Professional Documents
Culture Documents
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.
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 $$ $$$$ $-$$
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
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*
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
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