Description of the condition

Beta (β)‐thalassaemia is the inherited blood disorder that results when an individual is unable to produce sufficient levels of haemoglobin (Hb) (Zamani 2009). It is due to the imbalance of the alpha (α)‐ to β‐globin chain ratio due to decreased production of β‐globin. An excess in the α chain precipitates red blood cell precursors, which leads to their damage in the bone marrow and shortening the survival of the progeny in the peripheral blood (Weatherall 2001). This results in ineffective erythropoiesis and haemolysis. Enhancement of the gamma (γ)‐globin chains can decrease this imbalance (Bradai 2003). One of the major factors in modifying the clinical variability of β‐thalassaemia is a genetically determined ability to produce unusually high levels of foetal haemoglobin (HbF). A second factor that has been clearly identified is that the co‐inheritance of α‐thalassaemia will ameliorate the β‐thalassaemias (Weatherall 2001). In individuals with transfusion‐dependent β‐thalassaemia, the most severe form of β‐thalassaemia, the oxygen depletion in the body becomes apparent within the first six months of life. If left untreated, death usually occurs within a few years since most children with thalassaemia survive on regular blood transfusions. The disorder is prevalent worldwide; the WHO has estimated that approximately 1.5% of the global population might be carriers of β‐thalassaemia and that approximately 60,000 affected children are born every year (Higgs 2012). In the UK, approximately 214,000 to 300,000 people have the β‐thalassaemia trait, whilst 800 to 1000 have the disorder (NHS 2011; RCOG 2014). Approximately 79% of affected births are in the Asian population (NHS 2011; RCOG 2014). In Southeast Asia, 1% to 8% of people have the β‐thalassaemia trait (Rehman 2011), and untreated affected children die before the age of three years (Higgs 2012; Modell 2008). People in low‐ and middle‐income countries have poor access to safe blood and the majority of the people die due to transfusion‐associated complications. It has been reported that there is an increased likelihood of blood transfusion‐transmissible infections in transfusion‐dependent individuals (Vidja 2011). In addition, frequent blood transfusions lead to iron overload which results in various complications such as heart disease (heart failure and arrhythmias), chronic liver hepatitis and fibrosis, endocrine problems (hypogonadism, hypothyroidism), stunted growth, osteoporosis and delayed pubertal growth (Borgna 2011; Rachmilewitz 2011). These complications have been improved by the use of iron chelating agents; however, they still exist in those who are less compliant with iron chelator treatment (Rachmilewitz 2011). Furthermore, the cost of treating these complications, in addition to managing the disease itself, poses a financial burden on both families and healthcare systems.

Description of the intervention

Various therapeutic agents such as erythropoietin, 5‐azacytidine, butyrate derivatives, and hydroxyurea (hydroxycarbamide), have been investigated for their potential role in augmenting HbF and also their therapeutic role in treating haemoglobinopathies (Ansari 2011; Perrine 2005). Hydroxyurea induces the production of HbF. The clinical benefits of this agent in people with sickle cell disease has been demonstrated in several studies, but only a limited number of studies have assessed its role in people with β‐thalassaemia (Bradai 2003). Such observational studies have shown a therapeutic response in large numbers of people, resulting in an increase in the Hb level and a decrease or elimination of the transfusion requirements in around 30% to 40% of individuals (Ansari 2011; Italia 2009; Yavarian 2004). In β‐thalassaemia, due to a mutation of β‐globin gene, no β‐globin protein is produced. There are four α‐globin proteins which are associated with ineffective erythropoiesis and red blood cell lysis. The beneficial effect of augmenting HbF through hydroxyurea has been associated with the reactivation of the γ‐globin gene, which leads to γ‐globin chain formation. This γ‐globin chain combines with two α chains resulting in the formation of HbF.

How the intervention might work

Hydroxyurea is one of several agents capable of activating the γ‐globin gene associated with an improvement in α to non‐α globin ratios, thereby leading to an increase in the effectiveness of erythropoiesis after several months of therapy (Fucharoen 1996; Zeng 1995).

Mechanisms proposed for the induction of HbF by hydroxyurea include rapid erythroid regeneration, increased erythropoietin (EPO) production, apoptosis, nitric oxide production, increased guanylate cyclase activity and activation of the p38 MAPK pathway. Induction of HbF by hydroxyurea in people with β‐thalassaemia was reported to be of similar magnitude as found in the cells of healthy individuals (1.3‐fold to 3.5‐fold) and people with sickle cell disease (two‐fold to five‐fold). In erythroid progenitor cells treated with hydroxyurea in vitro, HbF induction was comparable to the increase of HbF in the peripheral blood of people with sickle cell disease following hydroxyurea therapy in vivo. The majority of individuals increase HbF production after treatment with hydroxyurea; however, HbF baseline levels and the size of the response varies greatly. The absolute response to hydroxyurea and the HbF baseline level is likely dependent on genetic factors that modulate different regulatory pathways and trans‐acting factors involved in γ‐globin production (Pourfarzad 2013). Hydroxyurea has been widely used, due to the fact it has the lowest toxicity profile among the chemotherapeutic agents (Zeng 1995). It has been found to increase total Hb and HbF levels and reduce the need for blood transfusion in a people with transfusion‐dependent β‐thalassaemia (Arruda 1997).

Hydroxyurea therapy is associated with an improvement in the ineffective erythropoiesis, as reflected by an increase in the Hb level, a reduction in red blood cell transfusion requirement and a decreasing trend in the serum lactate dehydrogenase (LDH) and serum unconjugated bilirubin levels. This favourable effect of hydroxyurea was observed as early as one to three months post treatment. In contrast, a significant decrease in spleen size reflecting a reduction in extramedullary erythropoiesis appeared to take place much later, after six months of hydroxyurea therapy with a maximal benefit observed at 12 months of therapy. These favourable effects of hydroxyurea appeared to be associated with an increase in the γ‐globin biosynthesis, because the percentage of HbF increased as well as the total Hb. This observation is in agreement with a short‐term study that showed a good correlation of Hb levels with the amount of HbF production in people with βº‐thalassaemia and haemoglobin E (HbE) treated with hydroxyurea for five months (Fucharoen 1996; Wahid 2007). In addition to the modest increase in the Hb, most people reported an increase in exercise tolerance and sense of well being in comparison with their symptoms before therapy. This feeling may reflect the significant decrease in ineffective erythropoiesis resulting in the replacement of the poorly haemoglobinised, prematurely dying erythroid progenitor and red blood cell population by another population of cells with higher Hb content and longer survival, the regeneration of which requires less energy and consumption (Loukopoulos 1998).

Hydroxyurea can be used as an alternative option to blood transfusion for people with transfusion‐dependent β‐thalassaemia in countries having limited blood supplies (Bradai 2007; Karimi 2012), particularly in those people having a favourable molecular background (Yavarian 2004). Bradai reported better response to hydroxyurea with older age groups at the first transfusion and Xmn1 polymorphism (Bradai 2007). Xmn 1 polymorphism is a polymorphism at position ‐158 in γ‐globin gene which is associated with increase HbF formation and hence a better response to a HbF augmenting agent like hydroxyurea. However, few studies have not found any significant association of response to hydroxyurea with Xmn1 polymorphism (Karimi 2012) or any specific β‐thalassaemia mutations or α‐globin deletions (Yavarian 2004).

Why it is important to do this review

Hydroxyurea is a low‐cost medicine which may reduce the need for blood transfusions. According to various studies, significant numbers of people with β‐thalassaemia have responded to this treatment and physicians regard this treatment positively (Ansari 2007; Koren 2008; Zamani 2009). Therefore, this Cochrane Review aims to gather evidence regarding the efficacy of hydroxyurea which can then inform guidelines that in turn can formulate evidence‐based recommendations impacting upon current treatment protocols.