Guideline:Alternative approaches to the treatment of thalassemia

There is currently no definitive treatment for any of the serious haemoglobin disorders, other than bone marrow transplantation—an option available only to a small minority of patients that have a suitable donor and are in good clinical condition. Another, promising, approach involves the use of therapeutics to definitively correct the globin chain imbalance in β-thalassaemia, by re-activating the foetal globin genes.

Modulation of fetal haemoglobin
Foetal haemoglobin is the predominant non- α globin produced in humans until around six months of age, when it is typically suppressed and the production of β-globin is increased. This pattern is the norm even when the genes are mutated, as in β- thalassaemia.

Patients with β-thalassaemia who continue to produce high levels of foetal globin, such as those with Hereditary Persistence of Foetal Haemoglobin, have less globin imbalance and less severe anaemia.

''The therapeutic stimulation of foetal globin could therefore benefit many patients, even rendering some transfusion independent.''

Several candidate therapies now offer the potential to correct or modulate the underlying pathology.

Cytotoxic agents Following observations that foetal haemoglobin synthesis is reactivated during recovery from bone marrow suppression after the use of cytotoxic drugs, attention has focused on the possible role of cytotoxic agents as therapies in the treatment of serious haemoglobin disorders. Several cytotoxic agents that alter the pattern of erythropoiesis, favouring the expression of foetal (γ)-globin genes and so increasing the number of red cells containing HbF (F-cells), have been explored over the past 20-25 years (Pace and Zei, 2006; Fathallah and Atweh, 2006; Gambari and Fibach, 2007).

The demethylating agents 5-azacytidine and decitabine have been administered to a few β-thalassaemia patients with good responses, raising total haemoglobin levels by a mean of 2.5 g/dl above baseline and clearly prolonging the lives of end-stage patients (Lowrey, 1993; Dunbar, 1989; Ley, 1982). The mutagenic potential and instability of formulations of 5-azacytidine have limited its investigation, but higher oral doses of decitabine have been effective in baboons (Lavelle, 2006), and studies are planned in selected patients.

Hydroxyurea has been studied in HbE/ β- thalassaemia patients, with lower responses but reduced haemolysis (Fuchareon, 1996; Zeng, 1995). Hydroxyurea has been less beneficial in thalassaemia intermedia than in sickle cell disease, in which the number of painful crises was reduced and overall health indicators improved. The lesser benefits in thalassaemia are perhaps due to the fact that the cytostatic effects of hydroxyurea are limited in the disease.

Other agents

Erythropoetins (EPOs) have increased haemoglobin levels significantly in some patients with thalassaemia intermedia, even eliminating transfusion requirements in some children. EPOs may thus be particularly helpful in patients with relatively low levels of endogenous erythropoietin for their degree of anaemia (Bourantas, 1997; Nisli, 1996 and 1997; Rachmilevitz, 1998; Singer, 2003). EPO promotes survival of red blood cells and may counteract the rapid cell death (apoptosis) caused by precipitation of excess α-globin chains in β-thalassaemia (review Silva, 1996; Perrine, 2005).

Short chain fatty acid derivatives Short chain fatty acid derivatives induce activity from the foetal globin gene promoter, resulting in two-to-six-fold higher foetal globin mRNA in some patients, especially those who have at least one ‚0- thalassaemia mutation and EPO levels >140 mU/ml (Collins, 1995; Perrine, 2005). Their acceptable toxicity profiles add to their potential as long-term therapeutic agents. Several preliminary trials with intravenous butyrate and oral phenylbutyrate compounds have shown increases in foetal and total haemoglobin levels in patients with thalassaemia intermedia, while a few previously transfusion-dependent thalassaemia major patients have been maintained transfusion-independent on home therapy for 5-7 years. Isobutyramide has induced foetal globin and reduced transfusion requirements in thalassaemia intermedia and major (Cappellini, 2000; Reich, 2000).

The most effective compound thus far is arginine butyrate, although this has the disadvantage of requiring intravenous infusion due to its rapid metabolism. Oral derivatives that persist for many hours after a single dose and which also stimulate erythroid cell proliferation and survival, similar to EPO, will enter clinical trials soon (e.g. sodium 2,2-dimethybutyrate) (Boosalis, 2001; review Perrine, 2005). Select hydroxamic acid derivatives have had high activity in transgenic mice (Cao, 2005).

The mechanisms by which short chain fatty acids stimulate Á-globin production are being elucidated. Some new derivatives displace a repressor complex and cause acetylation specifically of the foetal globin gene promoter (Mankidy et al, 2006).

Phenylbutyrate and butyrate cause general histone hyperacetylation, which inhibits cell proliferation, and are counter-productive in thalassaemia, requiring limited exposure (Pulse therapy). Butyrates have induced fetal globin production in approximately twothirds of patients with diverse molecular mutations and raised total haemoglobin levels an average of 2-3 g/dl above baseline when given intermittently to avoid antiproliferative effects (review Perrine, 2005). As differences in drug metabolism contribute significantly to responsiveness to any drug, these will certainly apply in the highly diverse thalassaemia syndromes. New generation agents which promote erythroid survival, and can be given daily, offer significantly more potential benefit than the first generation prototypes.

Combination therapy Although pharmacological induction of fetal haemoglobin in transfusion-dependent patients with thalassaemia will require highpotency induction of foetal globin, weaning of transfusions to allow renewal of patients’ own erythropoiesis, adequately high EPO levels to promote eyrthroid cell survival and iron availability for erythropoiesis, there is expectation that some of the agents, used in combination or properly scheduled, could result in complimentary effects and render even severe patients transfusion independent. For example, a demethylating agent and butyrate had synergistic activity, much higher than additive effects, in experimental studies (Constantoulakis, 1989). Such combinations offer excellent potential for patients with diverse syndromes.

''An approach to rational combinations can now be based on a patient’s baseline HbF, total haemoglobin and EPO levels (review Perrine, 2005). Clinical trials should be planned to find optimal drug combinations for different patient subsets.''