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Clinical Medicine: Therapeutics
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Management of Transfusional Chronic Iron Overload:
Focus on Deferasirox
Federica Pilo, Anna Angela Di Tucci, Laura Dessì and Emanuele Angelucci
Struttura Complessa di Ematologia e Centro Trapianti di Cellule Staminali Emopoietiche, Dipartimento di Oncologia
Medica. Ospedale Oncologico di Riferimento Regionale “Armando Businco”, Cagliari, Italy. Email: [email protected]
Abstract: Most patients with hereditary or chronic acquired anemias are dependent on regular red cell transfusions. Untreated iron
overload from transfusions is responsible for morbidity and mortality in patients with thalassemia major. However, clinical consequences
of parenchymal iron overload have been reported not only in thalassemia major but also in patients with myelodysplastic syndrome. The
current standard in iron chelation therapy is deferoxamine mesylate (Desferal®). Deferasirox is the first oral iron chelator approved in
the Europe Union for use in patients with transfusional iron overload with different diseases.The aim of this review is to examine the
properties and management of Deferasirox.
Keywords: review, iron chelation, thalassemia, MDS deferasirox
Clinical Medicine: Therapeutics 2009:1 735–745
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Clinical Medicine: Therapeutics 2009:1
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Pilo et al
Introduction to Iron Overload
Many patients with hereditary or chronic acquired
anemias are dependent on regular red cell transfusions.
Examples of such hereditary anemias include
β-thalassemia major, sickle cell disease, Diamond
Blackfan and Fanconi’s anemia;1,2 of acquired anemias
myelodysplastic syndromes (MDS), aplastic anemia
and primary myelofibrosis.
Iron loss by the human body is minimal; we are
the only species that has difficulties in maintaining
iron balance and, as a consequence, repeated blood
transfusions lead to iron overload.1,3
Untreated iron overload from transfusion is
responsible for morbidity and mortality in patients
with thalassemia major.4,5 Clinical consequences have
also been reported in acquired chronic anemias
requiring regular transfusions.6
Each blood unit contains 200–250 mg of iron.7 If
left untreated, iron accumulates in the liver, heart,
anterior pituitary, pancreas and joints leading to organ
dysfunction and early death.1 Iron overload became
detectable in the liver after approximately 20 Packed
Red Blood Cell (PRBC)8 transfusions leading to
ferritin levels of about 1,000 mg/L.
In patients with β-thalassemia major, transfusional
chronic iron overload complications, most frequently
associated with mortality, are those related to
myocardial dysfunction. Other common complications
include hepatic fibrosis,9 liver cirrhosis, diabetes
mellitus, osteoporosis and impaired growth and
development in children.2,3,10
During recent years methodologies to assess iron
overload have progressed with new technologies.
Today with direct (hepatic iron concentration on
biopsy species) or indirect measurements (serum
ferritin, transferrin saturation and magnetic imagine
resonance-MRI) adequate and quantitative evaluation
of body iron can be obtained. Particularly MRI T2*
and MRI R2,11 are validated as non-invasive methods
to assess cardiac and hepatic iron, respectively. The
Italian society of Hematology has recently extensively
reviewed methodology to assess iron overload.12,13
The majority of clinical research regarding
iron overload has been conducted in patients with
β- thalassemia major and limited data is available for
other patient populations.10
However, clinical consequences of parenchymal
iron overload have been reported not only in thalassemia
736
major but also in patients with myelodysplastic
syndrome. For the management of MDS patients
blood transfusions represent the main component of
supportive care. Ninety percent of all MDS patients
with permanent anemia become dependent on blood
transfusions to maintain their quality of life and to
survive. Therefore they are likely to develop iron
overload, proportionally to the duration and intensity
of transfusion dependency.13
Introduction to Deferasirox
The current standard in iron chelation therapy is
deferoxamine mesylate (Desferal®).12 Long-term data
collected since the drug was introduced in the early
1970s has demonstrated its safety and high efficacy in
reducing stored iron and related complications, thus
resulting in decreased mortality in iron-overloaded
thalassemia subjects.14
Unfortunately, deferoxamine has a short plasma
half-life and an insufficient oral bioavailability. These
features require an intravenous or subcutaneous
application of the drug over a period of 8 to 12 hours,
usually five to seven times a week. Alternatively,
deferoxamine can be administered as a subcutaneous
bolus injection with a markedly reduced efficacy.15
As a consequence of the cumbersome administration,
the compliance of the deferoxamine therapy is often
poor, resulting in limited efficacy. In MDS patients
the association with severe thrombocytopenia
and neutropenia further limits the applicability of
deferoxamine.
The first oral iron chelator Deferiprone (Ferriprox®)
was introduced 20 years ago. The use of the drug
remained limited to second-line therapy for patients
with thalassemia major. The risk of neutropenia
and agranulocytosis, with a frequency of about
0.5%–1% in thalassemia were the major limiting
factors.16–18 Recently a specific chelator effect on
myocardial iron has been reported from retrospective
analysis with a relevant decrease of cardiac deaths in
thalassemia.19 Sporadic effects has been reported in
MDS. Deferiprone is currently not licensed to MDS
patients.
Deferasirox (Exjade®), an orally administered once
daily iron chelator was first approved in the United
States in 2005 and in the European Union in 2006.
(Table 1 reports characteristics of the three chelators
available today). The aim of this review is examine
Clinical Medicine: Therapeutics 2009:1
Iron chelation with deferasirox
Table 1. Reports characteristic of the three chelators today available.
Property
Deferoxamine mesilate
Deferiprone
Deferasirox
Usual dose (mg/Kg/day)
25–60
75
20–30
Route
Subcutaneous intravenous
8–12 h, 5 days/week
Oral 3 times daily
Oral once daily
Half-life
20–30 minutes
3–4 hours
12–16 hours
Excretion
Urinary, fecal
Urinary
Fecal
Adverse effects
Local reactions,
ophthalmologic, auditory,
growth retardation, allergic
Gastrointestinal disturbance,
Agranulocytosis/neutropenia,
Arthralgia
Gastrointestinal disturbance,
rash, mild non progressive
creatinine increase,
ophthalmologic, auditory
Status
Licensed
Licensed outside US/Canada
Licensed
the proprieties and management relating to the use of
Deferasirox.
Pharmacodynamic Properties
Deferasirox is a tridentate iron chelator (Fig. 1), with
a higher affinity for iron as Fe3+ than Fe2+ and minimal
affinity for other divalent metal ions such as zinc or
copper.20
The active molecule is a highly lipofilic, 99%
protein-bound, N-substituted bis-hydroxypheniltriazole.21,22 Two molecules are required to form a
stable complex with each iron atom (Fe3+) because
three polar interactions sites in the binding pocket
results in Deferasirox binding with iron in a 2:1 ratio.
Orally administered Deferasirox, dispersed in
water, orange or apple juice, has an absolute bioavailability of 70%. Presence of food increases the
Deferasirox bioavailability to a variable extent. To ensure
appropriate systemic exposure Deferasirox should be
taken 30 minutes before food. Serum concentration is
proportional to the dose administered.23
Pharmacokinetic data recommend Deferasirox
dosage of 20 mg/kg/day. Deferasirox reaches
maximum plasma concentration (C max) at a median
Figure 1. Deferasirox is an orally active tridentate iron chelator with 3 polar interaction sites in the binding pocket.
Clinical Medicine: Therapeutics 2009:1
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Pilo et al
time of 1–2 hours after repeated administration
of 10 or 20 mg/Kg/day. Median time to C max was
independent of dose.24
The main pathway of Deferasirox metabolism
is hepatic predominantly by glucoronidation with
biliary excretion. Deferasirox is mainly excreted in
the feces (83%), predominantly as the unchanged
drug.25,26 A small proportion (6%–8%) of unchanged
Deferasirox and metabolites is excreted in urine25,27,28
with phenol glucuronide as main metabolite.26
As the iron–Deferasirox complex has a mean
elimination half-life of 17.2 hours after a single dose
of Deferasirox 20 mg/kg plasma levels are maintained
within the therapeutic range over a 24 hours,
therefore providing 24 hours chelation coverage and
protection from toxic labile iron with a once daily
administration.
The pharmacodynamic properties of Deferasirox
in patients with transfusional iron overload has been
evaluated using three key parameters (1: iron balance
2: myocardial iron levels, 3: labile plasma iron).
Iron balance (iron excretion: iron intake)
The effect of oral deferasirox on iron balance
in patients with β-thalassemia and transfusional
chronic iron overload has been examined in
phase II e III trials. These results indicate that deferasirox
dosages 20 mg/kg/day are unlikely to maintain net
iron balance or achieve net iron excretion29 in patients
receiving 2 packed red blood cells units/month. At
a deferasirox dose of 20 mg/kg per day, neutral iron
balance was achieved in 46% of patients with highest
transfusional iron intake and negative iron balance
in 75% of patients with lowest transfusional iron
intake; 30 mg/kg per day produced successful control
of iron stores in 96% of patients with a low rate of
transfusional iron intake.30
This data has been obtained using serum ferritin
and hepatic iron concentration as quantitative markers
of iron overload (see efficacy studies discussed
below).
Myocardial iron levels
Myocardial iron levels are estimated by calculating the
T2* phase using MRI (T2*  20 msec is considered
normal, 8–20 msec indicates moderate iron overload,
8 indicates severe myocardial iron overload).31,32
In vitro33 and in vivo34 preclinical data indicate that
738
Deferasirox has the capacity to enter and chelate iron
from myocardial cells.
One study in a gerbil model of iron overload found
that daily separated doses of Deferasirox reduced
cardiac iron more effectively than once-daily dosing,
although the difference between dosing regimens
was not statistically significant. Variation in the
pharmacokinetics of Deferasirox between humans
and gerbils could explain the differences between the
dosing regimens in human iron overload.35 In a study
of 29 patients who received Deferasirox in two pivotal
studies as described earlier36,37 the T2* magnetic
resonance imaging showed a significant reduction in
cardiac iron burden after 12 months of Deferasirox
treatment, which was maintained after 2 years.38
Preliminary clinical data reported that myocardial
iron levels were significantly reduced after Deferasirox
treatment in patients with transfusional chronic
iron overload.38 T2* mean improvement of 18.0 ms
to 23.1 ms.39 Data from a prospective, single-arm,
multicenter trial in patients with β-thalassemia also
show that after 6 months of Deferasirox treatment
patients experienced significant improvements in
cardiac T2*, liver iron concentration (LIC) and labile
plasma iron.40 These results show that in 93% of the
patients, Deferasirox achieved a negative cardiac and
liver iron balance.
Labile plasma iron (LPI)
LPI and non transferrin bound iron (NTBI) are
the effectors of iron related tissue damage by
OH− formation, lipid degradation and intracellular
damage.41
Labile plasma iron can be transported intracellularly
and lead to excessive storage of iron42 so it can be used
as an indicator of iron overload and its changes can be
used to assess effectiveness of chelation therapy. In
patients with β-thalassemia and transfusional chronic
iron overload who were treated with Deferasirox
20–30 mg/kg/day LPI was significantly reduced.43
Of relevance Deferasirox pharmacokinetic provides
efficient 24-hours/day protections from LPI and
NTBI. However so far LPI and NTBI are experimental
measurements to be validated and diffused.
Efficacy Studies
The efficacy of oral Deferasirox in patients with
transfusional chronic iron overload was evaluated
Clinical Medicine: Therapeutics 2009:1
Iron chelation with deferasirox
in three randomized, open-label, multicenter trials
comparing oral Deferasirox with subcutaneous
Deferoxamine36,44,45 and two non comparative
multicenter trials.29,46 The major of these trials
enrolled pediatric and young adults patients with
β-thalassemia major.29,36,44 The primary efficacy
endpoint was the success of deferasirox in reducing
or maintaining liver iron concentration which has
been demonstrated to be proportional to body iron
store,36,47 and serum ferritin level.29,44,45 Secondary
endpoints included safety and tolerability. Cappellini
et al in their phase III study evaluated the efficacy
of Deferasirox in regularly transfused patients with
β-thalassemia. They confirmed that in β-thalassemia
patients, receiving 2 to 4 PRBCs per month, oral
Deferasirox at a once-daily dose of 20 mg/Kg
maintained or decreased liver iron concentration, to
neutral iron balance and serum ferritin levels. Changes
in LIC were dependent on the Deferasirox dose
and amount of transfusional iron intake. In patients
with baseline LIC  7 mg iron/g dry weight (dw),
Deferasirox initiated at a dose of 20 or 30 mg/kg/day
produced statistically significant decreases in LIC.
No reduction was seen in those with a baseline
LIC  7 mg Fe/g dw who received Deferasirox
5–10 mg/Kg/day. Doses 5–10 mg/Kg were too low
to balance iron overload through transfusion in those
patients. Similar observation have been found in
other prospective non comparative trials evaluating
the efficacy of Deferasirox in regularly transfused
patients with myelodysplastic syndromes, Diamond
Blackfan anemia, β-thalassemia major and other rare
anemias.37 A dose of Deferasirox 10 mg/Kg was able
to maintain neutral iron balance in patients receiving
not more than 2 PRBCs transfusions per month.36
Extension and on Going Trials
In the subsequent ongoing 4-year extension trials,
dose adjustments were permitted to enable patients
to achieve their treatment goal. To date, patients
have been receiving treatment for a median period
of 3.4 years (range 0–4.5). Mean dose in the
5–10 mg/kg/day group increased in the extension
trials reaching around 20–25 mg/kg/day after
approximately 2 years of treatment.48 Mean dose
in the 20 mg/kg/day group has remained at around
20–25 mg/kg/day during the entire treatment period,
while those in the 30 mg/day group decreased to
Clinical Medicine: Therapeutics 2009:1
around 25 mg/kg after approximately 18 months.
Median serum ferritin levels in the lower dosage
group (5–10 mg/Kg/day) steadily increased during the
first 18 months of Deferasirox treatment. However,
subsequent dose increases during the extension trials
generally resulted in serum ferritin level decreasing
to below baseline at around 32 months and for the
remainder of the study. Deferasirox treatment in this
subgroup was generally well tolerated (including
doses 30 mg/Kg/day) with a low discontinuation
rate. In the 20-mg/kg/day group, median serum ferritin
levels were maintained throughout the treatment
period and following, serum ferritin levels decreased
overall from baseline to month 42. Overall, this data
has shown that patients can achieve a therapeutic goal
of maintenance or reduction in serum ferritin levels
with appropriate dose adjustments.
A large 1-year, multicenter, open-label study aiming
to enroll 1541 patients with various transfusion-related
anemias is currently ongoing to evaluate the efficacy
and safety of Deferasirox.49 The study is evaluating
the efficacy and safety of Deferasirox when initial
dose is based on transfusion history with subsequent
dose titration based on efficacy and safety markers.
Baseline data from a subgroup of MDS patients
enrolled in this study indicated significant iron burden
above thresholds associated with increased morbidity
and mortality. For the previously chelated patients
with Deferoxamine, this indicates that their treatment
regimen was not providing adequate management
of their iron burden, while for the chelation-naïve
patients this data clearly indicated a need for chelation
therapy.
A GIMEMA (Gruppo Italiano Malattie
Ematologiche dell’adulto) open label multicenter
study for valuation safety, tolerability and efficacy of
deferasirox in patients with myelodysplastic syndrome
and transfusionally chronic iron overload, is ongoing
in Italy. (www.clinicaltrials.gov NCT 00469560).
Safety and Tolerability
Evaluation of the safety and tolerability of Deferasirox
has been a key objective of all pivotal clinical trials.
Adverse events and serious adverse events have
been carefully monitored throughout the programme
and continue to be assessed in the extension phases.
The clinical programme has shown that Deferasirox
has a well-defined safety profile that is clinically
739
Pilo et al
manageable with regular monitoring both in adult and
pediatric patients.36,45
Of the more than 1000 patients enrolled in core
clinical studies, only 74 have discontinued treatment
due to adverse events.29,44,45 The most frequent
adverse events reported over a median 3.5 years
of treatment included transient, mild-to-moderate
gastrointestinal disturbances (nausea, vomiting,
abdominal pain, constipation and diarrhea) and skin
rash. Sporadic severe gastrointestinal disturbances
were described (gastrointestinal bleeding and
ulcers).
Most adverse events experienced by patients during
treatment with Deferasirox resolved spontaneously;
adverse events requiring dosage adjustments or
interruptions included rash, gastrointestinal disorders,
infections and elevated serum creatinine and
transaminase levels. Mild, non-progressive increases
in serum creatinine was observed in approximately
one-third of patients in the pivotal clinical trials of
Deferasirox. Creatinine levels returned spontaneously
to baseline in more than two-thirds of patients who
experienced these mild increases. There were no cases
of moderate-to-severe renal insufficiency or renal
failure, and no patients permanently discontinued
therapy due to creatinine rises. Data from up to 3.5 years
of treatment in 1034 patients50 confirmed that these
increases are non progressive. The majority of this
data emerged from studies regarding β-thalassemic
patients. Information about safety and tolerability of
Deferasirox in patients affected by other anemias is
scarce and further study in this area is needed. In fact
this cohort of patients differs from the thalassemics
for age and comorbidities. In particular in the Porter
et al study, only 29 of 47 myelodysplastic patients
completed the trial. The ongoing prospective open
label GIMEMA study, will better evaluate the profile
of safety and tolerability in this population.
Table 2 reports Deferasirox most common (4%)
adverse events registered during 3.5 years of treatment.
Table 3 reports Deferasirox-associated gastrointestinal adverse events and proposed management
approaches.
Post Marketing Surveillance
Post marketing experience in a large number of
patients has provided additional data that further
support the safety profile of Deferasirox in adults and
740
Table 2. Most common (4%) drug-related adverse events
during 3.5 years of Deferasirox treatment.
Adverse event
Frequency (%)
Nausea
10.3
Diarrhea
8.9
Vomiting
6.2
Abdominal pain
5.2
Rash
5.2
Upper abdominal pain
5.0
children with a range of underlying anemias. Cases of
acute renal failure have been reported following the
postmarketing use of Deferasirox.51
Other factors to explain renal failure were apparent
in most of these cases, such as preexisting renal
conditions, advanced age, comorbidity conditions,
or concomitant medication that may depress renal
function.52 Neutropenia and thrombocytopenia have
also been reported. However, most of these patients
had preexisting hematologic disorders that are
frequently associated with bone marrow failure and
the relationship of these episodes to treatment with
Deferasirox is uncertain and did not lead to label
modification.52
Product information for Deferasirox includes
monitoring serum creatinine levels in patients who
have preexisting renal conditions, are elderly, have
comorbid conditions that may affect renal function,
or are receiving medicinal products that depress
renal function. Blood counts and liver function
should also be monitored regularly. Most patients
receiving Deferasirox had normal levels of serum
alanine transaminase, although increased levels
were reported and sporadic acute hepatic failure,
sometimes fatal, occur especially in patient with a
previous cirrhosis.36,44
Deferasirox Indication, Dosage,
Monitoring
The Italian Society of Hematology guidelines for the
management of iron overload in thalassemia major
and related disorders recommended Deferasirox
(in patients without severe iron overload) as the
alternative therapy to Deferoxamina on the basis of
its better safety profile compared with Deferiprone,
which should be considered in the case of resistance or
Clinical Medicine: Therapeutics 2009:1
Iron chelation with deferasirox
intolerance to Deferasirox.12 Preliminary results from
ongoing trials will probably lead to a larger and earlier
indication. Recommendation for deferasirox dosage
and patients monitoring in the United States or the
European Union indicate a Deferasirox initial dosage
of 20 mg/Kg/day. Deferasirox dose adjustment should
depend on patient response, serum ferritin trends, goal
of therapy and serum creatinin levels (Deferasirox
doses adjustment is recommended to be performed
in steps of 5–10 mg/kg/day every 3–6 month).25,27
The drug is contraindicated in patients with creatinin
clearance 60 ml/min and it isn’t recommended for
patients with severe hepatic impairment as it has not
been investigated in those patient populations.
Table 4 reported recommendation for patients
monitoring.
Myelodysplastic Syndrome
and Iron Overload
Patients with MDS are usually adult—elderly patient
and have a range of age related comorbidities. They are
a completely different clinical scenario in contrast to
patients with thalassemia.13 Only recently MDS-iron
specific data is beginning to appear.
Low or intermediate I IPSS risk MDS patients with
transfusion dependency can survive enough to develop
iron related tissue damages. The new WHO classification
for MDS evaluated disease prognosis with respect to
risk factor in addition to age and gender and reported
that transfusion dependency was associated with a short
overall survival and leukemia free survival.53
In a Malcovati study, patients were grouped
according to transfusional burden i.e. 20, 20–40
or 40 RBC units received during the clinical course.
The effect of transfusion burden was calculated as the
number of transfusions per month, and a significant
effect was found both on overall survival and leukemia
free survival. Cardiac failure (51%), infection (31%),
hemorrhage (8%) and hepatic cirrhosis (8%) were
responsible for the majority of deaths.54 Among low
risk MDS patients who died as a result of a nonleukemic cause, cardiac failure was significantly
more frequent in transfused patients.
The prognostic value of iron overload was also
evaluated using serum ferritin as a marker of iron
overload. A ferritin level of 1000 ng/ml was chosen
as a threshold that distinguished between mild and
clinically relevant iron burden. A ferritin level of
1000 ng/ml was reached after a median number of
21 RBC units. The development of secondary iron
overload significantly affected overall survival
(P  0.001). After adjusting for transfusion burden
there was a 30% increase in the hazard rate for
every 500 ng/ml of increase in serum ferritin
above the threshold.54,55 Conflicting results about
the iron overload negative effect on survival are
coming from retrospective studies. The majority
of the studies suggest probable negative effects
in low-risk, Intermediate-I MDS patients. This is
usually attributed to longer survival and subsequent
increased transfusion burden in these categories of
patients.56,57
Cardiac iron accumulation has been demonstrated
to develop in unchelated MDS patients, who received
a very large (approximately 80 PBRCs units)8,58 amount
of transfusional iron intake, but this has not been
shown to be constantly associated with an impairment
of cardiac function. Cardiac iron overload can cause
Table 3. Deferasirox-associated gastroenteric adverse events and proposed management approaches.
Gastroenteric
adverse event
Management approaches
Diarrhea
Patients should take an anti-diarrheal for up to 2 days, and keep
hydrated. Deferasirox could be taken in the evening rather than in the
morning. Products such as Lactaid (if the patient is lactose intolerant)
or probiotics (Lactobacillus acidophilus) could be added to the diet
Abdominal pain
Patients should drink water or other clear fluids, and avoid solid
food for the first few hours. Avoid narcotic pain medications and
non-steroidal anti-inflammatory drugs. Deferasirox could be taken
in the evening rather than in the morning
Nausea/vomiting
Patients should drink small, steady amounts of clear liquids, such as
electrolyte solutions, and keep hydrated
Clinical Medicine: Therapeutics 2009:1
741
Pilo et al
dilated cardiomyopathy, manifesting as systolic or
diastolic dysfunction. One study in 46 patients with
MDS showed that 40% of patients have signs and
symptoms of heart failure, which in some patients
was accompanied by cardiac arrhythmias.53
In MDS, the relationship between cardiac iron
loading and cardiac function is more complex than
thalassemias. This is dependent on the coexistence of
several risk factors for cardiac disease. Hemoglobin
level fluctuation, preloading and after loading
transfusion related modification, phenomenon aging
related, like hypertension–diabetes–arterioscleroses,
have all independent effects on cardiac function
and may all contribute to cardiac-related death.
Large studies and multivariate analysis is required
to clarify these effects, but it is reasonable to predict
that cardiac iron could be an important co-factor for
cardiac morbidity and/or mortality.
Iron overload and an elevated serum ferritin
have been reported to be an important adverse
prognostic factors for patients with congenital59 or
acquired anemia undergoing allogeneic stem cell
transplantation.60
Pretransplantation elevated serum ferritin level
has been associated with lower overall and diseasefree survival in patients with malignancies. The lower
survival rate was attributable to a significant increase
in transplant-related mortality.
Indication for Chelation Therapy
in Myelodysplastic Syndrome
The most frequent cytopenia observed in
myelodysplastic syndromes is anemia. The majority
of MDS patients present with anemia at the time
of diagnosis. About 60% of all MDS patients will
experience severe anemia during the course of the
disease.
The need of transfusion therapy is based upon
clinical evaluation of anemia-related symptoms and
existence of comorbidities. Preserving patient’s quality
of life (QoL) is the main goal of transfusion therapy.
Managing the long-term efficacy of transfusion therapy
of a patient in relationship to his QoL is essential as is
improvement in organ function and survival.
According to evidence-based guidelines, red
blood cell transfusions will be the only therapeutic
option offered to 40% of MDS patients diagnosed
with anemia.61
742
Uncontrolled studies, reviewed by Alessandrino
et al,62 have been published on the efficacy of iron
chelation therapy on transfusion iron overload in patients
with myelodysplastic syndrome. One unconfirmed
study showed that subcutaneous bolus injection of
Deferoxamine is an acceptable alternative to slow, pumpdriven infusion.63 Based on the limited available evidence,
the Expert Panel of the Italian Society of Hematology62
agreed that iron chelation should be considered as a
therapy for myelodysplastic syndrome (The Italian
guidelines have been published in pre Deferasirox era;
a revision is currently in preparation). The Expert Panel
of the British Society of Hematology64 acknowledged
that their recommendations for iron chelation treatment
in myelodysplastic syndromes were based on limited
data. The British experts concluded that iron chelation
should be considered once a patient has received 5 gr
iron (approximately 25 units of red cells) but only in
patients for whom long-term transfusion therapy is
likely, such as those with pure sideroblastic anemia
or the 5q-syndrome. According the British guidelines,
Deferoxamine 20 to 40 mg/kg should be administered by
12-hour subcutaneous infusion 5 to 7 days per week.
The U.S. Food and Drug Administration have
approved Deferasirox for “treatment of chronic iron
overload caused by blood transfusions in patients
2 years of age and older.” The therapeutic indications
approved by the European Medicine Agency (EMEA)
are more detailed, and with respect to myelodysplastic
syndromes the drug is “indicated for the treatment
of chronic iron overload due to blood transfusions
when Deferoxamine therapy is contraindicated or
inadequate.” Thus, Deferasirox is now available for
treatment of transfusion iron overload in patients with
myelodysplastic syndrome because Deferoxamine is
inadequate in most of them. Data on the long-term
safety and effectiveness are needed.
Recently retrospective data suggest that patients
with iron overload related to allogeneic stem cell
transplantation could benefit from iron chelation
therapy.60
Monitoring Therapy
For monitoring iron overload and response to therapy,
serial measurements (monthly) of serum ferritin
levels together with liver enzymes and inflammation
parameters are recommend. Ferritin is a simple
objective test and a relatively reliable and reproducible
Clinical Medicine: Therapeutics 2009:1
Iron chelation with deferasirox
Table 4. Recommendations for patients monitoring.
Serum ferritin
Monthly
More frequently for patients with additional renal risk factors, if consistently 500 mg/L,
temporary dosage interruption may be considered.
Serum creatinin and
creatinin clearance
Monthly
Two baseline assessments are recommended with weekly assessments during the
first month and after dosage adjustment.
Proteinuria
Monthly
Serum transaminase levels
Monthly
Auditory and
ophthalmological exam
Yearly
marker of iron overload unless the patient is suffering
from an active hepatic disease or severe chronic
inflammation. In such cases, serial imaging studies
(MRI) may be required.12
Place in Therapy
Currently Deferasirox is approved in over 85 countries
worldwide, including the USA and Europe, and
is under review in many more for the treatment
of transfusional iron overload in adult and
paediatric patients. Deferasirox is the first oral iron
chelator approved in the EU for use in patients with
transfusional iron overload from different disease
processes.50
Finally the problem of cost should be mentioned.
A recent Italian study based on cost/benefit estimation
from a societal perspective, quantified tariffs, expenses,
generated an estimated mean direct cost of medical
therapy in thalassemia (transfusion + deferoxamine
chelation) of approximately 15,000 euros/year/patient.
Iron chelation therapy with Deferasirox costs about
twice, so it is expensive and clearly not commonly
accessible worldwide.
Conclusions
Effective and tolerable chelation therapy with
oral Deferasirox is an important development in
the treatment of transfusional iron overload. It is
significant to understand its capacity to provide
constant chelation exposure and the potential to
improve compliance. Results from up to 3.5 years
of treatment in approximately 1000 patients have
shown that deferasirox 20 mg/kg/day reduces overall
iron burden in patients with transfusion-dependent
anaemias.
Clinical Medicine: Therapeutics 2009:1
In most patients, a starting dose of 20 mg/kg/day
of deferasirox is suitable; however physicians should
continue to monitor transfusional iron intake, serum
ferritin, and safety markers on an ongoing basis to
certify that any necessary dose adjustments are
made in an opportune approach to meet patients’
needs. Deferasirox is generally well tolerated, with a
manageable safety profile.50
Disclosure
The authors report no conflicts of interest.
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