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RED CELLS

Randomized controlled trial of deferiprone or deferoxamine in beta-thalassemia

major patients with asymptomatic myocardial siderosis
Dudley J. Pennell, Vasili Berdoukas, Markissia Karagiorga, Vasili Ladis, Antonio Piga, Athanassios Aessopos, Efstathios D. Gotsis,
Mark A. Tanner, Gill C. Smith, Mark A. Westwood, Beatrix Wonke, and Renzo Galanello

Most deaths in beta-thalassemia major for 5.7 d/wk. Compliance was 94% 5.3% frequent adverse events were transient
result from cardiac complications due to and 93% 9.7% (P .81), respectively. gastrointestinal symptoms for deferiprone-
iron overload. Differential effects on myo- The improvement in myocardial T2* was treated patients and local reactions at the
cardial siderosis may exist between differ- significantly greater for deferiprone than infusion site for deferoxamine. There were
ent chelators. A randomized controlled deferoxamine (27% vs 13%; P .023). no episodes of agranulocytosis. Deferiprone
trial was performed in 61 patients previ- Left ventricular ejection fraction increased monotherapy was significantly more effec-
ously maintained on subcutaneous defer- significantly more in the deferiprone- tive than deferoxamine over 1 year in improv-
oxamine. The primary end point was the treated group (3.1% vs 0.3% absolute ing asymptomatic myocardial siderosis in
change in myocardial siderosis (myocar- units; P .003). The changes in liver iron beta-thalassemia major. (Blood. 2006;107:
dial T2*) over 1 year in patients main- level (0.93 mg/g dry weight vs 1.54 3738-3744)
tained on subcutaneous deferoxamine or mg/g dry weight; P .40) and serum fer-
those switched to oral deferiprone mono- ritin level (181 g/L vs 466 g/L;
therapy. The dose of deferiprone was 92 P .16), respectively, were not signifi-
mg/kg/d and deferoxamine was 43 mg/kg cantly different between groups. The most 2006 by The American Society of Hematology

Introduction
Iron-induced heart failure and arrhythmia are the most common for the human heart.20 Therefore, myocardial T2* can currently be
causes of death in beta-thalassemia major, accounting for up to used to determine changes in human myocardial iron but not the
71% of deaths in older series1-3 and 67% of deaths in a more recent absolute myocardial iron concentration. The T2* technique shows
report, despite improvements in overall survival.4 There is a need improvement in myocardial siderosis in response to intravenous
therefore to identify myocardial siderosis early and improve deferoxamine treatment in acute heart failure,11 and a case-
treatments for heart complications. Myocardial siderosis can be controlled study found significantly less myocardial siderosis and
identified by cardiovascular magnetic resonance (CMR) measure- improved LV ejection fraction (EF) in thalassemia patients treated
ment of myocardial T2*, which is highly sensitive to tissue iron with deferiprone compared with deferoxamine.21 These data sug-
concentration, and this has been validated in the United Kingdom5,6 gest that myocardial T2* has value for comparing the cardiac
and independently in the United States.7 Patients having increased efficacy of chelators. We therefore compared these 2 treatments as
myocardial siderosis have been shown to be at increased risk of left monotherapy in a prospective multicenter, randomized, controlled
trial, using the change over 1 year in myocardial T2* as the primary
ventricular (LV) systolic and diastolic dysfunction,5,7-9 arrhyth-
outcome measure to determine whether deferiprone had superior
mias,7 and heart failure.5,10 In one series, patients presenting with
cardiac efficacy compared with deferoxamine.
heart failure had a mean T2* of 5.1 ms,11 which is substantially
below the normal lower limit of 20 ms,5 and another series showed
89% of patients presenting in heart failure having a T2* less than
10 ms.10 Myocardial T2* in noniron loaded individuals is not Patients, materials, and methods
affected by impaired LV function, age, or infarction.12 The T2*
technique is fast13 and is highly reproducible between different MR Patient recruitment
scanners.5,14-17 T2* calibration has been achieved for the liver in This open-label trial was conducted in 4 centers in Italy and Greece. All
humans and5,18 in the heart in animals19 and will soon be available patients had homozygous beta-thalassemia major, were regularly transfused

From the National Heart and Lung Institute, Imperial College, London, United Several of the authors (D.J.P., V.B., A.P., E.D.G., R.G.) have declared a
Kingdom; Royal Brompton Hospital, London, United Kingdom; Aghia Sophia financial interest in Apotex, whose product, deferiprone, was studied in the
Childrens Hospital, Athens, Greece; Aghia Sophia Childrens Hospital, present work. Several of the authors (D.J.P., A.P., R.G.) have declared a
University of Athens, Athens, Greece; Centro Microcitemie, University of financial interest in Novartis, whose product, deferoxamine, was studied in the
Torino, Torino, Italy; Laikon Hospital, University of Athens, Athens, Greece; present work.
Institute Euromedica-Encephalos, Athens, Greece; Whittington Hospital,
London, United Kingdom; and Ospedale Regionale per le Microcitemie, Reprints: Dudley Pennell, Professor of Cardiology, Royal Brompton Hospital,
Cagliari, Italy. Sydney Street, London SW3 6NP, United Kingdom; e-mail: [email protected].

Submitted July 22, 2005; accepted December 1, 2005. Prepublished online as The publication costs of this article were defrayed in part by page charge
Blood First Edition Paper, December 13, 2005; DOI 10.1182/blood- payment. Therefore, and solely to indicate this fact, this article is hereby
2005-07-2948. marked advertisement in accordance with 18 U.S.C. section 1734.

Supported by Apotex Research Inc. 2006 by The American Society of Hematology

3738 BLOOD, 1 MAY 2006 VOLUME 107, NUMBER 9

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BLOOD, 1 MAY 2006 VOLUME 107, NUMBER 9 HEART CHELATION RCT 3739

and chelated with subcutaneous deferoxamine monotherapy, and had no being shipped to a central laboratory, where it was measured by micropar-
symptoms of heart failure prior to screening. The mean dose of deferox- ticle enzyme immunoassay (AXSYM System; Abbott Diagnostics, Abbott
amine in the randomized patients prior to entry into the trial was 39 8 Park, IL).
mg/kg/d for 5.7 d/wk (equivalent to 32 mg/kg/d). Patients aged 18 years or
older were screened (n 160) and selected if the myocardial T2* was Safety assessments
abnormal ( 20 ms) but not severe ( 8 ms) and if the LV EF was greater
than 56%. No patient with symptomatic heart failure was eligible for the Patients were monitored weekly for absolute neutrophil count (ANC) and
trial. This rationale excluded patients with no significant cardiac siderosis any adverse events. Serum alanine transaminase (ALT) levels were
and allowed patients with severe myocardial siderosis or LV dysfunction to measured quarterly, serum zinc levels were measured at baseline and every
receive the best current clinical management. Sixty-one patients were 6 months, and serum creatinine levels were measured at baseline and
randomized (Figure 1). The reasons for screening failure (n 99) were 12 months.
usually a myocardial T2* outside the required range ( 8 ms in 11%; 20
ms in 76%). Additional less common exclusions were LV EF less than 56% Statistical analysis
(2%); liver enzymes greater than 3 times upper limit (3%); unsuitable
The statistical analysis plan was defined prior to breaking the randomization
psychological condition (1%); age younger than 18 or older than 36 years
code and locking of the database of the study. All continuous parameters
(8%); claustrophobia (3%); pretransfusion hemoglobin (Hb) level less than
were analyzed using the 2-sample t test, using a P value of .05 as the
90 g/L (9 g/dL; 3%); refused or unable to participate (7%). Eighteen
threshold for statistical significance. Since tissue iron is linearly related to
patients failed more than one criterion. Each centers ethics committee
the inverse of T2*, this measure was log transformed prior to analysis to
approved the study and patients gave signed informed consent. Secondary
linearize the relationship and provide an unbiased estimate of relative
trial end points included cardiac volumes and function, liver iron concentra-
change from baseline for both treatments. Data are presented as mean plus
tion (LIC), and serum ferritin concentrations.
or minus standard deviation (SD), except for the T2* data, which used the
geometric mean (antilog of the mean of the log data) plus or minus the
Cardiovascular magnetic resonance coefficient of variation (CV), defined as [eMSE 1], where MSE is the
The T2* sequence was installed in Athens (GE CVi; GE Healthcare, mean square error (equivalent to the variance of the mean in log scale).
Slough, United Kingdom) and Cagliari (GE Signa Echo-speed; GE Proportions of patients between the treatment groups were compared by the
Healthcare). Validation at each site included scanning of phantoms of Fisher exact test. Trend analysis over time for ferritin and ALT data were
known T2* value, the scanning of 5 patients at each site twice for local performed using repeated-measure analysis of variance (ANOVA; MIXED
reproducibility, and rescanning within 3 days after flying to London for in SAS, SAS Institute, Cary, NC). Sample size calculations indicated that in
comparison with a reference scanner (Siemens Sonata; Siemens, Erlangen, the single-center setting, 32 patients would show a 5% difference in
Germany). We predefined a limit of acceptability of 15% variation in T2* myocardial T2* between drugs for a type 1 error of 0.05 and a power of
for each site compared with London. The variability compared with London 80%. This sample size was increased to 60 to allow for reproducibility
was 9.7% in Athens and 1.6% in Cagliari. Site interstudy variability was deterioration in the multicenter setting and to allow for 20% dropouts. All
3.5% and 2.4%, respectively. These results15 and full details of the T2* MR analyses presented are based on intention to treat. Last observation carried
sequence have been published.13 Myocardial T2* was analyzed using forward was used to fill in the missing data for withdrawn patients in the
dedicated software (Thalassemia-Tools; Cardiovascular Imaging Solutions, efficacy analyses. Deferiprone compliance was measured using the Medica-
London, United Kingdom) with consistent regions of interest in the tion Event Monitoring System device (Aardex, Zug, Switzerland) and
ventricular septum which avoid susceptibility artefacts,5,22 as previously calculated as the percent of openings with an interval longer than 4 hours
described.13,14 Cardiac volumes were acquired using contiguous steady- recorded, divided by number of doses prescribed. Deferoxamine compli-
state free-precession short-axis cines from base to apex,23 a technique with ance was calculated as the percentage of completed infusions, as deter-
excellent reproducibility.24 Measurements were scheduled for 3 to 10 days mined by the Crono pumps, divided by the number of infusions prescribed.
after transfusions. A core laboratory in London analyzed all CMR scans Statistical analysis was performed using SAS Institute (for PC, release 8.2).
using dedicated software (CMRtools; Cardiovascular Imaging Solutions).
All measurements were made in London by 2 reviewers in consensus who
were blinded to treatment allocation. Trial analyses were not fed back to the
centers during the trial.
Results
Patient characterization
Other iron measurements
The baseline characteristics are shown in Table 1. The groups were
LIC was assessed at baseline and 12 months using a superconducting
well matched for the primary end point of myocardial siderosis.
quantum interference device (SQUID).25 All the measurements were
centralized at the Turin University facility (Model 5700 3-Channel SQUID;
Matching was good for most other measures including liver iron
Tristan Technologies, San Diego, CA).26 Prior to the start of the trial, level and transfusional iron input, but significant differences were
SQUID was considered the best noninvasive technique for measuring liver present for the serum ferritin level, hemoglobin level, and white
iron level. Serum ferritin concentration was measured at baseline and every cell count.
3 months. Serum was separated, labeled, and stored frozen at 20C until The target dose for subcutaneous deferoxamine was 50 mg/kg/d
for at least 5 days per week. The actual dose prescribed for
deferoxamine was 43 mg/kg for 5.7 d/wk (equivalent to 35 mg/kg/d
for 7 days per week). This is equal to the recommended dose of 35
mg/kg/d for stable patients with similar ferritin levels from the
product data sheet and slightly higher than the 40 mg/kg/d for 5
d/wk from clinical recommendations,27 though lower than the
maximal dose sometimes used in clinical practice. Oral deferiprone
was initiated at 75 mg/kg/d and increased to the target of 100
mg/kg/d. The actual prescribed dose of deferiprone was 92
mg/kg/d. Compliance was similar (deferiprone 94% 5.3%; defer-
Figure 1. Screening, randomization, completion, and withdrawal patient num- oxamine 93% 9.7%; P .81). Five patients withdrew, 3 taking
bers. deferoxamine (1, deterioration of cardiac function; 2, personal
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3740 PENNELL et al BLOOD, 1 MAY 2006 VOLUME 107, NUMBER 9

Table 1. Descriptive statistics of the treatment groups at baseline

Deferiprone Deferoxamine P

No. randomized (%) 29 (48) 32 (52) NA

Age, y 25.1 3.8 26.2 4.7 .33
Sex, no. (%) .99
Male 15 (52) 16 (50)
Female 14 (48) 16 (50)
Ethnicity, no. (%) .99
Greek 16 (55) 18 (56)
Italian 13 (45) 14 (44)
Race, no. (%) .99
White 29 (100) 32 (100)
Heart measures
Myocardial T2*, ms (CV %) 13.0 (32) 13.3 (30) .77
End-diastolic volume, mL 134 32 132 23 .81
End-systolic volume, mL 43 14 41 13 .51
Ejection fraction, % 69.7 5.4 68.4 4.9 .34
Iron measures
Liver iron concentration, g/L 6.16 6.0 6.32 5.8 .92
Serum ferritin level, g/L 1791 1029 2795 2441 .039
No. with serum ferritin levels above 2500 g/L (%) 5 (17) 13 (41) .055
Blood measures
Transfusional iron input, mL/kg/year 152 43.4 144 44.4 .52
Hemoglobin level, g/L 105 12.0 113 11.9 .023
Total white blood cell count, 109/L 7.86 3.39 11.5 9.42 .047
Corrected white blood cell count, 109/L 7.68 2.96 9.79 4.49 .033
Absolute neutrophil count, 109/L 4.26 1.62 5.10 2.28 .11
Platelet count, 109/L 318 129 318 159 .99
Liver measure
Alanine transaminase, U/L 37.7 32.1 52.2 33.8 .093
Hepatitis C-positive, no. (%) .44
Yes 18 (62) 16 (50)
No 11 (38) 16 (50)
HIV-positive, no. (%) NA
Yes 0 (0) 0 (0)
No 29 (100) 32 (100)
Splenectomy, no. (%) .079
Yes 4 (14) 11 (34)
No 25 (86) 21 (66)
Other biochemistry
Creatinine level, M 71.0 12.5 69.1 12.8 .56
Zinc level, M 13.0 3.6 13.3 2.3 .78
Weight, kg 57.7 7.9 60.6 13.2 .30

Data are shown as number (%) or mean SD, except for the myocardial T2*, which is shown as geometric mean and coefficient of variation (CV).
NA indicates not applicable.

reasons) and 2 taking deferiprone (elevated liver enzymes, which in plan called for parametric analysis of the serum ferritin level, but
1 case was probably caused by cytomegalovirus hepatitis with on inspection of the data, we found 2 extreme outliers in the
increased IgM levels to CMV that fell but with negative polymer- deferoxamine-treated group with ferritin values of 9259 and 9300
ase chain reaction [PCR]). g/L, and the Shapiro-Wilk test indicated that the group was not
normally distributed (P .001). Accordingly, a log transformation
Myocardial T2*
was applied and this was successful in normalizing the ferritin data
Myocardial T2* rose with deferiprone at 6 and 12 months to 15.4 (P .76). In addition, the differences in white cell count and
ms (18%; CV 38%; P .001) and 16.5 ms (27%; CV 38%; hemoglobin level were examined, as both were significantly higher
P .001). The myocardial T2* rose with deferoxamine at 6 and 12 in the deferoxamine-treated group. These differences appear to
months to 14.4 ms (9%; CV 37%; P .003) and 15.0 ms have resulted from the difference in the number of splenectomized
(13%; CV 39%; P .001). The difference in the change between patients in the 2 therapy arms (34% in the deferoxamine-treated
drugs was significant at 6 months (ratio of geometric mean, 1.09; group vs 14% in the deferiprone-treated group). The splenecto-
P .040) and at 12 months (ratio, 1.12; P .023; Figure 2). A rise mized patients had significantly higher corrected white cell counts
in T2* and EF was seen in 19 (66%) deferiprone-treated patients than nonsplenectomized patients (P .001). Data review showed
and 14 (45%) deferoxamine-treated patients. 4 splenectomized patients in the deferoxamine-treated group had
Because of the baseline differences between groups in serum baseline corrected white cell counts greater than 20 109/L. The
ferritin level, white cell count, and hemoglobin level, further larger number of splenectomized patients in the deferoxamine-
analysis of these factors and their interaction with the outcome of treated group could also explain the higher hemoglobin level in the
the primary end point was performed. The predefined statistical deferoxamine-treated group because of decreased red blood cell
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BLOOD, 1 MAY 2006 VOLUME 107, NUMBER 9 HEART CHELATION RCT 3741

(RBC) consumption to maintain the same hemoglobin level despite

similar mean transfusional input between the 2 groups (151.6 43.4
mL/kg/y in the deferiprone-treated group vs 144.3 44.4 mL/kg/y
in the deferoxamine-treated group; P .52). Therefore, we con-
ducted a multivariate analysis of the effect on the myocardial T2*
of baseline differences in log serum ferritin level and splenectomy
status. This showed that the baseline ferritin level does not have a
significant impact on the improvement in T2* (P .66), but
splenectomy was significantly predictive (P .002). Thus splenec-
tomized patients exhibited greater T2* improvement than nonsple-
nectomized patients. The antilog of the estimated effect size
(e0.1850 1.20), which is equal to the ratio of geometric mean
between splenectomized and nonsplenectomized patients, indicates
that the splenectomized patients were 20% better in improving T2*
than nonsplenectomized patients. After controlling for the baseline Figure 3. The change in left ventricular (LV) ejection fraction at 12 months was
ferritin values and the splenectomy status, the difference in T2* significantly greater in the patients taking deferiprone rather than deferox-
amine. In this analysis, 29 deferiprone-treated patients and 31 deferoxamine-treated
favoring deferiprone remained significant and its significance was patients are included (1 deferoxamine-treated patient was excluded because T2* and
substantially greater (P .002). Since the deferoxamine-treated ejection fraction were not measured at 6 and 12 months, and the 4 dropouts were
group had more splenectomized patients than the deferiprone- included using last observation carried over). Standard error bars are shown.
treated group, an even greater difference in mean change from
baseline in T2* in favor of deferiprone would have been expected Other iron measures
had there been an equal number of splenectomized patients in the 2
treatment groups. One patient in the deferiprone-treated group did not have an LIC at
baseline and there were 3 patients (1 deferiprone and 2 deferox-
Cardiac function and volumes amine) who did not have an LIC value at 12 months. The last
observation carried over technique could not be used for those 3
At 12 months, there was a significant difference favoring de- patients and they were excluded from the analysis at 12 months.
feriprone for reduction in end-systolic volume (6.4 6.8 mL vs Therefore, LIC was assessed in 27 and 30 patients for the
0.6 7.9 mL; P .004) and a borderline difference in reduction deferiprone- and deferoxamine-treated groups, respectively. LIC
of end-diastolic volume (7.8 13 mL vs 1.2 13 mL; fell with deferiprone by 0.93 2.9 mg/g dry weight at 12 months
P .060). The EF rose with deferiprone by absolute units of (10.1%; P .11) compared with a fall with deferoxamine by
2.0% 2.7% at 6 months (P .001) and 3.1% 3.6% at 12 1.54 2.5 mg/g dw at 12 months (24.4%; P .002). The
months (P .001). The EF rose with deferoxamine by difference between groups at 12 months was not significant
0.52% 3.5% at 6 months (P .42) and 0.32% 3.4% at 12 (P .40). The change in ferritin level at 6 months with deferiprone
months (P .66). The difference in the change between groups and deferoxamine was 151 713 g/L and 314 921 g/L
was borderline at 6 months (P .074) and significant at 12 months (P .033 between groups) and at 12 months 181 826 g/L
(P .003; Figure 3). The percent change in T2* and EF with and 466 739 g/L (10.1% and 16.7% change from base-
deferiprone was significantly correlated (r2 0.21; P .012), line values, respectively; P .16 between groups). There was no
although this was relatively weak and not useful to predict the EF difference in trend of serum ferritin level over time between groups
change from the change in T2*. There was no correlation with (P .41).
deferoxamine (r2 0.036; P .49).
Vital signs

Weight gain was greater with deferiprone at 6 months (1.6 1.8 kg

vs 0.22 2.7 kg; P .004) and at 12 months (2.2 3.0 kg vs
0.1 2.7 kg; P .004). There were no significant differences
between groups in other vital signs.
Other laboratory measures

The difference between the deferiprone- and deferoxamine-treated

groups in change of ALT level at 12 months was not significant
(22.9 48.6 U/L vs 4.7 38.2 U/L; P .11). This includes the 2
patients who dropped out for increased serum enzyme levels. There
was no significant difference in trend of ALT level over time
between groups (P .32). The difference in percentage of patients
with ALT greater than twice the upper limit was not significant at
baseline or at 12 months.
Figure 2. The change in myocardial T2* at 6 and 12 months was significantly
There was no significant difference between groups in the
greater in the patients taking deferiprone rather than deferoxamine. In this change of zinc level at 12 months (0.80 2.8 M vs 0.23 2.3
analysis, 29 deferiprone-treated patients and 31 deferoxamine-treated patients are M; P .12). There was no significant difference between groups
included (1 deferoxamine-treated patient was excluded because T2* and ejection
in the change in creatinine level at 12 months (3.24 10.5 M vs
fraction were not measured at 6 and 12 months, and the 4 dropouts were included
using last observation carried over). The vertical axis shows the geometric mean of 0.06 12.7 M; P .29). There were no significant differences
T2*. Standard error bars are shown. between groups in other laboratory data, including ANC.
 From www.bloodjournal.org by guest on July 11, 2017. For personal use only.

3742 PENNELL et al BLOOD, 1 MAY 2006 VOLUME 107, NUMBER 9

Adverse events controls with a lower limit of up to 63%.5,7,30 Thus, because the EF
in thalassemia without myocardial siderosis is higher than in
The most frequent adverse events with deferiprone were gastroin-
healthy nonanemic individuals, we believe that our trial included
testinal symptoms (nausea, vomiting, or abdominal pain), which
patients with subclinical LV dysfunction. The increase in EF seen
occurred in 19 (66%) patients. These usually occurred in the first
in this trial accords with this view and suggests that deferiprone
weeks of treatment, were mild to moderate, and usually resolved
was effective in relieving this dysfunction. Reduced EF is linked
within a median of 3 days (range, 1-17 days) without discontinua-
with adverse survival not only in thalassemia31 but also in coronary
tion or decreasing the dose of deferiprone. Deferoxamine adverse
artery disease32 and heart failure,33 and improved prognosis occurs
events included reactions at the infusion site, which occurred in 12
with treatments that improve EF.34,35 Deferiprone also reduced
(38%) patients. Joint problems, including pain and/or swelling,
end-systolic volume, another prognostic parameter in large36 and
occurred in 8 (28%) deferiprone-treated patients and in 6 (19%)
normal-sized hearts.37 Heart failure treatments known to improve
deferoxamine-treated patients (P .30). Nine (31%) deferiprone-
prognosis reduce the end-systolic volume,38 although this has not
treated patients reported increased appetite (P .001). One epi-
been shown directly in thalassemia patients. These prospective
sode of neutropenia (1.01 109 neutrophils/L) occurred in one
randomized data are also consistent with a previous study showing
deferiprone-treated patient. The event resolved within 3 days
significantly superior EF with deferiprone.21
(2.69 109 neutrophils/L) without discontinuation or decreasing
It therefore appears that deferiprone could reduce the risk of
the dose of deferiprone. There were no episodes of agranulocytosis.
progression to iron-related cardiomyopathy by removing more
cardiac iron than subcutaneous deferoxamine, and the LV function
and volume improvements in patients with subclinical LV dysfunc-
tion could yield prognostic benefit. Lower levels of myocardial
Discussion
siderosis would allow an increased reserve for any future periods of
Heart disease, which results from myocardial iron deposition iron loading and the potential for greater resistance to catastrophic
associated with lifelong blood transfusions and increased gut iron heart failure that can be seen in thalassemia patients with intercur-
uptake, is the most common cause of death in beta-thalassemia rent infection. These interpretations accord with longitudinal
major. Recently, it has become possible to target therapy for studies of EF in thalassemia31 and previous retrospective survival
myocardial siderosis using myocardial T2*, allowing comparison data using deferiprone or deferoxamine.39 With more than 4 years
of the myocardial efficacy of iron chelators. Using myocardial T2*, of follow-up, cardiac dysfunction was newly diagnosed in 4% of
continuous intravenous deferoxamine has been shown to reduce the deferiprone-treated patients and 20% of the deferoxamine-
myocardial siderosis in acute heart failure,11 although iron clear- treated patients (P .007). This was accompanied by no deaths
ance was considerably slower from heart than liver. In the current with deferiprone but 3 cardiac-related deaths with deferoxamine.
trial, all screened patients had no cardiac symptoms and were These findings suggest differences in the in vivo myocardial
receiving chronic deferoxamine monotherapy, and those who were efficacy of these drugs. Deferoxamine is an important chelator40-42
subsequently randomized either continued deferoxamine at an but is a large positively charged molecule, relatively lipophobic,
increased dose (4 mg/kg/d; P .001) following entry into the and one that undergoes conformation change on binding of iron,
trial with standardization of treatment or were switched to de- which may lead to intracellular trapping.43 These properties
feriprone monotherapy. We found a significant reduction in our potentially limit its ability to chelate intracellular iron, unless there
primary trial end point of myocardial siderosis in the deferoxamine- is an active excretion pathway, as postulated for deferoxamine in
treated group (T2* increased by 13% at 12 months; P .001), hepatocytes.43,44 By contrast, deferiprone is a small, neutral mole-
which probably resulted from the increased dose of deferoxamine cule with greater lipophilicity and therefore has significantly
and/or improved compliance. Despite this improvement in the greater potential to chelate intracellular iron.45,46 This suggests that
control group, the deferiprone-treated group showed superior deferiprone may have preferential access to intracellular iron in
efficacy in reducing myocardial siderosis (T2* increased by 27% at tissues such as the myocardium, and in vitro and animal data
12 months, P .001; P .023 vs deferoxamine-treated group at support this hypothesis.47 Because of these variations in action,
12 months). These data accord with a previous retrospective study combination therapy with these chelators, for which there is
showing lower myocardial iron with deferiprone.21 Although the supportive in vitro47 and clinical evidence,48 may be attractive.
clinical efficacy of raising myocardial T2* for asymptomatic Combination therapy is being subjected to a further randomized
patients remains to be determined, it would appear that reduced controlled trial for cardiac efficacy.49
levels of myocardial iron are a favorable response. Three previous randomized trials have compared the myocar-
The deferiprone-treated group also exhibited significant improve- dial effects of chelators. Maggio et al50 compared deferiprone (75
ment in secondary trial end points compared with deferoxamine, mg/kg/d) with deferoxamine (50 mg/kg/d for 5 d/wk). No differ-
with a reduced end-systolic volume and increased EF. In this trial, ence was found between groups in serum ferritin level or T2-
we excluded patients with an EF less than 56% by CMR, which is weighted myocardial signal intensity ratio (SIR). Peng et al51
the lower limit for healthy nonanemic subjects.28 We believed this compared deferiprone (75 mg/kg/d) with deferoxamine (50 mg/
was sufficient evidence that significant LV systolic dysfunction was kg/d for 5 d/wk). Deferiprone resulted in a significantly larger
present and that the best current medical treatment should be improvement in SIR and EF. Galia et al52 compared deferiprone (75
offered outside the trial setting. However, normal cardiac vol- mg/kg/d) with deferoxamine (50 mg/kg/d for 6 d/wk). No signifi-
umes and function in thalassemia are not well defined. Compared cant differences between groups were demonstrated in myocardial
with healthy nonanemic subjects, thalassemia patients hearts have SIR or EF. Our current trial differs from these reports in several
larger end-diastolic volumes and increased cardiac output,7,29,30 ways that might explain the efficacy of deferiprone that we found.
which allows for increased perfusion for tissue oxygenation First, the current trial used deferiprone at 100 mg/kg/d. Second,
requirements. In addition, the ejection fraction in thalassemia compliance was high in the current study but was not quantified in
major patients with no iron loading (T2* 20 ms) is higher than in the previous reports and may have been lower. Third, the prior
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BLOOD, 1 MAY 2006 VOLUME 107, NUMBER 9 HEART CHELATION RCT 3743

studies used heart SIR to measure myocardial siderosis, which is 1.0 109/L. One patient experienced one episode of neutropenia,
not an absolute measure and is sensitive to noise, limiting both its which resolved without discontinuing deferiprone. No agranulocy-
reproducibility and interpretation. Fourth, the current trial is tosis was seen. Two deferiprone-treated patients discontinued the
multicenter and not single center. Our results are consistent with study due to increased liver enzymes, which returned to baseline
another randomized controlled trial from Olivieri et al53 that has levels upon interruption of therapy. One deferoxamine-treated
only been published in abstract form; deferiprone (75 mg/kg/d) patient developed arrhythmias and a reduction in EF, though still in
resulted in a significant increase in T2 relaxation time, which was the normal range, and an increase in the LV and atrial diameters and
not matched by deferoxamine (50 mg/kg/d). was withdrawn from the study for initiation of intensive chelation
The patients in the current study were well matched at baseline therapy. Two other deferoxamine-treated patients discontinued the
for the primary end point of myocardial T2*, and they were also study for personal reasons.
well matched for the secondary end point of liver iron. However,
the accuracy of SQUID may vary between machines, and direct Limitations
comparison of absolute liver iron levels with studies relating our
The results of this trial are relevant to patients with no symptoms of
single-center SQUID results to those from other centers may not be
heart failure and who are older than 18 years. Evidence that these
straightforward. Despite these issues, it is worth noting that at
findings apply to symptomatic patients or children awaits trials in
baseline our patients had a median LIC of 4.30 mg/g dw, with only
these specific populations.
8% having an LIC greater than 15 mg/g dw. Therefore, the patients
in the current study would appear to be reasonably well chelated by Conclusions
liver criteria. In the current study, the 1.5 mg/g dw reduction in LIC
over 12 months with deferoxamine was significant, whereas the At the doses used in this prospective trial, deferiprone was superior
0.94 mg/g dw reduction with deferiprone did not achieve signifi- to deferoxamine over 1 year in improving myocardial siderosis in
cance, although the between groups comparison was not signifi- asymptomatic patients with beta-thalassemia major and this con-
cant. This is the first randomized controlled study to compare firms previous retrospective data. This suggests that deferiprone
changes in LIC at the highest dose of deferiprone currently has superior access to myocardial iron stores compared with
approved in Europe (100 mg/kg/d). Deferiprone appeared to deferoxamine, which accords with in vitro data. The combination
prevent liver iron accumulation, even if the mean decrease of detection of myocardial siderosis by T2* CMR and the superior
appeared marginally less effective than deferoxamine. The patients effect of deferiprone in removal of cardiac iron allows a rational
in our study showed a difference at baseline for the secondary end paradigm of early management of cardiac siderosis in patients
point of serum ferritin level. The explanation for this difference is maintained on long-term deferoxamine, and this should translate
the presence of 2 extreme outliers in the deferoxamine-treated into improved survival.
group with very high ferritin levels. After log transformation to
achieve a normal distribution, no difference between groups at
baseline was present. This lack of difference accords with the lack Acknowledgments
of baseline statistical difference in the direct measures of liver or
myocardial iron. After controlling for the baseline serum ferritin This trial is registered in www.clinicaltrials.gov as NCT00105495.
status ( 2500 g/L or 2500 g/L) in a covariate analysis, the We thank Drs David Lee and Yu-Chung Tsang for expert
difference in myocardial T2* at month 12 between the treatment statistical advice on this study and the following doctors for their
groups remained significant (P .032), favoring the deferiprone important contributions. Cagliari: Gildo Matta, Carlo Dessi, Annal-
treatment group, and there was no difference in trend of serum isa Agus, Simona Piras, G. B. Melis, P. Bina; Torino: Filomena
ferritin level over time between treatment groups. Longo, Giulio Lupo; Aghia Sophia Childrens Hospital: Christina
Compliance with deferiprone at 100 mg/kg/d was excellent with Fragodimitri, Fotis Karabatsos, Antonia Hatziliami, Jacqueline
no new drug-related complications compared with previous lower- Youssef, Ekaterini Dokou, Helen Berdoussi, Helen Architek-
dose trials. Contrary to other trials where deferiprone was inter- tonidou, Dimitris Tsoussis; Royal Brompton Hospital: David
rupted at the first sign of neutropenia ( 1.5 109/L), we allowed Firmin, Lisa Anderson. We also thank Prof John Porter for his
continuation of deferiprone if the neutrophil count remained above constructive criticism of the manuscript.

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2006 107: 3738-3744

doi:10.1182/blood-2005-07-2948 originally published online
December 13, 2005

Randomized controlled trial of deferiprone or deferoxamine in

beta-thalassemia major patients with asymptomatic myocardial
siderosis
Dudley J. Pennell, Vasili Berdoukas, Markissia Karagiorga, Vasili Ladis, Antonio Piga, Athanassios
Aessopos, Efstathios D. Gotsis, Mark A. Tanner, Gill C. Smith, Mark A. Westwood, Beatrix Wonke
and Renzo Galanello

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