We wanted to find out if giving hydroxyurea to people with non-transfusion dependent beta thalassaemia would reduce the need for blood transfusion.
Thalassaemia is a genetic blood disorder causing defective adult haemoglobin (the oxygen carrying component of red blood cells). This causes anaemia with different degrees of severity. People with non-transfusion dependent beta thalassaemia do not depend on regular transfusions for survival, but may require blood transfusion from time to time. Persistent anaemia affects growth, may delay puberty and reduce quality of life. However, transfusion should be avoided, if possible, because it leads to excess iron being deposited in various organs affecting how they function.
People with non-transfusion dependent beta thalassaemia have higher levels of foetal haemoglobin (the main form of haemoglobin found during the development of a baby before birth). After birth, foetal haemoglobin gradually disappears and is replaced by the defective adult haemoglobin. A small amount of foetal haemoglobin remains after birth and is often present in people with non-transfusion dependent beta thalassaemia. The higher the level of foetal haemoglobin the less transfusion could be needed.
Hydroxyurea is an anti-cancer treatment which increases the level of foetal haemoglobin. Therefore, it might reduce the need for blood transfusion in people with non-transfusion dependent beta thalassaemia. However, it is not known whether hydroxyurea is effective and safe and if so, which is the best dose and at which age treatment should start.
The evidence is current to 30 April 2016.
We did not find any randomised controlled trials (where people taking part in the trial have equal chances of being in the treatment or the control group) comparing hydroxyurea with a placebo (a dummy drug) or usual care. However, we found one randomised controlled trial comparing two different doses of hydroxyurea (10 mg/kg/day versus 20 mg/kg/day given for 24 weeks) and included it in this review. A total of 61 people took part in this trial.
The lower dose of hydroxyurea appeared to increase levels of foetal haemoglobin, but the higher dose did not. We found some evidence that the higher dose was harmful, particularly to the bone marrow. The trial did not look at whether blood transfusions could be given less often or whether the effects of the anaemia were reduced. In the short term, the lower dose does not appear to have any side effects. The trial duration was very short and we need to know what might happen if treatment with hydroxyurea is continued for a longer period of time.
Quality of the evidence
We graded the quality of the evidence as very low. This was because our key results are based on only one small trial. In addition we can not be sure whether the trial methods were of high quality because the authors have not completely described them.
There is no evidence from randomised controlled trials to show whether hydroxyurea has any effect compared with controls on the need for blood transfusion. Administration of 10 mg/kg/day compared to 20 mg/kg/day of hydroxyurea resulted in higher haemoglobin levels and seems safer with fewer adverse effects. It has not been reported whether hydroxyurea is capable of reducing the need for blood transfusion. Large well-designed randomised controlled trials with sufficient duration of follow up are recommended.
Non-transfusion dependent beta thalassaemia is a subset of inherited haemoglobin disorders characterised by reduced production of the beta globin chain of the haemoglobin molecule leading to anaemia of varying severity. Although blood transfusion is not a necessity for survival, it is required when episodes of chronic anaemia occur. This chronic anaemia can impair growth and affect quality of life. People with non-transfusion dependent beta thalassaemia suffer from iron overload due to their body's increased capability of absorbing iron from food sources. Iron overload becomes more pronounced in those requiring blood transfusion. People with a higher foetal haemoglobin level have been found to require fewer blood transfusions. Hydroxyurea has been used to increase foetal haemoglobin level; however, its efficacy in reducing transfusion, chronic anaemia complications and its safety need to be established.
To assess the effectiveness, safety and appropriate dose regimen of hydroxyurea in people with non-transfusion dependent beta thalassaemia (haemoglobin E combined with beta thalassaemia and beta thalassaemia intermedia).
We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register, compiled from electronic database searches and handsearching of relevant journals. We also searched ongoing trials registries and the reference lists of relevant articles and reviews.
Date of last search: 30 April 2016.
Randomised or quasi-randomised controlled trials of hydroxyurea in people with non-transfusion dependent beta thalassaemia comparing hydroxyurea with placebo or standard treatment or comparing different doses of hydroxyurea.
Two authors independently applied the inclusion criteria in order to select trials for inclusion. Both authors assessed the risk of bias of trials and extracted the data. A third author verified these assessments.
No trials comparing hydroxyurea with placebo or standard care were found. However, we included one randomised controlled trial (n = 61) comparing 20 mg/kg/day with 10 mg/kg/day of hydroxyurea for 24 weeks.
Both haemoglobin and foetal haemoglobin levels were lower at 24 weeks in the 20 mg group compared with the 10 mg group, mean difference -2.39 (95% confidence interval - 2.8 to -1.98) and mean difference -1.5 (95% confidence interval -1.83 to -1.17), respectively. Major adverse effects were significantly more common in the 20 mg group, for neutropenia risk ratio 9.93 (95% confidence interval 1.34 to 73.97) and for thrombocytopenia risk ratio 3.68 (95% confidence interval 1.13 to 12.07). No difference was reported for minor adverse effects (gastrointestinal disturbances and raised liver enzymes). The effect of hydroxyurea on transfusion frequency was not reported.
The overall quality for the outcomes reported was graded as very low mainly because the outcomes were derived from only one small study with an unclear method of allocation concealment.