918
`
`THE NEW ENGLAND JOURNAL OF MEDICINE
`
`April 6, 1995
`
`IRON-CHELATION THERAPY WITH ORAL DEFERIPRONE IN PATIENTS
`WITH THALASSEMIA MAJOR
`NANCY F. 0LMERI, M.D., GARY M. BRITTENHAM, M.D., DOREEN MATSUI, M.D.,
`MATITIAHU BERKOVITCH, M.D., LAURENCE M. BLENDIS, M.D., Ross G . CAMERON, M.D.,
`ROBERT A. McCLELLAND, PH.D., PETER P. LIU, M.D., DOUGLAS M. TEMPLETON, PH.D., M.D.,
`AND GIDEON KOREN, M.D.
`
`Abstract Background. To determine whether the oral(cid:173)
`ly active iron chelator deferiprone (1,2-dimethyl-3-hydroxy(cid:173)
`pyridin-4-one) is efficacious In the treatment of iron over(cid:173)
`load in patients with thalassemia major, we conducted a
`prospective trial of deferiprone in 21 patients unable or
`unwilling to use standard chelation therapy with parenter(cid:173)
`al deferoxamine.
`Methods. Hepatic iron stores were determined yearly
`by chemical analyc;is of liver-biopsy specimens or mag(cid:173)
`netic-susceptibility measurements. Detailed clinical and
`laboratory studies were used to monitor safety and com(cid:173)
`pliance.
`Results. The patients received deferiprone therapy for
`a mean (±SE) of 3.1 ±0.3 years. Ten patients in whom
`previous chelation therapy with deferoxamine had been
`ineffective had initial hepatic iron concentrations of at
`
`values
`least 80 µ,mol per gram of liver, wet weight -
`associated with complications of iron overload. Hepatic
`iron concentrations decreased in all 10 patients, from
`125.3:<;11.5 to 60.3:t9.6 µ,rnol per gram (P<0.005). with
`values that were less than 80 µ,mol per gram in 8 of the
`10 patients (P<0.005). In all 11 patients in whom defer(cid:173)
`oxamine therapy had previously been effective, defer(cid:173)
`iprone maintained hepatic iron concentrations below 80
`µ,mol of iron per gram.
`Conclusions. Oral deferiprone induces sustained de(cid:173)
`creases in body iron to concentrations compatible with
`the avoidance of complications from iron overload. The
`risk of agranulocytosis associated with deferiprone may
`restrict its administration to patients who are unable or un(cid:173)
`willing to use deferoxamine. (N Engl J Med 1995;332:
`918-22.)
`
`I N patients with thalassemia major, a regular pro(cid:173)
`
`gram of transfusion sustains growth and develop(cid:173)
`ment during childhood, but without concomitant che(cid:173)
`lation therapy, iron within ~he transfused red cells
`accumulates inexorably. 1 Excess iron damages the liver,
`endocrine organs, and heart and may be fatal by ado(cid:173)
`lescence. 2 Two recent prospective trials have demon(cid:173)
`strated that treatment with deferoxamine B mesylate
`can prevent the complications of iron overload and im(cid:173)
`prove survival in thalassemia major.3•4 Both studies
`showed that the principal determinant of the clinical
`outcome was the magnitude of the body iron load. In
`patients able to take sufficient doses of deferoxamine to
`control the body iron load, the risk of cardiac disease
`and other complications was low, and survival after 15
`years exceeded 90 percent. Conversely, when the body
`iron load was not controlled, the risk of complic.ations
`was high, and the probability of survival to the age of
`25 years was only about 30 percent.
`Some patients are unable or unwilling to receive
`deferoxamine treatment, because of allergy, toxic ef(cid:173)
`fects,s an inability to comply with prolonged parenteral
`infusions, or unavailability of the drug. 1 A possible al-
`
`From the Department of Pediatrics. Hospiial for Sick Children (N.F.0., D.M.,
`M.8., G.K.): the Oepartmenis of Medicine (N.F.O .• L.M.B .. P.P.L.) and Pathology
`(R.0.C.), Thronto Hospital: and the Departments of Chemistry (R.A.M.) and
`Clinical Bioehami$try (D.M.T.), University of Toronto -
`all in Toronto; and the
`Dcpanment of Medicine. MelroHealth Mediul Center and Case Western Reserve
`University, Cleveland (G.M.B.). Address reprint requests to Dr. Olivieri at the
`Hemoglobinopathy Jjro~'l"l)m. flospita! fo• Sicl: Childrcr.. SSS Univen;itr Avo ..
`Toron1< .. Oh' W.50 l~l ~an';uJ:.
`·-
`·
`·
`·
`·
`Supponcd in pan by rc..,arch gr~~ from the Medical Rese<1rch Council of
`Canada, the Onlario Hean and StrdRe Foundation. the Cooley's Anemia Found•·
`1ion, the National Institutes of Health (HL 42824 and Al 35827), the Food and
`Drug Administration (Orphan Products Grant FD-R-000532), and the National
`Thalassemi3 Foundation of Canada. On:. Olivieri and Koren are Cateer Scientists
`of the Ontario Ministry of Health. Dr. Liu is a Career Scientist of the Ontario
`Hean and Stroke Foundation.
`
`ternative to deferoxamine, the orally active iron-chelat(cid:173)
`ing agent deferiprone (l,2-dimethyl-3-hydroxypyridin-
`4-one), has undergone preliminary evaluation in the
`United Kingdom, Canada, Europe, and India. 6. 16 Stud(cid:173)
`ies using the serum ferritin concentration as an indirect
`estimate of the body iron load suggest that the drug
`may be effective, but in some patients treated with de(cid:173)
`feriprone, reversible neutropenia or agranulocytosis
`has developed. 14•17•18 This adverse effect emphasizes the
`need to assess the balance between risk and benefit by
`directly measuring the efficacy of deferiprone in reduc(cid:173)
`ing body iron. We report the results of a prospective
`study of deferiprone in patients unable or unwilling to
`use deferoxamine in whom the effect of deferiprone on
`the body iron burden was assessed with serial direct de(cid:173)
`terminations of hepatic iron concentrations.
`
`METHODS
`
`Patients
`Patients with thalassem ia major who were unwilling or unable to
`use deferoxamine and who had completed one or more years of lrea1-
`mcnt were enrolled in the trial. Each patient received transfusions at
`three- to four-week intervals to maintain the hemoglobin concentra(cid:173)
`tion at a level above IO g per deciliter (approximately JO g of trans(cid:173)
`fused iron yearly in a 70.kg adult). Because of loxic effects of defer(cid:173)
`oxamine (hearing loss 19 or metaphyseal dysplasia'°), unmanageable
`local reactions, or infusions of Jess than 50 percent of the prescribed
`dose for at least one year, deferoxamine had been administered in
`doses insufficienl to maintain a negative iron balance in some pa·
`tients. Two patients with insulin·dcpende.nt diabetes had cardiac
`disease requiring medication. Fourteen palients had clevalcd serum
`alanine amino1ransferas: level• (i7-:!:.14 l: pee liter fnorma! ,·alu:.
`<40)}; 13 haci antiboOies .. iu ntpaLitis C. Five palienis Oad previouslr
`undergone short-term studies to determine dcferiprone-induced uri(cid:173)
`nary and fecal iron excrction.11
`The study was approved by lhe Hospital for Sick Children's hu·
`man-subjects commiuee and by lhe Health Protcclion Branch,
`Health and Welfare Canada (File No. 9427-HI 117-410). The proto·
`col for the magnetic-susceptibility studies was approved by the Com-
`
`
`1 of 5
`
`Taro Pharmaceuticals, Ltd.
`Exhibit 1012
`
`

`

`Vol. 332 No. 14
`
`IRON-CHELATION THERAPY WITH ORAL DEFERIPRONE lN THAI.ASSEMIA MJ\JOR
`
`919
`
`mittcc on Human Investigation, MetroHcalth Medical Center, Cleve(cid:173)
`land. Written informcc! consent was obtained from each patient or a
`parent of the patient.
`Patients were given a total daily dose of 75 mg of defcriprone per
`kilogram of body weight, to be taken orally every eight hours. Dcfer(cid:173)
`iprone was prepared according to published methods21 and encapsu(cid:173)
`lated by Novopharm Pharmaceuticals, Toronto.
`
`Efficacy
`
`We assessed body iron burden by measuring the hepatic iron con(cid:173)
`centration, using chemical analysis of tissue obtained by liver biopsy
`or noninvasive magnetic measurements in vivo. The iron content of
`biopsy specimens was determined as previously described.12.22 Mag(cid:173)
`netic measurements of hepatic iron were performed with a super(cid:173)
`conducting quantum-interference-device susceptomctcr (Biomagnet(cid:173)
`ic Technologies, San Diego, Calif.). The ability of this instrument
`lo provide measurements of hepatic iron that arc quantitatively
`equivalent to those obtained by a chemical analysis of tissue has been
`demonstrated elscwhcre.22 The results of the chemical and magnetic
`measurements were used interchangeably. Their quantitative equiva(cid:173)
`lence was verified throughout the course of the study by comparisons
`of paired chemical and magnetic determinations (n-66, r=0.98,
`P<0.001). Serum fcrritin concentrations were measured every two
`months with a commercial kit (Ramco Laboratories, Houston).
`To determine whether defcripronc could maintain body iron con(cid:173)
`centrations at levels below those associated with complications from
`iron overload, we used criteria established by two recent prospective
`trials of deferoxaminc in patients with thalasscmia.s,• In the first tri(cid:173)
`al, chelation therapy was defined as effective if the ratio of the total
`transfusional iron load to the cumulative use of deferoxaminc was
`Jess than 0.6 mmol of iron per gram of dcferoxamine; chelation ther(cid:173)
`apy was considered indfcctive if the ratio was greater than or equal
`to this value. As detailed prcviously,s a regression analysis indicated
`that the corresponding concentration of hepatic iron was about 80
`µ.mo! of iron per gram of liver, wet weight (normal range, I to 9). In
`the present trial, chelation therapy was considered effective if the he·
`patic iron concentration was less than 80 µ.mol per gram, and inef(cid:173)
`fective if the concentration was 80 µ.mol per gram or greater.
`In the second trial, chelation therapy was considered effective if
`the value of most scrum ferritin measurements was less than 2500 µ.g
`per liter, whereas therapy was considered ineffective if the value of
`most measurements was 2500 µ.g per liter or greater.• We used sim(cid:173)
`ilar criteria in the present trial.
`
`Safety
`Safety was determined by monitoring the patients for abnormalities
`reported in animal studics.?.!·2' Serum a.lanine aminotransferase, elec(cid:173)
`trolytes, urea nitrogen, crcatininc, glucose, cholcstero.I, triglyceride,
`albumin, bilirubin, alkaline phosphatase, calcium, phosphate, magne(cid:173)
`sium, zinc, copper, amylase, and uric acid concentrations and pro(cid:173)
`thrombin time were also monitored regularly.
`
`Compliance
`
`Compliance was assessed with the Medication Event Monitoring
`System,28 in which bottles with microprocessors in the caps arc used
`to monitor the frequency of bottle opening. Patients were instructed
`to supplement a missed dose at the time of the subsequent dose (re(cid:173)
`corded as a delay but not as noncompliance) but not to supplement
`more than one missed dose, in order to avoid excessive peak defer(cid:173)
`ipronc concentrations.
`
`Statistical Analysis
`Data are presented as means :tSE. Initial and fi nal (most recent)
`ciatt wer: con'iparec witi; Studen: '$ I-test for pai red data. The Fish(cid:173)
`er-Irwin exact test was used to determine the proportion$ of patients
`in two groups formed with the use of dichotomous variables. The re(cid:173)
`lation between hepatic iron and scrum ferritin concentrations was de(cid:173)
`termined with Pearson's coefficient of correlation and a linear regres(cid:173)
`sion analysis. The coefficient of determination was used to estimate
`the proportion of variation in serum fcrritin concentrations that could
`
`be accounted for by variation in hepatic iron stores. All tests were
`two-tailed; a P value of 0.025 was considered to indicate statistical
`significance.
`
`RESULTS
`Twenty-one patients (with a mean age of 22:!: 1.1
`years; range, 7.5 to 31) received deferiprone for a mean
`of 3. l :!:0.3 years (range, l to 4.8), yielding a cumulative
`total of 756 patient-months (63 patient-years) of obser(cid:173)
`vation.
`
`Efficacy
`Body Iron Stores
`Figure l shows the initial and final hepatic iron con(cid:173)
`centrations in all 21 patients. The mean hepatk iron
`concentration decreased from 80.7± 10.8 to 46.8:!:5.9
`µ,mo! per gram (P<0.005). In the IO patients who had
`previously received ineffective chelation therapy with
`deferoxamine, the mean initial hepatic iron concentra(cid:173)
`tion was 125.3 ± 11.5 µ,mo! per gram. After a mean of
`34.8:±:3.8 months of treatment with deferiprone, the
`mean concentration had decreased to 60.3:!:9.6 µ,mol
`per gram (P<0.005); in eight patients hepatic iron con-
`
`200
`
`150
`
`100
`
`50
`
`.....
`-§,
`-~
`~
`j
`0
`g;
`0
`~
`c _g
`.2 ro a.
`
`Q)
`:i::
`
`Initial
`
`Final
`
`Figure 1. Initial and Final Hepatic Iron Concentrations in 21 Pa-
`tients with Thalas1e!11ii3 f0ajor Treated with Deferlprone.
`(SC. ~mol of iron per gram
`Th& horizonta! iine indi'::3tef In!:: va1u€
`of liver) below which patients Ire~~ with deferoxamlne remain
`free of the complications of Iron overload3 (see text). Solid circles
`indicate the hepatic iron concentrations determined by chemical
`analysis of liver-biopsy specimens; open circles indicate the he-
`patic iron concentrations determined by magnetic(cid:173)
`susceptibility studies.
`
`
`2 of 5
`
`Taro Pharmaceuticals, Ltd.
`Exhibit 1012
`
`

`

`920
`
`THE NEW. ENGLAND JOURNAL OF MEDICINE
`
`April 6, 1995
`
`centrations had fallen to a level below 80 µ..mol per
`gram (P<0.005). In the JI patients who had previous(cid:173)
`ly received effective chelation therapy with deferoxa(cid:173)
`mine, the mean initial hepatic iron concentration was
`43.7±4.8 µ.mo! per gram. After a mean of 37.4±5.4
`months of deferoxamine therapy, the mean hepatic iron
`concentration was 32.5±4.3 µ.mo! per gram (P not sig(cid:173)
`nificant); the hepatic iron concentration remained be(cid:173)
`low 80 µ.mo! per gram in all 11 patients.
`
`Serum Ferritin Concentrafions
`Figure 2 shows the initial and final serum ferririn con(cid:173)
`centrations in the 21 patients. The mean serum ferritin
`concentration declined from 3975:!:766 to 2546±381
`µ.g per liter (P<0.005). Among 12 patients with initial
`serum ferritin concentrations equal to or exceeding
`2500 µ..g per liter (mean, 5759±1077), the mean value
`decreased progressively to 3273±568 µ..g per liter
`(P<0.005) during a mean of 38.5:!:3.5 months of defer(cid:173)
`iprone therapy. In 5 of these 12 patients, the final serum
`ferritin concentrations were less than 2500 µ..g per liter
`(P<0.02). Among nine patients with initial values below
`2500 µ.g per liter (mean, 1596±243), the mean serum
`ferritin concentration had not changed significantly af(cid:173)
`ter 33.5±6.2 months (1768±251 µ..g per liter).
`
`Comparison of Hepatic Iron and Serum Ferritin
`Concentrafions
`Figure 3 compares the indirect estimation of body
`iron, based on the serum ferritin concentration, with
`the reference method, based on the hepatic iron con(cid:173)
`centration. The correlation between these measure(cid:173)
`ments was significant (r=0.73, P<0.005).
`
`Safety
`Complete blood counts, obtained weekly in all pa(cid:173)
`tients, did not change significantly during treatment.
`Neither the reduction nor the cessation of deferiprone
`was required because of a change in the blood count in
`any patient.
`Because of reports of deferiprone-induced thymic at(cid:173)
`rophy in animals,27 we monitored immune function in
`the study patients. The results of tests for T-cell sub(cid:173)
`groups, lymphocyte proliferation, candida, immuno(cid:173)
`globulins, specific antibodies (to diphtheria, poliovirus,
`and measles), isohemagglutinin levels, and comple(cid:173)
`ment (C3, C4, and CH50) levels were similar to those in
`20 patients treated with deferoxamine (unpublished
`data).
`Annual rheumatologic examinations were performed
`because of reports of deferiprone-associated arthropa(cid:173)
`thy.14·1~ Joint pain developed in three patients, whose
`clinical course has been reported elsewhcre.29 Because
`of one report of deferiprone-associated S)'sremic lupus
`erythematosus,30 tests for antinuclear antibodies and
`rheumatoid factor were performed twice yearly; tests
`for anti-DNA and antihistone antibodies were per(cid:173)
`formed initially and yearly. No significant changes in
`
`16,001
`
`10,000
`
`-.:-
`$
`CE:
`~
`c:
`~
`<I> u..
`E
`2
`<I>
`Cl)
`
`8,000
`
`6,000
`
`4,000
`
`2,000
`
`0
`
`Initial
`
`Final
`
`Figure 2. Initial and Final Serum Ferritin Concentrations in 21
`Patients with Thalassemla Major Treated with Deferiprone.
`The horizontal line indicates the value (2500 J.£9 of ferritin per li(cid:173)
`ter) below which patients treated with deferoxamine remain free
`of the complications of iron overload' (see text).
`
`antinuclear antibodies or rheumatoid factor were not(cid:173)
`ed; anti-DNA and antihistone antibodies were not de(cid:173)
`tected at any time during the study.
`Reductions in serum alanine aminotransferase lev(cid:173)
`els were observed in most of the patients, whether or
`not they had evidence of previous hepatitis C infec(cid:173)
`tion. In one patient with a positive test for hepatitis
`C antibody, fluctuating elevations of alanine amino(cid:173)
`transferase levels were probably related to deferiprone
`treatment, since they declined after the withdrawal of
`the drug.
`The results of adrenal-stimulation tests, performed
`initially, after one and six months, and yearly thereaf(cid:173)
`ter, were normal. Decreases in serum zinc levels 14 were
`not observed.
`
`Compliance
`Data on compliance, determined according to the
`Medication Event Monitoring System, were available
`for 19 patients during the last year of deferiprone treat(cid:173)
`ment. The mean compliance. rate (percentage of pre(cid:173)
`scribed drug actually taken) was 85 ::t3 percent (range,
`41 to 98). The rate o!}.c~mpliance was very high (90± I
`percent) among ali nu·i tifree pauems; all rnree had
`also had a low rate of compliance with deferoxamine
`therapy. These three patients had high initial hepatic
`iron concentrations (88, 121, and I 78 µ.mo) per gram),
`which were substantially reduced (by 50, 85, and 36
`
`
`3 of 5
`
`Taro Pharmaceuticals, Ltd.
`Exhibit 1012
`
`

`

`Vol. 332 No. 14
`
`IRON-CHELATION THERAPY WITH ORAL DEFERIPRONE IN THALASSEMIA MAJOR
`
`921
`
`15,000
`
`-;:::-
`~
`c::
`~
`10,000
`c::
`:;:;
`"E
`Q) u..
`E
`2 Q)
`
`5,000
`
`•
`0
`0
`
`(/)
`
`50
`
`100
`
`150
`
`200
`
`Hepatic Iron (µ.mol/g of liver, wet weight)
`
`Figure 3. Comparison of Hepatic Iron and Serum Ferritin
`Concentrations.
`Indirect estimation of the body iron load, based on the serum fer(cid:173)
`ritin concentration, is compared with the reference method, based
`on the direct measurement of hepatic iron levels by chemical
`analysis or magnetic-susceptibility studies. Open oirctes denote
`the values at the start of the trial (before deferiprone therapy),
`and solid circles the values at the time of the final analysis. The
`diagonal line denotes the simple linear least-squares regression
`between the two variables.
`
`percent) with deferiprone therapy, despite compliance
`rates of only 63, 71, and 41 percent, respectively.
`
`DrscussroN
`Deferoxamine therapy ameliorates hepatic, cardiac,
`and endocrine dysfunction; improves growth and sP.xu(cid:173)
`al maturation; and prolongs survival in patients with
`iron overload.31 -36 Two recent prospective trials of de(cid:173)
`feroxamine in patients with thalassemia have shown
`that the magnitude of the body iron burden is the prin(cid:173)
`cipal determinant of the severity of iron-associated tox(cid:173)
`icity and of the clinical outcome.3·+ Thus, the ability of
`a new iron chelator to reduce body iron stores and
`maintain them at concentrations associated with a low
`risk of early death and complications of iron overload
`is a paramount consideration.
`In this trial, we evaluated the efficacy of deferiprone
`by direct determination of hepatic iron concentrations.
`In 10 patients in whom deferoxamine had failed to re(cid:173)
`duce hepatic iron stores to a level below 80 µmol of iron
`per gram (levels associated with an increased risk of
`cardiac disease and early death), the body iron load
`was uniformly reduced with deferiprone (P<0.005). In
`8 of the I 0 patients, hepatic iron concentrations de(cid:173)
`creased to less than 80 µ.mol per gram. In the other two
`patients, both with high initial hepatic iron concentra(cid:173)
`tions, iron storage was reduced by about 30 and 50 per(cid:173)
`cent after 15 and 39 months of treatment, respective(cid:173)
`ly. In all I I patients in whom previous deferoxamine
`therapy had been considered effective, the hepatic iron
`concentration was maintained at a level below 80 µ.mol
`per gram, with no significant change during defer(cid:173)
`iprone therapy.
`With the serum ferritin concentration used as an in(cid:173)
`direct means of assessing the body iron burden, the
`
`findings were similar, although the classiJkation of pa·
`tients according to the efficacy of previous therapy dif(cid:173)
`fered somewhat. In all 12 patients with initial serum fer(cid:173)
`ritin concentrations equal to or exceeding 2500 µ.g per
`liter (the criterion for previously ineffective chelation
`therapy), deferiprone induced reductions in serum fer(cid:173)
`ritin concentrations. During a mean period of 38.5±3.5
`months, the mean serum ferritin concentration in these
`patients declined from 5759± 1077 to 3273 ±568 µg
`per liter (P<0.005). Among the nine patients with ini(cid:173)
`tial serum ferritin concentrations below 2500 µ.g per
`liter, the mean concentration did not change signifi(cid:173)
`cantly. These data demonstrate that deferiprone can
`both reduce and maintain body iron at concentrations
`associated with a low risk of iron-related complica(cid:173)
`tions.
`In patients with a history of effective chelation thera(cid:173)
`py, deferiprone did not reduce body iron to a level below
`that achieved previously with deferoxamine. This ob(cid:173)
`servation is consistent with the finding that the daily
`dose of deferiprone used in our study (75 mg per kilo(cid:173)
`gram of body weight) induces less iron excretion than
`the standard daily dose of deferoxamine (50 mg per kil(cid:173)
`ogram).11•16 Nonetheless, deferiprone reduced body iron
`concentrations in all our patients with a history of inef(cid:173)
`fective chelation therapy with deferoxamine. Improved
`compliance almost certainly explains this apparent
`anomaly. Deferoxamine is the more efficient chelating
`agent, but the difficuJty of compliance with parenteral
`administration limits the drug's effectiveness. 36 In this
`study, a high rate of compliance improved the long(cid:173)
`term effectiven.ess of chelation therapy with deferiprone,
`even in patients who had not been able to use deferox(cid:173)
`amine successfully.
`The differences in the direct and indirect means of
`evaluating deferiprone therapy are apparent from the
`data in Figure 3. These data show that a reliance on the
`serum ferritin concentration alone can lead to an inac(cid:173)
`curate assessment of the body iron load in individual
`patients, in part because the serum ferritin concentra(cid:173)
`tion is influenced not only by body iron but also by in(cid:173)
`effective erythropoiesis, ascorbate deficiency, liver dis(cid:173)
`ease, and other conditions that are common in patients
`with thalassemia.37
`We used a hepatic iron concentration under 80 µ.mol
`per gram and a serum ferritin concentration under
`2500 µ,g per liter as the criteria for effective chelation
`therapy to facilitate the comparison between defer(cid:173)
`iprone and deferoxamine. These values may not repre(cid:173)
`sent the optimal goals for the treatment of iron over(cid:173)
`load. They are derived from prospective trials lasting
`more than a decade,3·+ but IO' years is still too short a
`period for the evaluatiC?f. of lifelong therapy. The op(cid:173)
`timal level of body iror:, which remains to be deter(cid:173)
`mined, may be considerably Iowef'than that reflected
`by these values.
`The adverse effects of deferiprone included joint
`pain in one patient29 and a reversible elevation in the
`
`
`4 of 5
`
`Taro Pharmaceuticals, Ltd.
`Exhibit 1012
`
`

`

`922
`
`THE NEW ENGLAND JOURNAL OF MEDICINE
`
`April 6, 1995
`
`serum alanine aminotransferase level in another. Al(cid:173)
`though not observed in our patients, severe neutrope(cid:173)
`nia or agranulocytosis has been reported in 11 patients
`worldwide (Hoffbrand AV: personal communication).
`This toxic effect has been transient in all patients to
`date, but the possibility of its occurrence mandates reg(cid:173)
`ular monitoring of neutrophil counts during treatment
`with deferiprone. The incidence of agranulocytosis is
`being determined in a prospective multicenter trial in
`Canada, Italy, and the United States, under corporate
`sponsorship (Apotex Research, Toronto) and approved
`by the Canadian Health Protection Branch, the Italian
`Ministry of Health, and the U.S. Food and Drug Ad(cid:173)
`ministration. The results of this study should determine
`the commercial availability of deferiprone. The costs
`associated with its administration, although likely to be
`less than those associated with parenteral administra(cid:173)
`tion of deferoxamine, have not yet been determined.
`Our data provide direct evidence of the efficacy of
`deferiprone for the treatment of iron overload in pa(cid:173)
`tients with thalassemia major. Deferiprone decreases
`body iron concentrations and maintains them at levels
`below those associated with the complications of iron
`overload. Nevertheless, until the risk of agranulocytosis
`is determined, deferiprone should be considered as an
`investigational drug for patients unable or unwilling to
`use parenteral deferoxamine.
`
`We arc indebted to Dr. R. Miller of Novopharm Pharmaceuticals
`for encapsulation of dcferiprone; to Dr. M. Spino of Apotex Research;
`to Ors. A. Collins, l'A. Olivieri, G.D. Sher, M.A. Baker, A. Zipursky,
`andJ. W. Harris for helpful advice; to D. Fernandes,]. Klein, N. Klein ,
`A. Muroff, P. Dakin, L. Dupuis, and S. Armstrong for technical as(cid:173)
`sistance; and to Dr. A. Klein of the Health Protection Branch, Health
`and Welfare, Ottawa, Canada, for facilitating early studies of dcfer(cid:173)
`ipronc.
`
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