Hydroxyurea therapy in β‐thalassaemia intermedia: improvement in haematological parameters due to enhanced β‐globin synthesis

Abstract

The beta-thalassaemias represent a heterogenous group of diseases resulting from decreased erythroid beta-globin mRNA expression and imbalanced alpha/beta-globin chain synthesis which are manifest clinically by ineffective erythropoiesis and excessive haemolysis. Increasing levels of haemoglobin F (HbF) by pharmacological agents has been proposed to ameliorate the severity of the disease by improving the balance in globin chain synthesis. Hydroxyurea (HU), as an effective agent with low toxicity for activating gamma-globin gene, has been shown to enhance HbF synthesis in experimental animals and in patients with sickle cell anaemia. However, previous trials of HU in beta-thalassaemia patients are ambiguous, with a small number having increased HbF synthesis. In a recent study of HU effects in Chinese beta-thalassaemia patients we unexpectedly found that two unrelated patients with beta-thalassaemia intermedia demonstrated an improvement in the effectiveness of erythropoiesis reflected by an increase in haemoglobin concentration (from 4.1 to 6.3 g/dl, patient 1; from 6.5 to 9.7 g/dl, patient 2) and in red cell volume (from 68 to 104 fl, patient 1; from 68 to 85 fl, patient 2) after a period of excess of 300d of low-dosage HU treatment. These effects, however, appear to be due to increased beta-globin biosynthesis, because the percentage of HbF decreased in each patient as total Hb increased. This was reflected by changes in the beta/alpha ratio (from 0.301 to 0.581, patient 1; from 0.348 to 0.487, patient 2) with minimal changes in gamma-globin biosynthesis. We conclude that in addition to its known effects in stimulating gamma-globin production, hydroxyurea may have a more general role in augmenting globin synthesis, including beta-globin in some thalassaemia intermedia patients who maintain the capacity to express normal beta-globin chains.

Hydroxyurea appears beneficial in patients with beta-thalassaemia major and intermedia

“…Hydroxyurea therapy could increase the HbF production in -thalassemia patients due to an improvement in the :non- globin ratio. 2,4 Hydroxyurea has been shown to increase total Hb and HbF levels and reduce the need for blood transfusion in a patient with transfusion-dependent -thalassemia. 8 In contrast, Loukopoulos et al 9 showed that HU therapy resulted in a significant increase in HbF with no change in total Hb levels in patients with -thalassemia intermedia.…”

“…Patients with severe -thalassemia require regular red cell transfusion to sustain their lives. 2 However, most individuals so affected usually die before the age of 25 as a direct result of cardiac iron deposition unless treated concomitantly with chelation therapy. 3 Thus, an important caveat in the management of -thalassemia is to find an alternative approach to red cell transfusion.…”

“…2,4 Because it has the lowest toxicity profile 2 among the chemotherapeutic agents thus far employed, HU has been widely used for this purpose. Numerous studies have demonstrated that HU therapy can enhance HbF production and ameliorate the clinical course of sickle cell disease (SCD) with three or more painful crises per year with only mild myelotoxicity.…”

Fetal hemoglobin chemical inducers for treatment of hemoglobinopathies

“…Early studies have documented only a moderate hemoglobin increase following HU therapy [181][182][183][184][185]. However, in these initial studies, it was remarked the capacity of HU to clearly improve symptomatic cord compression occurring in some β-thalassemic patients as a consequence of paraspinal extramedullary erythropoietic tissue [186][187][188][189].…”

“…It is of interest to note that the analysis of globin chain synthesis in some β-thalassemia intermedia patients responding to the treatment with HU showed a stimulatory effect caused by drug treatment at the level of β-globin synthesis and not of γ-globin synthesis [201].…”