International Journal of Clinical Medicine, 2011, 2, 224-230
doi:10.4236/ijcm.2011.23037 Published Online July 2011 (http://www.SciRP.org/journal/ijcm)
Management of Oral Iron Chelator Deferasirox for
Transfusion-Dependent Patients with
Hematological Disorders: 2-Year Experience at a
Single Institution in Japan
Michihide Tokuhira, Morihiko Sagawa, Reiko Watanabe, Tomoe Nemoto, Takeshi Tomikawa,
Shigehisa Mori, Masahiro Kizaki
Department of Hematology, Saitama Medical Center, Saitama Medical University, Kawagoe, Japan.
Received February 3rh, 2011; revised March 16th, 2011; accepted April 11th, 2011.
ABSTRACT
Introduction: Deferasirox is an oral iron chelator, approved worldwide for the treatment of chronic iron overload due
to transfusion. Deferasirox was permitted two years ago in Japan, but there is little known regarding its efficacy and
tolerability in clinical practice. Methods: We conducted a retrospective study of 18 patients with transfusion-dependent
anemias treated by deferasirox at our institution. The starting dose was individualized and ranged from 6.4 to 26.3
mg/kg/day. Routine clinical laboratory data were followed, and serum ferritin was assessed every 4 weeks. Results: The
mean serum ferritin level of 18 patients at the time of deferasirox induction was 3162 ng/ml. 10 of 18 patients could
sustain deferasirox treatment for at least 6 months, at an average maintenance dose of 10.8 mg/kg/day. Serum ferritin
reduction was observed in 4 patients, at doses less than 20 mg/kg/day. Eighty-nine percent of the patients had adverse
events and 13 of them in all ultimately discontinued. Myelodysplastic syndrome (MDS) patients showed poor tolerabil-
ity. Severe infections of grade 3 or more were documented in 6 patients, and 2 of them were fatal. Conclusions: The
potential for beneficial iron chelation of deferasirox at less than the recommended 20-mg/kg dose was demonstrated.
On the contrary, poor tolerability was documented, with adverse events such as severe infections, especially in MDS
patients. Although it was not clearly demonstrated that deferasirox was responsible for impaired immunity, careful
watching is required to administrate deferasirox.
Keywords: Omponent, Formatting, Style, Styling, Insert
1. Introduction
Patients with hematological disorders such as myelo-
dysplastic syndrome (MDS) and aplastic anemia (AA)
frequently require ongoing red blood cell (RBC) trans-
fusion support. The frequent transfusions result in iron
overload, leading to increased non-transferrin-bound
iron, which generates toxic oxygen free-radicals and
damage to multiple organs such as skin, liver, heart,
pancreas, and other organs [1-3]. As previous observa-
tions have demonstrated that severe iron overload is
associated with increased morbidity and mortality, iron
chelation therapy is important [4-6]. Deferoxamine
(DFO) is a chelation medication that has been effective
at achieving a negative iron balance when applied to
patients with transfusion-related iron overload [7,8]. On
the other hand, DFO requires intravenous injection or
subcutaneous administration every day, resulting in im-
paired quality of life. By contrast, deferasirox is a
once-daily, oral iron chelator approved for the treatment
of chronic iron overload due to blood transfusions [9-13].
The EPIC (Evaluation of Patients’ Iron Chelation with
Exjade™) study indicated that the overall med ian serum
ferritin level decreased significantly with deferasirox
administration, both in chelation-naïve patients and
those previously receiving chelation treatment [10]. The
current treatment guidelines, based on these clinical
studies and expert consensus, recommends chelation
therapy for transfusion-dependent patients with serum
ferritin levels > 1000 ng/mL, depending on the transfu-
sion rate [14-16]. In Japan, deferasirox was approved

Management of Oral Iron Chelator Deferasirox for Transfusion-Dependent Patients with Hematological Disorders: 225
2-year Experience at a Single Institution in Japan
about two years ago, and data such as efficacy and tol-
erability have accumulated; however, there have been
few publications regarding its use in clinical practice. In
this retrospective study, we share our 2-year experience
of deferasirox regarding clinical outcomes including
advers e ev en ts (A Es ).
2. Methods
Deferasirox was given to 18 hematological disorder pa-
tients with serum ferritin levels of >1000 ng/mL due to
frequent RBC transfusion. The starting dose was indi-
vidualized according to blood transfusion frequency or
age. Routine clinical laboratory data regarding CBC,
liver, renal, and other functions were followed, and se-
rum ferritin was assessed every 4 weeks. Efficacy was
evaluated as a change in the serum ferritin level and
clinical indicators (frequency of transfusion, skin pig-
mentation, liver function, cardiac function, glycoalbu-
min, etc., according to the organ damage in each patient).
Safety was evaluated by monitoring of laboratory data
and a medical physical exam. Dose adjustment was per-
formed according to the physician’s discretion based on
each patient’s clinical indicators. In the present study,
there were no patients in whom the serum ferritin values
fell to less than 500 ng/mL during the clinical course.
All patients had received previous DFO administra-
tion for iron chelation, but had not experienced success
with it. In Japan, subcutaneous DFO injection is not
permitted, and it is difficult to use intravenous infection
every day for chelation. Instead, the patients in this
study were given DFO in every transfusion, but the cu-
mulative effect of the transfusions had outweighed its
effect, resulting in gradually increased serum ferritin.
AEs were graded according to the National Cancer In-
stitute Common Toxicity Criteria (version 3). The inter-
action between total RBC transfusion units and serum
ferritin level in all patients was calculated by the Pear-
son product-moment correlation coefficient using JMP
software (Tokyo, Japan). The data of basal serum ferritin
was collected just before deferasirox induction. Changes
in serum ferritin levels and overall clinical improvement
were analyzed in the 10 patients who could sustain de-
ferasirox administration for at least 6 months.
3. Results
3.1. Patient Characteristics
Data from 18 patients who received deferasirox at our
institution were collected (Table 1). The sex ratio was
11:7 (male:female), and the median age at deferasirox
initiation was 67 years (range: 44 - 82 years). The un-
derlying diseases in patients were MDS (n = 10), AA (n
= 4), myeloproliferative neoplasm (MPN; n = 3) and
pure red cell aplasia (n = 1). The subtypes of MDS were
refractory anemia (RA; n = 5), refractory anemia with
excess blast (RAEB; n = 4), and refractory anemia with
ring sideroblasts (RARS; n = 1). The median duration
from diagnosis to deferasirox induction was 3.9 years
(range: 0.7 - 17.7 years). The average total RBC transfu-
sion already received before deferasirox initiation was
Table 1. Patients’ characteristics.
No Age Sex Diagnosis*1 Disease duratiion
(years)*2
Total
T/F dose
(Units)*3
Serum Ferritin
(ng/dl)*4
T/F
require-
ment*5 Complication*6
1 74 Female AA 3.4 170 6425 5 Skin, Herat
2 79 Female MDS(RA) 1.7 84 1806 4 Skin
3 65 Female MDS(RA) 2 60 1105 5 -
4 61 Male MDS(RARS) 5.6 146 4838 6 -
5 61 Female AA 0.7 66 1811 8 -
6 44 Male MDS(RA) 2 18 1247 2 -
7 82 Female MPN 4 191 6693 6 -
8 61 Male MDS(RAEB) 5.1 130 2561 9 Skin, Herat
9 69 Male AA 10.5 160 9423 6 Skin, Herat, DM, Liver
10 67 Male MPN 2.2 180 1440 14 Skin
11 67 Female AA 2.2 132 2327 4 Skin
12 67 Female MDS(RA) 3.4 102 2645 4 -
13 72 Male MDS(RAEB) 1 44 1265 7 -
14 71 Male PRCA 2.8 84 3980 6 -
15 63 Male MPN 17.7 206 1563 4 -
16 69 Male MDS(RAEB) 3.3 132 3328 6 -
17 75 Male MDS(RAEB) 1.8 116 2612 8 -
18 60 Male MDS(RA) 1 20 1851 6 -
Mean 67 3.9 113.8 3162 6.1
*1. AA, aplastic anemia; MDS, myelodysplastic syndrome; RA, refractory an emia; RARS, refracto ry anemia with ring sideroblas ts; MPN, myeloproliferative
neoplasm; RAEB, r ef ract or y ane mia wi th exces s blas ts ; PRCA, pu re red cell apl asi a. *2 . Dur ation from di agno sis t o th e time of d eferasirox induction. *3. Total
recieving RBC dose until deferasirox.

Management of Oral Iron Chelator Deferasirox for Transfusion-Dependent Patients with Hematological Disorders:
226 2-year Experience at a Single Institution in Japan
113.8 units (range: 18 - 206 units). The average serum
ferritin level was 3162 ng/ml (range: 1105 - 9423). The
average number of units of RBC transfusion per month
was 6.1 (range: 2 - 14). The complications assumedly
due to transfusion-induced iron overload were skin pig-
mentation (n = 1), skin pigmentation and heart failure (n
= 2), and skin pigmentation, heart failure, diabetes mel-
litus and liver dysfunction (n = 1). Statistical analysis
revealed a positive relationship between RBC total
transfusion units and serum ferritin level in 18 patients
(r = 0.85 in Figure 1).
3.2 Deferasirox Administration
The initial and maintenance doses, as well as any dose
modifications, were determined according to the physi-
cian's discretion, considering renal function, frequency
of transfusion, and serum ferritin level. The details of
deferasirox administration in each patient are shown in
Table 2. Th e av erag e in itiated d eferasirox do se was 11 .8
mg/kg (range: 6.4 - 26.3). The median duration of de-
ferasirox usage was 10.8 months (range: 0.2 - 24.5).
There were 10 patients who sustained treatment for over
6 months; in this group, the average maintenance dose
was 10.8 mg/kg/day (range; 6.4 - 17.9). Thirteen of 18
patients finally ceased deferasirox administration, and 5
patients were still receiving deferasirox at the latest ob-
served time point. The changes of serum ferritin in the
10 patients who could continue at least 6 months are
Figure 1. Relationship between total transfusi on and serum
ferritin level at start of deferasirox. A significant correla-
tion between total transfusion units and serum ferritin level
was demonstrated (r = 0.85).
displayed in Figure 2. Serum ferritin reduction more
than 1000 ng/ml was achieved in 4 patients, and 2 pa-
tients had decreases over 3000 ng/ml. Only 1 patient
showed a marked increase in serum ferritin levels after
deferasirox administration; the serum ferritin level in the
other 3 patients was stable. The reasons for discontinua-
tion were infection (n = 6), skin rash (n = 3), nausea (n
= 2), thrombocytopenia (n = 1), and fatigue with dry
mouth (n = 1), respectively (Table 2). Sixteen of 18
Table 2. Clinical course.
No Initial dose
(mg/Kg)
Duration*1
(Month)
Maintenance
dose *2
(mg/Kg) Continuation Reason of
Discontinuation*3
(grade)
Other Adverse
Events (grade) Outcome Clinical Improvements*4
1 12.8 14.2 12.8 - Infection (4) - Dead T/F requirement, Skin
2 11.4 0.2 - - Skin Rash (2) - Alive -
3 10.2 1.6 - - Infection (3) - Alive -
4 9.1 1.7 - - Fatigue (2) Dry Mouth (2) Dead -
5 9.6 11.2 9.6 - Nausea (2) - Alive -
6 6.7 0.7 - - Skin Rash (2) - Alive -
7 9.9 11.7 9.9 - Nausea (2) - Alive -
8 8.9 0.8 - - Skin Rash (2) - Dead -
9 17.9 24.5 17.9 + - Diarrhea(2), Renal
dysfunction (2) Alive Skin, Heart, DM, Liver
10 20.4 3.8 - - Infection (4) - Dead -
11 18.2 24.3 9.1 + - Renal
Dysfunction(2) Alive Skin
12 26.3 23.2 13.2 + - - Alive Skin
13 9.6 7.8 9.6 - Infection (5) - Dead -
14 7.7 2.1 - - Thrombocytopenia (2) - Alive -
15 8.6 17.8 8.6 + - Renal Dysfunction(2) Alive -
16 10.6 4.7 - - Infection (4) - Dead -
17 8.1 11.3 10.6 - Infection (5) - Dead -
18 6.4 7.2 6.4 + - - Alive -
*1. Duration of deferasirox administration. *2. Indicated the data of patients with recieving deferasirox over 6 months. *3. According to NCNI version 3. *4. At
the time of the final confirme d date. T/F, transfusion; s kin, Skin pigmentation; Herat, chronic hear failure; DM, diabetes mellitus; Liver, liver dysfuncti on.

Management of Oral Iron Chelator Deferasirox for Transfusion-Dependent Patients with Hematological Disorders: 227
2-year Experience at a Single Institution in Japan
Figure 2. Change of serum ferritin level under deferasirox
administration. Changes of serum ferritin in 10 patients
who could sustain at least 6 months of treatment are dis-
played. The solid line shows the 5 - 10 mg/kg administration
group (n = 7); dotted line, 11 - 15 mg/kg (n = 2), and bold
dotted line, 16 - 20 mg/kg (n = 1). Serum ferritin reduction
more than 1000 ng/ml was found in 4 patients, and 2 pa-
tients had over 3000 ng/ml decrease (patient 7 and 9). Only
one patient showed serum ferritin elevation under defera-
sirox administration (patient 16). pt, patient.
patients (89%) had AEs; all events other than infections
were less than grade 3. All infections that appeared in 6
patients were grade 3 or higher. Four of 6 patients were
MDS (3 was RAEB, and 1 was RA). Renal dysfunction
developed in 3 patients, two of whom were simultane-
ously receiving cyclosporin A (CyA). Improvement of
renal dysfunction was observed in these after withdrawal
of CyA.
Clinical benefits were documented in 4 patients. Pa-
tient 1 showed both reduction of transfusion frequency
and improvement of skin pigmentation, and 2 patients
(patient 11 and 12) showed improvement of skin pig-
mentation. Patient 9 showed improvement of skin pig-
mentation, chronic heart failure, diabetes mellitus, and
liver dysfunction, as described later. All 4 took defera-
sirox for at least 6 months. Although dose escalation was
attempted in 5 patients, 4 of these attempts failed be-
cause of AEs such as diarrhea, appetite loss, and renal
dysfunction (data not shown).
3.3. Case Presentation
Figure 3 shows a remarkably treatment-responsive
69-year-old male patient with AA, having skin pigmen-
serum glycoalbumin, cardiac function, and skin pig-
Figure 3. Case presentation. A 69-year-old male patient with severe-type AA, having skin pigmentation, diabetes mellitus,
liver dysfunction and chronic heart failure due to iron overload was administered deferasirox. The serum ferritin level at the
induction of deferasirox was 9423 ng/ml. The administration of deferasirox had remarkably beneficial effects such as the
improvement of liver function, serum glycoalbumin, cardiac function, and skin pigmentation in addition to decreasing the
serum ferritin level to 2231 ng/ml. Attempts to escalate the dose of deferasirox failed due to diarrhea, resulting in a 1000-mg
maintenance dose. The solid line shows the change of serum ferritin, and the dotted line shows the change hemoglobin (Hb).
AST, aspartate aminotransferase; ALT, alanine aminotransferase; CRTNN, creatinine; CTR, cardio-thoracic ratio.

Management of Oral Iron Chelator Deferasirox for Transfusion-Dependent Patients with Hematological Disorders:
228 2-year Experience at a Single Institution in Japan
mentation in addition to decreasing the serum ferritin
level to 2231 ng/ml. Dose escalation was attempted two
times, but 1250 or 1500 mg/day administration failed,
tation, diabetes mellitus, liver dysfunction and chronic
heart failure due to iron overload. His serum ferritin
level at the induction of deferasirox was 9423 ng/ml, and
the administration of deferasirox had numerous benefi-
cial effects such as the improvement of liver function,
and the maintenance dose was defined as 1000 mg (17.9
mg/kg). Though the frequency of transfusion was not
changed, the hemoglobin was gradually elevated from
its baseline value, showing the effectiveness of defera-
sirox. CyA was not effective and renal impairment was
found, so that CyA had to be eventually stopped. Liver
dysfunction, renal impairment, and diabetes mellitus
were improved as indicated in Figure 3. Although he
had a chronic heart failure leading to a wide cardio-
thoracic ratio (CTR), deferasirox administration seemed
to ameliorate the CTR, from 57% to 43%.
4. Discussion
Deferasirox, a once-daily oral iron chelator, has been
demonstrated in various studies worldwide involving
large numbers of patients with a variety of transfu-
sion-dependent anemias, with similar efficacy to DFO at
comparable doses. A phase I and extended study in Ja-
pan was developed with similar potential efficacy and
safety as those seen in several western clinical trials [17].
However, there have been few publications regarding
the outcome of its usage in clinical practice in Japan. To
discuss this point, we collected and analyzed data from
18 patients who have been treated with deferasirox at
our institution.
In this retrospective study, there were several impor-
tant findings regarding the usage of deferasirox in clini-
cal practice. First, this study showed that lower doses
(<20 mg/kg) had some extent of clinical efficacy. Pre-
vious clinical trials have clearly demonstrated the
dose-dependent iron-chelation effects of deferasirox
administration, and have implied that at least 20 mg/kg
is required for efficacy [18]. It was hard to evaluate this
effect because there were no patients in the present study
who could tolerate a dose greater than 20mg/kg; how-
ever, 4 patients who received a dose lower than 20mg/kg
showed decreased serum ferritin levels. In particular, the
ferritin reductions in 2 patients (patient 7 and 9, receiv-
ing 9.9 mg/kg and 17.9 mg/kg, respectively) were more
than 3000 ng/ml as shown in Figure 2. Considering that
these patients receive 6 units of RBC transfusion per
month, deferasirox achieved sustained iron chelation
even at lower-than-recommended doses. The clinical
course of the latter patient was remarkable (Figure 3),
showing improvement of multiple organs with iron che-
lation, and 7000 ng/dl serum ferritin reduction.
Second, the maintenance dose of deferasirox in 10 pa-
tients who sustained at least 6 months of treatment was
10.8 mg/kg on averag e, less than those of the previously
reported clinical studies. The 1-year EPI C study enrolled
1744 patients with transfusion-dependent anemias, of
whom 79.6% completed 1 year of treatment; over 90%
of these took doses more than 20 mg/kg [19]. In this
study, we tried with 4 patients to escalate the deferasirox
dose over 20 mg/kg, but these escalations failed due to
AEs; for some reason, it was difficult to maintain the
recommenced deferasirox dose in this study. The phase I
clinical study of deferasirox on Japanese patients with
transfusion-dependent anemias indicated that the phar-
macokinetics–dose relationship was similar in Japanese
and Caucasians [17]; hence, this phenomenon was not
likely due to race.
Third, the discontinuation rate (72%: 13 of 18 patients)
was higher than those of previous studies. For instance,
the phase I and extended study in Japan had a discon-
tinuation rate of only 19% (4 of 21 patients) [17]. To
understand this discrepancy, it is important to focus on
the underlying disease. The EPIC study demonstrated
that the incidence of AEs and discontinuation in MDS
patient groups was higher than those in other anemia
patient groups [19], and this study included 10 MDS
patients (55 %), of whom 8 ultimately discontinued the
medication because of AEs. In addition, with regard to
subtypes of MDS, 2 of 5 MDS-RA patients could sustain
deferasirox administration at the time of writing, and
improvement of skin pigmentation and the reduction of
serum ferritin was observed in patient 12; however, all 4
MDS-RAEB patients interrupted the medication because
of AEs. Moreover, 3 of them developed severe infec-
tions, resulting in fatality in 2 patients. Our data con-
firmed current consensus-driven guidelines in deferasi-
rox usage, recommending deferasirox usage for low-risk
MDS patients, not fo r high-risk g roups su ch as RAEB or
leukemic patients [20]. Meanwhile, it was surprising that
the leading AE type in this study was infection, and that
all of them were severe, i.e., grade 3 or more. It has been
suggested that iron chelation therapies enhance immu-
nity against infections, based on the fact that iron over-
load promotes free radical tissue damage and organ fail-
ure, undermines immune protection and facilitates
pathogen invasion [21]. On the contrary, DFO, an iron
chelator, is also a siderophore, which binds iron and
transports it into microorganisms to help maintain their
activity and grow, and thus exacerbates infections in
various immunosuppressive settings [22]. Indeed, 46 of
59 dialysis patients who received DFO developed mu-

Management of Oral Iron Chelator Deferasirox for Transfusion-Dependent Patients with Hematological Disorders: 229
2-year Experience at a Single Institution in Japan
cormycosis [23]. Of 1774 patients receiving deferasirox
in the EPIC study, serious pyrexia (n = 51; 2.9%),
pneumonia (n = 23; 1.3%), and sepsis (n = 20; 1.1%)
were observed [17]. Furthermore, 26 deaths occurred in
341 MDS patients including 3 cases of septic shock [18].
Although deferasirox is not a siderophore so it is not
clear-cut whether deferasirox might impair immunity
against bacteria and fungus as DFO does, the results of
the present study cannot rule out the possibility that de-
ferasirox impairs immunity, given the fact that 2 non-
MDS anemias developed (patient 1-AA and patient
9-MPN). Further clinical investigation and analysis of
this issue will be required.
In summary, the potential for beneficial iron chelation
of deferasirox was demonstrated in patients receiving
less than recommended 20-mg/kg dose in clinical prac-
tice. On the other hand, deferasirox did not show clinical
efficacy in high-risk MDS such as RAEB, as in other
recent clinical studies. Poor tolerability was indicated by
AEs, especially infections, 2 of which became fatal.
Considering the fact that 2 non-MDS patients developed
severe infection in this study, the possibility of defera-
sirox-mediated impaired immunity cannot be ruled out.
As this was a small study, further investigations in
clinical practice are very important to analyze strategies
focusing on the real efficacy of deferasirox among
transfusion-dependent anemia patients, including ways
of addressing the infection issue.
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2-year Experience at a Single Institution in Japan
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