Thalassemia is a monogenic hematological disorder caused as a result of defect in synthesis
of globin chains of hemoglobin (Rachmilewitz et al., 2011; Cappellini et al., 2018). It
causes ineffective erythropoiesis & lysis of red blood cells due to relative excess of
unaffected globin chain (Rachmilewitz et al., 2011; Chen et al.,2021).
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 (Hossain et al, 2017; Cappellini et al., 2018; Shah et al, 2019). About 70-75%
patients are found in southeast asia & eastern mediterranean region (Weatherall D.J., 2017).
Hematopoietic stem cell transplant (HSCT) is the only curative treatment option for
homozygous thalassemia patients (Cappellini et al., 2018; Costa et al.,2022) . 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
(Cappellini et al., 2018; Shah et al, 2019; Lu et al.,2022).
Regular blood transfusion is an essential life saving supportive care to maintain growth and
development in children with severe β-thalassemia (Cappellini et al., 2018; Shah et al, 2019;
Ansari et al, 2022). However, Long term blood transfusion causes iron overload with cardiac,
hepatic and endocrine coomplications , spread transfusion transmitted infections and
formation of antibody (Ansari et al, 2022; Shah et al, 2019). These limitations have
compelled researchers to search for novel therapeutic modalities (Fard et al., 2013; Ansari
et al, 2022 ).
In recent years, induction of Fetal Hemoglobin (HbF) production pharmacologically is an
promising treatment options for hemoglobinopathies (Fard et al., 2013; Thompson et al.,
2018). 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 (Fard et al., 2013). HU induces a 2-9 fold increase in
γ-globin gene and being used for decades in thalassemia treatment (Jain et al., 2021;
Fakredin et al., 2022). But its utility is limited due to its mild and ill sustained
therapeutic effect in HbF synthesis (Green et al., 2016; Rigano et al.,2010). Thalidomide, an
immunomodulatory drug also shown to produce significant and persistent rise in Hb in few
small studies and several case reports (Aguilar-Lopez et al., 2008; Jain et al., 2021; Masera
et al., 2010; Fakredin et al., 2022). It induces Gamma Globin gene expression by increasing
reactive oxygen species-mediated p38 mitogen-activated protein kinase (MAPK) signaling and
histone H4 acetylation (Aerbajinai et al., 2007).
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 (Shah et al., 2019) & The study population includes both adult and
children age group (Ansari et al., 2022). 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.