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`Long-Term Trial of Deferiprone in 51 Transfusion-Dependent
`Iron Overloaded Patients
`
`By A. Victor Hoffbrand, Faris AL-Refaie, Bernard Davis, Noppadol Siritanakatkul, Beverly F.A. Jackson,
`John Cochrane, Emma Prescott, and Beatrix Wonke
`
`Fifty-one transfusion-dependent iron-loaded adult patients
`(38 with thalassemia major) were treated with the orally
`active iron chelator deferiprone (1,2 dimethyl-3-hydroxypyrid-
`4-one, L1) at a dose of 75 mg/kg/d (range, 50 to 79). Twenty
`patients discontinued the drug and five died after a mean of
`18.7 months (range, 4 to 35). Of the 20, 5 had arthropathy, 5
`had gastrointestinal symptoms, 4 had a rising serum ferritin,
`3 had agranulocytosis or neutropenia, 1 had tachycardia, 1
`had renal failure, and 1 went abroad. Twenty-six patients
`continued deferiprone for a mean of 39.4 months (range, 12
`to 49). Among these patients, there was no overall signifi-
`cant change in serum ferritin (initial mean, 2,937 g/L; range,
`980 to 5,970; final mean, 2,323 g/L; range, 825 to 5,970) or in
`urine iron excretion (initial mean, 31.2 mg/24 h; range, 16.3
`to 58.2; final mean, 32.1 mg/24 h; range, 9.4 to 75.8), implying
`
`ONLY ONE DRUG, deferoxamine mesylate (DFX),
`
`is
`widely available for chelating iron from patients with
`refractory anemias, such as thalassemia major, who require
`regular blood transfusions. Iron accumulates in such patients at
`a rate of about 0.5 mg/kg/d and subcutaneous DFX 20 to 50
`mg/kg/d administered over 8 to 12 hours is sufficient to produce
`iron balance in most of these patients with a body iron burden
`about 5 to 10 times the normal level.1 DFX is unavailable to
`many patients worldwide because it is too expensive; also,
`patients may develop local or generalized sensitivity to the drug
`or may develop toxic side effects such as growth failure,
`deformities of the long bones and spine, and hearing and visual
`problems. These side effects occur, however, largely in patients
`administered excessive doses of DFX in the face of low iron
`burden. Many patients find difficulty in complying with daily
`subcutaneous DFX therapy, which is burdensome, painful, and
`time-consuming. Noncompliance becomes a major problem,
`particularly in adolescents, leading to iron induced cardiac
`damage and death.2,3 Calcium diethylenetriamine penta-acetic
`acid has been used as an alternative to DFX but it also has to be
`administered parenterally and it causes excessive zinc excre-
`tion. A potential orally active alternative to DFX is 1,2-dimethyl-
`3-hydroxypyrid-4-one (L1, deferiprone). Short-term clinical
`studies have shown the drug to be effective but to have toxic
`side effects including agranulocytosis, arthropathy, zinc defi-
`ciency, and gastrointestinal side effects.4-7 We now report the
`efficacy and side effects of deferiprone in a long-term trial of
`therapy in 51 transfusion-dependent patients.
`
`MATERIALS AND METHODS
`Fifty-one iron-overloaded regularly transfused patients who were
`unable to take DFX or not compliant with DFX were included in the
`trial. Thirty-eight patients (36 splenectomized) had -thalassemia major
`(TM), 1 had hemoglobin E/beta thalassemia, and 1 had sickle cell/-
`thalassemia. This group included 13 women and 27 men, mean age of
`30.5 years (range, 22 to 38). Additional patients included 4 with sickle
`cell anemia (2 women, 32 and 63 years and 2 men, 18 and 32 years), 3
`with sideroblastic anemia (1 woman, 46 years and 2 men, 16 and 45
`years), and 4 men with myelodysplastic syndrome, mean age of 71.5
`years (range, 58 to 83).
`The 36 splenectomized TM patients were administered transfusions
`
`no overall change in iron stores. When the patients who had
`received deferiprone for longer than 3 years were considered
`separately, there was also no significant change in serum
`ferritin or urinary iron excretion. The initial serum ferritin
`levels in the 26 patients who continued deferiprone treat-
`ment were significantly lower than in those who discontin-
`ued the drug (P F .01). The liver iron content in 17 patients
`who had received deferiprone for 24 to 48 months ranged
`from 5.9 to 41.2 mg/g dry weight, 50% having levels above
`15.0 mg, a level associated with a high risk of cardiac disease
`due to iron overload. In this study the drug caused fewer side
`effects and was more effective at maintaining iron status
`among patients previously well chelated and with lower
`initial serum ferritin levels.
`1998 by The American Society of Hematology.
`
`of red blood cells (RBCs) 3 to 4 U monthly to raise their hemoglobin
`(Hb) levels from 9.0 to 15.0 g/dL; overall yearly mean of Hb was 12.0
`g/dL. Their blood consumption ranged from 150 to 200 mL/kg/body
`weight of RBCs per year. Two nonsplenectomized TM patients required
`250 to 300 mL/kg/body weight of RBCs per year. Patients with sickle
`cell/-thalassemia required 260 mL/kg/body weight of RBCs per year
`to achieve an Hb S concentration of less than 30%. In one patient with
`Hb E/-thalassemia the Hb level ranged from 7 to 12.0 g/dL, the patient
`requiring only 120 mL/kg/body weight of RBCs per year. In the 11
`nonthalassemic patients, RBC requirements were similar to those of
`nonsplenectomized thalassemic patients. Deferiprone was administered
`orally in a total daily dose of 75 mg/kg/body weight (range, 50 to 79
`mg/kg) at least an hour before food every 8 to 12 hours. Deferiprone
`was manufactured according to published methods and marketed by
`Lipomed (Basel, Switzerland) and Vitra (Clavering, Essex, UK) Pharma-
`ceutical Companies. The study was approved by the Ethical Commit-
`tees of the Royal Free and Whittington Hospitals and exemption from
`license certificate was obtained from the Medical Control Agency,
`London, UK. Written informed consent was obtained from each patient.
`At each monthly visit detailed clinical examination was performed
`and laboratory tests included full blood count, liver and renal function,
`serum zinc and calcium levels, serum immunoglobulins, CD4/CD8
`lymphocyte numbers and ratio, and antinuclear and rheumatoid factor.
`Leukocyte ascorbic acid was measured every six months in all patients
`and those with low levels were given oral vitamin C (200 mg/d) with
`their daily dose of deferiprone. Urine zinc excretion was measured
`every three months. The patients were monitored for side effects; in
`particular, musculoskeletal complaints were noted and joints were
`carefully examined for warmth, crepitus, synovial swelling, effusion,
`
`From the Department of Hematology, The Royal Free Hospital
`School of Medicine, London, UK; and the Departments of Hematology
`and Surgery, Whittington Hospital, London, UK.
`Submitted February 19, 1997; accepted August 25, 1997.
`Address reprint requests to A. Victor Hoffbrand, FRCP, Department
`of Haematology, Royal Free Hospital, Pond St, London, NW3 2QG UK.
`The publication costs of this article were defrayed in part by page
`charge payment. This article must therefore be hereby marked ‘‘adver-
`tisement’’ in accordance with 18 U.S.C. section 1734 solely to indicate
`this fact.
`1998 by The American Society of Hematology.
`0006-4971/98/9101-0018$3.00/0
`
`Blood, Vol 91, No 1 (January 1), 1998: pp 295-300
`
`295
`
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`296
`
`HOFFBRAND ET AL
`
`and by the patellar compression test for retropatellar tenderness and
`stability. Special investigations of the painful joints included plain
`x-ray, magnetic resonance imaging, and isotope bone scans. Cardiac
`function was monitored by annual multiple uptake gated acquisition
`(MUGA) scans of the heart, and measuring the left ventricular ejection
`fraction at rest and under stress. Compliance to deferiprone was not
`assessed by computerized containers but we checked that patients had
`used up supplies and new prescriptions were administered with only a
`sufficient amount of drug until the next appointment.
`We assessed the efficacy of deferiprone treatment by monthly
`measurements of serum ferritin concentration and of 24-hour urinary
`iron excretion. In 17 patients on long-term deferiprone (mean, 39.4
`months; range, 24 to 48) hepatic iron concentrations were measured,
`using chemical analysis of tissue iron obtained by liver biopsy.8
`
`RESULTS
`Patients withdrawn from long-term therapy. Of the 51
`patients, 25 (49%) discontinued deferiprone or died after a
`mean of 18.7 months (range, 4 to 35). The reasons for stopping
`treatment in 20 of the patients are shown in Table 1. All five
`patients with arthropathy had TM. Their mean serum ferritin
`levels at the start of deferiprone treatment was 4,192 μg/L
`(range, 1182 to 9060). Arthropathy caused discontinuation of
`deferiprone during the second or third year of therapy. Joint
`symptoms had usually been present for several weeks and in
`these cases did not improve with lowering the dose of deferi-
`prone to 50 mg/kg/d. The knee joints were mainly affected and
`the clinical symptoms were of stiffness, crepitus, and effusion.
`Special tests including plain radiography, magnetic resonance
`imaging, and isotope scans were unhelpful in elucidating the
`pathophysiology of the arthropathy. There was no correlation
`between the presence of antinuclear factor (ANF) and rheuma-
`toid factor antibodies in the plasma of these patients suffering
`from arthropathy compared with those without. There was also
`no statistical significant difference between serum ferritin levels
`between the two groups.
`Four TM patients stopped deferiprone treatment because of
`rising serum ferritin levels. Their mean initial serum ferritin
`level of 4,925 μg/L had increased to 7,569 μg/L. The mean
`urinary iron excretion in these four patients was 9.1 mg/24 h
`(range, 5.6 to 18.5). Their blood consumption was not signifi-
`cantly different from that of the other TM patients. One
`63-year-old myelodysplastic patient developed agranulocytosis
`after 6 weeks of deferiprone therapy (79 mg/kg/d). Details of
`this patient have been reported elsewhere.9 His neutrophil count
`recovered after 7 days. Two TM patients developed neutropenia
`(⬍1.5 ⫻ 109/L) after 13 and 22 months of therapy. Both were
`
`Table 1. Reasons for Stopping Deferiprone Therapy
`
`No. (%)
`of Patients
`
`Duration of Deferiprone
`Therapy mo/mean (range)
`
`Reason for Stopping
`Deferiprone Therapy
`
`5 (9.8)
`5 (9.8)
`5 (9.8)
`4 (7.8)
`2 (5.8)
`1 (1.9)
`1 (1.9)
`1 (1.9)
`1 (1.9)
`
`22.2 (7-35)
`20.8 (14-29)
`11.2 (7-30)
`21.7 (5-31)
`(2-12)
`
`1.5
`14
`4
`27
`
`Died
`Arthropathy
`Nausea, anorexia
`Rising ferritin
`Neutropenia
`Agranulocytosis
`Tachycardia
`Renal failure
`Went abroad
`
`Table 2. Clinical Findings and Serum Ferritin Levels
`Among Five Patients Who Died
`
`Age Sex
`
`Diagnosis
`
`23 M
`
`24 F
`
`TM
`
`TM
`
`30 M
`
`TM
`
`48 M Congenital SA
`34 F
`TM
`
`Length of
`Time on
`Deferiprone
`(mo)
`
`26
`
`19
`
`24
`
`7
`35
`
`Serum Ferritin (µg/L)
`
`Initial
`
`4,122
`
`8,130
`
`8,750
`
`2,055
`4,720
`
`Final
`
`Cause of Death
`
`4,024 CHF Diabetes-
`mellitus
`9,060 CHF Diabetes-
`mellitus
`infection
`6,721 CHF Diabetes-
`mellitus
`2,100 CHF Infection
`720
`ARDS
`
`Abbreviations: CHF, congestive heart failure; ARDS, adult respira-
`tory distress syndrome.
`
`administered a much lower dose of deferiprone but developed a
`second decrease in neutrophils which recovered on stopping
`deferiprone therapy.9 Severe gastrointestinal symptoms such as
`nausea, anorexia, or vomiting necessitated the discontinuation
`of deferiprone therapy in five patients. Two of these patients had
`poor renal function; one with sickle cell anemia and chronic
`glomerulonephritis; the other with myelodysplasia was 82 years
`old.
`Fatalities during the study. Five patients died, four of
`congestive heart failure due to iron overload. Their mean serum
`ferritin at the time of death was 5,112 μg/L (range, 2,100 to
`9,060) (Table 2). The fifth patient died of adult respiratory
`distress syndrome. She had received deferiprone for 35 months
`and her serum ferritin level at the time of death was 720 μg/L.
`None of these patients had neutropenia. The 23-year-old male
`patient with TM and diabetes mellitus died of bronchopneumo-
`nia and cardiac failure. Four months before his death deferi-
`prone treatment was stopped and an attempt was made to
`reintroduce subcutaneous DFX with poor compliance. The
`initial MUGA scan showed moderately severe cardiomyopathy
`with a left ventricular ejection fraction (LVEF) of 55% at rest
`and 40% on cold stress, and 2 years later (2 months before he
`died), LVEF was 54% decreasing to 42% on cold stress.
`The 24-year-old female patient with TM and diabetes melli-
`tus was admitted to the hospital with high fever, and septicemia
`was diagnosed. Her cardiac condition rapidly deteriorated and
`she died of heart failure secondary to iron overload. The MUGA
`scan remained unchanged, showing moderately severe cardio-
`myopathy initially with an LVEF of 48% at rest and 40% on
`cold stress, a year later with an LVEF of 46% at rest and 40% on
`cold stress.
`The 30-year-old male thalassemia patient, noncompliant to
`DFX, with diabetes mellitus, gonadal failure, and hypothyroid-
`ism, was taken off deferiprone treatment 4 months before his
`death. He was admitted with a short history of breathlessness
`and irregular heart beat. His cardiac condition rapidly deterio-
`rated despite continuous intravenous DFX treatment and he
`died of congestive heart failure. His MUGA scan did not show
`deterioration from a moderately severe cardiomyopathy on
`routine yearly testing, initially LVEF 51% at rest falling to 43%
`on stress and at 2 years, 49% at rest falling to 41%.
`The 48-year-old patient with congenital sideroblastic anemia
`
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`LONG-TERM TRIAL OF DEFERIPRONE
`
`297
`
`had taken deferiprone irregularly for 2 months before he died
`because of anorexia, nausea, and joint pains. He contracted an
`infection and 2 days before he died, developed cardiac failure.
`His MUGA scan, which initially showed moderately severe
`cardiomyopathy (LVEF 60% at rest decreasing to 52% on
`stress), had remained consistent throughout the study. He had
`shown pulmonary hypertension with pulmonary artery systolic
`pressure of 99 mm Hg and concentric left and right ventricular
`hypertrophy.
`Patients continuing to take deferiprone. Twenty-six pa-
`tients (20 TM, 1 sickle cell anemia, 1 sickle/-thalassemia, 1 Hb
`E/-thalassemia, 2 sideroblastic anemia, and 1 myelodysplastic
`syndrome) have taken deferiprone for a mean of 39.4 months
`(range, 12 to 49). We have analyzed RBC consumption in
`milliliters per kilogram per year for the 26 patients whose serum
`ferritin levels are given in Fig 1. There was no significant
`correlation between RBC consumption and initial or final serum
`ferritin or with the liver iron levels in 17 patients (see Fig 3).
`The initial mean serum ferritin level was 2,937 μg/L (range, 980
`to 9,090) and at the end of the study 2,323 μg/L (range, 825 to
`5,970), with no significant change (Fig 1). Fifteen patients have
`taken deferiprone for more than 36 months without significant
`change in serum ferritin and urine iron excretion. Among the 17
`patients with initial serum ferritin levels less than 2,500 μg/L,
`three rose to above this level. In the remaining nine patients
`serum ferritin levels initially ranged from 2,920 to 9,090 μg/L.
`In all but one patient final values were still above 2,500 μg/L
`(range, 1,250 to 5,972). The initial serum ferritin levels in these
`26 patients were significantly lower than in the 25 patients who
`died or discontinued deferiprone, mean, 5,095 μg/L (range,
`2,170 to 13,900) (P ⬍ .01) (Fig 2), or than in the 20 patients
`who discontinued deferiprone considered alone (P ⬍ .01).
`Figure 3 shows the chemical liver iron content and serum
`ferritin levels taken at the time of biopsy in 17 iron-overloaded
`TM patients. The mean liver iron content was 17.4 mg/g dry
`weight (range, 5.9 to 41.2). Two patients had a liver iron content
`below 7.0 mg/g dry weight, which has been considered the
`threshold where life expectancy is not affected. Five patients
`had liver iron content between 7.9 and 14.1 mg/g dry weight
`
`Fig 2. The initial and final serum ferritin concentrations in 25
`patients who discontinued deferiprone therapy. (S), Agranulocyto-
`sis; (---䊊), renal failure; (—䊉), increasing ferritin; (M†), death; (䊔),
`nausea; (—䊊), neutropenia; (䊐), tachycardia; (––䊉), anthropathy; (Q),
`went abroad; threshold of effective treatment: (d), USA; (¢), WHO.
`
`and the remaining 10 patients had a liver iron content above
`15.0 mg/g dry weight, ie, falling within the range that has been
`associated with cardiac disease. Overall, the serum ferritin and
`chemical liver iron values did not correlate. Five of 17 patients
`had chronic liver disease caused by hepatitis C virus (HCV).
`There was no correlation between serum ferritin and liver iron
`in the 12 patients without cirrhosis or hepatitis C infection. Five
`of the patients were hepatitis C-RNA positive and these all
`showed cirrhosis of the liver. Among the 12 patients who were
`anti-HCV and hepatitis C-RNA negative,
`the liver biopsy
`samples showed that none had cirrhosis and they showed either
`no fibrosis (11 patients) or mild fibrosis (1 patient). This patient
`began with the highest initial serum ferritin level, 9,087 μg/L.
`Urine iron excretion in response to deferiprone among the 26
`patients initially ranged from 16.3 to 58.2 mg/24 h (mean, 31.2).
`There was no significant overall change in urine iron excretion
`among the 26 patients who had received treatment for a mean of
`
`Fig 1. The initial and final serum ferritin concentrations in 26
`patients who continue deferiprone therapy for a mean of 39.4 (range,
`12 to 49) months. (䊊), Chronic liver disease caused by hepatitis C;
`threshold of effective treatment: (d), USA; (¢), WHO.
`
`Fig 3. The serum ferritin and liver iron concentrations (measured
`during the same admission) in 17 TM patients who underwent liver
`biopsy after 2 to 4 years of deferiprone therapy. (䊊), Chronic liver
`disease caused by hepatitis C. Liver iron: 1 mg/g ⴝ normal; G22 mg/
`g ⴝ cirrhosis develops with time.
`
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`
`HOFFBRAND ET AL
`
`39.4 months. The mean urine iron excretion at the end of the
`study was 32.1 mg/24 h (range, 9.4 to 75.8). There was also no
`overall change in urine iron excretion in the 15 patients who had
`received deferiprone for more than 36 months (Table 3).
`Regular blood counts were performed in all patients during
`the study period. No changes in renal function, white blood cell,
`or platelet counts were observed in the 26 patients. No changes
`were seen in aspartate aminotransferase and alanine aminotrans-
`ferase levels except for the six patients with chronic hepatitis C,
`where fluctuating liver enzyme levels were observed. During
`treatment with deferiprone, marginally low serum zinc levels
`developed in eight patients. All eight had biochemical evidence
`of diabetes or insulin dependent diabetes. These patients were
`given oral zinc supplements (220 mg/d). MUGA scan results
`showed no significant change at rest and on stress between
`initial and final values in the 26 patients.
`
`DISCUSSION
`The results of this study show that long-term (more than 4
`years) iron chelation therapy is feasible using the orally active
`drug deferiprone. They also confirm the findings of previous
`studies in which different side effects of deferiprone therapy
`have been reported.9-11
`Our earliest short-term clinical trials showed that 24-hour
`urine iron excretion equivalent to that induced by subcutaneous
`DFX (40 to 50 mg/kg administered over 8 to 10 hours) could be
`achieved with 100 mg/kg deferiprone given in two to four doses
`each day.12,13 No change in overall mean serum ferritin levels
`was achieved in up to 1 year of treatment.14 A number of
`subsequent abstracts showed decreases in serum ferritin levels,
`particularly in patients starting with high serum ferritin lev-
`els.10,11,15,16 One study, published only in abstract form, reported
`that deferiprone (75 mg/kg/d) was more effective in treating TM
`over 1- to 2-year periods than was subcutaneous DFX.17 A
`subsequent abstract by the same investigators showed that
`hepatic iron concentration was in an optimal range after 2 years
`of therapy in 64% of patients receiving DFX, but in only 7% of
`patients receiving deferiprone.18 This same group reported
`decreases in liver iron in 10 previously poorly chelated patients
`with initial liver iron levels above 80 μmol/g wet weight treated
`with deferiprone for 1 to 3 years. There was a decrease from a
`mean of 125.3 ⫾ 11.5 to 60.3 ⫾ 9.6 μmol, 8 of the 10 patients
`achieving a level less than 80 μmol/g.19 In a further 11 patients,
`previously better chelated, liver iron content remained below 80
`μmol/g. These workers also reported among the 21 patients a
`significant decrease in mean serum ferritin concentration from
`3,975 to 2,546 μg/L. Because of these encouraging results and
`because of our previous experience of important side effects
`with deferiprone at a dose of 100 mg/kg/d, we chose for the
`
`Table 3. Initial and Final Serum Ferritin and Urine Iron Excretion
`in 15 Patients Who Have Received Deferiprone
`for More Than 36 Months
`
`Serum Ferritin
`(µg/L)
`
`Urinary Iron Excretion
`(mg/24 h)
`
`Initial
`
`Final
`
`Initial
`
`Final
`
`Range
`Mean
`
`976-7,875
`3,060
`
`1,100-5,972
`2,360
`
`16.0-58.00
`31.10
`
`13.0-75.90
`33.15
`
`P ⫽ not significant.
`
`present long-term study deferiprone doses of 75 mg/kg/d, in the
`hope of experiencing fewer side effects without significant loss
`of efficacy.
`The serum ferritin concentration is a relatively inaccurate
`measure of body iron burden compared with liver iron estima-
`tion. Nevertheless, the results here show that for the 15 patients
`who have taken the drug constantly for over 3 years, there has
`been no significant change in serum ferritin concentration or in
`urine iron excretion in response to deferiprone, implying no
`significant overall change in iron stores. Deferiprone, therefore,
`has been effective in these patients at balancing iron input from
`blood transfusions by iron excretion in the urine. This is
`consistent with a mean urinary excretion of about 25 mg/24 h in
`these patients, representing 0.5 mg/kg/24 h for a 50-kg indi-
`vidual. Whether additional iron excretion occurs through the
`stools in response to deferiprone is uncertain.
`The results of our liver iron estimations were disappointing.
`Among the 17 patients tested, after a mean of 40 months therapy
`(range, 27 to 49 months) only 2 showed liver iron levels below 7
`mg/g, a level considered safe,20 while 8 had levels above 15
`mg/g, levels at which liver and cardiac damage are likely to
`occur.21 In a group of 12 patients who had received subcutane-
`ous DFX for 4 to 8 years, we found 50% had liver iron levels
`less than 7 mg/g.1 Moreover, in contrast to Olivieri et al,19 we
`found no significant correlation between serum ferritin and liver
`iron. Nine of the 15 patients who have received deferiprone for
`more than 3 years show serum ferritin levels over 2,500 μg/L, a
`level taken by some to indicate inadequate chelation therapy.22
`The discrepancies between our results and that reported by
`Olivieri et al19 may be more apparent than real. In both studies,
`the majority of patients starting therapy with serum ferritin
`levels greater than 2,500 μg/L still showed levels in this range
`after several years of therapy. Also, the majority of previously
`poorly chelated patients in both studies showed hepatic iron
`levels greater than 15 mg/g dry weight after more than 2 years
`of deferiprone therapy.
`Our study included a substantial number of nonthalassemic
`patients, but overall there were no significant differences either
`in efficacy or incidence of side effects among the 40 patients
`with thalassemia syndromes or the 11 patients with other
`diseases. Our liver biopsy samples showed no evidence of direct
`toxicity of the drug to hepatic cells. Fibrosis was mild in only 1
`of 12 patients without hepatitis C infection. Among the hepatitis
`C positive patients,
`the appearances were consistent with
`changes known to be associated with the virus infection.
`The wide variation in iron excretion among the patients may
`relate partly to a wide range in body iron stores, with iron
`excretion being greater in those with greater body iron bur-
`den.12,13 Iron excretion also relates to the area under the curve of
`free deferiprone in plasma after a single oral dose.23 The drug is
`glucuronidated at a different rate in different patients. Efficacy
`will be affected since glucuronidation inactivates the drug’s iron
`binding site. The lack of efficacy in some patients despite high
`iron body loads, as in four patients with rising serum ferritin
`levels during treatment, may be the result of particularly fast
`glucuronidation of deferiprone.
`Nearly 50% of the patients commencing deferiprone discon-
`tinued the drug. Overall, these patients initially showed signifi-
`cantly higher iron stores, assessed by serum ferritin, than the
`
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`LONG-TERM TRIAL OF DEFERIPRONE
`
`299
`
`patients who were able to continue the drug. Five patients died,
`but in none could this be attributed a toxic effect of the drug. In
`four previously, poorly chelated patients, death was due to
`cardiac disease induced by iron overload. However,
`these
`findings imply that deferiprone is inappropriate therapy for
`patients with iron-induced cardiomyopathy in whom continu-
`ous intravenous DFX is needed to cause continuous removal of
`toxic, nontransferrin-bound iron from plasma. Moreover, sub-
`stantially more iron excretion can be achieved with continuous
`DFX administered intravenously than with either intermittent
`subcutaneous infusion of DFX or with oral doses of deferi-
`prone.
`Joint symptoms in association with deferiprone therapy were
`first reported by Bartlett et al.24 They occurred in up to 33% of
`patients in the Indian trial,11 a study showing that high doses of
`deferiprone and greater degrees of iron overload of the patient
`were both predisposing factors. No relation with changes in
`ANF or rheumatoid factor titres have been shown in this or any
`other study, and the mechanism of the damage, whether free
`radical generation or immunological, remains to be determined.
`Agranulocytosis is the most serious complication so far
`reported with deferiprone therapy. The incidence of this and of
`lesser degrees of neutropenia as occurred in two patients here
`(and previously reported9) is not yet determined. It may depend
`partly on the dose of deferiprone, the iron load of the patient, the
`patient’s ethnic group, and the nature of the underlying disease.
`Among 13 patients reviewed by Hoffbrand,6 nine were female,
`suggesting a possible increased susceptibility in females as
`occurs with other idiosyncratic drug agranulocytosis. Patients
`with TM, myelodysplasia, and Blackfan-Diamond anemia have
`all suffered agranulocytosis but all have recovered. Despite
`experiments designed to elucidate a toxic or immune mediated
`mechanism, no evidence for either has been established.25,26
`The licensing of deferiprone in India and its subsequent
`widespread use in therapy of thalassemia is likely to result in
`new cases of agranulocytosis or neutropenia and it is hoped that
`any such cases will be fully documented and reported. A
`recently completed multicenter Italian trial will give additional
`information on the incidence of neutropenia.
`Five patients withdrew from the present study because of
`gastrointestinal symptoms on taking the drug. Two of the
`patients showed renal impairment at the start of therapy and in
`one of these, which involved a man of 82 years, pharmacoki-
`netic studies have shown prolonged accumulation of deferiprone-
`glucuronide in plasma after a single oral dose. A significant
`correlation between creatinine clearance and area under the
`curve for the glucuronide derivative in plasma after a single oral
`dose has been shown.23 It may be that nausea in these two
`patients was caused by accumulation of the glucuronide in
`plasma. At all events this side effect, not previously highlighted,
`resulted in 10% of our patients reverting back to subcutaneous
`DFX for chelation therapy.
`How can we improve on these results? The efficacy of
`deferiprone is dose related and it might be that increasing the
`dose from 75 to 100 mg/kg/d in those that can tolerate it may be
`more effective in some patients. In preliminary studies we have
`increased the dose of deferiprone to 85 mg/kg in 10 of the 26
`patients still taking the drug, with no new side effects and with
`increased iron excretion. Another possibility is to administer
`
`intravenous DFX therapy at the time of blood transfusion and
`deferiprone between transfusions or to use the newly introduced
`DFX continuous infusers27 for a day or two each week with
`chelation with deferiprone on the same and other days, possibly
`increasing overall iron excretion but reducing side effects of
`both drugs in this way.
`
`REFERENCES
`1. Aldouri MA, Wonke B, Hoffbrand AV, Flynn DM, Laulicht M,
`Fenton LA, Scheuer PJ, Kibbler CC, Allwood CA, Brown D, Thomas
`HC: Iron state and hepatic disease in patients with thalassemia major,
`treated with long term subcutaneous desferrioxamine. J Clin Pathol
`40:1353, 1987
`2. Wolfe L, Olivieri N, Sallan D, Steven Colan RN, Rose V, Propper
`R, Freedman MH, Nathan DG: Prevention of cardiac disease by
`subcutaneous deferoxamine in patients with thalassemia major. N Engl
`J Med 312:1602, 1985
`3. Aldouri MA, Wonke B, Hoffbrand AV, Flynn DM, Ward SE,
`Agnew JE, Hilson AJW: High incidence of cardiomyopathy in beta
`thalassemia patients receiving regular transfusion and iron chelation:
`Reversal by intensified chelation. Acta Haematol 84:113, 1990
`4. Al-Refaie FN, Hoffbrand AV: Oral iron chelation therapy. Recent
`Adv Haematol 7:185, 1993
`5. Al-Refaie FN, Hoffbrand AV: Oral iron chelation therapy: The L1
`experience. Baillieres Clin Haematol 7:941, 1994
`6. Hoffbrand AV: Oral iron chelation. Semin Hematol 33:1, 1996
`7. Olivieri NF, Brittenham GM: Iron chelation therapy and treatment
`of thalassemia. Blood 3:739, 1997
`8. Barry M, Sherlock S: Measurement of liver iron concentration in
`needle biopsy specimen. Lancet 1:100, 1971
`9. Al-Refaie FN, Wonke B, Hoffbrand AV: Deferiprone-associated
`myelotoxicity. Eur J Haematol 53:298, 1994
`10. Al-Refaie FN, Wonke B, Hoffbrand AV, Wickens DG, Nortey P,
`Kontoghiorghes GJ: Efficacy and possible adverse effects of the oral
`iron chelator 1,2dimethyl-3-hydroxypyrid-4-one (L1) in thalassemia
`major. Blood 3:593, 1992
`11. Agarwal MB, Gupta SS, Vismanathan C, Vasandani D, Ra-
`manathan J, Desai N, Puniyani RR, Chhablani T: Long-term assessment
`of efficacy and safety of L1, an oral iron chelator, in transfusion
`dependent thalassaemia: Indian trial. Br J Haematol 82:460, 1992
`12. Kontoghiorghes GJ, Aldouri MA, Hoffbrand AV, Barr J, Wonke
`B, Kourouclaris T, Sheppard L: Effective chelation of iron in 
`thalassaemia with the oral chelator 1,2-dimethyl-3-hydroxyprid-4-one.
`BMJ 295:1509, 1987
`13. Kontoghiorghes GJ, Aldouri MA, Sheppard LN, Hoffbrand AV:
`1,2-dimethyl-3-hydroxypyrid-4-one, an orally active chelator for the
`treatment of transfusional iron overload. Lancet 1:1294, 1987
`14. Kontoghiorghes GJ, Bartlett AN, Hoffbrand AV, Goddard JG,
`Sheppard L, Barr J, Nortey P: Long-term trial with the oral iron chelator
`1,2-dimethyl-3-hydroxypyrid-4-one (L1). Br J Haematol 76:295, 1990
`15. Olivieri NF, Koren G, Hermann G, Bentur Y, Chung D, Klein J,
`St Louis P, Freedman MH, McClelland RA, Templeton DM: Compari-
`son of oral iron chelator L1 and desferrioxamine in iron-loaded patients.
`Lancet 336:1275, 1990
`16. To¨ndury P, Wagner HP, Kontoghiorghes GJ: Update of long term
`clinical trials with L1 in beta thalassaemia major patients in Bern,
`Switzerland. Drugs Today 28:115, 1992 (suppl A)
`17. Olivieri NF, Brittenham GM, Armstrong SAM, Basran RK,
`Daneman R, Daneman N, Ivanchko RM, Talbot AL, Koren G: First
`prospective randomized trial of the chelators deferiprone (L1) and
`deferoxamine. Blood 86:249a, 1995 (abstr, suppl 1)
`18. Olivieri NF, for The Iron Chelation Research Group (Toronto,
`Canada): Randomised trial of deferiprone (L1) and deferoxamine
`(DFO) in thalassemia major. Blood 88:651a, 1996 (abstr, suppl 1)
`
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`HOFFBRAND ET AL
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`19. Olivieri NF, Brittenham GM, Matsui D, Berkovitch M, Blendis
`LM, Cameron RG, McClelland RA, Lin PP, Templeton DM, Koren G:
`Iron-chelation therapy with oral deferiprone in patients wit