Hydroxyurea therapy for sickle cell disease in BritainBMJ 1998; 316 doi: https://doi.org/10.1136/bmj.316.7146.1689 (Published 06 June 1998) Cite this as: BMJ 1998;316:1689
Disappointing recruitment despite promising results
- A Olujohungbe, Senior registrar in haematology,
- Kornelia I Cinkotai, Acting consultant haematologist,
- A Yardumian, Consultant haematologist
Sickle cell disease is the commonest inherited haemoglobinopathy in Britain and affects over 9000 people.1 Clinical severity varies considerably, but patients with the most severe disease have a life expectancy of just over 40 years. Conventional management of the disease is largely supportive, highlighting a pressing need for approaches that can alter the course of the disease. Trials in America have suggested that hydroxyurea can have a significant impact on the course of the disease, but in Britain it is proving virtually impossible to recruit patients into trials to confirm these results in a British population.
The fact that the clinical severity of the sickle cell disease varies even within groups of patients with the same β globin genotype2 has led to the concept that the disease is a multigene disorder, with inheritance of α thalassemia and genes controlling the concentration of fetal haemoglobin, among others, modulating disease expression. 2 3 In those severely affected debilitating bone pain crisis is responsible for 60-90% of sickle related admissions in Britain,3 while the chest syndrome contributes another 15-30%. The adverse effects of these acute events on life expectancy is borne out by results from the cooperative study of sickle cell disease. 4 5 This showed a median survival of just over 40 years in adults with HbSS who have three or more pain crises a year and about 53 years in those who had fewer than three. The risk of severely symptomatic disease and early death is correlated with the fetal haemoglobin concentration.5 For years effort has been directed into the investigation of pharmacological agents which may raise concentrations of fetal haemoglobin.
Hydroxyurea is the first widely available and affordable agent that appears to have a real impact on the course of sickle cell disease. Its precise mechanism of action is unknown but it causes an increase in fetal hameoglobin concentrations in most subjects, which physically interferes with the polymerisation process of deoxyhaemoglobin S. In 1994 a large multicentre, randomised, double blind placebo study in America of 299 subjects showed that the drug significantly reduced the frequency and severity of painful crises, the incidence of acute chest syndrome, and blood transfusion requirements.6 These results were communicated as a “clinical alert” by the National Institutes of Health.
With appropriate monitoring, side effects are few, and pilot schemes using hydroxyurea in children with sickle cell disease have now been reported from America and Belgium.7 A theoretical risk exists that hydroxyurea may transform chronic granulocytic leukaemia and myeloproliferative disorders into acute leukaemia,8 although these are themselves premalignant conditions. The increased risk of leukaemogenesis in non-malignant conditions is unquantified but appears to be low. No evidence of malignant transformation was seen in 64 patients with secondary polycythaemia reported by Triadou et al.9
British haematologists think that the single American study should be repeated in Britain. We need to study the reproducibility of the results in a British population. Also, we do not yet know which patients are likely to respond nor do we have a full understanding of the best regimen, whether by daily or intermittent administration. Combination therapy with hydroxyurea and other agents acting on fetal haemoglobin concentrations may provide optimum therapy. For the 20% of people who do not respond alternative strategies will be required. However, several studies started in Britain have not been completed because many patients are unwilling to take the drug.
Studies at the North Middlesex, Whittington, and King's College hospitals and Manchester Royal Infirmary have failed to recruit enough patients to be continued. Although patients' spoken fears are about the possibility of secondary malignancies, reasons for their reluctance to try new drugs such as this are probably complex and include wariness in patient-doctor relationships, peer group criticism, and anxiety about change. Support groups have campaigned openly against the use of hydroxyurea. As a result only a few severely affected patients are taking hydroxyurea, in a variety of different regimens. It will not be possible to make clinical decisions from the results of this unstandardised approach.
Hydroxurea is not a cure for sickle cell disease and it should at present be offered only to severely affected patients who are fully informed about the treatment, its potential benefits, and possible side effects. However, for selected patients it is likely to be the best we have to offer in the near future, and it may transform the life of patients who respond to it. It is therefore regrettable that so few patients in Britain currently feel able to avail themselves of it.