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Leukemia Research 35 (2011) 1131– 1135

Contents lists available at ScienceDirect

Leukemia Research

jo ur nal homep age: www.elsev ier .com/ locate / leukres

eeting report

linical management of gastrointestinal disturbances in patients withyelodysplastic syndromes receiving iron chelation treatment with deferasirox

lorian Noltea,∗, Emanuele Angeluccib, Photis Berisc, Alan Macwhannelld, Dominik Selleslage,hristiane Schumanna, Blanca Xicoyf, Antonio Almeidag, Agnés Guerci-Breslerh,hamer Sliwai, Petra Muusj, John Porterk, Wolf-K. Hofmanna

Department of Hematology and Oncology, University Hospital, Theodor-Kutzer-Ufer 1-3, D- 68167 Mannheim, GermanyHematology Unit, Ospedale Oncologico di riferimento regionale “Armando Businco”, Cagliari, ItalyHematology Service, Geneva University Hospitals, SwitzerlandNew Cross Hospital Wolverhampton, United KingdomDepartment of Hematology, Hospital St-Jan, Bruges, BelgiumDepartment of Hematology, Hospital Germans Trias i Pujol, Badalona, SpainInstituto Português de Oncologia de Lisboa, PortugalService d’Hématologie,CHU Brabois, Vandoeuvre-lès-Nancy, FranceHietzing Hospital 5.Med, Oncology, AustriaRadboud University Nijmegen Medical Centre, The NetherlandsUniversity College London, London, United Kingdom

r t i c l e i n f o

rticle history:eceived 31 May 2011eceived in revised form 10 June 2011ccepted 11 June 2011vailable online 6 July 2011

a b s t r a c t

Myelodysplastic syndromes are characterized by ineffective hematopoiesis resulting in peripheralcytopenias. The majority of patients is dependent on regular transfusions of packed red blood cells lead-ing to a secondary iron overload which might result in organ damage. Therefore, sufficient iron chelationtherapy in selected patients is mandatory. Deferasirox (DFX) is an orally administered iron chelator whichhas been highly efficient in the treatment of secondary iron overload. Most frequent side effects of DFX are

eywords:yelodysplastic syndrome

ransfusionron overloadhelationastrointestinal disturbanceseferasirox

gastrointestinal disturbances, which leads in some patients to low adherence to the therapy. An expertpanel met in Lisbon in July 2010 to develop recommendations on prevention and management of GIdisturbances based on existing data and personal experiences.

© 2011 Elsevier Ltd. All rights reserved.

. Introduction

Myelodysplastic syndromes (MDS) comprise a heterogenousroup of clonal myeloid disorders characterized by ineffectiveematopoiesis resulting in peripheral cytopenias and an increasedisk of evolution to acute myeloid leukemia (AML). The overallncidence of MDS is 5/100.000/year. However, MDS are mainly

disease of the elderly with an sharp increase in the incidencen the decades above 60 years [1]. Diagnosis of MDS is based on

orphological findings and cytogenetical analyses. Classification

ystems as the FAB- and WHO-classification and the Interna-ional Prognostic Scoring System provide useful tools to estimatehe prognosis of these patients [2,3]. Little is known about the

∗ Corresponding author. Tel.: +49 621 383 6955; fax: +49 621 383 6969.E-mail address: florian.nolte@medma.uni-heidelberg.de (F. Nolte).

145-2126/$ – see front matter © 2011 Elsevier Ltd. All rights reserved.oi:10.1016/j.leukres.2011.06.013

underlying pathomechanisms causing MDS. Epigenetic changessuch as DNA hypermethylation and histone deacetylation havebeen identified as potential mechanisms in the development andprogression of MDS which already resulted in promising thera-peutic approaches in a subset of patients. In addition, the activityof immune modulatory agents in patients with early stage MDSand isolated deletion 5q has significantly improved the therapeuticoptions in MDS.

Despite these recent advances in the management of MDS, themajority of patients will depend on regular transfusions of packedred blood cells (PRBC) during the course of their disease. Recur-rent PRBC transfusions lead to iron overload which might causeorgan damage of the liver, the heart and the endocrine glands.

Introduction of deferoxamine in the treatment of patients with tha-lassemia and other inheritable anemias led to a significant increaseof survival. Several publications indicate that compliance withiron chelation therapy in patients with transfusion dependent iron

1 Resear

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verload might result in a survival benefit in these patients [4–6].eferioxamine has been the standard of care over the last 30 years

or removal of excess body iron. However, due to the low bioavail-bility and the short plasma half-life, it has to be administered as aontinuous subcutaneous infusion which particularly in the olderDS patients often is inconvenient and leads to low complianceith the therapy [5].

Deferasirox (DFX) is a once-daily, orally administered ironhelator that has been approved for the treatment of iron overloadn patients with transfusion dependent anemias. Although usually

ell tolerated, gastrointestinal disturbances particularly diarrheare well recognized adverse events and do affect the quality of lifef treated patients.

. Pharmacokinetics of deferasirox

DFX is a once-daily, orally administered tridentate iron chelator.f DFX is taken concomitantly with food, bioavailability is highlynfluenced by the type of food, e.g. the caloric content and theat content. In contrast, this is not the case when DFX is taken ateast 30 min before a meal [7]. Pharmacokonetic studies point ton mean oral bioavailability rate of about 70–100%, which mighte increased when taken with food. DFX is mainly excreted viahe feces. It is estimated that of the excreted dose fraction about0% is unchanged DFX consisting of (1) a small fraction unabsorbedFX, (2) DFX that has been eliminated via the bile or the gut wall,artly due to a first-pass elimination and (3) the DFX metabolites8]. Since DFX is metabolized by CYP3A4 and CYP2C8 enzymeso-administration of inducers and/or inhibitors of these enzymeshould be avoided or done with caution. Maximum plasma concen-rations occur after a median time of 2.5 h and plasma half-time ofFX is about 10 h.

. Iron chelation treatment in MDS

Recently, DFX has been approved for treatment of transfusionependent iron overload by the EMEA and the FDA. Treatmentuidelines mainly from consensus panels recommend initiation ofron chelation for transfusion dependent low and intermediate-1

DS patients with serum ferritin levels >1000 ng/ml, depending onransfusion rate and life expectancy of at least one year. Moreover,ince iron overload might adversely affect outcome after allogenictem cell transplantation (alloSCT), patients who are candidates forlloSCT might be considered for iron chelation therapy as well [9].n most trials on iron chelation therapy number of MDS patientss small and therefore only preliminary conclusions concerning

anagement of iron chelation in MDS can be drawn [10–14]. In phase II trial 176 MDS patients with low and intermediate-1 risknd transfusional iron overload were treated with DFX. Besides aecrease in serum ferritin, List and co-workers could show thatFX also led to a sustained suppression in labile plasma iron (LPI),

redox active form from transferrin-free plasma iron, that is rapidlyemoved by iron chelation [15]. The largest trial on DFX in treat-ent of transfusion dependent iron overload was the so-called

PIC trial (Evaluation of Patients’ Iron Chelation with Exjade) whichas prospective, multicentric and open-labeled. More than 1700atients were enrolled including 341 MDS patients. Median agef MDS patients was 68 years and baseline serum ferritin was730 ng/ml (range: 951–9465). Approximately 50% of the patientsad received prior iron chelation therapy. The mean average dosef DFX was 19 mg/kg/d. Median serum ferritin levels significantly

ecreased from baseline (median 253 ng/ml). In patients who com-leted 1 year of DFX treatment (n = 175; 51%) median decrease inerum ferritin was 606 ng/ml. As in the aforementioned trial, DFXas able to eliminate LPI in these patients [16].

ch 35 (2011) 1131– 1135

Beside the fact that DFX can reduce serum ferritin levels aswell as LPI levels there is still debate on whether iron chelationmight prolong survival in transfusion dependent MDS patients.High transfusion burden and high serum ferritin levels are associ-ated with inferior outcome [17]. In a prospective non-randomizedstudy by Rose and co-workers, MDS patients adequately treatedwith iron chelation showed a longer overall survival as comparedto the suboptimally chelated and non-chelated patients [18]. How-ever, since this study was not randomized and the causes of deathwere similar between the subgroups conclusions from this studyshould be drawn with caution.

The only cure for patients with MDS is alloSCT. The introduc-tion of reduced intensity conditioning (RIC) regimen allows for thetransplantation of older and often co-morbid patients. It has beenrecognized that transfusion burden as well as elevated serum fer-ritin levels prior to alloSCT are associated with inferior outcome[19,20].

In summary, several lines of evidence suggest a need for ade-quate iron chelation in selected patients with low risk MDS or thosebeing considered for alloSCT. Since iron chelation is a chronic treat-ment in most MDS patients, prevention and management of sideeffects is an absolute requirement.

4. Gastrointestinal side effects of iron chelation treatmentin MDS-patients using Deferasirox

Most frequent AEs in the EPIC trial were gastrointestinal distur-bances. Diarrhea was observed in 111 (33%) patients: mild in 74patients (22%), moderate in 29 (8%) and severe in 8 (2%) patients,respectively. Of 166 patients who did not complete 1 year ofDFX treatment 44 (13%) discontinued due to adverse events beingrelated to the study drug. Of these 25 had AEs that were gastroin-testinal in nature. GI problems such as nausea, vomiting, abdominalpain and constipation occurred in 45 (13%), 26 (8%), 26 (8%) and 21(6%) patients, respectively, but were mild or moderate and did notlead to discontinuation of DFX treatment in the majority of patients.Interestingly, GI disturbances were much more frequent in the MDScohort when compared to the non-MDS cohort (mainly thalassemiapatients) in this trial, indicating that elderly MDS patients might bemore susceptible to drug related AEs compared to younger (tha-lassemia) patients. In addition, in a post hoc analysis GI disturbancesin MDS patients were not related to the different dose categoriesused in the trial and were not related to age in this cohort. Ithas been assumed that particularly GI events might increase withdecreasing ferritin levels in a sense of a relative overdosing of DFX.Nonetheless, the EPIC trial could not show a significant associationof a decrease in serum ferritin with an increase in GI events. Thisissue, however, is under further investigation. Dose escalation ofDFX did not lead to an increase in GI AEs. This is in accordance withthe fact that there was no difference in the incidence of diarrheabetween MDS patients of the EPIC trial and patients in the US108trail which included 47 MDS patients receiving lower doses of DFX.However, the exact mechanisms of gastrointestinal intolerabilitiesare not yet fully understood. Osmotic mechanisms might play a rolein the development of diarrhea. Moreover, since DFX contains lac-tose, patients with lactose intolerance might be more susceptibleto GI disturbances such as diarrhea.

About 50% of the MDS patients in the EPIC trial were chelation-naive, the remaining patients had received different prior chelationtherapies, e.g. deferioxamine, deferiprone, combination therapiesand one patient had previously received DFX. However, AEs were

not significantly different between the chelation-naive and notnaive cohort but there seemed to be a trend towards a higherdiarrhea rate and abdominal pain rate in the pretreated patients.However, numbers were small and therefore clear conclusions

Research 35 (2011) 1131– 1135 1133

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Table 1Recommendations for preventing GI disturbances.

Time of administration– Discuss with the patient taking DFX (at least 30 min) before breakfastor dinner– Suggest a pre-prandial evening DFX dosing for practical reasons (basedon expert experience)– Do not recommend to take with food– Need data from randomized clinical trials

Starting dose and escalation– Different approaches exist regarding the initial dosing in naivepatients and dose-escalation studies– Concern that escalation, if not done in timely fashion, might affect the(perceived) efficacy of the treatment and therefore adherence– Need further trial data about the impact of dose-escalation (startingwith a lower dose) on the frequency and severity of GI AEs before anyrecommendation can be given– Anecdotal reports suggest reduction of the frequency and severity ofGI disturbances with b.i.d. dosing. Considering the negative impact onpatient adherence and the lack of PK and clinical data experts adviseagainst divided dosing

Use of prophylactics– Do not use prophylactic anti-acidic drugs (PPI); treat onlysymptomatically if needed– Patients with lactose intolerance are not frequent. There is not enoughevidence to recommend excluding for lactose intolerance beforetreatment with deferasirox, or to recommend the prophylactic use of

F. Nolte et al. / Leukemia

ould not be drawn from this finding. In thalassemia the propor-ion of patients with abdominal pain and diarrhea decreased overime during a 5 year follow-up. For MDS patients, however, it isot clear whether this observation might rather be a drop-out biasince patients who discontinued from the trial were included in thenalysis.

MDS is typically a disease of the elderly. Elderly patients are at anncreased risk of toxicity due a decreased hepatic, renal, or cardiacunction, or due to comorbidity or other drug therapies. Preven-ion and optimal management of AEs in this elderly population ismportant to improve drug compliance.

Although guidelines on management of increase of serum cre-titine and skin rash do exist, there is only little guidance for therevention and management of GI-disturbances in MDS patientsreated with DFX. Therefore, an expert panel met in Lisbon on Julynd 2010 to develop recommendations based on existing data andersonal experiences.

. Prevention of gastrointestinal disturbances

Although participants of the consensus panel differed withegard to the type of GI disturbance as the leading causes foriscontinuation of DFX treatment (“diarrhea”, “abdominal pain”,vomiting”, “constipation” etc.) “GI disturbances” in general wereonsidered as the most important reason for discontinuation.oreover, GI disturbances were recognized as events interferingith the daily routines of the patients and their quality of life. More-

ver, for many patients it is not the diarrhea as such, that affectsheir quality of life, but it is the threat of incontinence. The panelnderscores the importance of informing the patients that some GIisturbances can be expected and that they are usually transient.

According to the label, DFX should be taken as a fasting dose0 min before food, preferably at the same time every day. Mostatients do take their medication in the mornings mainly dueo their routine habits. The panel agreed, that patients who willeceive DFX for the first time should take it 30 min prior to break-ast or dinner. Although evidence from randomized clinical trialss lacking, personal experience from the panel members suggestshat pre-prandial evening dosing might reduce the frequency andeverity of GI disturbances and might be superior to the morn-ng dosing. Giving DFX before bed-time was also discussed butue to safety concerns was not considered as a first-line approach.s post-prandial administration might affect the pharmacokinet-

cs of the drug by increasing or decreasing absorption dependingn the type of food taken at the time, it is not recommended toake DFX with food until more is known about the variability ofhis effect [7]. Splitting of the daily dose in DFX naïve patients as

way to prevent GI disturbances was discussed but due to phar-acological and compliance concerns the panel agreed that this

pproach should not be considered in initial setting. In addition,tarting with a low dose of DFX followed by dose escalation mightead to undertreatment and inefficacy if dose escalation is not donen a timely fashion. The panel recommends further trials evaluat-ng the impact of dose escalation on frequency and severity of AEsefore a comprehensive recommendation can be given. Anecdotaleports suggest a reduced frequency and severity of GI disturbancesith bi-daily dosing. However, taking into consideration the nega-

ive impact on patient adherence and the lack of pharmacokineticnd clinical data, experts advised against divided dosing. The panelgreed not to give prophylatic anti-acidic drugs since this might

ecrease the absorption of the DFX. In case of lactose intolerancerophylactic use of Lactobacillus preparation might be helpful. Theecommendations on prevention of GI disturbances are summa-ized in Table 1.

Lactobacillus preparations

6. Management of gastrointestinal disturbances

For the management of diarrhea during DFX treatment the panelrecommended the algorithm shown in Fig. 1. The participants of theexpert panel used different definitions of diarrhea so it was agreedby the panel to use the common toxicity criteria (CTC) grading as astandard for mild, moderate and severe diarrhea. For practical rea-sons a simple guidance using the frequency of bowel movementshas been applied in the diarrhea management algorithm.

Management of abdominal pain requires an exact diagnosissince management of upper and lower abdominal pain differs.Switching the dose to an evening pre-prandial dosing should beconsidered. Due to the risk of oesophageal irritation and bleeding,the panel does not recommend a before bedtime dosing. Althoughanecdotal, patients with abdominal pain might benefit if theyrefrain from solid food for 2 h after DFX. If the aforementionedapproaches are not successful, the use of anti-acidics for upperabdominal pain might be considered. Spasmolytic drugs mightbe helpful as well for lower abdominal pain. The panel does notrecommend the use of narcotic analgetic drugs and non-steroidalanti-inflammatory drugs due to the common GI side effects of thesedrugs. In cases of persisting mild-to-moderate abdominal pain dosereductions should be considered before treatment interruptions.Reduction should be done in steps of 5 mg/kg/day. If abdominalpain has resolved DFX dosis should be increased in 5 mg/kg/daysteps on target dose. In case of persisting severe abdominal pain thepanel agreed to temporarily interrupt DFX treatment until abdom-inal pain has disappeared. DFX should then be reinitiated anddose should be escalated in 5 mg/kg/day steps. Moreover, seriousreasons for severe abdominal pain should be ruled out. Recommen-dations are summarized in Table 2.

Vomiting was considered by the panel as a severe manifestationof nausea and both should be treated similarly with anti-emeticssuch as metoclopramide. Since vomiting is the only AE which doesnot seem to improve with long-term use, preprandial adminis-tration of DFX in the evening should be considered especially if

vomiting (and nausea) are related to the morning dose. Reductionof DFX in steps of 5 mg/kg/day should be done in cases of severenausea/vomiting. Re-initiation of DFX and increase on target should

1134 F. Nolte et al. / Leukemia Research 35 (2011) 1131– 1135

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e done when symptoms have resolved. Recommendations for theanagement of nausea and vomiting are summarized in Table 3.

. Summary and practical advise

Iron overload as a consequence of repetitive PRBC transfusionsccurs in the majority of MDS patients, particularly in low and

ntermediate-1 risk patients, with the risk of organ damage andncreased morbidity and mortality. Iron chelation therapy in inher-ted transfusion dependent anemias such as thalassemia and sickle

able 2ecommendations for management of abdominal pain. Patients with constipationave to be managed by another algorithm!.

Diagnosis is important– Management of upper abdominal pain differs from lower abdominalpain (with constipation and/or diarrhea and/or bloating)

Time of administration– Consider switching to evening pre-prandial DFX dosing if not alreadyused– Anecdotal reports of benefit: patient is advised to refrain from solidfoods for– 2 h after deferasirox– Do not recommend DFX dosing before bedtime

Use of medication– For upper abdominal pain, use anti-acidic drugs– Consider using spasmolytic drugs– Do not use narcotic pain medications and non-steroidalanti-inflammatory drugs

Dosing– Mild-to-moderate cases, consider DFX dose reduction beforetreatment interruptions

– Reduce DFX dose in steps of 5 mg/kg/day– Increase DFX dosing in steps of 5 mg/kg/day on target when

abdominal pain has been resolved– Severe cases: temporarily interrupt deferasirox until abdominal painhas been resolved. Restart at low dose and increase in steps

based on the number of episodes of bowel movements per day. If diarrhea does notding to the next higher grading algorithm and so on. If diarrhea persists even after

arrhea but DFX treatment were excluded DFX treatment should be discontinued.

cell anemia illustrated the prognostic importance of compliancewith treatment.

GI disturbances have been recognized as the main cause for dis-continuation of DFX treatment in different trials and reports. Duringthe expert meeting held on July 2nd 2010 in Lisbon, Portugal, dataon GI disturbances under DFX treatment in MDS patients werereviewed and discussed and consensus based recommendationswere made where possible. Information of the patients concern-ing GI side effects prior to initiation of DFX treatment is pivotal.Patients should be told that GI disturbances are frequently tran-sient in nature. If possible, DFX dosing should be initiated and thenmaintained at an efficient level, which means that dose reductionor treatment interruption should only be considered if disturbancesare severe or not manageable otherwise. Especially shifting theadministration from a breakfast dosing to a dinner dosing mightbe beneficial and circumvent the need of dose reduction or inter-ruption.

Diarrhea is the most frequent AE in DFX treated MDS patients.The panel recommends the algorithm shown in Fig. 1 to keeppatients adhered to the treatment.

Table 3Recommendations for management of nausea/vomiting.

Vomiting considered as a severe expression of nausea– Management of both similar

Use anti-emetics (metoclopramide)

Time of administration– Strong notion that nausea (especially vomiting) might be related to themorning dosing, especially since vomiting is the only AE that does notshow a trend towards reduction with long-term use– Advise to administer DFX in the evening (pre-prandial)

Reduce DFX dosing in steps of 5 mg/kg/day in case of severenausea/vomiting– Increase dosing in steps of 5 mg/kg/day on target whennausea/vomiting has been resolved

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The participants of the expert panel recognize that clinical trialsnvestigating different dosing schedules (morning vs. evening) areeeded. Moreover, whether DFX treatment improves survival in

ow and intermediate-1 MDS patients with transfusion dependentron overload still is a matter of debate and randomized clinical tri-ls on this issue are warranted. However, iron chelation in selectedatients with low or intermediate-1 MDS or those being candidatesor alloSCT might result in a better outcome in some patients.

onflict of interest

All authors declare no conflict of interest.

cknowledgements

Contributions. FN, EA, PB, AM, DS, BX, AA, AB, TS, JP, WKH con-ributed to the acquisition, analysis and interpretation of data,rafting the article and revising it critically. CS, PM contributed torafting the article and revising it critically.

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