Hydroxyurea Treatment in Beta-Thalassaemia Inter media
Hydroxyurea is a cytotoxic, which is found to be useful in increasing the haemoglobin level of thalassaemia subjects, though the mechanism of actions is still unclear. Two patients with thalassaemia intermedia received hydroxyurea treatment were presented. Treatment with hydroxyurea increases the haemoglobin level by 1-2 g/dl in a sustained manner. There was improvement in patients' general condition without causing any significant side effect.
Keyword : Hydroxyurea; Thalassaemia
β-thalassaemia intermedia is due to decreased production of the β-subunit of adult haemoglobin, resulting in α/β globin imbalance. Induction of γ-globin production by hydroxyurea has been reported to be useful in the management of thalassaemia by reducing the degree of imbalance.1 The elevated fetal haemoglobin (HbF) will in turn ameliorating the degree of ineffective erythropoiesis and lessening the extent of erythroid hyperplasia.2,3 Hydroxyurea, an S-phase specific cytotoxic, has been used extensively to manage myeloproliferative conditions with satisfactory toxicity profile. Induction of HbF synthesis could be due to the rapid regeneration of erythroid precursors following a cytoreduction phase.
A four years old girl with β-thalassaemia intermedia initially presented with two years history of paleness, signs of thalassaemic facies and hepatosplenomegaly. The haemoglobin at diagnosis was 5.7 g/dl, with typical microcytosis and hypochromia. Haemoglobinopathy study revealed marked increase in HbF of 85%, and normal HbA2 level. Both of her parents were β-thalassaemia carriers. Blood transfusion was necessary. Splenectomy was subsequently performed at five years old. Her haemoglobin was maintained around 7-8 g/dl independently. Hydroxyurea (~10 mg/kg/day) was started because of the low haemoglobin level at six years old, now more than three years. Increase in haemoglobin by around 1 g/dl was noted without any need for further blood transfusion. The rise in haemoglobin was noted two months after hydroxyurea treatment.
The second subject was a boy diagnosed to have β-thalassaemia intermedia at age of one. His HbF was 79%, and HbA2 was normal. During the initial follow up, his haemoglobin was maintained satisfactorily around 9-10 g/dl. His haemoglobin dropped below 8 g/dl gradually as he grew up. Splenectomy was performed at age of eight. However, the rise in haemoglobin was minimal post-operatively. Hydroxyurea (~10 mg/kg/day) was started at age of 10, now more than a year. Thereafter his haemoglobin was increased by around 2 g/dl. The rise in haemoglobin was present again two months after initiation of hydroxyurea treatment. The patient characteristics and treatment effects are summarised in Table 1.
In both patients, we did not encounter leucopenia or abnormality in renal and liver function. The first patient had reduction in the nucleated red blood cell in peripheral blood, while it was not appreciated in the second patient. Both of them did not have significant hepatomegaly, but there were persistent signs of thalassaemic facies. Their body weight and height were close to the 25th centile of the growth curve. There was no complaint of systemic upset or infection during the long-term treatment. Their activity level was comparable to their peers at school on average. In general, the compliance was satisfactory without any apparent side effect.
The increase in haemoglobin level in these two patients with β-thalassaemia intermedia was encouraging, corresponding to reported literature.4,5 The elevated HbF would be expected to reduce the symptoms from severe anaemia, iron overload as well as the erythroid hyperplasia in thalassaemic subjects. However, only one patient was noted to have reduction in nucleated red blood cell in circulation, in support of reduction in erythroid hyperplasia. It will be more benefit to thalassaemia patients who are blood transfusion dependent and heavily iron overloaded, yet with poor compliance to iron chelation treatment. The rise in fetal haemoglobin level will reduce the amount of blood transfused, and hence decreasing the iron intake with each transfusion. Hydroxyurea impairs DNA synthesis by acting as a ribonucleotide reductase inhibitor. It imposes carcinogenic risk, though the risk is currently undefined for its long-term use in thalassaemic subjects. A more marked clinical response in subjects with Xmn I polymorphism, namely, -158C>T of the G-γ-globin gene has been reported.3 The screening for polymorphism may identify subjects with better haemoglobin response at the beginning of treatment. We think the development of a more efficient γ-globin inducer will be of much benefit to patient with thalassaemia, especially in areas without facilities for regular blood transfusion program internationally. Screening of agents in Traditional Chinese Medicine would hopefully identify novel active pharmacological substance in stimulating high level of fetal haemoglobin production.6 In fact, there are encouraging results reported in Chinese literature from China.
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