Desferrioxamine mesylate (DFX) is the main agent licensed in all countries in clinical use at present. It is not absorbed orally and, after parenteral injection, it is rapidly cleared from the plasma, being excreted in the urine, taken up by hepatocytes or metabolized in the tissues (Table 4.3). This accounts for the much greater mobilization of iron by continuous intravenous (i.v.) or slow subcutaneous (s.c.) infusions, which allow more prolonged exposure of the drug to the chelatable iron than with i.m. injection.

DFX is a trihydroxamic acid (hexadendate) (Figure 4.7), one molecule binding covalently to all six oxygen sites on one ferric ion to form the red chelate, ferrioxamine. This is excreted in urine and bile. Faecal iron is derived from hepatocytes. Urine iron also derives, at least in part, from hepatocytes, although other body sources, especially iron released from macrophages, contribute. Urinary iron excretion tends to level off at higher doses, but this does not occur with bile excretion, which increases linearly with the dose. Bile iron may therefore predominate at high doses, and this is also the major route of excretion when total body iron has been reduced to relatively low levels. Urine iron excretion tends to be less immediately after blood transfusions, but this is accompanied by a reciprocal increase in faecal iron excretion. Increased erythropoiesis, as in haemolytic anaemias, is associated with an increase in urine iron excretion in relation to body iron stores.

Clinical studies

Therapy with DFX is expensive and inconvenient. Its use should, therefore, be restricted to those patients in whom iron overload is the main threat to life. Most studies have been with thalas-saemia major, but patients with other inherited anaemias, e.g.



Figure 4.7 Chemical structures of three iron chelators. (a) ICL 670. (b) Deferiprone. (c) Desferrioxamine.

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Figure 4.7 Chemical structures of three iron chelators. (a) ICL 670. (b) Deferiprone. (c) Desferrioxamine.

Diamond-Blackfan, Fanconi, sickle cell, sideroblastic anaemia or acquired disorders, especially myelodysplasia, myelofibrosis red cell aplasia or aplastic anaemia, may require iron chelation therapy. In elderly patients with acquired, transfusion-dependent, refractory anaemias, the prognosis of the underlying haematological disease may not justify the inconvenience of s.c. DFX therapy. In children, tissue damage from iron may be present from very early life; regular iron chelation should begin in thalassaemia major after transfusion of about 12 units of blood or when the serum ferritin exceeds 1000 |ig/L. In young children, treatment should be started at 20 mg/kg to prevent tissue damage due to iron without causing toxicity due to excess DFX. A local anaesthetic cream (e.g. EMLA) reduces pain from the needle insertion.

The standard adult dose is 40 mg/kg, given as an 8- to 12-h infusion s.c. or at least 5 days each week. DFX may also be given intravenously via a separate line at the time of blood transfusion. To avoid toxic effects, the dose should be restricted to a maximum of 1 g with each unit of blood.

Repletion of ascorbic acid deficiency, which sometimes accompanies iron overload, or ascorbate therapy even in those with normal tissue levels of ascorbate, increases urinary iron excretion but has no effect on bile iron excretion. Supplements of vitamin C should be 100-200 mg per day. In some less severely anaemic patients with chronic ineffective erythropoiesis and iron loading from the gut (e.g. with thalassaemia intermedia or sideroblastic anaemia), cautious phlebotomy may be used instead of or added to regular s.c. DFX to produce a rate of iron mobilization similar to that achieved in the treatment of hereditary haemochromatosis.

In patients unable to comply with s.c. DFX or those with iron-induced cardiomyopathy, continuous intravenous (i.v.) DFX may be given via an indwelling catheter (e.g. Hickman) or Port-a-Cath chamber. Removal of liver iron is more rapid than removal of cardiac iron with this intensive chelation regime. Continuous s.c. DFX can also be administered using a disposable balloon infuser system with pre-prepared DFX solution (e.g. 4 g of DFX to be infused over 48 h) rather than using a battery-operated infusion pump. Continuous infusion avoids the reappearance of toxic NTBI in plasma. Twice-daily i.m. injections of DFX produce significant iron excretion, but these are painful and the long-term efficacy of this approach is unproven. Trials of DFX bound to starch to prolong its action are in progress.

Body iron stores can be restricted to 5-10 times normal in well-chelated, regularly transfused patients. There is improved cardiac function and survival in patients who comply with the rigorous therapy. Iron-induced cardiomyopathy can be reversed in some, but not all, patients with continuous DFX therapy. Growth and pubertal development are improved in many, but not all, patients; diabetes and other endocrine abnormalities still occur frequently. Serum ferritin levels in well-chelated thalassaemia major patients usually plateau between 1500 and 2500 |g/L. Unfortunately, through lack of compliance, premature deaths usually from iron-induced cardiac damage occur in a substantial proportion of thalassaemia major patients. In Turin, 95% of compliant (250 or more DFX infusions per year) patients were alive at 30 years compared with only 12% of non-compliant patients. In the UK, only 50% of thalassaemia major patients were alive at 35 years, deaths being largely due to failure of compliance with DFX.


The adverse effects possible with DFX include rare generalized sensitivity reactions, local soreness related to the site of injection (usually due to the needle being inserted too superficially) and exacerbation of some infections, notably of the urinary tract and precipitation of Yersinia enterocolitis. Auditory (high-tone sensorineural hearing loss) and visual neurotoxicity (night blindness, visual field loss, retinal pigmentation and changes on electrical tests) are relatively frequent. Growth and bone defects may also occur. The spine may be affected, with sitting height reduced; rickets-like bone lesions, genu valgum and metaphysical changes are described, especially in children (Figure 4.8).

Auditory, visual and growth side-effects of DFX occur mainly if the body iron burden is low and doses of DFX high, and particularly in children. A therapeutic index = mean daily dose (mg/kg)/current serum ferritin (|g/L) can be calculated. If this is below 0.025 at all times, these side-effects of DFX do not occur.

Figure 4.8 Bone and cartilage defects due to DFX.

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