have been well studied but association of these genetic factors with response
      to thalidomide therapy still needs to be explored. A study conducted on 48 Chinese patients
      showed association of Xmn1 HBG2, BCL11A & HBSIL-MYB single nucleotide polymorphisms (SNPs)
      with response to thalidomide therapy. .

      Improved terminal erythroid maturation and red blood cells stability are considered effective
      therapeutic approaches in the treatment of thalassemia. GATA1 and KLF1 are important
      transcription factor in erythroid differentiation which play critical role in regulation of
      globin gene expression. Studies reveal that increased expression of GATA1 and KLF1 causes
      induction of fetal hemoglobin (HbF) leading to reduced accumulation of α-globin chains in
      erythroid precursors and betterment of imbalance between α and β chains thus diminished
      ineffective erythropoiesis.

      The current study aims to determine the in-vivo effects of thalidomide on GATA1 & KLF1 gene
      expression in transfusion dependent β-thalassemia patients. Findings of the study will
      provide scientific evidence in support or against the off- label use of thalidomide in
      β-thalassemia patients. Results of the study regarding association of β-globin mutations and
      Xmn1 HBG2 BCL11A & HBSIL-MYB single nucleotide polymorphisms with response to thalidomide
      therapy will explain variation in inter-individual response to the drug and thus help in
      predicting response before starting thalidomide therapy.
    

Intervention name(s): Thalidomide
Intervention type(s): Drug
Intervention description(s): Thalidomide given at an average dose of 1.5mg/kg/day
Other intervention name(s): Bludomide
Intervention MeSH terms: Thalidomide
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Intervention model description: Patients will be grouped into thalidomide and non-thalidomide groups on the basis of their willingness to receive thalidomide therapy. Thalidomide will be given at an average dose of 1.5mg/kg/day (range 1-2mg/kg/day). Patients will be followed up for 12 months and data will be collected at different visits.
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: β-thalassemia; Thalidomide; β- globin mutations; Single Nucleotide Polymorphisms