Journal of lmerna/ Medldne 1997: 242 (Supplement 740): 37-41
`
`Iron chelation therapy
`
`A. V. HOFFBRAND* & B. WONKEt
`•oepartmellt of Haematology. Ro!Jal Free llosplt.al and School of Medicine. Pond Street. 1.ondon. and tDeparlment of Haematology. Whittington
`Hospital. Highgate Hill. T,ondon. UK
`
`Abstract. Desferrloxamine (DFX) remains the most
`effective and safe iron chelator for treatment of
`patients with transfusional iron overload. It is usually
`given by intermittent subcutaneous infusions for
`8-12 h on 4-6 days weekly using a battery-driven
`pump. Disposable balloon infusers provide a suitable
`method of giving continuous subcutaneous infusions
`with improved patient compliance. For patients with
`cardiac abnormalities due to iron overload. continu(cid:173)
`ous intravenous desferrioxamine is essential to elimi(cid:173)
`nate toxic plasma non-transferrin bound iron and to
`reduce body iron stores.
`Deferiprone (L1 • 1-2 dimethyl-3hydroxy-pyrid-4-
`one) is a less effective iron chelator but has the advan(cid:173)
`tage of being orally active. Long-term trials in which
`patients have taken 75 mg/kg/day have shown that
`deferiprone is capable of maintaining body iron stores
`at safe levels in a proportion of thalassaemia major
`patients but body iron stores. assessed by liver biopsy
`remain at high levels (> 15.0 mg/g dry weight) in a
`substantial number of patients. These concentrations
`have been associated with tissue damage. Trials of
`increased doses of deferiprone (up to 100 mg/kg/day)
`or of combined therapy with daily deferiprone and
`DFX or 1 or 2 days each week are being carried out in
`an attempt to achieve lower body iron burden in these
`patients. Preliminary results show that the drugs can
`
`be given safely together and urine iron excretion
`produced is additive, implying that the drugs chelate
`different body iron pools.
`Patients previously well chelated with serum
`ferritin levels less than 2500 µg/L have the fewest
`side-effects from deferiprone and usually may be kept
`at the same level of body iron for periods of at least 4
`years. assessed by serum ferritin and urine iron excre(cid:173)
`tion. The side-effects of def eriprone result in some
`patients discontinuing therapy. These side-effects,
`especially arthropathy. mainly occur in previously
`poorly chelated and so the most heavily iron-loaded
`patients. Nausea and other gastrointestinal symp(cid:173)
`toms. agranulocytosis or milder degrees of neutrope(cid:173)
`nia account with arthropathy for nearly all the
`withdrawals from deferiprone therapy. Patients with
`cardiomyopathy due to iron overload should be given
`intravenous DFX rather than deferiprone. Deferi(cid:173)
`prone. licensed for pharmaceutical use in India,
`awaits official approval for widespread clinical use in
`Western Europe and North America. Meanwhile.
`attempts to find new orally active iron chelators and
`improved methods of administration of desferrioxa(cid:173)
`mine are in progress.
`
`Keywords: iron chelation. desferrioxamine. deferi(cid:173)
`prone. thalassaemia major.
`
`Patients with refractory anaemias requiring regular
`blood transfusions accumulate iron at the rate of
`approximately 0.5 mg/kg/day. This iron is toxic to
`the heart. liver and endocrine system. In thalas(cid:173)
`saemia major approximately 70% of deaths are
`because of cardiac failure or arrythmia. Infections
`and liver disease account for almost all of the
`remainder. Chelation with desferrioxamine (DFX) by
`regular subcutaneous infusions has been shown to
`improve life expectancy and to prevent cardiac. hep(cid:173)
`atic and endocrine damage [ 1. 2]. Compliance (use of
`infusions 4-6 times weekly) has resulted in 9 2 % sur-
`
`viva! of thalassaemla major patients to 30 years of
`age (3]. In myelodysplasia. removal of excess iron
`may also improve bone marrow function. not only in
`the formation of haemoglobin but also in produc(cid:173)
`tion of neutrophils and platelets [ 4].
`
`Desferrioxamine
`DFX is usually administered over 8- 12 h nightly using
`a battery operated infusion pump. Although this main(cid:173)
`tains body iron stores at about 5-10 times normal (in
`the range 7 .0-15 mg/ g dry weight of liver) it may allow
`
`0 199 7 Blackwell Science Ltd
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`38
`
`A. V. HOFFBRAND & B. WON KE
`
`the accumulation of toxic non-transferrin bound iron
`(NTBI) in plasma during the hours when the infusion is
`discontinued [5]. Continuous intravenous DFX is the
`optimum way of eliminating NTBI and, at least in some
`cases. reversing cardiac complications. Recently, dis(cid:173)
`posable balloon pumps have been introduced as an
`improved method of DFX administration for regular
`home use. These balloons deliver a pre-mixed DFX solu(cid:173)
`tion at a constant rate, the pressure being produced by
`filling the expandable balloon in a closed component.
`Infusions are set to last for 2 4 h or 48 h for over 1 week.
`Because of increased patient compliance and continu(cid:173)
`ous drug delivery reduction of iron stores and of
`plasma NTBI can be achieved in patients previously
`chelated using an intermittent pump [ 6].
`For most patients with thalassaemia major world(cid:173)
`wide and with other refractory anaemias. DFX is not
`available because of its cost and the cost of the infusion
`pump. The disposable balloon inf users with pre-mixed
`drug are even more expensive. Moreover. some patients
`cannot use DFX because of hypersensitivity while oth(cid:173)
`ers develop toxic side-effects such as severe local skin
`reactions, retinal or auditory disturbances. growth fail(cid:173)
`~re. or bone abnormalities. especially if doses of more
`than 40 mg/kg are used in patients with relatively low
`iron stores. Yersinia and more rarely other infections.
`e.g. pneumocytis carinii and mucormycosis have been
`associated with DFX therapy. Finally compliance with
`subcutaneous DFX infusions is poor. especially in
`teenagers. Alternative iron chelatiors are clearly
`needed. Diethylenetetra-penta-acetic acid (DTPA). like
`DFX. is a hexadentate chelator which binds one iron
`molecule of chelation to one atom of iron. Like DFX it
`has to be given parenterally by slow infusions in order
`effectively to remove iron. However. DTPA also chelates
`zinc avidly and it is difficult to maintain body zinc stores
`when DTPA is used Jong term.
`The only other iron chelator which has been tried
`in long-term clinical trials is 1.2 dimethyl-3-hydroxy(cid:173)
`pyrid-4 one (DMHP. deferiprone also known as L1 •
`CP20 and in India. as Keifer). Itis now licensed for the
`treatment of thalassaemia major in India but remains
`unlicensed although in clinical trials in many other
`countries of the world.
`
`Deferiprone
`Pharmacology
`
`Deferiprone has a molecular weight of 139 and is a
`bidendate chelator. Three molecules are needed to
`
`chelate one atom of iron. The drug appears in plasma
`5-10 min after a single oral dose and reaches a peak
`concentration over 300 µMat 5 7. 7 ± 3 3 .2 min in our
`own studies [7] compared with 45-50 min observed
`by Matsui et al. [8]. Most of the absorbed deferiprone is
`converted to a g]ucuronide [9] the peak concenlralion
`of which occurs at 151.4 ± 51.9 min [7]. The glu(cid:173)
`curonide derivative is unable to bind iron so the more
`rapid the glucuronidation the less iron chelation and
`iron excretion. The drug and its metabolites are
`excreted mainly if not entirely in the urine. DFX
`increases iron excretion in both urine and faeces and
`iron in the stools may account for over half the iron
`excreted. Whether there is significant excretion of
`deferiprone in faeces or by how much dcferiprone
`increases faecal iron excretion is uncertain. Sludies
`this Department have failed to show any
`from
`deferiprone excretion in faeces [ 1 O]. but increased fae(cid:173)
`cal iron excretion ranging from 0 to approximately
`20% of that found in urine has been reported in
`metabolic studies [ 11-13].
`The mean plasma half-life has been estimated to be
`74.3. 91.1 and 159.6 min in different studies [8-1 O].
`Urine iron excretion relates to the area under the
`curve of free or iron bound deferiprone in plasma: on
`the other hand, the rate of elimination of deferipronc(cid:173)
`glucuronide correlates with creatinine clearance.
`This metabolite could accumulate. therefore. in
`patients with renal failure. The chelation efficacy of
`deferiprone in heavily iron-loaded patients has been
`estimated as 4.4% and 6.3% [7. 9).
`
`Efficacy in long-term trials
`
`Initial short-term studies established that dcfcri(cid:173)
`prone at doses of 50- 100 mg/kg/day caused in(cid:173)
`creased urine iron excretion in myelodysplasia.
`thalassaemia major and other iron-loaded patienls.
`the amount of which related to the iron load of the
`patient as well as to the dose of drug [14. 15]. A dose
`of at least 75 mg/kg/day promoted negalive iron
`balance (iron excretion >0.5 mg/kg/day) in most
`heavily iron-loaded patients. Initial trials in which
`the drug was given daily over a few months failed to
`show significant changes in the patients' serum fcr(cid:173)
`ritin levels but longer-term studies in London. India
`and Canada have shown falls in serum ferritin, par(cid:173)
`ticularly in previously poorly chelated patients starl(cid:173)
`ing with the highest levels (16-18]. Plasma NTBI
`may also fall [16). The Canadian study also showed
`
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`that when initial liver iron levels were < 80 µmol/g
`wet weight ( 15 mg/ g dry weight) these generally fell
`after a mean of approximately 3 years of drug ther(cid:173)
`apy while in those with liver iron < 80 µmol/g wet
`liver iron generally remained
`initially.
`weight
`unchanged [18). Our studies of 16 thalassaemia
`major patients receiving deferiprone 7 5 mg/kg daily
`for between 2-4 years showed that eight had liver
`iron levels of > 15 mg/kg/dry weight [19). The con(cid:173)
`centration of liver iron which may be considered
`'safe' in thalassaemia major is. however. uncertain.
`Brittenham et al. [20) consider patients with levels of
`> 15 mg/g dry weight at particular risk of death
`from cardiac disease and patients with levels
`between 8 .0 and 15 mg/ g dry weight at risk of organ
`damage. These levels are based on liver biopsy data
`in patients with primary haemochromatosis. It is
`unclear however whether safe (or dangerous levels)
`in primary haemochromatosis where excess iron is
`exclusively in parenchymal cells can be directly
`applied to patients with transfusional iron overload.
`In them. iron is both in reticulo-endothelial and
`parenchymal cells. Most recently, Olivieri [21) has
`suggested that deferiprone may lose its efficacy with
`time because in her studies there has been a 16%
`rise in liver iron after 3 years of chelation. with 30%
`of her patients having levels > 15 mg/g dry weight.
`Based on long-term assessment of serum ferritin
`levels and urine iron excretion in response to
`deferiprone. however. our data do not suggest loss of
`efficacy of deferiprone with time of administration.
`Further long-term studies in larger numbers of
`patients are clearly needed.
`For patients who are not adequately chelated by
`deferiprone 75 mg/kg/day. increased doses (up to
`100 mg/kg/day) may be tried. Recent studies have
`established that DFX can be given safely and effec(cid:173)
`tively in terms of iron excretion on the same day that
`deferiprone is taken [13. Hoffbrand A.V. & Wonke B ..
`unpubl. data] . The use of DFX for 1 or 2 days each
`week in combination with daily deferiprone is being
`investigated as a means of reducing body iron in
`patients for whom deferiprone alone is inadequate.
`
`Side-effects
`
`Agranulocytosis and neutropenia Deferiprone is asso(cid:173)
`ciated with more frequent toxicity than DFX. The
`most serious side-effect has been agranulocytosis.
`first reported in a patient with Blackfan Diamond
`
`IRON CHELATION THERAPY
`
`39
`
`anaemia. but described subsequently in patients with
`thalassaemia major and myelodysplasia [22). Com(cid:173)
`plete loss of neutrophils or lesser degrees of neutro(cid:173)
`penia have been described with onset between 6
`weeks and over 1 year after starting deferiprone ther(cid:173)
`apy. From the published data. it appears that females
`are most frequently affected. The incidence of agran(cid:173)
`ulocytosis is approximately 1 %. with neutropenia in
`a further 2-4% but because intercurrent viral infec(cid:173)
`tions may cause neutropenia during long-term trials.
`an exact incidence of drug-induced neutropenia is
`difficult to establish. In all cases who have survived.
`the neutrophil count has recovered but in most cases
`rechallenge with the drug has caused the count to
`fall again. The length of time agranulocytosis persists
`is variable ranging from approximately 1 week to
`many months of severe neutropenia in one case. Two
`recent large-scale studies have addressed the inci(cid:173)
`and neutropenia.
`dence of
`agranulocytosis
`Choudhry & Pali [23) report on 51 children (age
`4- 14 years) receiving deferiprone at 50 mg/kg (30
`patients, Group 1) and 7 5 mg/kg (21 patients, Group
`2). Seven of the Group 1 patients developed neu(cid:173)
`tropenia (neutrophil count 0. 18 x 109/L) after 3-13
`months. One Group 1 patient with agranulocytosis
`died of infection. The neutropenia recovered in the
`other six patients within 3-7 weeks. Five patients in
`Group 2 developed neutropenia (0.6-1.6 x 109/L)
`after 2-7 months. all recovering 1-3 months after
`stopping deferiprone. Surprisingly. in these Indian
`studies. rechallenge in 10 patients caused neutro(cid:173)
`penia in only one. Cohen [24) has reported in
`abstract form the results of a large multi-centre
`safety trial carried out in Cagliari. T.urin. Ferrara.
`Philadelphia and Toronto. One hundred and sixty(cid:173)
`two patients were treated for 1 year at a mean dose of
`73 mg/kg per day. Neutropenia (absolute neutrophil
`count 0.5-1.5 x 109/L) occurred in nine patients.
`agranulocytosis ( <O. 5 x 109 /L) in one. In this
`patient. the neutrophil count recovered after 1 week
`of treatment with G-CSF. Neutropenia occurred from
`6-50 weeks after starting deferiprone therapy and
`was frequently accompanied by a febrile illness
`suggesting either a febrile reaction to the drug or an
`intercurrent viral infection causing the neutropenia.
`The mechanism for the agranulocytosis or neu(cid:173)
`tropenia associated with the deferiprone has not been
`elucidated. Studies of immune mechanisms have
`been negative and an idiosynchratic toxic reaction
`appears most likely [25).
`
`rO 199 7 Blackwell Science Ltd journal of Internal Medicine 242 (Supplement 740): 3 7-41
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`40
`
`A. V. HOFFBRAND & B. WON KE
`
`Arthropathy Bartlett et al. [2 6] first reported mus(cid:173)
`culo-skeletal and joint pains in three patients receiv(cid:173)
`ing deferiprone. This and other groups have
`subsequently reported joint pains and joint effusions
`in up to 30% of patients. The Indian studies showed
`that the arthropathy (mostly affecting the large joints.
`especially the knees) were most common in patients
`the highest
`dose
`of
`deferiprone
`rece1vmg
`(100 mg/kg/day), and in those with the highest iron
`burden. assessed by serum ferritin [17). In previously
`well-chelated patients the arthropathy is rare. In some
`patients. the arthropathy disappears on reducing the
`dose of
`the drug. Despite the suggestion that
`deferiprone can cause a systemic lupus-like syndrome
`[2 7). no overall relation has been found in any study
`between the presence or absence of anti-nuclear fac(cid:173)
`tor or DNA antibodies in serum and the occurrence of
`arthropathy. The suggestion that 2: I or 1: I com(cid:173)
`plexes of deferiprone with iron may be formed in the
`joints and lead to free radical generation remains
`hypothetical. Deferiprone certainly enters joint fluid
`as well as other body fluids. An Italian thalassaemic
`female aged 24 years. developing sequentially
`agranulocytosis. arthritis and systemic vasculitis has
`recently been reported [28). She developed anti(cid:173)
`nuclear. anti-DNA and anti-extractable nuclear anti(cid:173)
`gen antibodies 6 months after receiving deferiprone.
`50 mg/kg daily. It has previously been suggested that
`an Indian patient receiving deferiprone died of acute
`systemic lupus erythematosus [2 7] but the evidence
`for this has been challenged.
`
`Gastrointestinal symptoms Some patients feel nause(cid:173)
`ated while receiving the drug and this may be accom(cid:173)
`panied by abdominal pain and diarrhoea. In our
`studies this has occurred in two patients with renal
`failure. In one of these patients. an 82-year-old man,
`renal failure was associated with poor clearance of
`deferiprone-glucuronide. Nausea has also occurred,
`however. In thalassaemia patients with normal renal
`function. As many as 10% of patients have discontin(cid:173)
`ued deferiprone because of these symptoms in our
`own studies. In the Italian multi-centre study. 16% of
`the patients developed gastrointestinal symptoms.
`with four patients requiring withdrawal of the drug
`[24].
`
`Zinc deficiency Initial animal and human studies
`showed that deferiprone may increase urine zinc
`excretion. This becomes clinically important in dia-
`
`betics where low zinc serum levels and features of zinc
`deficiency such as hair loss, dry scaling itching skin
`and diarrhoea have been described [29). lt is therefore
`important to monitor serum zinc levels in patients
`receiving deferiprone therapy particularly in diabetic
`patients. If levels fall below normal. zinc supplements.
`e.g. 200-400 mg orally should be given daily. sepa(cid:173)
`rately from deferiprone.
`
`Deaths Some patients receiving deferiprone have
`died. usually of cardiac failure or infection (with nor(cid:173)
`mal neutrophil counts). There is no evidence to
`incriminate deferiprone as the cause of death in these
`cases. Cardiac failure has been due to iron overload.
`Fatal infections have occurred in patients with nor(cid:173)
`mal neutrophil counts but at least one patient has
`died of agranulocytosis with infection [2 31. No neuro(cid:173)
`logical. renal. pulmonary or cC1rdiac toxicity has been
`ascribed to deferiprone and no consistent change in
`immune function. serum immunoglobulins. C04:
`CD8 T-lymphocyte counts. white cell or platelet
`counts or in transfusion requirements has been
`reported. Fluctuating
`liver function
`tests have
`occurred. particularly in patients with hepatitis C
`infection [26,30]. Our own studies do not show evi(cid:173)
`dence of direct liver toxicitv as among nine patients
`receiving the drug for a me .. n of 40.9 months (range
`32-51 months) all HCV negative. no fibrosis or other
`evidence of liver damage could be seen on liver biopsy
`or detected by liver function tests.
`
`Future prospects
`
`Attempts are being made to improve delivery of DFX
`by use of a subcutaneous depot preparation.
`Novartis. the pharmaceutical firm who manufacture
`DFX. also have an active research programme aimed
`at developing a new orally active chelator which is
`more effective and has fewer toxic side-effects than
`deferiprone. The most promising compounds are now
`undergoing chronic toxicity studies in monkeys. If
`clinical trials are then considered worthwhile, sev(cid:173)
`eral years will be needed before any new compound
`can become widely available for therapeutic use. For
`patients receiving deferiprone whose iron stores
`remain at levels associated with organ damage. pro(cid:173)
`tocols using higher doses than that generally used
`(75 mg/kg/daily) or combining daily ingestion of
`deferiprone with DFX infusions on 1 or 2 days each
`week are being investigated.
`
`0 199 7 Blackwell Science Ltd /011rnal ofllllmral Medicine 242 (Supplement 740): 3 7-4 I
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`

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`30 Al-Refale FN. Hershko C. HofTbrand AV. tt al. Results of long(cid:173)
`term deferiprone (L1) therapy: a report by the International
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`
`Correspondence: Professor A.Victor HofTbrand. Royal Free Hospital
`School of Medicine. Pond Street. London NW 3 2QG. UK.
`
`C> 1997 Blackwell Science Ltd Journal of lmerna/ Medicine 242 (Supplement 7401: 3 7-41
`
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`5 of 5
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`Taro Pharmaceuticals, Ltd.
`Exhibit 1006
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`