Long-Term Trials of Deferiprone in
`Cooley’s Anemiaa
`
`NANCY F. OLIVIERI,b,d,e AND GARY M. BRITTENHAMc
`bDepartments of Medicine and Pediatrics, University of Toronto,
`Canada
`cDepartment of Medicine, MetroHealth Medical Center, Case Western
`Reserve University, Cleveland, USA
`
`ABSTRACT: Deferoxamine is the currently available agent for the iron-chelation ther-
`apy required by Cooley’s anemia patients. The difficulties associated with parenteral
`administration have mandated a search for alternative therapies, especially orally
`active iron chelators, to remove excess iron that results in damage to the liver,
`endocrine organs, and heart. Four orally active agents have reached clinical trials in
`the last decade. The agent under consideration in this paper, deferiprone (1,2-
`dimethyl-3-hydroxypyridin-4-one), has shown some promise, but, according to the
`studies discussed here, may not provide adequate sustained control of body iron in a
`substantial proportion of Cooley’s anemia patients.
`
`In patients with Cooley’s anemia and hereditary hemochromatosis, excess iron acquired
`
`through transfusions or absorption results in damage to the liver, endocrine organs and
`heart.1 Several studies have highlighted the importance of sustained reduction of body
`iron burden as the principal determinant of clinical outcome in these disorders.2–5 While
`venesection can effectively and safely reduce body iron in individuals homozygous for
`hereditary hemochromatosis,2 patients with Cooley’s anemia require life-long chelating
`therapy to promote the excretion of iron accumulated from transfusions.6 The only iron-
`chelating agent available for clinical use is deferoxamine, long-term compliance which
`with prevents the complications of iron overload, and improves survival, in Cooley’s ane-
`mia.4,7 The difficulties associated with parenteral administration of deferoxamine have
`mandated a search for safe and effective therapeutic alternatives, including orally active
`iron chelators,1 four of which have reached clinical teals in the past decade. The com-
`pounds N,N’-bis (2-hydroxybenzoyl) ethylenediamine N,N’-diacetic acid (HBED), the
`aryl hydrazone pyridoxal isonicotinoyl hydrazone (PIH), and the diethyl hydroxypyridi-
`none CP94, have all been evaluated in short-term trials over the last five years, but are
`not under clinical development at this time.6 The orally active iron-chelating agent most
`extensively evaluated to date is 1,2-dimethyl-3-hydroxypyridin-4-one (deferiprone; L1),
`
`aSupported in part by research grants from: The Medical Research Council of Canada, The Ontario
`Heart and Stroke Foundation, The Ontario Thalassemia Foundation, APOTEX Inc., The United States
`Cooley’s Anemia Foundation, The National Institutes of Health Grants #HL 42824 and AI 35827, and
`The Food and Drug Administration Orphan Products Grant FD-R-000532.
`dAddress correspondence and reprint requests to Dr. N.F. Olivieri, The Hospital for Sick Children,
`Division of Hematology, University Of Toronto, 555 University Avenue, Toronto, Ontario, Canada
`M5G 1X8; Tel: (416) 813-6823; Fax: (416) 813-5346; E-mail: noliv@sickkids.on.ca
`eDr. Olivieri is a recipient of a Scientist Award from the Medical Research Council of Canada.
`
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`one of the 3-hydroxypyridin-4-one iron chelators patented in 1982 as an potential alter-
`native to deferoxamine for the treatment of chronic iron overload.8
`Animal studies of deferiprone have reported variable efficacy in rodents and rabbits,
`and insufficient efficacy for maintenance of negative iron balance in iron-loaded primates.6
`In transfused patients with Cooley’s anemia, 75 milligrams of deferiprone per kilogram
`body weight induces urinary iron excretion approximately equivalent to that achieved with
`30–40 milligrams of deferoxamine per kilogram.1,9,10 Because fecal iron excretion induced
`by deferiprone is much less than that by deferoxamine,9,10 the short-term efficacy of
`deferiprone is acknowledged to be inferior to that of deferoxamine.
`
`Effectiveness of Deferiprone as Estimated by Serum Ferritin Concentration
`
`While the earliest studies reported no sustained decrease in serum ferritin concentration
`over one to 15 months of deferiprone therapy,11,12 two short-term trials subsequently
`reported statistically significant reductions in mean serum ferritin concentration in patients
`with Cooley’s anemia, with the most substantial declines observed in patients whose pre-
`study ferritin concentrations exceeded 5000 µg/L.13,14 As previously noted, reliance on
`changes in the concentration of serum ferritin alone may lead to inaccurate assessment of
`body iron burden in individual patients; direct assessment of tissue iron is crucial in the
`evaluation of any new potential iron-chelating agent.6 Such studies therefore could not
`establish convincingly the efficacy of deferiprone in the reduction of body iron burden.
`
`Effectiveness of Deferiprone as Estimated by Hepatic Iron Concentration
`
`Reduction in hepatic iron stores during deferiprone therapy was first demonstrated in a
`patient with thalassemia “intermedia.”15 In a subsequent study in patients with Cooley’s ane-
`mia unable or unwilling to use deferoxamine, short-term deferiprone treatment was shown
`to reduce hepatic storage iron in many patients over three years.16 As emphasized at the time
`of that report, the long-term effectiveness of this agent remained undetermined.17
`To assess the effectiveness of deferiprone in the long-term control of body iron in
`Cooley’s anemia we have continued to determine hepatic iron concentration in these
`patients, in whom results through June 1994 were reported previously.16 As of June 1996,
`18 of 21 patients remain evaluable; one patient interrupted deferiprone for 0.7 years, and
`two patients stopped deferiprone after one year. These 18 patients constitute the only
`group worldwide to receive long-term deferiprone in conjunction with serial measure-
`ments of hepatic iron concentration to accurately determine body iron. As in our previ-
`ously reported analysis,16 hepatic iron concentration, determined in tissue obtained at
`biopsy or by magnetic susceptometry,4 was the primary endpoint of effectiveness. The
`criteria used are those derived from long-term studies of morbidity and mortality associ-
`ated with increasing concentrations of hepatic storage iron in vivo.2–5,18 These will be
`briefly reviewed.
`Information about the risks associated with lower levels of body iron arises from expe-
`rience in patients heterozygous for the iron-loading disorder hereditary hemochromatosis,
`in a proportion of whom maintenance of modestly elevated concentrations of hepatic iron
`(approximately 3.2 to 7 milligrams iron per gram liver, dry weight) is associated with nor-
`mal life expectancy and no evidence of iron-induced toxicity.18 Individuals with body iron
`burdens above this range, and up to about 15 milligrams iron per gram liver, dry weight,
`are at an increased risk of hepatic fibrosis and other complications of iron overload.2,3,5
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`Patients who sustain hepatic storage iron concentrations exceeding 15 milligrams iron per
`gram liver, dry weight have a greatly heightened risk of cardiac disease and early death.4
`Accordingly, patients who reduce and maintain hepatic storage iron concentrations within
`the range of 3.2 to 7 milligrams iron per gram liver, dry weight are considered to have
`maintained body storage iron within optimal range while receiving deferiprone. Patients in
`whom long-term chelating therapy fails to maintain hepatic storage iron in this range are
`considered to be at risk for iron-induced complications of iron overload. Finally, those
`patients in whom therapy fails to maintain hepatic storage iron below 15 milligrams iron
`per gram liver, dry weight, are considered to be at risk of cardiac disease and early death.4
`Although support for Toronto’s long-term trial was terminated prematurely in 1996 by
`the corporate sponsor, continued follow-up of hepatic storage iron concentrations has pro-
`vided information regarding the long-term effectiveness of deferiprone in Cooley’s ane-
`mia. Our most recent analysis of this cohort shows that, in one-third of patients, hepatic
`iron concentrations presently exceed the threshold associated with increased risk of heart
`disease and early death in Cooley’s anemia.4 Of the 16 patients with a hepatic iron con-
`centration below this threshold when previously reported,16 the hepatic iron concentration
`now exceeds the threshold in four patients (p = 0.05); in the two other patients, the hepatic
`iron concentration has continued to exceed the threshold during 2.3 and 3.9 years of
`deferiprone, respectively. In these six patients. mean compliance with deferiprone exceed-
`ing 90% drug taken of that prescribed.19 Another interpretation of these data has recently
`been presented.20,21
`In parallel, investigators in the United Kingdom reported the results of deferiprone ther-
`apy over 42.5 months (range, 8 to 56 months) in 42 patients with Cooley’s anemia aged
`29.9 years (range, 20 to 58 years).22,23 No significant declines in serum ferritin concentra-
`tion were reported in these patients over this period of therapy. In the 17 patients in whom
`hepatic iron concentrations were determined after therapy, concentrations exceeded the
`threshold for cardiac disease and early death4 in ten patients. The conclusion of this analy-
`sis is similar to those in the Canadian study:19 the U.K. investigators have now concluded
`that “long-term therapy with deferiprone may not provide adequate control of body iron in
`a substantial proportion of patients with thalassemia major.”22,23
`In summary, two interpretation of the results obtained from the only centers to quanti-
`tatively determine body iron burden in patients receiving long-term deferiprone therapy
`raise concerns that long-term deferiprone may not provide adequate sustained control of
`body iron in a substantial proportion of patients with Cooley’s anemia.19,22,23
`
`Toxicity Studies
`
`As detailed previously,6 deferiprone did not receive full formal toxicologic evaluation
`before being given to humans; permission to administer the drug in early studies in the
`United Kingdom, India, Europe and Canada was granted on the basis of limited toxicity
`studies in rodents. Adrenal hypertrophy, gonadal and thymic atrophy, bone marrow atrophy
`and pancytopenia, growth retardation, and embryotoxicity have also been reported in ani-
`mals. In humans, the most common adverse effect associated with administration of
`deferiprone has been arthralgias, primarily of the large joints, the etiology of which remains
`elusive.6 The most serious adverse effect associated with the administration of deferiprone
`has been severe neutropenia or agranulocytosis, first reported in 1989.24 To date, this com-
`plication has been reported in several patients, most with Cooley’s anemia, as early as six
`weeks and up to 21 months after the initiation of deferiprone. The mechanism of
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`deferiprone-induced neutropenia is unknown; this adverse effect appears not to be dose-
`dependent, but idiosyncratic and unpredictable.6
`No study of long-term toxicity of deferiprone has been conducted. Monitoring of the
`safety of deferiprone in most prospective studies continues to be directed to abnormali-
`ties reported in animal studies.23–29 Treatment of iron-loaded Mongolian gerbils with a
`hydroxypyridinone closely related to deferiprone (1,2-diethyl-3-hydroxypyridin-4-one)
`has been associated with the acceleration of hepatic fibrosis and the development of car-
`diac fibrosis in these animals, the only species which develops hemochromatosis of the liver
`and heart in the same manner as patients with Cooley’s anemia.29 While hepatic iron accu-
`mulation was inhibited during co-administration of 1,2-diethyl-3-hydroxypyridin-4-one
`over the short-term in the gerbils, hepatic iron increased significantly during extended drug
`administration.29 Of further concern, accelerated fibrosis was noted in both the livers and
`hearts of animals in which 1,2-diethyl-3-hydroxypyridin-4-one was co-administered with
`iron, compared to animals treated with iron alone. These observations, and the theoretical
`concerns with respect to the toxicity of a bidentate ligand, discussed elsewhere in this vol-
`ume, have raised concerns as to whether long-term deferiprone therapy may be associated
`with worsening of hepatic fibrosis, and cardiac iron loading and fibrosis, in humans.
`By oversight, in this and all other trials of deferiprone worldwide, hepatic histology has
`never been evaluated prospectively in patients receiving long-term therapy. As well, the
`effect of deferiprone on cardiac iron loading and fibrosis has not been been the primary
`endpoint of any prospective trial. Nevertheless, the studies by the group in the United
`Kingdom have provided indirect information regarding cardiac disease in patients with
`Cooley’s anemia treated with long-term deferiprone. In this long-term treatment cohort,23
`18 of 42 patients left the study, a dropout rate of 43 percent. Review of these 18 patients
`shows that five dropouts had died, four of cardiac disease, while on deferiprone therapy,
`while another patient withdrew from treatment because of tachycardia. In all the study
`dropouts, mean initial serum ferritin concentration, which exceeded 4,500 µg/L, report-
`edly did not change significantly during deferiprone therapy.23 These data underscore the
`concerns that long-term deferiprone may not adequately reduce body iron burden below
`concentrations that are associated with an increased risk of cardiac disease and early death
`in Cooley’s anemia,4 confirming the findings summarized above.19,22,23
`In summary, data from two centers conducting long-term trials of deferiprone support
`our previous conclusion that “long-term therapy with deferiprone may not provide ade-
`quate control of body iron in a substantial proportion of patients with thalassemia
`major.”19 Further prospective trials may be indicated to address these potential toxicities
`of deferiprone.
`
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