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THALASSEMIA

Update on Iron Chelators in Thalassemia


Ellis J. Neufeld1

1Children’s Hospital Boston, Dana Farber Cancer Institute, and Harvard Medical School, Boston, MA

Over the past four decades, there have been dramatic improvements in survival for patients with thalassemia major
due in large measure to improved iron chelators. Two chelators are approved for use in the United States and Canada,
parenteral deferoxamine and oral deferasirox. Three are available in much of the rest of the world, where oral
deferiprone is also approved (in the United States, deferiprone is only available in studies, for emergency use, or on a
“compassionate-use” basis). Many trials and worldwide clinical experience demonstrate that each of the three drugs
can chelate and remove iron, and thereby prevent or improve transfusional hemosiderosis in thalassemia patients.
However, the chelators differ strikingly in side-effect profile, cost, tolerability and ease of adherence, and (to some
degree) efficacy for any specific patient. The entire field of chelator clinical trials suffers from the fact that each drug (as
monotherapy or in combination) has not been tested directly against all of the other possibilities. Acknowledging the
challenges of assessing chelators with diverse properties and imperfect comparative data, the purpose of this review
is to summarize the last 4 years of studies that have improved our understanding of the applications and limitations of
iron chelators in various settings for thalassemia patients, and to point out areas for much-needed future research.

Introduction population at baseline. Finally, the primary results of the multina-


Properties of the iron chelators deferoxamine, deferiprone, and tional EPIC trial are now available.15 This study includes many
deferasirox are compared in Table 1. Beyond the scope of this disorders other than thalassemia, but more than 1000 thalassemic
review are the use of chelators for myelodysplastic syndrome1 and subjects.
novel chelator applications such as in the treatment of neurodegen-
erative diseases2 or treatment of infections based on sequestration of Secondary manuscripts analyzing in-depth the characteristics of
iron.3 Deferoxamine, with 40 years of accumulated use, is still deferasirox use from these manufacturer-sponsored trials have
highly relevant (e.g., in combination regimens), but new mono- examined critical questions about deferasirox efficacy and dosing.
therapy trials of this drug are few and it is usually included only as a Cohen et al. examined the effect of transfusion burden on defera-
comparator. Since 2006, more than 100 publications each on the use sirox chelation effectiveness in a pivotal trial, demonstrating that
of deferasirox and deferiprone in thalassemia have been listed on transfusion burdens in excess of 0.5 mg Fe/kg body weight/d were
PubMed, but only a small fraction of these are primary reports of associated with a higher chance of rising iron burden (assessed in
clinical trials, key secondary analyses from trials, or informative that trial by liver biopsy at the start and after 1 year).16 Taher et al.
studies of pharmacokinetics and ancillary biology. Recent reviews presented reassuring safety data on patients who had received doses
have provided additional information about deferiprone,45 defera- of deferasirox above 30 mg/kg/d17 (the original upper limit ap-
sirox,6 and optimizing chelation strategies.7,8 From the large pool of proved by FDA; in 2009, based on these and related data, the upper
references, selected key studies of both drugs are summarized in limit of dosing was raised to 40 mg/kg/d). Pennell et al. reported
Table 2 and in the text below. cardiac status in a preplanned subgroup analysis of the large EPIC
trial, focusing on patients at risk of heart disease, and demonstrated
Deferasirox efficacy of deferasirox in the improvement of myocardial iron.18
Patients with severe and symptomatic cardiac dysfunction were not
Update on Clinical Trials
included in this trial. A prospective, investigator-initiated trial by
When chelation in thalassemia was last reviewed for the ASH
Hematology Education Program in 2006,9 deferasirox (Exjade®, Wood et al. also found that in patients with moderate, but not severe,
Novartis) had only recently achieved US Food and Drug Adminis- cardiac iron overload (as assessed by cardiac magnetic resonance
tration (FDA) approval based upon the pivotal phase 3 randomized imaging [MRI] transverse relaxation time [T2*] values), deferasirox
study of deferasirox vs. deferoxamine in pediatric and adult could improve cardiac siderosis in about one-half of heavily
thalassemia patients,10 as well as phase 2 studies in adults11 and iron-overloaded patients (with hepatic iron status as a key determi-
children12 with thalassemia. Subsequently, primary trial results were nant of success).19
reported from a large, phase 2 study that included non-hemoglobi-
nopathy disorders as well as thalassemia patients ineligible for the Due most likely to patients’ preference and their ability to adhere to
pivotal trial because they were intolerant of deferoxamine.13 More prescribed therapy, deferasirox has become the predominant chela-
recently, two additional large, open-label clinical trials of defera- tor over deferoxamine in North America over just a 3-year span
sirox monotherapy have been published. The ESCALATOR trial since its initial commercial launch. As of mid-2009, deferasirox was
was the first to test doses of deferasirox above 30 mg/kg.14 being used in the majority of thalassemia major patients on
Conducted predominantly in the Middle East, this was the first chelation in the National Heart, Lung, and Blood Institute (NHLBI)-
large-scale study for which ferritin levels were used as a defined sponsored Thalassemia Longitudinal Cohort study of about 400
index for deferasirox dose adjustments in a heavily iron-overloaded thalassemia major patients from the United States, Canada, and

Hematology 2010 451


Table 1. Properties of iron chelators
Deferoxamine Deferasirox Deferiprone
Stoichiometry of iron 1:1 (hexadentate) 1:2 (tridentate) 1:3 (bidentate)
chelation
Route and timing of Subcutaneous or IV as continuous infusion 5-7 Oral, as a suspension, once daily Oral as tablets, generally in three
administration; typical days weekly; not orally available; 20-60 (or in some circumstances divided divided doses; 75 mg/kg/day
dosing mg/kg/day averaged over a week if not given daily twice daily); 20-40 mg/kg/day,
highly individualized and
dependent on transfusion rate
Plasma half-life Short (~20-30 min) Long (11-16h)* Intermediate (~2-3 hours)
Known or theoretical Long-term safety record Oral administration Oral administration
advantages Highly effective at maintaining iron balance in Majority of thalassemia patients Epidemiologic evidence for best long-
compliant patients who tolerate the drug tolerate well, able to maintain or term cardiac outcomes compared to
Strongest chelator on a molar basis reduce iron burden – at higher deferoxamine
24 hour continuous administration indicated for doses, equivalent to deferoxamine May allow ongoing aggressive
life-threatening cardiac siderosis Daily dosing provides 24 hour chelation when body iron stores are
chelator “coverage” to prevent free low, with minimum excess toxicity
(non-transferrin-bound) iron

Known or theoretical Parenteral administration GI symptoms limit maximal Side effect profile (see below) limits
disadvantages Local skin reactions limit tolerability in many pts tolerated dose in some pts. use in many patients (e.g. GI or joint
Epidemiologic and head to head data suggest Significant fraction of patients symptoms)
that deferoxamine may be inferior to deferiprone have inadequate response at Rare agranulocytosis and infrequent
for cardiac protection maximal tolerated dose neutropenia require weekly CBC
Challenging for patient compliance Not yet demonstrated to be able to monitoring.
reduce cardiac siderosis in Not yet available commercially in US
patients with most severe cardiac or Canada
siderosis (T2*<6 msec)
Common side effects Local skin reactions; sensorineural hearing loss Rash (can often “treat through”) GI distress; joint pain and erosive
and bone problems (both mostly in current older GI upset, diarrhea (dose related); arthritis (especially in South Asian
patients treated with high doses when younger); mild abnormalities in creatinine or patients)
proteinuria; transient elevation in
transaminases
Severe and/or dangerous Siderophore for some bacteria (e.g. Listeria); Peptic ulcers; liver dysfunction Agranulocytosis (<1% in
side effects Retinopathy and acute pulmonary disease are including failure; renal dysfunction thalassemia);
possible when given in excess of iron burden. including failure; cytopenias
(chiefly in non-thalassemia
patients with underlying MDS or
other marrow disorders)
Relative price 36 $$ $$$$ $-$$

*Half-life shorter in young children

London (58% vs. 27% on deferoxamine as monotherapy, and a a second-line agent in Europe and is used as the primary agent for
small number on combinations).20 iron overload in some parts of the world, including southern Asia.
The drug is still under consideration by the FDA. Several interesting
Knowledge about the side-effect profile of deferasirox has been studies over the past 4 years have highlighted an apparent advantage
evolving since its commercial launch in 2006, as often happens with of deferiprone in speeding removal of cardiac iron in patients
drugs new to the market. The current FDA-approved label includes without advanced cardiac dysfunction from iron overload. These
a boxed warning related to post-marketing data and pharmaco- studies have been incremental in nature. In 2006, Galanello et al.
vigilance reports of bleeding peptic ulcers and both hepatic and reported results of a randomized trial demonstrating that deferiprone
renal dysfunction, sometimes severe. Close monitoring for toxicity given 5 d weekly alternating with deferoxamine 2 d weekly was as
is suggested by the manufacturer. successful as continued deferoxamine in lowering serum ferritin and
liver iron.24 Pennell et al. then demonstrated improved myocardial
While the large majority of deferasirox users tolerate the drug well, T2* in a randomized trial in the deferiprone arm in patients without
a greater challenge to deferasirox monotherapy is that it is insuffi- heart disease.25 Next, Tanner et al., in a randomized trial, showed
ciently effective at reducing high iron burden (or maintaining low that the combination of deferoxamine ⫹ deferiprone achieved more
iron burden) in a significant minority of patients (up to 30% in rapid improvement in cardiac parameters and ferritin levels com-
several reports). Potential reasons for the limited effect in these pared with deferoxamine ⫹ placebo in patients with asymptomatic
patients might include inadequate dosage, problems with compli- and mildly low cardiac T2* MRI assessments.26 The Tanner group
ance, or simply iron burden in excess of chelator capacity.16,19,21 also presented non-randomized follow-up data from patients ex-
Recent availability of an intravenous preparation of deferasirox (for cluded from their randomized trial. Among those patients were 15
investigational use only) has allowed pharmacokinetic assessments with severe cardiac iron overload, who responded well to combined
of bioavailability and volume of distribution,22 and a radiolabeled deferiprone/deferoxamine.27 A logical next step from that trial
form allows detailed description of metabolism in thalassemic would have been a randomized evaluation of the same arms
patients.23 We have studied patients with inadequate responses in (deferoxamine ⫹ deferiprone vs. deferoxamine ⫹ placebo) in
liver iron or ferritin at doses above 30 mg/kg and compared them symptomatic heart disease, and indeed such a trial was launched by
against patients with good response at lower doses. The two groups the NIH-supported Thalassemia Clinical Research Network, but the
are distinguished by much lower exposure (area under the concentra- trial was closed early due to slow accrual. Results have been
tion/time curve) in the poor responders, an effect likely due to submitted for publication.
differential bioavailability (and not compliance or transfusion
burden alone).21 An interesting chart-review study from Farmaki et al.28 explores a
cohort of patients treated prospectively in a single-center setting
with a regimen of aggressive combination chelation with deferox-
Deferiprone amine ⫹ deferiprone to start, and then reduction of deferoxamine
The oral chelator deferiprone (Ferriprox®, Apopharma, and others) after ferritin levels normalized; the results showed dramatic endocri-
is not approved in the United States or Canada, but it is approved as nologic improvement and little toxicity While this regimen as

452 American Society of Hematology


Table 2. Selected oral chelator trials published since 2006
First Author, Number of Trial design, outcome measures Key findings Ref
trial nickname thalassemia
subjects

RECENT PRIMARY DEFERASIROX TRIALS

Porter; 184 including 88 Open label, one year phase 2 Deferasirox efficacious in majority of subjects for 13

Novartis ICL670-108 thalassemia pts not trial. Hepatic iron content by liver hepatic iron balance or reduction at 20-30 mg/kg/d
eligible for pivotal biopsy (depending on transfused iron burden)
phase 3 trial
Taher, 237 Open label, one year trial, with 57% of intention to treat cohort achieved primary 14

ESCALATOR dose escalation allowed based outcome of hepatic iron improvement. Most patients
on ferritin levels. Hepatic iron had upward dose adjustments based on ferritin,
content by liver biopsy usually to 30 mg/kg/day
Cappellini, 1115 enrolled One year, Open label, At doses less than 30 mg/kg/day deferasirox, median 15

EPIC thalassemia (of 1744 prospective trial to assess ferritin levels stable. At doses more than 30
total); 1010 completed whether choosing dose by mg/kg/day, median ferritin significantly improved.
trial transfusion burden , ferritin, and
safety labs could allow effective
chelation
Wood 28 Prospective trial of doses >30 19
Cardiac and liver MRI assessments over 18 months.
US04 trial mg/kg/day in heavily iron 48% of patients achieved improved cardiac iron over
overloaded patients. Primary the course of the trial. Patients could be grouped into
endpoint improvement in cardiac good and poor responders
T2*

SECONDARY AND SUBGROUP ANALYSES AND ADDITIONAL STUDIES

Pennell, 18;
192 Thalassemia pts, 114 Primary endpoint was change in Higher doses of deferasirox (many patients on 40
Cardiac sub-study of with T2*<20 msec, 78 with myocardial T2* over one year. mg/kg/d) effective in raising cardiac T2* when mildly or comment
Epic (a preplanned T2*>20 msec moderately low to start, i.e. >6 msec. in 35
analysis with cardiac
MRI measures)
Cohen, 541 patients Secondary analysis of Novartis Rate of transfusional iron intake affects deferasirox 16

Effect of transfusion phase III trial results efficacy: achievement of neutral or negative iron
burden on deferasirox balance more likely with doses of 20 or 30 mg/kg/day
efficacy (secondary when transfusional iron burden is lower than 0.5
analysis of pivotal mg/kg/day
Novartis trial, ref 810
17
Taher 225 with thalassemia of 264 Secondary analysis of high dose Relative improvement in ferritin levels as doses
High dose subset from total cohorts from prior Novartis trials, exceeded 30 mg/kg/day
various Novartis clinical 107E, 108E, and Escalator
trials
Chirnomas 21
15 24 hour inpatient PK Significantly lower AUC for patients with inadequate
Pharmacokinetic assessments and follow up response, independent of other factors such as
assessment of outpatient levels comparing transfusion burden; suggests lower bioavailability in
deferasirox in poor vs patients with rising hepatic iron at poor responders to deferasirox
good responders doses >30 mg/kg/d to good
deferasirox responders

Lal 15 Open label, pilot scale safety 29


Preliminary results presented at ASH 2009; improved
Combination therapy study of combination therapy - cardiac and hepatic iron; therapy well tolerated
deferasirox/deferoxami Hepatic iron by magnetic
ne susceptometry, cardiac iron by
T2*, one year follow up

Key trials including deferiprone for thalassemia patients


Trial nickname Number of thalassemia Trial design, outcome Key findings ref
subjects measures
25
Pennell 61 Primary end point change in Greater improvement in cardiac T2* in
Randomized trial vs cardiac t2* after one year of deferiprone group compared to
deferoxamine for deferiprone vs deferoxamine deferoxamine. Greater improvement in left
asymptomatic cardiac ventricular ejection fraction in deferiprone
siderosis group, but within normal range
Tanner 65 patients with 26
Randomized trial of More rapid improvement in cardiac
thalassemia excluding deferoxamine plus placebo or parameters and in ferritin in the combined
severe cardiac siderosis deferoxamine plus deferiprone. treatment group compared to deferoxamine
(see next line of table) Primary end point change in plus placebo
T2* after 1 year.
Tanner Of 22 patients with 27
These patients were excluded The 15 patients on combination therapy had
Severe cardiac siderosis severe cardiac siderosis, from the randomized trial (ref improved LV ejection fraction and improved
15 received combined 28, previous line), and treated cardiac T2*.
deferiprone/deferoxamine at center discretion (not
randomized)
37
Maggio 213 Randomized comparison of 3 Trial planned for five years. Mean duration of , analysis of
Sequential d/week deferoxamine, 4 follow up 2.5-2.9 years. Trial stopped early mortality and
deferiprone/deferoxamine deferiprone, to 7 d deferiprone; for interim analysis demonstration of greater complications
vs deferiprone Primary outcome: repeated ferritin reduction in the sequential two drug in ref 38
measures ferritin levels regimen; costs and toxicities similar.
Porter, Phase 2, randomized, blinded Trial closed by NIH (sponsor) for slow Submitted for
Deferiprone/DFO cardiac trial of deferoxamine plus accrual. publication
trial (Clinicaltrials.gov placebo vs deferoxamine plus; (Porter J et
designation primary endpoint left ventricular al)
NCT00115349) ejection fraction after one year
therapy

Farmaki 28
52 Retrospective cohort study Global improvements in Endocrinopathies
Aggressive combination Combination DFO and and heart disease with mean ferritin
therapy deferiprone therapy until ferritin decrease from 3421 ng/ml to 87 ng/ml
normal, then continued
deferiprone with reduced DFO

described is based in part on the (unproven) hypothesis that among the chelators as iron status approaches normal. This kind of
deferiprone is the least toxic among the chelators at low iron burden, regimen would probably not be possible with deferasirox mono-
the literature does not provide much guidance on relative safety therapy in the absence of direct safety trials, because the therapeutic

Hematology 2010 453


margin for this drug does not support aggressive chelation when the Cost and International Perspectives on Iron
body iron stores are normal. (The manufacturer suggests a drug Assessment and Chelation Strategies
holiday for deferasirox at ferritin levels less than 500 ng/mL, for In a disorder such as thalassemia, for which the majority of patients
example). live in the developing world, the high cost of new therapies such as
deferasirox cannot be ignored. Viprakasit et al. have addressed the
Deferoxamine current state of affairs for chelators in Asia.34 Cohen has pointed out
a vital corollary to the EPIC trial cardiac substudy results, namely
The role of deferoxamine in the armamentarium against transfu-
that if doses near 40 mg/kg/d of deferasirox are required for optimal
sional iron overload continues to evolve. The experience with this
monotherapy in many patients, the cost per patient per year may be
drug goes back to the 1960s, and the advent of convenient
on the order of $80,000 (based on US wholesale prices).35
subcutaneous pumps and compelling data for subcutaneous efficacy
led the way for widespread deferoxamine therapy beginning more
than 30 years ago. A subset of U.S. and European patients prefer Imperatives for Future Chelator Research in
deferoxamine to the oral options presently, and another subset of Thalassemia
patients have returned to deferoxamine if deferasirox was ineffec- In 2010, heart disease from transfusional iron overload is the main
tive or intolerable for them. cause of death from thalassemia major in countries with safe,
adequate blood supplies. While life expectancy continues to im-
The main challenge now with deferoxamine is to understand how prove, the fact remains that optimal individualized chelation has not
best to use it in combination regimens. As noted above for been achieved for many patients. Adherence to prescribed chelator
deferiprone, various examples of overlapping or sequential use of regimens is an area that deserves great attention, distinct from the
deferiprone and deferoxamine have been reported. Only very biological activity of the chelators themselves. Additional trials of
preliminary trials of deferasirox and deferoxamine in combination combination chelators are needed. The author suspects that it will be
have been published. In this case, clinical practice may be outstrip- impossible for these to be randomized among the currently available
ping the speed of clinical science, because many patients unrespon- medications, for both practical and ethical reasons. For example,
sive to deferasirox alone have been started on combination with with effective oral drugs now available, it is unlikely that subjects
deferoxamine at our site and others. Unfortunately, aside from will accept randomization to deferoxamine arms any longer. This is
recent pilot safety studies,28,29 few data are published on what might an opportunity to use methods of comparative effectiveness re-
be the optimum way to use deferoxamine and deferasirox together. search to compare strategies for improving iron overload even when
confounders are present among patient populations. This will be the
job for the next several years in our field.
Management of Severe Iron Overload, Combination
Therapies, and Head-To-Head Clinical Trials
Where do the recent studies described here leave the field in
Disclosure
Conflict-of-interest disclosure: The author has received research
understanding chelator therapy for severe complications, in particu-
funding from Novartis and Ferrokin.
lar cardiac disease from severe myocardial iron overload? Since the
work of Davis and Porter a decade ago, continuous high-dose
Off-label drug use: Combination chelation regimens are discussed.
deferoxamine has been one accepted approach to congestive heart
failure,30 and now other strategies are in use as well. Understanding
that cardiac disease incidence increases markedly at low cardiac Correspondence
MRI T2* values (high cardiac iron)31 has led by extension to the use Ellis J. Neufeld, MD, PhD, Division of Hematology, Children’s
of intensive regimens, including deferiprone monotherapy,32 for the Hospital Boston, 300 Longwood Ave., Karp 08210, Boston, MA
treatment of low T2* itself as a surrogate marker of cardiac risk. To 02115; Phone: (617) 919-2139; Fax: (617) 730-0934; e-mail:
date, it has not been demonstrated that deferasirox monotherapy, ellis.neufeld@chboston.org
even at high doses, is a satisfactory substitute for continuous
deferoxamine in the setting of the most severe cardiac iron overload, References
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