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Ann. N.Y. Acad. Sci. ISSN 0077-8923 ANNALS OF THE NEW YORK ACADEMY OF SCIENCES Issue: Cooley’s Anemia: Ninth Symposium Deferasirox—current knowledge and future challenges John B. Porter Department of Haematology, University College London, London, United Kingdom Address for correspondence: Prof. John B. Porter, Department of Haematology, University College London, Paul O’Gorman Cancer Institute, 72 Huntley Street, London WC1E 6DD, UK. [email protected] Since the last Cooley’s symposium in 2005, our knowledge and clinical experience with deferasirox had advanced considerably. This has been based on prospective multicenter clinical trials, on a scale hitherto unprecedented for chelation therapy, now totalling over 7,400 patients. Here, current knowledge about the clinical effects of deferasirox is described in key areas, namely, the pharmacokinetics and its relevance to mechanisms of action; effects on iron balance; effects on serum ferritin; long-term tolerability; and effects on cardiac iron removal. Challenges for future research include a better understanding of the relationship of serum ferritin to iron balance; the optimal target level and rate of decrease in serum ferritin to achieve a “soft landing,” as ferritin values fall below 500–1,000 μg/L; the use of surrogate markers, such as mT2 , to infer the likely effects on long-term survival; and the safety and efficacy of deferasirox when combined with other chelators. Keywords: deferasirox; pharmacokinetics; matabolism; safety; efficacy; efficiency Pharmacokinetics: relationship to efficacy and clearance of labile plasma iron Because chelateable iron is both transient and fi- nite at any moment in time, effective and efficient chelation therapy requires continuous exposure of chelators to these iron pools. This is achieved most efficiently when a drug, or combination of drugs, have pharmocokinetics that allow effective concen- trations to be present at all times. Previous work with deferoxamine showed that iron excretion was proportional to the area under the curve (AUC) of the chelator 1 and early clinical studies also showed that this was true for deferasirox 2 which has a rel- atively long plasma half life of 11–19 h 3 achieving steady state trough concentrations of approximately 20 M at once daily doses of 20 mg/kg/day. 4 Good dose proportionality has also been demonstrated at single doses between 2.5 and 80 mg/kg/day. 3 Interestingly, the current recommendation in the drug labelling of administering deferasirox before meals may not be optimal, as PK single-dose stud- ies have shown increased absorption after meals. 5 Further work is ongoing to determine the relative tolerability and efficacy of repeated administration post-prandially. There are at least two potential consequences of continuous exposure to effective chelator concen- trations: first, increased efficacy of iron chelation and second, improved removal of labile iron pools. There is good evidence of both with deferasirox. The efficiency of iron chelation can be defined as the percentage of the administered dose that is ex- creted in the iron bound form. The efficiency of de- ferasirox in 1-year preregistration studies was 27% and remained constant over dose ranges between 10 and 30 mg/kg/day. 6 This compared with 13% (range 10–17%) efficiency with deferoxamine given five nights a week sc in the same study. Reports with deferiprone given at 25 mg/kg/day show low efficiencies with approximately 4% of administered dose eliminated in urine bound to iron. 7 This high efficiency for deferasirox is most likely to be con- sequent to the prolonged plasma half life which is proportionately linked to AUC values. 2 Additional factors that contribute to this relatively high effi- ciency are the high iron binding constant and the metabolism of deferasirox mainly to species that re- tain their ability to bind iron. 8 Transferrin independent plasma iron species, that are present in iron overload, can be measured in several ways, either as total nontransferrin plasma doi: 10.1111/j.1749-6632.2010.05582.x Ann. N.Y. Acad. Sci. 1202 (2010) 87–93 c 2010 New York Academy of Sciences. 87

Deferasirox—current knowledge and future challenges

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Page 1: Deferasirox—current knowledge and future challenges

Ann. N.Y. Acad. Sci. ISSN 0077-8923

ANNALS OF THE NEW YORK ACADEMY OF SCIENCESIssue: Cooley’s Anemia: Ninth Symposium

Deferasirox—current knowledge and future challenges

John B. PorterDepartment of Haematology, University College London, London, United Kingdom

Address for correspondence: Prof. John B. Porter, Department of Haematology, University College London, Paul O’GormanCancer Institute, 72 Huntley Street, London WC1E 6DD, UK. [email protected]

Since the last Cooley’s symposium in 2005, our knowledge and clinical experience with deferasirox had advancedconsiderably. This has been based on prospective multicenter clinical trials, on a scale hitherto unprecedented forchelation therapy, now totalling over 7,400 patients. Here, current knowledge about the clinical effects of deferasiroxis described in key areas, namely, the pharmacokinetics and its relevance to mechanisms of action; effects on ironbalance; effects on serum ferritin; long-term tolerability; and effects on cardiac iron removal. Challenges for futureresearch include a better understanding of the relationship of serum ferritin to iron balance; the optimal target leveland rate of decrease in serum ferritin to achieve a “soft landing,” as ferritin values fall below 500–1,000 μg/L; the useof surrogate markers, such as mT2∗, to infer the likely effects on long-term survival; and the safety and efficacy ofdeferasirox when combined with other chelators.

Keywords: deferasirox; pharmacokinetics; matabolism; safety; efficacy; efficiency

Pharmacokinetics: relationship to efficacyand clearance of labile plasma iron

Because chelateable iron is both transient and fi-nite at any moment in time, effective and efficientchelation therapy requires continuous exposure ofchelators to these iron pools. This is achieved mostefficiently when a drug, or combination of drugs,have pharmocokinetics that allow effective concen-trations to be present at all times. Previous workwith deferoxamine showed that iron excretion wasproportional to the area under the curve (AUC) ofthe chelator1 and early clinical studies also showedthat this was true for deferasirox2 which has a rel-atively long plasma half life of 11–19 h3 achievingsteady state trough concentrations of approximately20 �M at once daily doses of 20 mg/kg/day.4 Gooddose proportionality has also been demonstratedat single doses between 2.5 and 80 mg/kg/day.3

Interestingly, the current recommendation in thedrug labelling of administering deferasirox beforemeals may not be optimal, as PK single-dose stud-ies have shown increased absorption after meals.5

Further work is ongoing to determine the relativetolerability and efficacy of repeated administrationpost-prandially.

There are at least two potential consequences ofcontinuous exposure to effective chelator concen-trations: first, increased efficacy of iron chelationand second, improved removal of labile iron pools.There is good evidence of both with deferasirox.The efficiency of iron chelation can be defined asthe percentage of the administered dose that is ex-creted in the iron bound form. The efficiency of de-ferasirox in 1-year preregistration studies was 27%and remained constant over dose ranges between10 and 30 mg/kg/day.6 This compared with 13%(range 10–17%) efficiency with deferoxamine givenfive nights a week sc in the same study. Reportswith deferiprone given at 25 mg/kg/day show lowefficiencies with approximately 4% of administereddose eliminated in urine bound to iron.7 This highefficiency for deferasirox is most likely to be con-sequent to the prolonged plasma half life which isproportionately linked to AUC values.2 Additionalfactors that contribute to this relatively high effi-ciency are the high iron binding constant and themetabolism of deferasirox mainly to species that re-tain their ability to bind iron.8

Transferrin independent plasma iron species, thatare present in iron overload, can be measured inseveral ways, either as total nontransferrin plasma

doi: 10.1111/j.1749-6632.2010.05582.xAnn. N.Y. Acad. Sci. 1202 (2010) 87–93 c© 2010 New York Academy of Sciences. 87

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Deferasirox: An update Porter

Figure 1. LPI is shown at baseline 12, 28, and 52 weeks, pre andpost daily dosing with deferasirox for thalassemia major patientstreated on the EPIC study. The broken line represents the upperlimit of “normal” values for LPI. Reprinted from Porter et al.,13

with permission from Elsevier.

bound iron (NTBI) or as a component that iscapable of generating oxidative stress namely la-bile plasma iron (LPI). These are only transientlyand incompletely removed while chelators remainpresent in this compartment.9,10 Deferasirox hasbeen shown to remove LPI effectively and rapidlyafter singe doses, but also progressively with longer-term exposure in thalassemia major patients bothin the Escalator trial11 and in the EPIC trial in over1,000 patients12,13 (Fig. 1). This contrasts with theintermittent and transient removal, with deferox-amine and deferiprone, that is consistent with theirknown pharmacokinetics.10,14

Probability of iron balance: impact of doseand transfusion rate

Despite clinical experience with deferoxamine anddeferiprone going back several decades, it is im-portant to note that knowledge of the impact ofdose and transfusional iron loading rates on ironbalance had been lacking until now. Short-termformal metabolic iron balance studies previouslyshowed that iron excretion averaged 0.13, 0.34, and0.56 mg/kg/day at doses of 10, 20, and 40 mg/kg/day,respectively, predicting equilibrium or negative ironbalance at daily does of 20 mg and above.2 Recentprospective studies of iron balance over one year,with a range of doses and transfusion rates15 haveshown that the blood transfusion rate has a keyimpact on the necessary effective dose of both de-ferasirox and deferoxamine. This understanding hasbeen made possible by the key findings of Angelucciand colleagues,16 who previously showed that liveriron concentration (LIC) relates precisely to total

body iron stores and hence changes in LIC, togetherwith the iron loading rate from transfusion can beused to derive in iron balance over defined peri-ods of time. One-year studies show that proportionof patients in negative iron balance at 20 mg/kg is75% at low transfusion rates (<0.3 mg/kg/day) butfalls to 55% and 47%, respectively, at intermedi-ate (0.3–0.5 mg/kg/day) and high (>0.5 mg/kg/day)transfusion rates15 (Fig. 2). This can be increased at30 mg/kg to 96% in those who have a low transfu-sional loading, but at intermediate and high trans-fusional loading rates, the proportion falls to ap-proximately 80% of patients. An important findinghere is that at low transfusion rates, 96% of patientsare in negative iron balance. This means that socalled “nonresponders” at higher transfusion ratesare likely to result from relative rather than absolutedifferences in drug metabolism between patients.In other words, there is unlikely to be a substantialsubset of patients whose drug metabolism differsfundamentally from the patient majority. This im-plies that increased dosing and optimizing of timingof drug administration in relation to meals is likelyto maximize the proportion of responders with re-spect to iron balance.

Effects on serum ferritin

Although body iron load has been estimated to ac-count for only between 30%17 and 60%18 of thevariability in serum ferritin, this remains the mostconvenient and repeatedly performed estimate ofbody iron load. At least six studies have shown aclear effect of long-term control of serum ferritinon prognosis and therefore ferritin trends with de-ferasirox are important to monitoring response totherapy. A study relating changes in LIC to serumferritin over a range of underlying anemias, includ-ing thalassemia major, has shown a significant cor-relation (r = 0.59) between the serum ferritin trendand LIC trend with deferasirox19 (Fig. 3). Of interestin this study, the intercept of the delta LIC and fer-ritin ferritin axes shows that a reduction in LIC overone year (and hence a negative iron balance) of be-tween 4 and 7 mg/day dry wt may not be associatedwith a decrease in serum ferritin (Fig. 3). This mayexplain why some patients receiving what appear tobe adequate deferasirox doses do not show an earlyfalls in serum ferritin. A mechanistic explanationfor this may reside from the preferential removal ofiron from the hepatocytes, rather than macrophages

88 Ann. N.Y. Acad. Sci. 1202 (2010) 87–93 c© 2010 New York Academy of Sciences.

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Figure 2. The change in LIC at one year is shown, analysed according to deferasirox dose and the ongoing transfusional ironlading rate. Iron loading rates are divided into low (<0.3 mg/kg/day), intermediate (0.3–0.5 mg/kg/day, representing the majorityof patients), and high (>0.5 mg/kg/day). It can be seen that LIC decreases (negative iron balance) in 96% of patients receiving lowtransfusion and 30 mg/kg/day of deferasirox. At intermediate and high transfusion rates, a lower proportion of patients (82–83%)are in negative iron balance at the same dose. Reproduced with permission of the American Society of Hematology (ASH), fromBlood, Cohen AR, et al. 111, 2, 2008; permission conveyed through Copyright Clearance Center, Inc.

that was demonstrated in a study of iron distribu-tion taken from liver biopsies taken at baseline (BL)and at one year.20 Since glycosylated serum ferritin isderived from marcrophages rather than hepatocytesfor values up to approximately 4000 �g/L,17 prefer-ential removal from hepatocytes by deferasirox maynot be proportionately reflected by the serum fer-ritin trend.

It is clear however that with longer-term treat-ment, the proportion of patients with falling ferritinvalues increases. Indeed, the percentage of patientsachieving serum ferritin levels <1000 �g/L in longterm follow up increases gradually from 13.5% inyear 1, 18.6% in year 2, 25.7% in year 3, 32.5% in year4, and 36.7% at 4–5 years.21 Encouragingly, this hasbeen achieved without signs of decreased drug tol-erability in 174 adults and pediatric patients achiev-ing serum ferritin values <1,000 �g/L with increasein the proportion of patients with creatinine in-creases > 33% above BL and ULN or with ALTs >

10x ULN.21 Furthermore the large scale one yearEPIC study involving >1,700 patients, 937 with tha-lassemia major, shows that dosing can be adjustedsuccessfully based on baseline ferritin, trends in fer-ritin and rates of transfusional iron loading.22 Inthis study, dose adjustment occurred at a median of24 weeks of treatment. Based on these findings, aswell as the theoretical considerations discussed ear-lier, dose escalation based on ferritin trends would

typically be considered only after at least threemonths of treatment.

Tolerability profile

Because iron chelation therapy has the potential notonly to remove potentially damaging iron speciesbut also potentially useful iron pools that are nec-essary for synthesis of key metalloenzymes, the po-tential unwanted effects of over chelation need tobe looked for, especially when iron is removed toorapidly or to critically low levels. As experience withdeferasirox has now extended to five years, its safetyprofile is increasingly understood.23

In the core pre-registration trials, adverse effectswere generally mild, including transient gastroin-testinal events in 15%, skin rash in 11% and mild,dose-dependent increases in serum creatinine in38% of patients which generally remained withinthe normal range and never exceeded two timesthe upper limit of normal. Increased liver enzymes,judged to be related to deferasirox were observedin two patients only. No drug-related agranulocy-tosis was observed. These pre-registration studies(studies 107 and 108) have now been extended, upto 4.5–5 years of treatment with the emergence ofimportant principles for management. Importantly,the incidence of adverse events has gradually de-creased over this time in 345 TM patients, at a meanfinal dose of 22 mg/kg/day.24 Importantly, the mean

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Figure 3. Relationship of changes in ferritin to LIC changes is shown for different disease groups (squares, thalassemia major;diamonds, MDS; triangles, DBA; circles, other anemias). When analyzing the data across combined disease groups (regressionline not shown), an overall LIC change over one year is predicted as −3.36 + 0.003 times change in ferritin (Pearson’s correlationcoefficient = 0.59). Based on the slope of this linear model, a reduction in ferritin of 1000 �g/L predicts a reduction of approximately6 mg Fe/g dw in LIC. NB: Based on the y axis intercept when there is no change in ferritin (x = 0), a decrease in LIC of 4–7 mg/g dwis seen without a decrement in serum ferritin. Based on the x-axis intercept when y = 0, a ferritin increase may be seen when LIC isunaltered. (Porter, Galanello et al., EJH (2008) 80, 168–76). c©2008 John Wiley & Sons, Inc.

serum creatinine has shown no signs of long-termprogression. In 137 pediatric patients, followed fora median of 51 months, the mean change in ferritinwas 947 �g/L, the frequency of investigator-reportedAEs decreased over long-term treatment with noprogressive effects on renal or hepatic function andwith no negative impact on growth or sexual devel-opment.25

A further emerging aspect of tolerability is ex-perience at doses >30 mg/kg/day. This has beengained in extension phases of the core studies, aswell as with a subset of patients 252 Middle East-ern patients with heavy liver iron loading (meanLIC 19 mg/day dry wt) taking part, in a trial knowsas the “Escalator” study.26 Reported experience to-tals 228 patients at >30 mg/kg/day for a medianof 36 weeks without a trend for increasing serumcreatinine but with a clear trend for decreasingserum ferritin after dose escalation.26 Understand-ing of the tolerability of deferasirox has also beenincreased as a result of the large-scale one year EPICtrial.22 Tolerability was generally in line with pre-registration studies: approximately 4% of patientshad serum creatinine increases >33% above BL andabove the ULN on two consecutive visits but therewere no progressive increases. 0.5% of patients hadincrease in ALT >10 x ULN on two consecutive vis-

its while levels were elevated at BL in four of thesepatients.22

Prevention and removal of cardiac irondeposition

Following initial observational studies of significantimprovements in myocardial T2∗ with deferasiroxover one year of treatment,27 large-scale prospec-tive studies have now been undertaken. In a sub-study of the large EPIC trial, in 105 patients withestablished mild to moderate excess of myocardialiron, a significant reduction in cardiac iron wasseen at a mean dose of 32.6 mg/kg/day. For pa-tients with BL T2∗ values of 10–20 ms, the T2∗ in-creased significantly from 14.6 to 17.4 ms, whereasfor patients with BL T2∗ values <10 ms the T2∗

also increased significantly from 7.4 to 8.2 ms over1 year28 (Fig. 4). Experience for up to 2 years nowshows further progressive improvement in mT2∗.29

A further sub-study examined trends of mT2∗ in75 patients without preexisting myocardial loading.Deferasirox prevented accumulation of cardiac ironin all cases and significantly increased LVEF eventhough this was within the accepted limits of nor-mal at BL.30 It is not clear whether this increase inLVEF results from removal of small amounts of my-ocardial iron that is not detectable by mT2∗ or is due

90 Ann. N.Y. Acad. Sci. 1202 (2010) 87–93 c© 2010 New York Academy of Sciences.

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Figure 4. Mycocardial T2∗

is shown at baseline (BL) and after 12 months of deferasirox treatment for all patients (n = 105, solidline) as geometric mean ± 95% confidence intervals, as well as for patient subsets with BL values 10–20 ms or < 10 m (brokenlines). The mean actual dose over one year was 32.6 mg/kg/day. c© 2009 Ferrata Storti Foundation. Pennell D, Porter JB, CappelliniMD, Chan LL, El-Beshlawy A, Aydinok Y, et al. Efficacy and safety of deferasirox in reducing myocardial siderosis in patients withb-thalassemia major. Haematologica 2009; 94(Suppl 2):abst 193.

to other effects such as those on vascular endothelialfunction.

Future challenges

Rapid advances in understanding of the efficacy andsafety of deferasirox of the last five years, based onlarge scale prospective trials, mean that evidence-based information about the probability of bothresponse and the probability of side effects are avail-able in a way that has not been previously possiblewith other chelation therapy regimens. Despite this,there remains important work to do and questionsto answer for thalassemia patients.

Further work on the use of serum ferritin to mon-itor response and to maximise tolerability would bevaluable. There may be factors that impact on fer-ritin trends in addition to those already identifiedsuch as dose, compliance, and transfusional load-ing rates. It is worth noting that such understand-ing is also required with other chelation regimes.Preliminary work suggesting that deferasirox has apropensity for hepatocellular rather than reticulo-endothelial iron (see earlier), in contrast to de-feriprone where the converse occurs, may explainwhy initial deceases in LIC may not be immedi-ately reflected by changes in serum ferritin (Fig. 3).As the proportion of patients with serum ferritinvalues <1,000 �g/L increases, there will be a needto understand whether there is a minimum ferritin

that can be safely achieved. An important questionis whether the principle driver of drug related tox-icity is the rate of decrease in body iron and/or theabsolute body iron level; in short, how slowly do weneed to reduce serum ferritin in order to achievea “soft landing” as we achieve low serum ferritinvalues? As the rate of transfusion has been shownto impact on chelation efficiency,6 it is also possi-ble that the rate of iron loading from transfusionimpacts on optimal rate of ferritin reduction andits safe minimal value; an ongoing trial with un-transfused thalassemia intermedia is likely to clarifythis latter point.

The long-term effects on survival and morbidityare unknown at this time for obvious tautologicalreasons. However, it is going to be difficult to infersuch effects in the very clear way that was previ-ously possible in cohorts of patients treated withdeferoxamine, where the comparator to deferoxam-ine was “no chelation” therapy. Retrospective at-tempts to ascribe changes in long-term survival toshort term changes in chelation regimens or otherchanges in management are open to a variety ofinterpretations. On the other hand, a 10 or 20 yearprospective study, comparing deferasirox with otherforms of chelation in matched populations is un-likely to be practically achievable. Therefore surro-gate markers of survival are likely to be the best indi-cators of long-term effects on mortality for the time

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being. The most important of these is the recentlyestablished link of myocardial T2∗ to the risk of de-veloping iron mediated heart failure prospectively.31

The absence of new cases of myocardial iron loadingin prospective one year studies is encouraging. Fu-ture studies therefore should aim to establish in thelong term whether the proportion of patients withincreased myocardial iron loading steadily dimin-ishes with deferasirox therapy. Finally there is in-creasing interest in the use of deferasirox combinedwith deferoxamine in selected cases. The safety andefficacy of such an approach will need to be tested inwell designed prospective trials in order to establishwhere this might fit in with overall management oftransfusional iron overload in thalassemia major.

Conflicts of interest

The author declares no conflicts of interest.

References

1. Porter, J.B. et al. 1998. Iron balance and chelation efficiencyfollowing single dose depot desferrioxamine. Blood 92(Suppl1): 325a (Abstract).

2. Nisbet-Brown, E. et al. 2003. Effectiveness and safety ofICL670 in iron-loaded patients with thalassaemia: a ran-domised, double-blind, placebo-controlled, dose-escalationtrial. Lancet 361: 1597–1602.

3. Galanello, R. et al. 2003. Safety, tolerability, and pharmacoki-netics of ICL670, a new orally active iron-chelating agent inpatients with transfusion-dependent iron overload due tobeta-thalassemia. J. Clin. Pharmacol. 43: 565–572.

4. Piga, A. et al. 2006. Randomized phase II trial of deferasirox(Exjade, ICL670), a once-daily, orally-administered ironchelator, in comparison to deferoxamine in thalassemia pa-tients with transfusional iron overload. Haematologica. 91:873–880.

5. Galanello, R. et al. 2008. Effect of food, type of food, and timeof food intake on deferasirox bioavailability: recommenda-tions for an optimal deferasirox administration regimen.J. Clin. Pharmacol. 48: 428–435.

6. Porter, J. et al. 2005. Iron chelation efficiency of de-ferasirox (Exjade, ICL670) in patients with transfusionalHemosiderosis. Blood 106: 2690 (Abstract).

7. Hoffbrand, A.V., A. Cohen & C. Hershko. 2003. Role ofdeferiprone in chelation therapy for transfusional iron over-load. Blood 102: 17–24.

8. Waldmeier, F.J. et al. 2010. Pharmacokinetics, metabolismand disposition of deferasirox in {beta}-thalassemia pa-tients with transfusion-dependent iron overload who are atpharmacokinetic steady state. Drug Metab. Dispos. 38: 808–816.

9. Porter, J.B. et al. 2005. Recent insights into interactionsof deferoxamine with cellular and plasma iron pools: im-plications for clinical use. Ann. N.Y. Acad. Sci. 1054: 155–168.

10. Cabantchik, Z.I. et al. 2005. LPI-labile plasma iron in ironoverload. Best Pract. Res. Clin. Haematol. 18: 277–287.

11. Daar, S. et al. 2009. Reduction in labile plasma iron duringtreatment with deferasirox, a once-daily oral iron chelator,in heavily iron-overloaded patients with beta-thalassaemia.Eur. J. Haematol. 82: 454–457.

12. Porter, J. et al. 2008. Effect of deferasirox (Exjade R©) onlabile plasma iron levels in heavily iron-overloaded pa-tients with transfusion-dependent Anemias enrolled in thelarge-scale, prospective 1-year EPIC trial. Blood 112: 3881(Abstract).

13. Porter, J.B. 2009. Optimizing iron chelation strategies inbeta-thalassaemia major. Blood Rev. 23(Suppl 1): S3–S7.

14. Zanninelli, G., W. Breuer & Z.I. Cabantchik. 2009. Dailylabile plasma iron as an indicator of chelator activity inthalassaemia major patients. Br. J. Haematol. 147: 744–751.

15. Cohen, A.R., E. Glimm & J.B. Porter. 2008. Effect of trans-fusional iron intake on response to chelation therapy in-thalassemia major. Blood 111: 583–587.

16. Angelucci, E. et al. 2000. Hepatic iron concentration andtotal body iron stores in thalassemia major. N. Engl. J. Med.343: 327–331.

17. Worwood, M. et al. 1980. Binding of serum ferritin to con-canavalin A: patients with homozygous beta thalassaemiaand transfusional iron overload. Br. J. Haematol. 46: 409–416.

18. Brittenham, G.M. et al. 1993. Hepatic iron stores and plasmaferritin concentration in patients with sickle cell anemia andthalassemia major. Am. J. Hematol. 42: 81–85.

19. Porter, J. et al. 2008. Relative response of patientswith myelodysplastic syndromes and other transfusion-dependent anaemias to deferasirox (ICL670): a 1-yr prospec-tive study. Eur. J. Haematol. 80: 168–176.

20. Deugnier, Y. et al. 2005. Semi-quantitative assessmentof hemosiderin distribution accurately reflects reductionsin liver iron concentration following therapy with de-ferasirox (Exjade R©, ICL670) or deferoxamine in patientswith transfusion-dependent anemia. Blood 106(Suppl 11):2708 (Abstract).

21. Porter, J.B. et al. 2008. Safety of deferasirox (Exjade(R))in patients with transfusion-dependent anemias and ironoverload who achieve serum ferritin levels <1000 Ng/Mlduring long-term treatment. Blood 112: 5423 (Abstract).

22. Cappellini, M. et al. 2010. Tailoring iron chelation by ironintake and serum ferritin: the prospective EPIC study of de-ferasirox in 1744 patients with transfusion-dependent ane-mias. Haematologica. 95: 557–566.

23. Cappellini, M.D. et al. 2006. A phase 3 study of deferasirox(ICL670), a once-daily oral iron chelator, in patients withbeta-thalassemia. Blood 107: 3455–3462.

24. Cappellini, M. et al. 2008. Efficacy and safety of deferasirox(Exjade R©) with up to 4.5 years of treatment in patientswith thalassemia major: a pooled analysis. Blood 112: 5411(Abstract).

25. Piga, A. et al. 2008. Cumulative efficacy and safety of 5-yeardeferasirox (Exjade R©) treatment in pediatric patients withthalassemia major: a Phase II Multicenter prospective trial.2008 112: 5413 (Abstract).

92 Ann. N.Y. Acad. Sci. 1202 (2010) 87–93 c© 2010 New York Academy of Sciences.

Page 7: Deferasirox—current knowledge and future challenges

Porter Deferasirox: An update

26. Taher, A. et al. 2009. Efficacy and safety of deferasirox dosesof >30 mg/kg per d in patients with transfusion-dependentanaemia and iron overload. Br. J. Haematol. 147: 752–759.

27. Porter, J.B. et al. 2005. Improved myocardial T2∗ in trans-fusion dependent anemias receiving ICL670 (Deferasirox).Blood 106: 3600 (Abstract).

28. Pennell, D.J. et al. 2008. Efficacy and safety of deferasirox(Exjade R©) in reducing cardiac iron in patients with �-thalassemia major: results from the cardiac substudy of theEPIC trial. Blood 112: 3873 (Abstract).

29. Pennell, D.J. et al. 2010. Efficacy of deferasirox in reducingand preventing cardiac iron overload in beta-thalassemia.Blood 115: 2364–2371.

30. Pennell, D. et al. 2008. Efficacy and safety of deferasirox(Exjade R©) in preventing cardiac iron overload in �-thalassemia patients with normal baseline cardiac iron: re-sults from the cardiac substudy of the EPIC trial. Blood 112:3874 (Abstract).

31. Kirk, P. et al. 2009. Cardiac T2∗ magnetic resonance forprediction of cardiac complications in thalassemia major.Circulation 120: 1961–1968.

Ann. N.Y. Acad. Sci. 1202 (2010) 87–93 c© 2010 New York Academy of Sciences. 93