Drug Evaluation
10.1517/14656560802335333 © 2008 Informa UK Ltd ISSN 1465-6566 2391All rights reserved: reproduction in whole or in part not permitted
Long-term experience with deferasirox (ICL670), a once-daily oral iron chelator, in the treatment of transfusional iron overload MD Cappellini † & A Taher †University of Milan, Department of Internal Medicine, Policlinico Foundation IRCCS, Milan, Italy
Background : Chronic iron overload from frequent blood transfusions to treat patients with severe anaemias leads to significant morbidity and mortality. While deferoxamine, the current standard of care, is an effective iron chelator, it requires subcutaneous infusion for 8 – 12 h/day, 5 – 7 days/week. This regimen is problematic and impacts significantly on patients’ daily life. Objective : To evaluate the efficacy and tolerability of deferasirox, a once-daily oral iron chelator. Method : To review the available data reported in peer-reviewed journals (using PubMed) and at medical conferences. Results/conclusions : Deferasirox is effective in reducing or maintaining iron burden in patients with transfusion-dependent anaemias. As deferasirox is orally administered, the inconvenience of parenteral administration with deferasirox is avoided. Deferasirox improves patient satisfaction and is expected to improve compliance with iron chelation therapy.
Keywords: deferasirox , effective , Exjade , transfusional iron overload
Expert Opin. Pharmacother. (2008) 9(13):2391-2402
1. Introduction
Chronic iron overload is the main complication resulting from regular blood transfusions used to treat severe, genetically based, haemolytic anaemias such as β -thalassaemia and sickle cell disease (SCD), as well as rarer conditions causing anaemia such as myelodysplastic syndromes (MDSs). If left untreated, chronic iron overload causes significant damage to the heart, liver and endocrine glands and can lead to premature death [1,2] . It is widely accepted that, without adequate iron chelation therapy, patients with iron overload experience greater morbidity and mortality, as well as higher hospitalisation rates and medical care costs, than patients who are adequately chelated. More than half of all deaths in patients with β -thalassaemia, for example, are attributable to cardiac complications as a result of inadequate iron chelation rather than the underlying disease [3] . Several studies have shown that reduction of body iron levels through chelation therapy provides significant benefits in patients with transfusional haemosiderosis [4-7] .
While deferoxamine (DFO), the current reference standard of care in iron chelation, is an effective chelator, it requires subcutaneous infusion lasting 8 – 12 h per day, 5 – 7 days a week for as long as the patient continues to receive blood transfusions. This regimen is problematic for most patients, interfering significantly with their daily life and, subsequently, often resulting in poor patient compliance [8] . The introduction of the first oral chelator, three times daily deferiprone, seemed a promising step forward for the treatment of patients with transfusional iron overload. However, the use of deferiprone has been limited due
1. Introduction
2. Overview of the market
3. Introduction to deferasirox
4. Chemistry
5. Pharmacokinetics and
pharmacodynamics
6. Clinical experience
with deferasirox
7. Safety and tolerability
8. Regulatory affairs
9. Conclusions
10. Expert opinion
11. Five-year view
Exp
ert O
pin.
Pha
rmac
othe
r. D
ownl
oade
d fr
om in
form
ahea
lthca
re.c
om b
y Q
ueen
's U
nive
rsity
on
08/1
8/14
For
pers
onal
use
onl
y.
Deferasirox (ICL670)
2392 Expert Opin. Pharmacother. (2008) 9(13)
to the occurrence of serious adverse events during treatment, such as neutropenia and agranulocytosis [9,10] .
Deferasirox (ICL670) is a novel, orally active iron chelator that provides effective 24 h chelation, 7 days per week, with one daily dose. An extensive clinical trial programme has demonstrated that deferasirox 20 – 30 mg/kg/day is as effective as DFO in reducing or maintaining iron burden in adult and paediatric patients ( ≥ 2 years) with a variety of transfusion-dependent anaemias, including β -thalassaemia, SCD and MDS. Moreover, as deferasirox is orally active and dispersed in water or juice, the inconvenience of parenteral administration and disruption to daily life with DFO is avoided. It has also been shown that deferasirox is more cost-effective than deferoxamine, due to the cost and quality of life benefits derived from the more straightforward and convenient oral mode of administration [11] .
Transfusions and iron chelation therapy have dramatically improved the quality of life for patients with severe anaemias. Previously a rapidly fatal disease in early childhood, β -thalassaemia, for instance, is now a chronic disease compatible with prolonged life. Today, life expectancy varies between 25 and 55 years, depending on patient compliance with medical treatment, particularly iron chelation. Due to its oral formulation, deferasirox could be expected to improve patient satisfaction and compliance with iron chelation therapy and, ultimately, quality of life.
2. Overview of the market
Orally bioavailable chelators for transfusional iron overload have been sought since the introduction of DFO. Despite great effort, only deferiprone and deferasirox have successfully reached the market, reflecting the difficulty in combining oral activity and safety/tolerability. All currently available iron chelators require careful patient monitoring to ensure iron burden is being actively reduced within specific safety parameters. A brief summary of characteristics and established monitoring guidelines for DFO, deferiprone and deferasirox are presented in Table 1 .
DFO is the current reference standard for iron chelation therapy and has been available in clinical practice for more than 40 years. Numerous studies have shown that iron-overloaded patients who receive regular chelation therapy with DFO experience substantial clinical benefits due to a reduction in iron burden, including a significant improvement in overall survival [4,12] . However, the effectiveness of chelation therapy is heavily reliant on good compliance. In one study, patients with β -thalassaemia who received 225 – 300 infusions of DFO annually were found to have a 95% chance of survival to age 20 and a 90% chance to age 30. In contrast, those with a low number of annual DFO infusions (0 – 75) had survival rates of 20% to age 20 and 0% by age 30 [4] . Treatment with DFO is demanding and inconvenient, as the regimen requires regular subcutaneous infusions over 8 – 12 h, 5 – 7 days per week, which often results in poor
patient compliance [8] , particularly in adolescents and children. The drawbacks of chelation therapy with DFO led to the search for effective oral iron chelators with a good tolerability profile.
Deferiprone was the first oral chelator to be licensed and is approved in a number of countries outside the USA and Canada for the treatment of adult patients with β -thalassaemia major for whom DFO therapy is contraindicated or inadequate [13] . However, the use of deferiprone is limited partly due to the occurrence of serious adverse events during treatment, such as neutropenia and, less frequently, agranulocytosis [9,10] . Deferiprone is most commonly used in combination with DFO for patients with a high iron burden and serious iron-mediated cardiac disease. Studies evaluating the administration of both drugs sequentially have observed agranulocytosis only rarely using this administration regimen [14-16] . Nevertheless, both the safety profile and patient compliance with combination therapy require further research.
Despite the availability of these agents, some heavily transfused patients are unable to achieve successful iron chelation, most likely due to poor compliance with DFO monotherapy or DFO plus deferiprone combination therapy.
3. Introduction to deferasirox
Deferasirox was developed in response to the significant clinical need for a convenient, effective and well tolerated iron chelator. Approximately 700 compounds were synthesised and subjected to a rigorous filtering process, which included the determination of iron-binding potency, selectivity, oral activity, and subchronic tolerability in animals at a very early stage [17] . Of these compounds, deferasirox showed the most promising preclinical profile and was developed further.
4. Chemistry
Deferasirox is a novel, orally active tridentate ligand with a high affinity and specificity for iron [17] . The active molecule in deferasirox is a highly lipophilic, 99% protein-bound, N-substituted bis-hydroxyphenyl-triazole [17,18] . Three polar interaction sites in the binding pocket results in deferasirox binding with iron in a 2:1 ratio. That is, two deferasirox molecules are required to form a stable complex with each iron (Fe 3+ ) atom ( Figure 1 ).
5. Pharmacokinetics and pharmacodynamics
Preclinical studies in a range of animal models have demonstrated that single, oral doses of radio-labelled deferasirox are rapidly absorbed and maximal concentrations are reached 0.5 – 1 h postdose [17] . Deferasirox efficiently and selectively mobilises iron from liver and heart tissue, thereby promoting iron excretion [18,19] . In preclinical studies, deferasirox was more effective than DFO in
Exp
ert O
pin.
Pha
rmac
othe
r. D
ownl
oade
d fr
om in
form
ahea
lthca
re.c
om b
y Q
ueen
's U
nive
rsity
on
08/1
8/14
For
pers
onal
use
onl
y.
Cappellini & Taher
Expert Opin. Pharmacother. (2008) 9(13) 2393
Table 1 . Characteristics of currently available iron chelators.
DFO Deferiprone Deferasirox
Dose range 20 – 60 mg/kg/day 50 – 100 mg/kg/day 20 – 30 mg/kg/day
Half-life 20 min 2 – 3 h 8 – 16 h
Administration Subcutaneous or intravenous Oral, three times daily Oral, once daily
Iron excretion Urine/stool Urine Stool
Guidelines for monitoring therapy
Quarterly: serum ferritin levels Weekly: CBC with differential Ongoing: blood transfusion rate
Quarterly: serum ferritin levels Monthly: serum ferritin, serum creatinine and ALT levels, proteinuria
Annually: auditory/eye exams, liver iron assessment, cardiac iron assessment in patients ≥ 10 years old
Annually: liver iron assessment, cardiac iron assessment in patients ≥ 10 years old
Annually: liver iron assessment, cardiac iron assessment in patients ≥ 10 years old, auditory and ophthalmic testing, paediatric growth
Other: ALT level monthly for 3 – 6 months, then every 6 months
Advantages Long-term experience Orally active Orally active
Effective in reducing body iron stores
Well established safety profi le
May reverse cardiac disease Enhanced removal of cardiac iron Once-daily administration
May be combined with deferiprone May be combined with DFO Equivalent effi cacy to DFO at doses ≥ 20 mg/kg/day
Disadvantages Requires continuous infusion May not achieve negative iron balance at 75 mg/kg/day
Need to monitor renal function
Poor compliance Risk of agranulocytosis Long-term data gathering is ongoing
Potential ear, eye, bone toxicity Need for weekly blood counts May not achieve negative iron balance at lower doses
Adapted from research originally published in Cohen [49] , Copyright (2006) The American Society of Hematology. ALT: Alanine aminotransferase; CBC: Complete blood count; DFO: Deferoxamine.
mobilising iron from the hepatocellular pool [17] and from cardiomyocytes [20,21] . Deferasirox is predominantly metabolised by glucoronidation, with subsequent biliary excretion [19] . Deferasirox and its metabolites are mainly excreted in the faeces (84% of the dose); renal excretion is minimal (8% of the dose, 6% as hydroxylated deferasirox). Importantly, deferasirox does not promote uptake of dietary iron, which was considered a potential complication during the search for oral iron chelators [17] .
Early studies demonstrated that the oral bioavailability of deferasirox is 70% and serum concentration is proportional to the dose administered [22,23] . As deferasirox has a mean elimination half-life of 8 – 16 h, plasma levels are maintained within the therapeutic range over a 24 h period. Deferasirox can therefore provide 24 h chelation coverage with once-daily administration ( Figure 2 ) [23,24] , thus providing sustained protection from toxic labile iron [25] . The efficiency of deferasirox in terms of iron-binding capacity is estimated to be approximately 27% [26] .
6. Clinical experience with deferasirox
The deferasirox clinical development programme is the largest ever conducted for any chelation therapy and has to date enrolled more than 1000 patients. Five pivotal clinical studies have assessed the efficacy, safety and tolerability of deferasirox across a number of transfusion-dependent anaemias. Around half of all enrolled patients were children, some as young as 2 years old. Older patients were also well represented in the β -thalassaemia and MDS populations. To date, some patients in the deferasirox clinical programme have been receiving treatment for up to 4 years.
A randomised, double-blind, placebo-controlled, dose-escalation study in 24 iron-overloaded patients with β -thalassaemia first demonstrated that deferasirox could reduce iron burden in humans [23] . Pharmacokinetic evaluations in this study were consistent with preclinical evidence that deferasirox is absorbed promptly and is detectable in the blood for 24 h. The plasma concentration of deferasirox was
Exp
ert O
pin.
Pha
rmac
othe
r. D
ownl
oade
d fr
om in
form
ahea
lthca
re.c
om b
y Q
ueen
's U
nive
rsity
on
08/1
8/14
For
pers
onal
use
onl
y.
Deferasirox (ICL670)
2394 Expert Opin. Pharmacother. (2008) 9(13)
also found to be proportional to dose. Although three dose groups (10, 20 or 40 mg/kg/day) were evaluated and all three doses resulted in a positive net iron excretion, the investigators concluded that deferasirox 20 – 30 mg/kg/day offered the most effective chelation combined with reasonable tolerability. Based on these findings, the recommended starting dose of deferasirox for most patients is 20 mg/kg/day, although this should be modified depending on the number of transfusions a patient is receiving and whether the patient’s therapeutic goal is to decrease or maintain body iron levels.
Another open-label, noncomparative, 48-week trial of deferasirox 10 mg/kg/day assessed the safety, tolerability, long-term pharmacokinetics and efficacy [via changes in liver iron concentration (LIC) and serum ferritin] in 40 paediatric patients (2 – 17 years old) with β -thalassaemia and transfusional overload ( Table 2 ) [27] . After 48 weeks, the mean deferasirox dose was 11.3 mg/kg/day. Results showed that overall LIC was initially stable and then increased gradually from week 12 as the mean iron intake from transfusions exceeded excretion. These results confirm that deferasirox 10 mg/kg/day is too low to induce a negative iron balance in most patients, and suggest that doses higher than 10 mg/kg/day are needed to achieve negative iron balance.
Data from subsequent randomised, controlled clinical trials have shown that deferasirox has comparable efficacy to DFO ( Table 2 ) [24,27-30] . In a multicentre, open-label trial, deferasirox 10 and 20 mg/kg/day were compared with a standard dose of DFO 40 mg/kg/day in 71 patients with
N
N N
O
–OOC
COO–
NN
N
O–
O
O
Fe3+
Figure 1 . Chemical structure of deferasirox.
β -thalassaemia and transfusional iron overload over 48 weeks [24] . Based on changes in levels of LIC and serum ferritin, results demonstrated that deferasirox 20 mg/kg/day had comparable efficacy to DFO 40 mg/kg/day ( Table 2 ).
A large multinational, double-blind, randomised study in 586 patients with β -thalassaemia further established the efficacy and safety of deferasirox compared with DFO [28] . Overall, 296 and 290 adult and paediatric patients with β -thalassaemia were enrolled and randomised to receive deferasirox or DFO, respectively, for 1 year ( Table 2 ). Initial dosing was based on LIC – patients with baseline LIC of 2 – 3, > 3 – 7, > 7 – 14 or > 14 mg Fe/g dry weight received deferasirox 5, 10, 20 or 30 mg/kg/day, or DFO 20 – 30, 25 – 35, 35 – 50 or ≥ 50 mg/kg, respectively. Both deferasirox 20 – 30 mg/kg/day and DFO > 35 mg/kg provided significant and dose-dependent reductions in LIC and serum ferritin levels by study end. Deferasirox 5 and 10 mg/kg/day removed iron effectively but they were insufficient to balance the iron uptake from regular blood transfusions. A prospective, 1-year, multicentre, open-label study in patients aged 3 – 81 years with MDS (n = 47), Diamond-Blackfan anaemia (DBA) (n = 30), β -thalassaemia (n = 85) and other rare anaemias (n = 22) assessed the efficacy and safety of deferasirox in patients across various underlying anaemias [29] . Results were similar to those reported by Cappellini et al. [28] ; changes in LIC were dependent on dose and transfusional iron intake.
Vichinsky et al. [30] compared the safety and efficacy of deferasirox with DFO in patients with SCD and transfusional iron overload ( Table 2 ). Overall, 195 adult and paediatric patients received either deferasirox (n = 132) or DFO (n = 63). Over 1 year, similar dose-dependent reductions in LIC were observed between the two cohorts, demonstrating noninferiority for deferasirox in patients with SCD.
Taken as a whole, it is notable that the pivotal deferasirox studies have demonstrated significant, dose-dependent changes in iron burden, as measured by LIC and serum ferritin, in patients with a range of severe chronic anaemias, including β -thalassaemia, SCD, MDS, DBA and other rare anaemias. Importantly, the magnitude of improvement in iron burden has been similar across all patient groups evaluated ( Figure 3 ) [28-30] .
6.1 Long-term clinical effi cacy and safety with deferasirox As most patients receiving regular transfusions require lifelong iron chelation therapy, the long-term efficacy and safety of deferasirox is continuing to be assessed in more than 900 patients in 4-year extension phases to the 1-year core trials. Results from the extension phases, with a median follow-up of 3.4 years, have confirmed deferasirox efficacy is dose and transfusion dependent [31] .
A large number of patients in the core studies initially received deferasirox 5 and 10 mg/kg/day doses, which were insufficient to balance iron intake from ongoing
Exp
ert O
pin.
Pha
rmac
othe
r. D
ownl
oade
d fr
om in
form
ahea
lthca
re.c
om b
y Q
ueen
's U
nive
rsity
on
08/1
8/14
For
pers
onal
use
onl
y.
Cappellini & Taher
Expert Opin. Pharmacother. (2008) 9(13) 2395
100
80
60
40
20
00 4 8 12
Time post dose with deferasirox 20 mg/kg/day (h)
Trough deferasirox plasma concentration with 20 mg/kg dose
Pla
sma
con
cen
trat
ion
iro
n-f
ree
def
eras
irox
(mm
ol/l
)
16 20 24
Figure 2 . Steady-state levels after daily dosing with deferasirox. Mean ( ± SD) values of measurements taken on weeks 2, 4, 8 and 12 are presented. Adapted from Piga et al. [24] with kind permission of the Ferrata Storti Foundation, Pavia, Italy.
Table 2 . Summary of pivotal studies for deferasirox and core phase (1-year) fi ndings.
Trial/design n Treatments Patient population Key fi ndings
Piga et al. [24] , Phase II, open-label randomised, comparative versus DFO
71 Deferasirox 10 and 20 mg/kg/day versus DFO 40 mg/kg/day (1 year)
β -thalassaemia; adult patients Deferasirox 20 – 30 mg/kg/day needed to deplete iron stores in majority of patients. Deferasirox 10 mg/kg/day may be suitable maintenance dose
Galanello et al. [27] , Phase II, open-label, single-arm, noncomparative
40 Deferasirox 10 mg/kg/day (1 year)
β -thalassaemia; paediatric patients ( ≥ 2 years)
Deferasirox was well tolerated in the paediatric population. Deferasirox 10 mg/kg/day did not induce a negative iron balance
Cappellini et al. [28] , Phase III, randomised, open-label comparative versus DFO
586 Deferasirox 5, 10, 20, 30 mg/kg/day versus DFO 20 – 60 mg/kg/day (1 year)
β -thalassaemia; adult and paediatric patients ( ≥ 2 years)
Noninferiority to DFO ≥ 35 mg/kg was achieved in patients who received deferasirox 20 – 30 mg/kg for baseline LIC levels of ≥ 7 mg Fe/g d.w. (69% of effi cacy population)
Porter et al. [29] , Phase II, open-label, single-arm, noncomparative
184 Deferasirox 5, 10, 20, 30 mg/kg/day (1 year)
β -thalassaemia, MDS, Diamond-Blackfan anaemia and other rare anaemias; adult and paediatric patients ( ≥ 2 years)
In patients with LIC ≥ 7 mg Fe/g d.w., deferasirox 20 – 30 mg/kg/day produced signifi cant decreases in LIC. LIC changes were dependent on dose and transfusional iron intake
Vichinsky et al. [30] , Phase II, randomised, open-label, comparative versus DFO
195 Deferasirox 5, 10, 20, 30 mg/kg/day versus DFO 20 – 60 mg/kg/day (1 year)
SCD; adult and paediatric patients ( ≥ 2 years)
Over 1 year, dose-dependent LIC reductions were observed with deferasirox and DFO
DFO: Deferoxamine; d.w.: Dry weight; LIC: Liver iron concentration; MDS: Myelodysplastic syndromes; SCD: Sickle cell disease.
Exp
ert O
pin.
Pha
rmac
othe
r. D
ownl
oade
d fr
om in
form
ahea
lthca
re.c
om b
y Q
ueen
's U
nive
rsity
on
08/1
8/14
For
pers
onal
use
onl
y.
Deferasirox (ICL670)
2396 Expert Opin. Pharmacother. (2008) 9(13)
transfusions. In the subsequent ongoing 4-year extension trials, dose adjustments were permitted to enable patients to achieve their treatment goal (maintenance or reduction of iron burden). 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 from 9 to 12 mg/kg/day during the core trials and has continued to increase in the extension trials, reaching around 20 – 25 mg/kg/day after approximately 2 years of treatment [32] . Mean dose in the 20 mg/kg/day group has
remained at around 20 – 25 mg/kg/day during the entire treatment period, while that in the 30 mg/kg/day group decreased to around 25 mg/kg/day after approximately 18 months [32] .
Median serum ferritin levels in the 5/10 mg/kg/day dose group steadily increased during the first 18 months of deferasirox treatment. However, subsequent dose increases during the extension trials generally resulted in serum ferritin levels decreasing to below baseline at around 32 months and for the remainder of the study ( Figure 4 ) [32] . In the
-1500
-1000
-500
0
500
1000
2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42Time since start of treatment (months)
Med
ian
ch
ang
e in
ser
um
fer
riti
n le
vels
(n
g/m
l)
0
Core Extension
5/10 20 30Initial deferasirox dose (mg/kg/day)
Figure 4 . Median change in serum ferritin levels by initial dose group during 3.5 years of deferasirox treatment. Data from [32] .
Planned starting doses (mg/kg/day)
-10
-8
-6
-4
-2
0
2
4
6
8
10
Ch
ang
e in
LIC
* (m
g F
e/g
d.w
.)
DFO 35 – 50 ≥ 50
DFO (β-thalassaemia)
DFO (SCD)
Deferasirox 20 30
Deferasirox (β-thalassaemia)
Deferasirox (rare anaemias)
Deferasirox (SCD)
Figure 3 . Decreases in liver iron concentration during 1 year of deferasirox treatment in patients with a range of transfusion-dependent anaemias. Data from [28-30] . *LIC = SQUID × 2. DFO: Deferoxamine; d.w.: Dry weight; LIC: Liver iron concentration; SCD: Sickle cell disease; SQUID: Superconducting quantum interference device.
Exp
ert O
pin.
Pha
rmac
othe
r. D
ownl
oade
d fr
om in
form
ahea
lthca
re.c
om b
y Q
ueen
's U
nive
rsity
on
08/1
8/14
For
pers
onal
use
onl
y.
Cappellini & Taher
Expert Opin. Pharmacother. (2008) 9(13) 2397
20 mg/kg/day group, median serum ferritin levels were maintained throughout the treatment period and in the 30 mg/kg/day group, serum ferritin levels decreased overall from baseline to month 42. Overall, these data have also shown that patients can achieve a therapeutic goal of maintenance or reduction in serum ferritin levels with appropriate dose adjustments.
The deferasirox clinical trial programme is continuing; more than 900 patients are enrolled in extension phases to the core registration studies for deferasirox and are continuing to be monitored for long-term efficacy and safety data.
6.2 Additional studies In addition to the extension phases of the pivotal deferasirox trials, the efficacy and safety profile of deferasirox is continuing to be assessed in several studies including adult and paediatric patients with β -thalassaemia, SCD, DBA, MDS, aplastic anaemia and other very rare anaemias. Ongoing results from two of these studies are currently available.
The ESCALATOR trial was a prospective, open-label, 1-year, multicentre study conducted in the Middle East to evaluate the effects of deferasirox treatment on LIC in heavily iron-overloaded patients with β -thalassaemia who were unable to achieve successful chelation with prior mono or combination therapy with DFO and/or deferiprone [33] . The primary efficacy end point was treatment success, defined as a reduction in LIC of ≥ 3 mg Fe/g dry weight (d.w.) if a patient’s baseline LIC was ≥ 10 mg Fe/g d.w. or a final LIC of 1 – 7 mg Fe/g d.w. if a patient’s baseline LIC was between 2 and < 10 mg Fe/g d.w. Overall, patients began treatment with deferasirox 20 mg/kg/day, except for three patients who received an initial dose of 10 mg/kg/day (which was later increased to 20 mg/kg/day based on a protocol amendment), and doses were adjusted in response to efficacy and safety markers. Consistent with findings from previous deferasirox studies, the 20 mg/kg/day starting dose was insufficient to achieve a reduction in LIC in this heavily transfused, iron-overloaded population. Dose escalation was required in 76% of these patients because they had not achieved their target reduction in iron burden. After 1 year’s treatment, the intent-to-treat population (n = 247) experienced a statistically significant treatment success rate of 56.3% (p = 0.022) and a mean reduction in LIC of 3.5 mg Fe/g d.w. [33] . Median serum ferritin also significantly decreased by 458 ng/ml at 1 year (p < 0.001). These results highlight the importance of timely deferasirox dose adjustments based on serum ferritin levels and transfusional iron intake to ensure that patients achieve their therapeutic goal of maintenance or reduction in iron burden. Most patients enrolled in the 2402 study are continuing to receive deferasirox in an extension phase.
A large 1-year, multicentre, open-label study aiming to enrol 1541 patients with various transfusion-related anaemias is currently ongoing to evaluate the efficacy and safety of deferasirox [34] . 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 indicate significant iron burden above thresholds associated with increased morbidity and mortality [5] . For the previously chelated patients, this indicates that their treatment regimen was not providing adequate management of their iron burden, while for the chelation-naive patients these data clearly indicate a need for chelation therapy.
6.3 Effect on cardiac iron The risk of cardiac complications and early death are greatly increased in heavily iron-overloaded, transfusion-dependent patients. In vitro , in vivo and clinical data all support the ability of deferasirox to decrease cardiac iron [20,21,35,36] . One study in a gerbil model of iron overload found that daily divided dosing of deferasirox reduced cardiac iron to a greater extent than once-daily dosing, although the difference between dosing regimens was not statistically significant. The authors acknowledged that the differences between the dosing regimens may be even less in humans due to likely variation in the pharmacokinetics of deferasirox between humans and gerbils [37] . In a study of 29 patients who received deferasirox in two pivotal studies described earlier [28,29] , T2 * magnetic resonance imaging showed a significant reduction in cardiac iron burden after 12 months of deferasirox treatment, which was maintained after 2 years [35] . Preliminary data from a prospective, single-arm, multicentre trial in patients with β -thalassaemia also show that after 6 months of deferasirox treatment, patients experienced significant improvements in cardiac T2*, LIC and labile plasma iron [36] . These results show that deferasirox achieved both a negative cardiac and liver iron balance in 93% of the patients. In the ESCALATOR trial, a statistically significant improvement in left ventricular ejection fraction was observed by week 52 in the intent-to-treat population (p < 0.001), which may also suggest a positive effect of deferasirox on cardiac function.
7. Safety and tolerability
7.1 Adverse event profi le 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 defined safety profile that is clinically manageable with regular monitoring in adult and paediatric patients [28-30] . Of the more than 1000 patients enrolled in the deferasirox core clinical studies, only 74 have discontinued treatment due to adverse events [24,27-30] .
The most frequent adverse events reported over a median 3.4 years’ treatment with deferasirox include transient,
Exp
ert O
pin.
Pha
rmac
othe
r. D
ownl
oade
d fr
om in
form
ahea
lthca
re.c
om b
y Q
ueen
's U
nive
rsity
on
08/1
8/14
For
pers
onal
use
onl
y.
Deferasirox (ICL670)
2398 Expert Opin. Pharmacother. (2008) 9(13)
mild-to-moderate gastrointestinal disturbances and skin rash. During the extension phases to the deferasirox registration studies, drug-related adverse events were generally transient and of mild-to-moderate severity. Table 3 presents the most common (> 4% overall) drug-related adverse events during 3.5 years of deferasirox treatment (n = 964) [31] . Most adverse events experienced by patients during treatment with deferasirox resolve spontaneously and do not require discontinuation or interruption of treatment.
Mild, nonprogressive increases in serum creatinine (generally within the upper limit of normal) were 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 patients have confirmed these increases are nonprogressive.
7.2 Postmarketing surveillance Postmarketing experience in a large number of patients has provided additional data that further support the safety profile of deferasirox in adults and children with a range of underlying anaemias. Cases of acute renal failure have been reported following the postmarketing use of deferasirox [38] . Confounding factors to explain renal failure were apparent in most of these cases, such as preexisting renal conditions, advanced age, comorbid conditions, or concomitant medication that may depress renal function [39] . Neutropenia and thrombocytopenia have also been reported. However, most of these patients had preexisting haematologic disorders that are frequently associated with bone marrow failure and the relationship of these episodes to treatment with deferasirox is uncertain [39] .
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.
8. Regulatory affairs
Deferasirox is currently 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. In Europe, deferasirox is indicated in the management of chronic iron overload in patients with transfusion-dependent anaemias aged 6 years or older, and for the management of chronic iron overload in patients with transfusion-dependent anaemias aged 2 – 5 who cannot be adequately treated with DFO. Deferasirox is the first oral iron chelator approved in the EU for use in patients with transfusional iron overload who have a wide range of underlying diseases.
9. Conclusions
Convenient, effective and tolerable chelation therapy with oral deferasirox is a significant development in the treatment of transfusional iron overload due to its ability to provide constant chelation coverage 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. In most patients, a starting dose of 20 – 30 mg/kg/day of deferasirox is suitable; however, transfusional intake and the overall goal of therapy (e.g., maintenance or reduction in iron burden) should be considered carefully to determine the appropriate deferasirox dose on an individual patient basis.
Physicians should continue to monitor transfusional iron intake, serum ferritin, and safety markers on an ongoing basis to ensure that any necessary dose adjustments are made in a timely manner to meet patients’ needs. Deferasirox is generally well tolerated, with a manageable safety profile,
Table 3 . Most common (> 4% overall) drug-related adverse events during 3.5 years of deferasirox treatment (n = 964).
Adverse event Frequency, n (%) Severity, n (%)
Mild Moderate Severe
Nausea 99 (10.3) 84 (8.7) 14 (1.5) 1 (0.1)
Diarrhoea 86 (8.9) 68 (7.1) 16 (1.7) 2 (0.2)
Vomiting 60 (6.2) 46 (4.8) 13 (1.3) 1 (0.1)
Abdominal pain 50 (5.2) 36 (3.7) 10 (1.0) 4 (0.4)
Rash 50 (5.2) 28 (2.9) 19 (2.0) 3 (0.3)
Upper abdominal pain 48 (5.0) 37 (3.8) 10 (1.0) 1 (0.1)
Data pooled from the core and extension Phases of studies 106 – 109 [31] .
Exp
ert O
pin.
Pha
rmac
othe
r. D
ownl
oade
d fr
om in
form
ahea
lthca
re.c
om b
y Q
ueen
's U
nive
rsity
on
08/1
8/14
For
pers
onal
use
onl
y.
Cappellini & Taher
Expert Opin. Pharmacother. (2008) 9(13) 2399
over a median treatment period of 3.5 years. The results from ongoing trials of deferasirox in patients with a variety of transfusion-dependent anaemias are eagerly anticipated.
10. Expert opinion
β -thalassaemia is one of the most common inherited single-gene disorders in the world, with the highest prevalence in areas where malaria was or still is endemic. β -thalassaemia is mainly observed in ethnic groups originating from around the Mediterranean (e.g., Cypriot, Italian, Greek) and Asia (e.g., Indian, Pakistani, Chinese). Sickle cell anaemia affects millions throughout the world. It is particularly common among people whose ancestors come from sub-Saharan Africa, South America, Cuba, Central America, Saudi Arabia, India, and Mediterranean countries such as Turkey, Greece and Italy. While MDS is considered a fairly rare condition, with a worldwide prevalence of approximately 5 per 100,000 in the general population, it is four to five times more common in Asian populations and its prevalence is rising with an ageing population.
Clearly, the burden of these disorders in many regions is of such a magnitude that it represents a major public health concern. Worldwide, there is a considerable impact on health-care systems not only in terms of the transfusion dependency for patients with these severe anaemias but also of the considerable comorbid conditions that can arise if patients are not properly chelated from an early age.
The current standard treatment, DFO, effectively controls iron overload and extends survival in patients with transfusion-dependent anaemias. However, DFO is associated with potentially poor patient compliance due to its demanding infusion regimen. DFO can have a negative impact on multiple areas of patients’ lives, including their emotional well-being, physical functioning, self-esteem, sex life, work and sleep. Injections are associated with site soreness and other adverse events including infection and inflammation, and if a battery-operated pump is used for infusion, this can be noisy and lead to disturbed sleep. Although the introduction of oral deferiprone initially seemed a promising step forward, its use has been limited due to the occurrence of serious adverse events.
Deferasirox addresses an unmet need for an effective but simple and convenient iron chelation agent and represents an advance in the treatment of transfusion-dependent anaemias. The evidence reported from a range of clinical studies has shown deferasirox 20 – 30 mg/kg/day to be as effective as DFO, across a range of patient populations with chronic iron overload.
Intuitively, the oral formulation is likely to confer significant benefits with respect to quality of life and compliance. Compliance with chelation therapy is critical for maintaining long-term control of iron concentration levels and, therefore, long-term treatment benefits and improved survival. Greater satisfaction with, and convenience
of, deferasirox treatment could potentially improve patient compliance compared with current chelation therapy. A subanalysis of a pivotal deferasirox study evaluated adult- and child-reported satisfaction with treatment, convenience, and daily impact of deferasirox versus DFO in patients with β -thalassaemia and chronic iron overload and prior experience of DFO [40] . Overall, 86% of patients with β -thalassaemia who had previously been treated with DFO indicated that they would be willing to remain on deferasirox, compared with 13% willing to remain on DFO. In a subgroup analysis of a study in iron-overloaded patients with SCD, only 10.5% indicated a willingness to continue DFO therapy compared with 84.3% in the oral deferasirox group [41] .
Long-term data from extension phases of the deferasirox clinical programme highlight that deferasirox dose must be titrated for each patient according to the rate of iron intake from ongoing blood transfusions, current iron burden, safety markers and target serum ferritin levels for individual patients. A patient’s iron burden should be regularly assessed and deferasirox dose titrated in steps of 5 – 10 mg/kg/day every 3 – 6 months if a patient is not achieving their target serum ferritin level [42] . However, it is not possible to comment on the response rates relative to individual target serum ferritin levels as these were not specified in the extension studies. Deferasirox was generally well tolerated with a manageable safety profile over the median treatment period of 3.4 years. Given the long-term data now accumulated on deferasirox, in combination with the convenience of oral therapy, deferasirox represents an opportunity for clinicians to improve the lives of their patients with transfusion-dependent anaemias and iron toxicity.
11. Five-year view
Owing to the risk of failure, few new oral chelators can be expected in the future for the treatment of transfusional iron overload. As such, the results of prospective ongoing studies of deferasirox across various transfusion-dependent anaemias are eagerly anticipated. It is hoped that these studies will help to elucidate fully the clinical benefits of iron chelation therapy in several patient populations.
Patients with high-risk MDS have a poor prognosis and will most likely not survive long enough to develop iron overload-related complications from blood transfusions. However, as patients with low- or intermediate-risk MDS have a better prognosis and will receive supportive care with regular transfusion therapy, iron overload is a significant potential complication. Published guidelines therefore suggest that chelation therapy would be of benefit to patients with transfusion-dependent low- or intermediate-risk MDS whose serum ferritin levels have exceeded 1000 ng/ml [43] . Although studies evaluating chelation therapy in MDS are limited, a survival benefit in favour of chelation therapy has recently been suggested [44,45] . The mechanism for prolonged survival
Exp
ert O
pin.
Pha
rmac
othe
r. D
ownl
oade
d fr
om in
form
ahea
lthca
re.c
om b
y Q
ueen
's U
nive
rsity
on
08/1
8/14
For
pers
onal
use
onl
y.
Deferasirox (ICL670)
2400 Expert Opin. Pharmacother. (2008) 9(13)
Bibliography Papers of special note have been highlighted as either of interest (•) or of considerable interest (••) to readers.
1. Cunningham MJ, Macklin EA, Neufeld EJ, et al. Complications of β -thalassemia major in North America. Blood 2004 ; 104 : 34 -9
2. Olivieri NF. The β -thalassemias. N Engl J Med 1999 ; 341 : 99 -109
3. Borgna-Pignatti C, Rugolotto S, De Stefano P, et al. Survival and disease complications in thalassemia major. Ann N Y Acad Sci 1998 ; 850 : 227 -31
4. Gabutti V, Piga A. Results of long-term iron-chelating therapy. Acta Haematol 1996 ; 95 : 26 -36
5. Olivieri NF, Nathan DG, MacMillan JH, et al. Survival in medically treated patients with homozygous β -thalassemia. N Engl J Med 1994 ; 331 : 574 -8
6. Olivieri NF, Brittenham GM. Iron-chelating therapy and the treatment of thalassemia. Blood 1997 ; 89 : 739 -61
7. Rose C, Gattermann N, Glimm E, et al. Deferasirox (Exjade ® , ICL670), the novel, once-daily oral iron chelator, is well tolerated and effective in treating transfusional iron overload in patients with a range of rare anaemias [abstract 22]. Haematologica 2006 ; 91 (Suppl 1)
8. Delea TE, Edelsberg J, Sofrygin O, et al. Consequences and costs of noncompliance
with iron chelation therapy in patients with transfusion-dependent thalassemia: a literature review. Transfusion 2007 ; 47 : 1919 -29
9. Ceci A, Baiardi P, Felisi M, et al. The safety and effectiveness of deferiprone in a large-scale, 3-year study in Italian patients. Br J Haematol 2002 ; 118 : 330 -6
10. Cohen AR, Galanello R, Piga A, et al. Safety and effectiveness of long-term therapy with the oral iron chelator deferiprone. Blood 2003 ; 102 : 1583 -7
11. Karnon J, Tolley K, Oyee J, et al. Cost–utility analysis of deferasirox compared to standard therapy with desferrioxamine for patients requiring iron chelation therapy in the United Kingdom. Curr Med Res Opin 2008 ; 24 : 1609 -21
12. Brittenham GM, Griffi th PM, Nienhuis AW, et al. Effi cacy of deferoxamine in preventing complications of iron overload in patients with thalassemia major. N Engl J Med 1994 ; 331 : 567 -73
13. Ferriprox. Summary of product characteristics. Apotex, 1999
14. Abdelrazik N. Pattern of iron chelation therapy in Egyptian beta thalassemic patients: Mansoura University Children’s Hospital experience. Hematology 2007 ; 12 : 577 -85
15. Aydinok Y, Nisli G, Kavakli K, et al. Sequential use of deferiprone and desferrioxamine in primary school children with thalassaemia major in Turkey. Acta Haematol 1999 ; 102 : 17 -21
16. Galanello R, Kattamis A, Piga A, et al. A prospective randomized controlled trial on the safety and effi cacy of alternating deferoxamine and deferiprone in the treatment of iron overload in patients with thalassemia. Haematologica 2006 ; 91 : 1241 -3
17. Nick H. Deferasirox (Exjade ® , ICL670) Preclinical overview. Semin Hematol 2007 ; 44 : S12 -5
18. Nick H, Acklin P, Lattmann R, et al. Development of tridentate iron chelators: from desferrithiocin to ICL670. Curr Med Chem 2003 ; 10 : 1065 -76
19. Nick H, Wong A, Acklin P, et al. ICL670A: preclinical profi le. Adv Exp Med Biol 2002 ; 509 : 185 -203
20. Glickstein H, Ben El R, Link G, et al. Action of chelators in iron-loaded cardiac cells: accessibility to intracellular labile iron and functional consequences. Blood 2006 ; 108 : 3195 -203
21. Wood JC, Otto-Duessel M, Gonzales I, et al. Deferasirox and deferiprone remove cardiac iron in the iron-overloaded gerbil. Translational Res 2006 ; 148 : 272 -80
remains unclear due to the retrospective nature of the analysis. Further studies of chelation therapy in MDS are needed to establish the impact on survival, cardiac function, patient quality of life, and any potential improvements in bone marrow function.
The success of stem cell transplantation, the only cure for patients with MDS, may be potentially improved with iron chelation therapy both pre- and post-transplant [46,47] . Deferasirox may therefore have a role for treating iron overload in this particular subgroup of the MDS patient population. Further studies are needed to determine the effect of iron overload and transfusion dependency in patients with MDS who are eligible for stem cell transplantation.
Although the most common method for treating hereditary haemochromatosis is therapeutic phlebotomy, iron chelation therapy may be considered for patients with poor venous access or poor tolerance to phlebotomy, or for patients who would prefer convenient chelation over phlebotomy. There is an inter-patient dose escalation study ongoing that is evaluating the safety of once-daily oral deferasirox 5, 10, 15 and 20 mg/kg/day in patients with hereditary haemochromatosis [48] . To date, 11 patients (mean
age 56 years) with a mean of 7 years since hereditary haemochromatosis diagnosis have been treated at 5 mg/kg/day for at least 4 weeks, and dose escalated up to 10 mg/kg/day after no patients were reported to have severe adverse events. This ongoing study will generate preliminary safety and efficacy data for deferasirox use in iron-overloaded hereditary haemochromatosis patients, indicating whether deferasirox could be an alternative to phlebotomy in selected patients. In addition, there may be a role for iron chelation therapy in the treatment of ferroportin disease (also known as type IV haemochromatosis). Type IV haemochromatosis leads to increased function of the iron exporter ferroportin, which can lead to iron deposition in organs such as the heart and liver. If untreated, this potentially has serious clinical consequences.
Declaration of interest
MD Cappellini and A Taher have received research funding from Novartis and are members of the Novartis’ Speaker Bureau. They received no payment in preparation of this manuscript.
Exp
ert O
pin.
Pha
rmac
othe
r. D
ownl
oade
d fr
om in
form
ahea
lthca
re.c
om b
y Q
ueen
's U
nive
rsity
on
08/1
8/14
For
pers
onal
use
onl
y.
Cappellini & Taher
Expert Opin. Pharmacother. (2008) 9(13) 2401
22. Galanello R, Piga A, Alberti D, et al. Safety, tolerability, and pharmacokinetics of ICL670, a new orally active iron-chelating agent in patients with transfusion-dependent iron overload due to beta-thalassemia. J Clin Pharmacol 2003 ; 43 : 565 -72
23. Nisbet-Brown E, Olivieri NF, Giardina PJ, et al. Effectiveness and safety of ICL670 in iron-loaded patients with thalassaemia: a randomised, double-blind, placebo-controlled, dose-escalation trial. Lancet 2003 ; 361 : 1597 -602
• The fi rst study to demonstrate a linear relationship between deferasirox exposure and total iron excretion .
24. Piga A, Galanello R, Forni GL, et al. Randomized Phase II trial of deferasirox (Exjade, ICL670), a once-daily, orally-administered iron chelator, in comparison to deferoxamine in thalassemia patients with transfusional iron overload. Haematologica 2006 ; 91 : 873 -80
25. Daar S, Taher A, Pathare A, et al. Sustained protection from labile plasma iron (LPI) with the once-daily, oral iron chelator deferasirox (Exjade ® , ICL670) in iron-overloaded β -thalassemia patients [abstract 1773]. Blood 2006 ; 108 (11)
26. Porter J, Borgna-Pignatti C, Baccarani M, et al. Iron chelation effi ciency of deferasirox (Exjade ® , ICL670) in patients with transfusional hemosiderosis [abstract 2690]. Blood 2005 ; 106 (11)
27. Galanello R, Piga A, Forni GL, et al. Phase II clinical evaluation of deferasirox, a once-daily oral chelating agent, in paediatric patients with β -thalassaemia major. Haematologica 2006 ; 91 : 1343 -51
• This paper evaluates the safety, tolerability and pharmacokinetics of deferasirox in children and adolescents, highlighting a 20 – 30% lower exposure in paediatric patients compared with adults .
28. Cappellini MD, Cohen A, Piga A, et al. A phase 3 study of deferasirox (ICL670), a once-daily oral iron chelator, in patients with β -thalassemia. Blood 2006 ; 107 : 3455 -62
•• This paper describes the largest randomized, open-label, comparative, phase III clinical trial conducted to demonstrate the effi cacy of deferasirox in regularly transfused patients aged ≥ 2 years .
29. Porter J, Galanello R, Saglio G, et al. Relative response of patients with
myelodysplastic syndromes and other transfusion-dependent anaemias to deferasirox (ICL670): a 1-yr prospective study. Eur J Haematol 2008 ; 80 : 168 -76
• This paper describes the effi cacy of deferasirox in patients with a variety of transfusion-dependent, rare anaemias, including myelodysplastic syndromes, aplastic anaemia, and Diamond-Blackfan anaemia .
30. Vichinsky E, Onyekwere O, Porter J, et al. A randomized comparison of deferasirox versus deferoxamine for the treatment of transfusional iron overload in sickle cell disease. Br J Haematol 2007 ; 136 : 501 -8
• This paper shows that deferasirox has acceptable tolerability and similar effi cacy to deferoxamine in reducing iron burden in transfused patients with sickle cell disease .
31. Cappellini MD, Vichinsky E, Galanello R, et al. Long-term treatment with deferasirox (Exjade ® , ICL670), a once-daily oral iron chelator, is effective in patients with transfusion-dependent anemias [abstract 2777]. Blood 2007 ; 110 (11)
32. Porter JB, Cohen AR, Ford JM, et al. Impact of dose adjustments on serum ferritin (SF) levels during long-term treatment with once-daily, oral deferasirox (Exjade ® , ICL670) [abstract 2778]. Blood 2007 ; 110 (11)
33. Taher A, El-Beshlawy A, Al Jefri A, et al. Treatment with the once-daily, oral iron chelator deferasirox is effective and well tolerated in β -thalassaemia patients with a high iron burden [abstract 0808]. Haematologica 2007 ; 92 (Suppl 1)
34. Gattermann N, Schmid M, Vassilieff D, et al. Severe iron overload in patients with myelodysplastic syndromes enrolled in a large study of deferasirox (Exjade ® , ICL670) [abstract P129]. Leuk Res 2007 ; 31 (Suppl 1): S109 -10
35. Eleftheriou P, Tanner M, Pennell D, et al. Response of myocardial T2 * to oral deferasirox monotherapy for 1 year in 29 patients with transfusion-dependent anaemias: a subgroup analysis [abstract 999]. Haematologica 2006 ; 91 (Suppl 1)
36. Wood J, Thompson AA, Paley C, et al. Exjade reduces cardiac iron burden in chronically transfused β -thalassemia patients: an MRI T2 * study [abstract 2781]. Blood 2007 ; 110 (11)
37. Otto-Duessel M, Aguilar M, Nick H, et al. Comparison of twice-daily vs once-daily deferasirox dosing in a gerbil model of iron cardiomyopathy. Exp Hematol 2007 ; 35 : 1069 -73
38. Exjade (deferasirox) Summary of product characteristics. Novartis Pharma AG. 2006. Available from: http://www.emea.europa.eu/humandocs/PDFs/EPAR/exjade/H-670-PI-en.pdf accessed 15 July 2008
39. Vichinsky E. Clinical application of deferasirox: practical patient management. Am J Hematol 2008 ; 83 : 398 -402
40. Cappellini MD, Bejaoui M, Agaoglu L, et al. Prospective evaluation of patient-reported outcomes during treatment with deferasirox or deferoxamine for iron overload in patients with beta-thalassemia. Clin Ther 2007 ; 29 : 909 -17
41. Vichinsky E, Pakbaz Z, Onyekwere O, et al. Patient-reported outcomes of deferasirox (Exjade ® , ICL670) versus deferoxamine in sickle cell disease patients with transfusional hemosiderosis: substudy of a randomized open-label Phase II trial. Acta Haematol 2008 ; 119 : 133 -41
42. Exjade basic prescribing information. Basel, Switzerland: Novartis Pharma AG 2006
43. Gattermann N, Porter J, Lopes LF, et al. Consensus statement on iron overload in myelodysplastic syndromes. Hematol Oncol Clin North Am 2005 ; 19 (Suppl 1): 18 -25
44. Leitch HA. Improving clinical outcome in patients with myelodysplastic syndrome and iron overload using iron chelation therapy. Leuk Res 2007 ; 31 (Suppl 3): S7 -9
45. Rose C, Brechignac S, Vassilief D, et al. Positive impact of iron chelation therapy (CT) on survival in regularly transfused MDS patients. A prospective analysis by the GFM [abstract 249]. Blood 2007 ; 110 (11)
46. Mahindra A, Bolwell B, Sobecks R, et al. Elevated pretransplant serum ferritin in autologous stem cell transplant [abstract 606]. Blood 2007 ; 110 (11)
47. Platzbecker U, Germing U, Stumpf J, et al. The impact of transfusion-dependency on the outcome of patients with myelodysplastic syndromes (MDS) receiving allogeneic peripheral blood stem cell transplantation after myeloablative
Exp
ert O
pin.
Pha
rmac
othe
r. D
ownl
oade
d fr
om in
form
ahea
lthca
re.c
om b
y Q
ueen
's U
nive
rsity
on
08/1
8/14
For
pers
onal
use
onl
y.
Deferasirox (ICL670)
2402 Expert Opin. Pharmacother. (2008) 9(13)
conditioning [abstract 1467]. Blood 2007 ; 110 (11)
48. Pietrangelo A, Brissot P, Bonkovsky H, et al. Design of an ongoing Phase I/II open-label, dose-escalation trial using the oral chelator deferasirox to treat iron overload in HFE-related hereditary hemochromatosis (HH) [abstract 2680]. Blood 2007 ; 110 (11)
49. Cohen AR. New advances in iron chelation therapy. Hematology Am Soc Hematol Educ Program 2006 ; 42 -7
Affi liation MD Cappellini † 1 MD & A Taher 2 MD † Author for correspondence 1 University of Milan, Department of Internal Medicine, Policlinico Foundation IRCCS, Milan, Italy Tel: +39 2 5503358 ; Fax: +39 2 50320296 ; E-mail: [email protected] 2 American University of Beirut Medical Center, Beirut, Lebanon
Exp
ert O
pin.
Pha
rmac
othe
r. D
ownl
oade
d fr
om in
form
ahea
lthca
re.c
om b
y Q
ueen
's U
nive
rsity
on
08/1
8/14
For
pers
onal
use
onl
y.
