Foetal haemoglobin inducers and thalassaemia: novel achievements

Beta-thalassaemias are a group of hereditary human diseases caused by more that 200 mutations of the human β-globin gene, leading to low or absent production of adult β-globin and an excess of α-globin, causing ineffective erythropoiesis and low or absent production of adult haemoglobin (HbA)¹. The conventional treatment for these patients is based on regular blood transfusions and chelating therapy¹.

Recently, a novel therapeutic strategy (induction of foetal haemoglobin, HbF) has been hypothesized for β-thalassaemia, based on the observation that the co-existence of hereditary persistence of foetal haemoglobin in patients with β-thalassaemia reduces the severity of the disease^2,3. An example is the case recently reported by Feriotto et al.⁴, who described a transfusion-independent patient exhibiting hereditary persistence of foetal haemoglobin in the presence of a novel thalassaemia mutation (insertion of a single A nucleotide within the exon 1, at codon 18, of the β-globin gene causing a frameshift-based generation of an UGA stop codon) associated with a deletion of the δβ-globin gene region.

In this respect, the case reported in this issue of the journal by Masera et al.⁵ on the impressive response to thalidomide in a thalassaemia major patient carrying a IVS1-6/cd44-C genotype and resistant to conventional therapy is of great interest, especially when considered together with other recent reports in the field of induction of HbF in patients affected by β-thalassaemia.

It is firmly established that increasing the production of γ-globin leads to a decrease in the imbalance between β and non-β-chains and the consequent reduction of haemolysis⁵. Accordingly, several studies have concentrated on potential inducers of HbF, including histone deacetylase (HDAC) inhibitors, DNA-binding drugs and inhibitors of the mTOR pathway^2,3,6.

While several reports are available on in vitro experimental systems, in vivo trials on HbF inducers are still scarce. Hydroxyurea is the most widely used HbF inducer in both moderate and severe forms of β-thalassaemia^2,6. More than 500 patients with β-thalassaemia have been treated with hydroxyurea worldwide^2,6 and about 50% of them responded to the treatment, exhibiting a clear improvement of clinical parameters². Other inducers of HbF synthesis, such as butyrates, 5-azacytidine and, more recently, decitabine, have also been employed⁵. However, these HbF inducers have produced only modest responses in the majority of β-thalassaemia patients as well as some degree of toxicity^2,3,5,6.

Despite the limited number of in vivo observations available, the issue of reactivation of HbF in adults is very important, especially when we consider the worldwide geographic distribution of thalassaemia and sickle cell anaemia, which are among the major health problems in developing countries, where affected patients and healthy carriers are numerous, mainly due to the absence of genetic counselling and antenatal diagnosis². Several developing countries are unable to efficiently sustain the high-cost clinical management of β-thalassaemia patients requiring a regular transfusion regimen, chelating therapy and advanced hospital facilities. It is well known that, in addition to “direct costs”, blood transfusions require accurate monitoring of the safety of the product and this involves expensive technologies, some of which are based on multiple polymerase chain reaction analyses covering all the possible haematological infectious diseases². As far as alternative therapeutic approaches are concerned, gene therapy⁷ and bone-marrow transplantation⁸ are very promising strategies, but they are expected to be useful for only a minority of patients, selected on the basis of biological/genetic parameters and the economic possibility of affording these therapies. For all these reasons, pharmacological therapy of β-thalassaemia, including possible exploitation of HbF inducers, is expected to be crucial.

One class of drugs described to be HbF inducers is represented by agents already used in the therapy of other diseases. For instance, Fibach et al. studied the use of rapamycin (used as an immunosuppressant in the treatment of patients undergoing kidney transplantation)⁹; Rodrigue et al. reported for the first time the possible use of the antioxidant resveratrol.¹⁰ This research field is relevant, considering that large investments by pharmaceutical companies finalised to the design, production and testing of novel drugs for the treatment of β-thalassaemia is discouraged by the fact that this pathology is a rare disease in developed countries, due to the recurrent campaigns for prevention, genetic counselling and antenatal diagnosis². The employment of this class of HbF inducers was considered by the sub-committee on Foetal Haemoglobin (co-ordinated by Jeff Miller and Yogen Saunthararajah) at the recent NIH-NIDDK workshop on “Thalassaemia: Clinical Priorities and Clinical Trials”¹¹. During this workshop, clinical investigators, scientists and patients discussed the future of clinical trials on thalassaemia, the specific focus of trials, recruitment of patients and international collaboration being the main topics addressed¹¹. The important issue of HbF induction has also been included within the activities of the large scientific collaborative networks ITHANET (Eleotronic Infrastructures for the Thalassaemia Research Network)¹².

Among the possible molecules for clinical trials on β-thalassaemia, thalidomide, a drug known for its immunomodulating and anti-angiogenic properties, has recently been demonstrated to induce γ-globin gene expression and to increase the proliferation of erythroid cells^13,14. In this issue of Blood Transfusion, Masera et al.⁵ report the very interesting case of a young girl with β-thalassaemia (β+/β°) in a very severe clinical condition, who could not be transfused anymore, given the occurrence of severe post-transfusion reactions. This patient showed an outstanding response to thalidomide, achieving a large high increase of the production of HbF (from 3–3.8 to 6.7–7.5 g/dL) and high levels of total Hb content (from 7–8 to 9–10 g/dL)⁵. This case, when considered together with another report on the successful treatment of a β-thalassaemia major patient with thalidomide¹⁴, allows this strategy to be included among those deserving possible consideration in clinical trials and encourage further efforts in this direction. We expect that this particular field of investigation will be followed in the near future.

We believe that this field, exciting from a scientific point of view, also represents a hope for those patients whose survival will depend on the possible use of drugs rendering blood transfusions and chelating therapy unnecessary.