Profile of deferasirox for the treatment of patients with non-transfusion-dependent thalassemia syndromes
Drug Design, Development and Therapy
Profile of deferasirox for the treatment of patients with non-transfusion-dependent thalassemia syndromes
Paolo Ricchi 1
Maria Marsella 0 1
0 UOC Pediatria, Azienda Ospedaliera di Rilievo Nazionale G. Rummo , Benevento, italy
1 UOSD Malattie Rare del Globulo Rosso, Azienda Ospedaliera di Rilievo Nazionale “Antonio Cardarelli” , Naples
It has been clearly shown that iron overload adds progressively significant morbidity and mortality in patients with non-transfusion-dependent thalassemia (NTDT). The lack of physiological mechanisms to eliminate the excess of iron requires effective iron chelation therapy. The reduced compliance to deferoxamine and the risk of severe hematological adverse events during deferiprone treatment have limited the use of both these drugs to correct iron imbalance in NTDT. According to the principles of evidence-based medicine, following the demonstration of the effectiveness and the safety of deferasirox (Exjade®) in a prospective, randomized, controlled trial, deferasirox was approved by the US Food and Drug Administration in May 2013 for the treatment of iron overload associated with NTDT. This review, assessing the available scientific literature, will focus on the profile of DFX in the treatment of non-transfusional hemosiderosis in patients with NTDT.
The data presented are based on the retrieval of relevant medical literature by searching
PubMed with the terms “deferasirox (DFX)” and “non-transfusion-dependent
thalassemia (NTDT)” for studies published between 2000 and 2015.
The Cochrane database for systematic reviews and clinical trial registries
was also searched, and pertinent reviews were identified (searches last updated
August 1, 2015).
Thalassemia is a complex entity related to a group of inherited diseases, caused
by defective or absent hemoglobin chain synthesis leading to anemia. In general, the
severity of the disease depends on the genotype inherited without a definite genotype–
phenotype correlation due to the presence of several genetic, along with environmental
factors, which can alter clinical expression jointly to secondary and tertiary genetic
modifiers.1 However, patients with NTDT do not require regular RBC transfusions
for survival, but may require occasional transfusions owing to infection or pregnancy
or may require more regular transfusions later in life due to splenomegaly or other
complications.2 Therefore, NTDT encompasses a great variety of syndromes mixed
in terms of their molecular background, clinical course, and severity, with the sole
common characteristic of independence from regular transfusions.3 Currently,
betathalassemia intermedia, alpha-thalassemia (mainly HbH disease), and mild/moderate
forms of HbE/beta-thalassemia are the most prevalent forms in the world.4
Despite the lack of a stable transfusional iron overload, the majority of patients with
NTDT accumulate iron. Ineffective and expanded erythropoiesis are both responsible
Drug Design, Development and Therapy 2015:9 6475–6482 6475
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for the activation of known and unknown signals of
epcidin suppression and of a consequent increased intestinal
absorption of iron.5 Thus, patients with NTDT progressively
increase their iron stores which may become clinically
significant in the second decade of life and is responsible,
along with chronic anemia and hemolysis, for most
compli801 cations observed in older untreated patients.6 However, it
l-2u is conceivable that, particularly in the more severe forms,
-J12 some complications could be ascribed to transfusion therapy
no (either intermittent or regular) as observed for the increased
.207 risk of endocrinopathy.7
.964 Patients with NTDT accumulate iron chiefly in the liver
.735 and scantly in the heart, which may explain the tendency to
/yb not develop myocardial siderosis as compared to patients
com with thalassemia major (TM).8,9 However, the liver iron
.sse overload shown in patients with NTDT has been found to be
rpe similar to that of patients with beta TM.10 The elevated iron
.dow l.y burden, despite occurring with differences in iron
metaboww no lism, pathophysiology and loading rate, is directly involved
:/ttsp lseu in the development of several complications or may add
h na in some way to their severity.11 In fact, evaluating a series
from rsoe of unchelated patients by R2 and R2* magnetic resonance
deda ropF imaging (MRI), a liver iron concentration (LIC) of 5 or more
lon mg/g dry weight (dw) was found to be the cut-off able to
odw accurately discriminate between patients with and without
rypa morbidities.12 Recently, patients with NTDT were also found
heT to have an increased risk of hepatocellular carcinoma and
dan those affected showed a LIC of 8.5 mg/g dw (median: 8.5;
ten interquartile range: 4.5–17.8).13
Chelation in NTDT
Obviously, chelation practice has been routinely performed
in the management of iron overload in patients with NTDT,
as their anemia contraindicates phlebotomy, but for a long
time only as good clinical practice and without both the use
of guidelines and the evidence of clinical benefit as observed
in their TM counterparts. The optimal care study was the first
retrospective study highlighting a protective effect of iron
chelation therapy against several complications of NTDT
such as pulmonary hypertension and endocrinopathies and
thus reinforced the indication to accurately chelate this
category of patients.7 On the other hand, it was demonstrated that
an increase in serum ferritin level over time was associated
with worsening of hepatic fibrosis in patients with NTDT who
are not receiving iron chelation treatment.14 The evidence of
these studies suggested to scrupulously estimate iron loading
particularly at liver level to control and prevent such iron
burden with effective iron chelation therapy.
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Guidelines on NTDT chelation treatment have been
recently established and recommend initiation of chelation
therapy in patients with either ferritin levels higher than
800 ng/L or LIC above 5 mg/g dw.15 However,
measurement of ferritin may underestimate the level of iron and
sometimes among the main NTDT subtypes an irregular
correlation exists between ferritin level and LIC, as measured
by R2 MRI or superconducting quantum imaging device.16,17
Therefore, a decision-making algorithm has also been created
to aid monitoring of iron burden and initiation of chelation
Until 2005, the two drugs were available to treat iron
overload in a variety of hematologic disorders:
deferoxamine (DFO), administered mainly using continuous slow
subcutaneous infusion, and the oral iron chelator deferiprone
(DFP).19,20 The DFO, a hexadentate chelator binding iron at
a 1:1 molar ratio, was introduced in clinical practice over
40 years ago to decrease iron overload.21 However, the need
for frequent and prolonged subcutaneous administration
has been associated with undesirable adverse effects and
noncompliance to treatment resulting in elevated risk of
ironinduced complications.22,23 The oral three times a day agent
DFP, a bidentate hydroxypyridone with a small molecular
weight, was first used and approved in Europe in 1999 for
the treatment of iron overload in TM when DFO was
contraindicated or inadequate. US Food and Drug Administration
approval for clinical use of DFP was delayed until October
2011 because of the lack of traditional safety and efficacy
trials comparing DFP and DFO. While DFO and DFP alone
and in combination have been widely used in several trials
involving patients with TM and proved to be effective in
the reduction of iron burden,24–27 the scientific evidence of
their efficacy in the setting of NTDT is very incomplete and
limited to specific subpopulations.28 Recently, Calvaruso
et al described the first 5-year long-term randomized clinical
trial comparing the effectiveness of DFP vs DFO in patients
with thalassemia intermedia (TI) showing that long-term iron
chelation therapy with DFP is similarly effective as DFO.
However, the use of DFP was accompanied by the occurrence
of rare but serious adverse events during treatment, such as
neutropenia and agranulocytosis.29
The once daily oral iron chelator, DFX (Exjade®, Novartis
Pharmaceuticals Corporation, Basel, Switzerland), was
introduced later, but has rapidly shown to be effective for
reduction of body iron in iron-overloaded patients with
transfusion-dependent anemias. It is a tridentate chelator
that mobilizes iron stores by binding selectively to the ferric
(Fe3+) form of iron.30,31 The efficacy of DFX has also been
demonstrated in sickle-cell disease and in bone marrow
failure syndromes, such as myelodysplastic and aplastic
syndromes, Diamond–Blackfan and Fanconi anemia.32–34
In a Phase I/II trial with 49 patients with HF-related
hereditary hemochromatosis, DFX also proved to be effective
in reducing iron overload.35 In the past few years, several
clinical trials have shown that accurate monitoring and dose
adjustment of DFX was safe and effective in the long-term
management of iron-overloaded patients with TM. Briefly,
it has been assessed that DFX at a dose of 20 mg/kg per day
can stabilize serum ferritin levels and LIC, while at doses of
30–40 mg/kg per day is able to reduce these parameters and
achieve negative iron balance in patients with transfusional
The DFX profile in NTDT
Pharmacokinetic and pharmacodynamic properties of DFX
have been mainly assessed among patients with TM and have
been extensively reviewed elsewhere.37,38 However, studies
from the myelodysplasia population seem to indicate that
DFX has a constant pharmacological profile, independently
from the underlying disease or race.39
The DFX is currently the only chelator to have gained
approval for the treatment of iron overload in patients with
NTDT in the USA (patients $10 years of age with an
LIC $5 mg Fe/g dw and SF .300 ng/mL) and in Europe
(LIC $5 mg Fe/g dw and SF .800 ng/mL with inadequate
response or contraindication to DFO).40 To date three small
studies and one large randomized trial have evaluated the
safety and efficacy of DFX in patients with NTDT with iron
overload (Table 1).
In the prospective open label study by Voskaridou et al
11 patients received DFX at a starting dose of 10–20 mg/kg
per day, according to the baseline iron burden, with
subsequent dose adjustments according to efficacy and adverse
events. After 1 year of treatment, significant improvement of
mean liver T2* (P=0.02) was observed in the eight patients
who completed the study.41
In the study by Ladis et al,42 eleven patients were enrolled
to receive DFX at 10 or 20 mg/kg per day for 24 months.
Mean LIC, measured by MRI-T2*, and mean serum ferritin
were significantly reduced (P=0.005 and P,0.05,
respectively) in the nine patients completing the study both at 12 and
24 months and five patients achieved LIC ,3 mg Fe/g dw.
In both studies, cardiac T2* and left ventricular ejection
fraction remained normal in all patients.41,42
THALASSA, a randomized, double-blind, placebo
controlled phase II trial, is the largest study to investigate
the safety and efficacy of DFX in reducing iron overload in
patients with NTDT.43 The trial included 166 patients with
β-thalassemia intermedia (n=95), α-thalassemia (n=22) and
HbE/β-thalassemia (n=49), and was conducted over 1 year.
Iron-overloaded patients ($10 years of age with LIC $5 mg
Fe/g dw and serum ferritin .300 ng/mL) were randomized
to DFX starting doses of 5 or 10 mg/kg per day or
matching placebo. After 1 year of treatment with DFX mean
LIC decreased significantly from baseline in both starting
dose groups (DFX 5 mg/kg per day: -2.33±0.70 mg Fe/g
dw; P=0.001 and 10 mg/kg per day: -4.18±0.69 mg Fe/g
dw; P,0.001) compared to placebo. The decrease in LIC,
measured by R2-MRI, was more significant (P=0.009) for
the DFX 10 mg/kg per day group compared with the lower
dose group (-1.85±0.70 mg Fe/g dw). For both groups LIC
reductions were observed from week 24. Similarly, serum
ferritin decreased significantly with DFX from baseline to
week 52 compared to placebo (least squares mean 121 ng/mL
in 5 mg/kg per day group, -222 ng/mL in 10 mg/kg per day
group, +115 ng/mL for placebo; P,0.001).
Patients who completed the THALASSA core study were
eligible to enter the 1-year extension phase, where patients
were continued on DFX or were switched from placebo.44
Overall, 133 patients entered the extension phase, including
48 who crossed over from placebo. The LIC and serum
ferritin continued to decrease throughout the extension phase.
Patients randomized to receive DFX in both phases (n=110)
achieved a mean absolute reduction of LIC of 7.14 mg Fe/g
dw from baseline and a mean decrease of serum ferritin of
Patients who switched over from placebo achieved a
mean absolute reduction of -6.66 mg Fe/g dw from baseline.
At the end of the extension phase the proportion of patients
achieving an LIC of ,5 mg Fe/g was 38.6% overall (39.1%
randomized to DFX in the core study; 37.5% originally
randomized to placebo). Serum ferritin also continued to
decrease over the extension study.
A subanalysis was performed evaluating LIC reduction
in various subgroups, based on baseline LIC, baseline serum
ferritin, age, sex, race, splenectomy status, and underlying
NTDT syndrome.45 Across all subgroups, patients
receiving DFX showed a greater reduction in LIC compared with
patients who received placebo with better results in patients
in the 10 mg/kg per day starting dose group.
DFX was in general well tolerated in all studies. The most
frequently reported adverse events were mild to moderate in
severity. In the THALASSA study adverse events assessed to
be drug related by the investigators were reported in 24.1%
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Drug Design,Development andTherapy 2015:9
of the patients and were mostly gastrointestinal disorders
(mostly nausea and diarrhea), which resolved spontaneously
or with dose adjustment or drug interruption. Eight patients
discontinued the study because of adverse events. The safety
profile in the extension phase and in the smaller studies was
As for renal function, no progressive increases in serum
creatinine were observed. In patients treated for 2 years, five
experienced two consecutive increases .33% above baseline
and above upper limit of normal.43,44 No similar reports by
Voskaridou et al41 and Ladis et al,42 although in the latter at the
end of the 2nd year of treatment serum creatinine increased
and creatinine clearance decreased compared to baseline, but
neither reached abnormal values.
In all three studies mean ALT levels decreased over time,
suggesting a corresponding improvement in liver function.
Only one patient in the THALASSA extension study
experienced hepatitis, which was suspected to be drug related.42
In general efficacy was achieved at relatively lower
doses compared to patients with transfusional iron overload.
However, monitoring for efficacy and adverse events with
adequate dose adjustments remains pivotal in all patients.
The most recent study was a multicenter trial performed
in Iran by Karimi et al who treated 50 β-thalassemia
intermedia patients with serum ferritin .1,000 ng/mL with DFX
for 12 months, observing a significant decrease of ferritin
starting at 4 months of treatment.46
The recent definition of serum ferritin thresholds to predict
clinically relevant LICs together with more and more wide
access to MRI technology have led to the frequent diagnosis
of iron overload in patients with NTDT, where initiation
of chelation therapy is indicated. As a consequence, to
control iron imbalance and to prevent iron toxicity, the
long term use of a safe and effective chelator is required.
An extensive experience gained from studies in patients
with TM with over 150,000 patient years of drug exposure
has definitively shown that DFX has a favorable side-effect
profile in patients with transfusion-dependent thalassemia
(TDT), with treatment-related adverse events comprising
gastrointestinal, renal and dermatologic effects that were
generally mild and reversible on cessation of treatment.47
In this review the restricted experience from the results on
238 patients with NTDT under continuous DFX treatment
were evaluated. These studies involve small numbers of
patients followed for 1–3 years who generally had never
been transfused and encompasses two pilot studies, a
prospective, placebo-randomized trial with its 2-year extension
study and a retrospective study.41–46 Overall, DFX, at doses
ranging from 10 to 20 mg and in a dose-dependent manner,
was effective in reducing LIC and/or ferritin in patients
with different subgroups of NTDT. Similarly to TDT,
drugrelated adverse events reported during these studies, were
manageable, self-resolving, and typically did not necessitate
discontinuing therapy, even as patients achieved low LIC
levels toward the end of the study.48 Following monthly
monitoring, incidences of liver and renal abnormalities were
low and nonprogressive. Mild, nonprogressive increases in
serum creatinine levels were also observed in a few patients;
these increases were generally within the normal range and
rarely exceeded twice the upper limit of normal.
Future perspectives and open questions
Taken together, these data suggest that the use of DFX can
successfully manage iron overload in patients with NTDT.
However, further data and larger study populations are
needed to explore the safety profile of this drug in this group
of patients (Table 2). Post-marketing surveillance studies
and information from the ongoing THETIS trial will provide
additional assessment of the long-term efficacy and safety
of DFX.49 Given the need for lower doses as compared to
TM, less toxicity and less morbidity are expected in NTDT
than that observed when DFX was initially administered in
patients with TM. Obviously, in most NTDT forms, lifelong
treatment with iron chelation may not be necessary and
several attempts at improving drug efficacy and reducing drug
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toxicity have been given particular attention, as the need to
interrupt chelation if treatment goals are reached. In fact, a
prudent and conservative approach has been adopted in the
THALASSA trial in the sense that LIC ,3 mg Fe/g dw was
used as an indicator to interrupt iron chelation therapy in the
hypothesis that it could represent a low, acceptable iron
bur081 den.43 In the described post hoc analysis, a consistent safety
l-u2 profile was nevertheless demonstrated as patients approached
-J12 this target, indicating that such low iron burdens may be
on obtained with minimal risk of overchelation.48 This approach,
.702 now included in current guidelines for chelation therapy in
.946 NTDT, obviously will guarantee from the observed risk in
.573 TDT that overchelation could further reduce glomerular
/yb filtration rate also in NTDT.50 However, it should be taken
com into account that cases of glomerular hyperfiltration may be
.sse observed in patients with NTDT and that the administration
rvpe of DFX could bring the glomerular filtration rate levels under
.dow l.y control.51 Thus, it could be argued that occasionally a
potenww no tial adverse event may become a useful strategy against the
:/s se potential damage of persistent glomerular hyperfiltration.
h na While a severe or .5 mg Fe/g dw LIC was clearly
associfrom rsoe ated with complications, the level of “acceptable” iron burden
deda ropF and iron associated toxicity in NTDT may be different and
lno transiently modifiable by occasional transfusional
requiredow ment. Currently, in line with the Thalassemia International
rypa Federation guidelines for DFX use in patients with NTDT,
heT iron chelation should be stopped in patients reaching LIC of
dna 3 mg Fe/g dw or SF of 300 ng/mL, when MRI is unavailable,
tne as safety data do not exist to support continued chelation
pom with DFX below this level.15 On the other hand, due to the
vee permanent progressive iron accumulation, therapy should be
,nD restarted when patients re-achieve a LIC of 5 mg Fe/g dw thus
iseg realizing a gray zone (from 3 to 5 mg Fe/g dw), where patients
guD are either interrupting treatment or waiting to restart it. It has
rD also been observed that each genetic entity of NTDT has
different erythroid activity, hepcidin levels and occasional
transfusional iron loading, which may generate in some cases
and in the presence of nearly normal LIC level, high levels
of saturation of transferrin which in turn produces labile iron
species and potential organ damage.52,53 Given that DFX has
been shown not only to control iron burden but also labile
plasma iron, the chelatable form of non-transferrin-bound
iron, there could be the space to test DFX for a maintenance
and or a transient therapy in such circumstances.54 As DFX
remains within the therapeutic range over a 24-hour period,
it offers a complete chelation coverage at standard doses
and can therefore better control labile plasma iron.55 Further
studies are needed to fully evaluate the efficacy and the
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safety of alternative administration schedules (ie, alternate
days, three times/week) and/or reduced doses of DFX to
control iron stores in this gray zone, where a maintenance
chelation therapy could be acceptable. Further studies are
also needed to better delineate the appropriate schedule of
treatment of DFX to induce a neutral iron balance according
to the increased risk of renal injury when a considered safe
or normal iron burden has been reached. On the other hand,
consideration should be given in the future also to better
tailor initial DFX therapy to the basal iron depot, to
different subtypes of NTDT, to splenectomy status and to the rate
of occasional transfusional iron intake, all conditions which
may affect iron balance in NTDT. Of particular interest,
over the long-term use of DFX, will be also the prospective
determination of the impact of iron chelation on most
common complications and survival in patients with NTDT. The
THETIS trial will focus on the effects of 5-year treatment
with DFX on the endocrine profile. The favorable outcome
of DFX on osteopenia and osteoporosis observed in patients
with TM could be expected also in NTDT.56 Similarly, the
reported long-term effects of DFX treatment on liver fibrosis
should be also readdressed in NTDT.57
Currently, to improve anemia and reduce the occasional
transfusional requirements, patients with NTDT are
frequently treated with “older” drugs such hydroxycarbamide58
and new agents such as those interfering with the activity
of several transforming growth factor-β family cytokines
involved in late stages of erythropoiesis59,60 and JAK2
inhibitors.61 Thus, the efficacy, safety, and pharmacokinetics
of DFX should also be evaluated in patients concomitantly
receiving some of these drugs, taking into account that the
potential interference of such drugs with mechanisms
regulating the iron absorption, could further address and limit
In conclusion, following the results of the THALASSA
and extension studies, DFX has become the current
goldstandard for iron chelation in patients with NTDT. However,
prospective data from a randomized comparison with other
chelating agents and from a magnitude of drug-exposure
comparable to that obtained for patients with TM should be
performed to obtain a more accurate and complete evaluation
of its profile in patients with NTDT.
The authors report no conflicts of interest in this work.
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1. Galanello R . Recent advances in the molecular understanding of nontransfusion-dependent thalassemia . Blood Rev . 2012 ;26S: S7 - S1 .
2. Weatherall DJ . The definition and epidemiology of non-transfusiondependent thalassemia . Blood Rev . 2012 ; 26 ( Suppl 1 ): S3 - S6 .
3. Ricchi P , Filosa A , Maggio A , Fucharoen S . Non-transfusion-dependent thalassemia: a complex mix of genetic entities yet to be fully discovered . Biomed Res Int . 2015 ; 2015 : 161434 .
4. Musallam KM , Rivella S , Vichinsky E , Rachmilewitz EA . Nontransfusion-dependent thalassemias . Haematologica . 2013 ; 98 ( 6 ): 833 - 844 .
5. Origa R , Galanello R , Ganz T , et al. Liver iron concentrations and urinary hepcidin in b-thalassemia . Haematologica . 2007 ; 92 : 583 - 588 .
6. Taher AT , Musallam KM , El-Beshlawy A , et al. Age-related complications in treatment-naive patients with thalassaemia intermedia . Br J Haematol . 2010 ; 150 ( 4 ): 486 - 489 .
7. Taher AT , Musallam KM , Karimi M , et al. Overview on practices in thalassemia intermedia management aiming for lowering complication rates across a region of endemicity: the optimal care study . Blood . 2010 ; 115 ( 10 ): 1886 - 1892 .
8. Origa R , Barella S , Argiolas GM , et al. No evidence of cardiac iron in 20 never-or minimally-transfused patients with thalassemia intermedia . Haematologica . 2008 ; 93 : 1095 - 1096 .
9. Roghi A , Cappellini MD , Wood JC , et al. Absence of cardiac siderosis despite hepatic iron overload in Italian patients with thalassemia intermedia: an MRI T2* study . Ann Hematol. 2010 ; 89 : 585 - 589 .
10. Taher AT , Musallam KM , Wood JC , Cappellini MD . Magnetic resonance evaluation of hepatic and myocardial iron deposition in transfusionindependent thalassemia intermedia compared to regularly transfused thalassemia major patients . Am J Hematol . 2010 ; 85 ( 4 ): 288 - 290 .
11. Taher AT , Viprakasit V , Musallam KM , Cappellini MD . Treating iron overload in patients with non-transfusion-dependent thalassemia . Am J Hematol . 2013 ; 88 ( 5 ): 409 - 415 .
12. Musallam KM , Cappellini MD , Wood JC , et al. Elevated liver iron concentration is a marker of increased morbidity in patients with b-thalassemia intermedia . Haematologica . 2011 ; 96 : 1605 - 1612 .
13. Borgna-Pignatti C , Garani MC , Forni GL , et al. Hepatocellular carcinoma in thalassaemia: an update of the Italian Registry . Br J Haematol . 2014 ; 167 ( 1 ): 121 - 126 .
14. Musallam KM , Motta I , Salvatori M , et al. Longitudinal changes in serum ferritin levels correlate with measures of hepatic stiffness in transfusion-independent patients with β-thalassemia intermedia . Blood Cells Mol Dis . 2012 ; 49 ( 3-4 ): 136 - 139 .
15. Taher A , Vichinsky E , Musallam K , et al. Guidelines for the management of non transfusion dependent thalassaemia (NTDT) . Thalassaemia International Federation . 2013 . Available from: http://www.thalassaemia.org.cy/wp-content/uploads/eBook-publications /guidelines_for_ the_management_of_non_transfusion_dependent_thalassaemia/#/0 . Accessed March 14, 2014 .
16. Taher A , El Rassi F , Isma'eel H , et al. Correlation of liver iron concentration determined by R2 magnetic resonance imaging with serum ferritin in patients with thalassemia intermedia . Haematologica . 2008 ; 93 : 1584 - 1586 .
17. Pakbaz Z , Fischer R , Fung E , et al. Serum ferritin underestimates liver iron concentration in transfusion independent thalassemia patients as compared to regularly transfused thalassemia and sickle cell patients . Pediatr Blood Cancer . 2007 ; 49 : 329 - 332 .
18. Taher AT , Porter JB , Viprakasit V , et al. Defining serum ferritin thresholds to predict clinically relevant liver iron concentrations for guiding deferasirox therapy when MRI is unavailable in patients with non-transfusion-dependent thalassaemia . Br J Haematol . 2015 ; 168 ( 2 ): 284 - 290 .
19. Novartis . Desferal (deferoxamine): prescribing information 2011 . Available from: https://www.pharma.us.novartis.com/product/pi/pdf/ desferal.pdf. Accessed July 27 , 2015 .
20. ApoPharma Inc . Ferriprox (deferiprone): prescribing information and medication guide . 2012 . Available from: http://www.ema.europa. eu/docs/en_GB/document_library/EPAR_-_ Product _Information/ human/000236/WC500022050.pdf. Accessed July 27 , 2015 .
21. Ma Y , Zhou T , Kong X , Hider RC . Chelating agents for the treatment of systemic iron overload . Curr Med Chem . 2012 ; 19 : 2816 - 2827 .
22. Delea TE , Sofrygin O , Thomas SK , Baladi JF , Phatak PD , Coates TD . Cost effectiveness of once-daily oral chelation therapy with deferasirox versus infusional deferoxamine in transfusion-dependent thalassaemia patients. US healthcare system perspective . Pharmacoeconomics . 2007 ; 25 : 329 - 342 .
23. Delea TE , Edelsberg J , Sofrygin O , et al. Consequences and costs of noncompliance with iron chelation therapy in patients with transfusiondependent thalassemia: a literature review . Transfusion . 2007 ; 47 : 1919 - 1929 .
24. Daar S , Pathare AV . Combined therapy with desferrioxamine and deferiprone in beta thalassemia major patients with transfusional iron overload . Ann Hematol . 2006 ; 85 : 315 - 319 .
25. Origa R , Bina P , Agus A . Combined therapy with deferiprone and desferrioxamine in thalassemia major . Haematologica . 2005 ; 90 : 1309 - 1314 .
26. Ricchi P , Ammirabile M , Spasiano A , et al. Combined chelation therapy in thalassemia major with deferiprone and desferrioxamine: a retrospective study . Eur J Haematol . 2010 ; 85 : 36 - 42 .
27. Pepe A , Meloni A , Rossi G , et al. Cardiac and hepatic iron and ejection fraction in thalassemia major: multicentre prospective comparison of combined deferiprone and deferoxamine therapy against deferiprone or deferoxamine monotherapy . J Cardiovasc Magn Reson . 2013 ; 15 ( 1 ): 1 - 11 .
28. Taher A , Hershko C , Cappellini MD . Iron overload in thalassaemia intermedia: reassessment of iron chelation strategies . Br J Haematol . 2009 ; 147 ( 5 ): 634 - 640 .
29. Calvaruso G , Vitrano A , Di Maggio R , Lai E , Colletta G , Quota A . Deferiprone versus deferoxamine in thalassemia intermedia: Results from a 5-year long-term Italian multicenter randomized clinical trial . Am J Hematol . 2015 ; 90 ( 7 ): 634 - 638 .
30. Stumpf JL. Deferasirox. Am J Health Syst Pharm . 2007 ; 64 : 606 - 616 .
31. Vanorden HE , Hagemann TM . Deferasirox - an oral agent for chronic iron overload . Ann Pharmacother . 2006 ; 40 : 1110 - 1117 .
32. Porter J , Galanello R , Saglio G , et al. Relative response of patients with myelodysplastic syndromes and other transfusion-dependent anemias to deferasirox (ICL670): a 1-yr prospective study . Eur J Haematol . 2008 ; 80 ( 2 ): 168 - 176 .
33. Lee JW , Yoon SS , Shen ZX , et al. Hematologic responses in patients with aplastic anemia treated with deferasirox: a post hoc analysis from the EPIC study . Haematologica . 2013 ; 98 ( 7 ): 1045 - 1048 .
34. Tunc B , Tavil B , Karakurt N , et al. Deferasirox therapy in children with Fanconi aplastic anemia . J Pediatr Hematol Oncol . 2012 ; 34 ( 4 ): 247 - 251 .
35. Pietrangelo A , Brissot P , Bonkovsky H , et al. A phase I/II, open-label, dose-escalation trial using the once-daily oral chelator deferasirox to treat iron overload in HFE-related hereditary hemochromatosis . Hepatology . 2010 ; 52 ( 5 ): 1671 - 1679 .
36. Saliba AN , Harb AR , Taher AT . Iron chelation therapy in transfusiondependent thalassemia patients: current strategies and future directions . J Blood Med . 2015 ; 6 : 197 - 209 .
37. Taher AT , Temraz S , Cappellini MD . Deferasirox for the treatment of iron overload in non-transfusion-dependent thalassemia . Expert Rev Hematol . 2013 ; 6 ( 5 ): 495 - 509 .
38. Shirley M , Plosker GL . Deferasirox: a review of its use for chronic iron overload in patients with non-transfusion-dependent thalassaemia . Drugs . 2014 ; 74 ( 9 ): 1017 - 1027 .
39. Miyazawa K , Ohyashiki K , Urabe A , et al. A safety, pharmacokinetic and pharmacodynamic investigation of deferasirox (Exjade, ICL670) in patients with transfusion-dependent anemias and iron-overload: a Phase I study in Japan . Int J Hematol . 2008 ; 88 ( 1 ): 73 - 81 .
40. Novartis Pharmaceuticals. EXJADE (deferasirox) US Prescribing Information ( 2013 ). Available from: www.pharma.us.novartis.com/ product/pi/pdf/exjade.pdf. Accessed July 27 , 2015 .
41. Voskaridou E , Plata E , Douskou M , et al. Treatment with deferasirox (Exjade) effectively decreases iron burden in patients with thalassaemia intermedia: results of a pilot study . Br J Haematol . 2010 ; 148 : 332 - 334 .
42. Ladis V , Berdousi H , Gotsis E , Kattamis A . Deferasirox administration for the treatment of non-transfusional iron overload in patients with thalassaemia intermedia . Br J Haematol . 2010 ; 151 : 504 - 508 .
43. Taher AT , Porter J , Viprakasit V , et al. Deferasirox significantly reduces iron overload in non-transfusion-dependent thalassemia: 1-year results from a prospective, randomized, double-blind, placebo-controlled study . Blood . 2012 ; 120 : 970 - 977 .
44. Taher AT , Porter JB , Viprakasit V , et al. Deferasirox effectively reduces iron overload in non-transfusion-dependent thalassemia (NTDT) patients: 1-year extension results from the THALASSA study . Ann Hematol . 2013 ; 92 ( 11 ): 1485 - 1493 .
45. Taher AT , Porter JB , Viprakasit V , et al. Deferasirox demonstrates a dose-dependent reduction in liver iron concentration and consistent efficacy across subgroups of non-transfusion-dependent thalassemia patients . Am J Hematol . 2013 ; 88 ( 6 ): 503 - 506 .
46. Karimi M , Arandi N , Haghpanah S , et al. Efficacy of Deferasirox (Exjade®) in modulation of iron overload in patients with β-thalassemia intermedia . Hemoglobin . 2015 ; 26 : 1 - 3 .
47. Riva A. Comment on: a record number of fatalities in many categories of patients treated with deferasirox: loopholes in regulatory and marketing procedures undermine patient safety and misguide public funds? Expert Opin Drug Saf . 2013 ; 12 ( 5 ): 793 - 795 .
48. Taher AT , Porter JB , Viprakasit V , et al. Approaching low liver iron burden in chelated patients with non-transfusion-dependent thalassemia: the safety profile of deferasirox . Eur J Haematol . 2014 ; 92 ( 6 ): 521 - 526 .
49. No authors listed. Efficacy and safety study of deferasirox in patients with non-transfusion dependent thalassemia (THETIS) . Available from: https://clinicaltrials.gov/ct2/show/NCT01709838?term=deferasirox+n tdt& rank=1. Accessed July 27 , 2015 .
50. Mallat NS , Mallat SG , Musallam KM , Taher AT . Potential mechanisms for renal damage in beta-thalassemia . J Nephrol . 2013 ; 26 ( 5 ): 821 - 828 .
51. Ziyadeh FN , Musallam KM , Mallat NS , et al. Glomerular hyperfiltration and proteinuria in transfusion-independent patients with β-thalassemia intermedia . Nephron Clin Pract . 2012 ; 121 ( 3-4 ): c136 - c143 .
52. Origa R , Cazzola M , Mereu E , et al. Differences in the erythropoiesishepcidin-iron store axis between hemoglobin H disease and β-thalassemia intermedia . Haematologica . 2015 ; 100 ( 5 ): e169 - e171 .
53. Taher A , Musallam KM , El Rassi F , et al. Levels of non-transferrin-bound iron as an index of iron overload in patients with thalassaemia intermedia . Br J Haematol . 2009 ; 146 : 569 - 572 .
54. Porter JB , El-Alfy M , Viprakasit V , et al. Utility of labile plasma iron and transferrin saturation in addition to serum ferritin as iron overload markers in different underlying anemias before and after deferasirox treatment . Eur J Haematol. Epub 2015 Feb 18 .
55. Daar S , Pathare A , Nick H , et al. Reduction in labile plasma iron during treatment with deferasirox, a once-daily oral iron chelator, in heavily iron-overloaded patients with beta-thalassaemia . Eur J Haematol . 2009 ; 82 ( 6 ): 454 - 457 .
56. Casale M , Citarella S , Filosa A , et al. Endocrine function and bone disease during long-term chelation therapy with deferasirox in patients with β-thalassemia major . Am J Hematol . 2014 ; 89 ( 12 ): 1102 - 1106 .
57. Deugnier Y , Turlin B , Ropert M , et al. Improvement in liver pathology of patients with β-thalassemia treated with deferasirox for at least 3 years . Gastroenterology. 2011 ; 141 ( 4 ): 1202 - 1211 .
58. Musallam KM , Taher AT , Cappellini MD , Sankaran VG. Clinical experience with fetal hemoglobin induction therapy in patients with β-thalassemia . Blood . 2013 ; 121 ( 12 ): 2199 - 2212 .
59. Suragani RN , Cawley SM , Li R , et al. Modified activin receptor IIB ligand trap mitigates ineffective erythropoiesis and disease complications in murine beta-thalassemia . Blood . 2014 ; 123 ( 25 ): 3864 - 3872 .
60. Dussiot M , Maciel TT , Fricot A , et al. An activin receptor IIA ligand trap corrects ineffective erythropoiesis in beta-thalassemia . Nat Med . 2014 ; 20 ( 4 ): 398 - 407 .
61. Rivella S. The role of ineffective erythropoiesis in non-transfusiondependent thalassemia . Blood Rev . 2012 ; 26 ( Suppl 1 ): S12 - S15 .