Efficacy of Combination of Hdroxyurea and Thalidomide Over Hydroxyurea or Thalidomide in the Treatment of Transfusion Dependent Thalassemia in Children

Thalassemia is a monogenic hematological disorder caused as a result of defect in synthesis of globin chains of hemoglobin. It causes ineffective erythropoiesis & lysis of red blood cells due to relative excess of unaffected globin chain.

Annually about 50,000 children with a severe form of thalassemia (β-thalassemia major and HbE β-thalassemia) born globally among which 26,000 patients are regular blood transfusion dependent. About 70-75% patients are found in southeast asia & eastern mediterranean region.

Hematopoietic stem cell transplant (HSCT) is the only curative treatment option for homozygous thalassemia patients. Unfortunately its application is limited due to scarcity of HLA-matched donor, high cost , lack of specialized dedicated centers and risk of transplant related morbidity and mortality.

Regular blood transfusion is an essential life saving supportive care to maintain growth and development in children with severe β-thalassemia. However, Long term blood transfusion causes iron overload with cardiac, hepatic and endocrine coomplications , spread transfusion transmitted infections and formation of antibody. These limitations have compelled researchers to search for novel therapeutic modalities.

In recent years, induction of Fetal Hemoglobin (HbF) production pharmacologically is an promising treatment options for hemoglobinopathies. Different HbF inducing agents like Hydroxyurea (HU), Butyrate derivatives, Azacitidine, Decitabine, Tricostatin-A are shown to be effective in decreasing clinical severity and complications of TDT. HU induces a 2-9 fold increase in γ-globin gene and being used for decades in thalassemia treatment. But its utility is limited due to its mild and ill sustained therapeutic effect in HbF synthesis. Thalidomide, an immunomodulatory drug also shown to produce significant and persistent rise in Hb in few small studies and several case reports. It induces Gamma Globin gene expression by increasing reactive oxygen species-mediated p38 mitogen-activated protein kinase (MAPK) signaling and histone H4 acetylation.

Recent studies with combination of HU and Thalidomide have shown promising results in treatment of Thalassemia patients. However, most of those studies are retrospective or single arm nonrandomized trials & The study population includes both adult and children age group. So the effectiveness of combination therapy of Thalidomide and HU needs to be established in children through randomized trials.

So the goal of our study to evaluate the effectiveness of combination of Thalidomide and HU in comaprison to Thalisomide or HU alone in children with TDT through a three arm quasi randomized trial.

Inclusion criteria

• Patients diagnosed as transfusion dependent thalassemia
• Age ranged from 3-18 years
• Blood transfusion more than 1 year.
• no bleeding disorder

Exclusion criteria

• Active systemic co-morbidity,
• Past personal or family history of thrombophilia,
• Recent fracture or recent major surgery
• Use of drugs that might affect Hb levels 15 days before enrollment