Efficacy of Combination of Hdroxyurea and Thalidomide Over Either Hydroxyurea or Thalidomide Alone in the Treatment of Transfusion Dependent Thalassemia in Children: A Quasi-Randomised Clinical Trial

Transfusion Dependent Thalassemia (TDT) is an emerging global public health concern. Hemopoietic stem cell transplantation (HSCT) is the only curative treatment. But its adoption is limited due to lack of HLA matched donor, experienced centers and high initial cost. So, researches are going on in search of an effective, safe, easily available treatment option. Use of fetal haemoglobin inducing agents shows promising effects in treatment of TDT patients. Thalidomide an immunomodulating and anti-angiogenic drug has been shown to induce γ-globin gene expression and increase the proliferation of erythroid cells. Furthermore Hydroxyurea (HU) is known to increase haemoglobin (Hb) by HbF induction and reduction of inflammation and hypercoagulability.

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 through randomized trials.

This single centered non blinded quasi randomized clinical trial will be conducted at the Department of Pediatric Hematology and Oncology in Bangabandhu Sheikh Mujib Medical University (BSMMU), Bangladesh for one year of period. Thirty transfusion dependent thalassemia children of 3-18 years old will be included in each group. The objective of this study is to assess the effectiveness of combination of Thalidomide and Hydroxyurea in TDT children. It will play an important role in planning a cost effective and affordable treatment option for TDT children.This study will involve minimum physical risk to the patient. Written informed consent will be taken from parents or study subjects after brief explanation of the purpose and procedure. They will also be informed about the freedom to participate or not to participate at any time. Privacy and confidentiality will be safe guarded. History regarding age, sex, height, weight of these patients will be taken. Thorough physical examinations and laboratory investigations including CBC, Hb electrophoresis, serum Ferritin, serum creatinine, SGPT will be done. Data will be collected in a predesigned questionnaire and will be kept confidential. Statistical analysis will be done using the statistical software SPSS.

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.

Eligibility Criteria:
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