iron overload and chelation therapy in myelodysplastic syndromes

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ARTICLE IN PRESSNCH-1833; No. of Pages 10

Critical Reviews in Oncology/Hematology xxx (2014) xxx–xxx

Iron overload and chelation therapy in myelodysplastic syndromes

Sally Temraz a, Valeria Santini b, Khaled Musallam a, Ali Taher a,∗a Department of Internal Medicine, Division of Hematology/Oncology, American University of Beirut Medical Center (AUBMC), Beirut, Lebanon

b Division of Hematology, AOU Careggi, University of Florence, Firenze, Italy

Accepted 14 January 2014

ontents

. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

. Iron overload. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 002.1. Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 002.2. Impact of IO on survival . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 002.3. Impact of IO on cardiac, hepatic and endocrine function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 002.4. Diagnosis and evaluation of IO . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

. Iron chelation therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 003.1. Chelation therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 003.2. Effect of chelation therapy on survival in MDS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 003.3. Efficacy of chelation therapy in MDS patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 003.4. Hematological improvement with iron chelation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00Funding source . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00Conflicts of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00Biography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

bstract

Iron overload remains a concern in MDS patients especially those requiring recurrent blood transfusions. The consequence of iron overloaday be more relevant in patients with low and intermediate-1 risk MDS who may survive long enough to experience such manifestations. It

s a matter of debate whether this overload has time to yield organ damage, but it is quite evident that cellular damage and DNA genotoxicffect are induced. Iron overload may play a critical role in exacerbating pre-existing morbidity or even unmask silent ones. Under theseircumstances, iron chelation therapy could play an integral role in the management of these patients. This review entails an in depth analysis
f iron overload in MDS patients; its pathophysiology, effect on survival, associated risks and diagnostic options. It also discusses managementptions in relation to chelation therapy used in MDS patients and the impact it has on survival, hematologic response and organ function.
2014 Elsevier Ireland Ltd. All rights reserved.

; Transf
eywords: MDS; Myelodysplastic syndrome; Iron chelation; Iron overload
Please cite this article in press as: Temraz S, et al. Iron overload aOncol/Hematol (2014), http://dx.doi.org/10.1016/j.critrevonc.2014.01.0

∗ Corresponding author at: P.O. Box 11 0236, Riad El Solh, 110 72020eirut, Lebanon. Tel.: +961 1 350000x5392; fax: +961 350000x7942.

E-mail address: [email protected] (A. Taher).

1

oip

ttp://dx.doi.org/10.1016/j.critrevonc.2014.01.006040-8428/© 2014 Elsevier Ireland Ltd. All rights reserved.

usion-dependent; Deferasirox; Deferoxamine; Deferiprone

. Introduction

Myelodysplastic syndromes (MDS) represent a group

nd chelation therapy in myelodysplastic syndromes. Crit Rev06

f hematologic disorders characterized by dysplastic andneffective hematopoiesis. Approximately 80% of patientsresent with anemia and a substantial percentage of them

dx.doi.org/10.1016/j.critrevonc.2014.01.006


mailto:[email protected]


ARTICLE IN PRESSONCH-1833; No. of Pages 10

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S. Temraz et al. / Critical Reviews in

ill become transfusion-dependent during the course of theirisease [1].

Chronic transfusions lead to secondary iron overload (IO).he relatively longer survival of low and intermediate-1 riskDS groups classified by the International Prognostic Sco-

ing System (IPSS) [2,3] places them at an increased riskf damage by IO from prolonged red cell transfusions com-ared to high risk patients who have a markedly reducedurvival [1]. MDS population consists mainly of elderly witho-morbid conditions and a propensity to have cardiac failure,nfection, hemorrhage and hepatic cirrhosis IO may rapidlyxacerbate these pre-existing conditions [4].

In this review, we provide an overview of IO in MDSatients, its pathophysiology, associated risks and manage-ent options as recent and more systematic data on chelation

herapy in MDS patients has become available in the past fewears.

. Iron overload

.1. Pathophysiology

The pathophysiology of IO in MDS patients is related tohat observed in thalassemia syndromes and consists of inef-ective erythropoiesis and hepcidin dysregulation in someubtypes of MDS (primary IO) as well as transfusional sidero-is (secondary IO). There are however some differences.epcidin is a key hormone mediating iron homeostasis. Hep-

idin has a role in the down-regulation of ferroportin, theembrane transporter delivering duodenal iron from entero-

ytes to transferrin, thus resulting in decreased duodenal ironbsorption [5,6]. In disease states of ineffective erythropoei-is, serum hepcidin levels are low that result in unrestraineduodenal iron absorption and subsequent IO [7]. Recently,e measured serum hepcidin by mass-spectrometry in 113DS patients, and found the lowest levels in refractory ane-ia with ring sideroblasts (RARS, 1.43 nM) and the highest

n refractory anemia with excess blasts (RAEB 11.3 nM) [8].ARS patients are particularly refractory to therapy withrythropoietic stimulating factors, and thus are frequentlyransfusion dependent, have a particularly expanded erythro-oiesis, with an extremely frequent presence of acquiredutations in SF3B1, a gene encoding a core component of

he RNA splicing machinery in MDS patients with ring sider-blasts [8,9]. A genetic study has confirmed our findings,orrelating SF3B1 with ring sideroblasts and low hepcidinevels [10]. The growth differentiation factor 15 (GDF15),hich has been shown to suppress the activity of hepcidin

n thalassemia [11], did not seem to regulate hepcidin in ourork and that of our authors. Therefore, low levels of hep-

idin further predispose patients with RARS subtype of MDS


o the risk of IO.Anemia affects 80% of MDS patients and in their disease

ourse many of them will receive transfusions. Red bloodell transfusions, while alleviating anemia may improve

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gy/Hematology xxx (2014) xxx–xxx

uality of life and prolong survival, but expose to severalisks [12]. Patients with MDS may have an extremely highrequency of transfusions and may accumulate excess ironn a short time lapse. The rapidity and intensity of transfu-ions accounts for IO more than the total number [13]. Inhis state of iron repletion, ferritin production is increasedo permit adequate storage of iron and transferrin receptorroduction is decreased to prevent further entry of iron intohe cell [14,15]. When the binding capacity of transferrin inhe blood is exceeded, iron is found in the plasma as non-ransferrin bound iron (NTBI) [16]. Since iron cannot bectively excreted out of the body, it initially accumulates inhe reticuloendothelial macrophages and is later deposited inhe parenchymal cells of liver, heart and endocrine organs17]. Intracellular iron can be found in endocytotic vesiclesollowing entry of iron into the cell through the transferrineceptor-1, in ferritin where each ferritin molecule can holdp to 4500 atoms of iron or in association with proteins thatorm prosthetic groups involved in biological reactions [18].n this IO state, NTBI changes to its redox active form termedabile plasma iron (LPI). Patients with low risk MDS havehe higher NTBI levels compared to high risk MDS; high-st levels are seen in RARS followed by 5 q-syndromes andMML, respectively [8]. Entry of LPI into cells is mediatedia several transporters; DMT1 in enterocytes [19], Zrt-Irt-ike protein in hepatocytes [20] and L-type voltage dependentalcium channels in cardiac myocytes [21]. LPI is a toxicompound that enters the cell forming the labile cell ironLCI) [22]. LPI in MDS is high and correlates with ferritinevels quite well. LCI results in the formation of reactive oxy-en species (ROS) that can suppress renewal and number ofematopoietic stem cells [23] and can induce DNA damagend genomic instability [24]. This results in tissue damagend subsequent fibrosis which could result in complicationss cardiomyopathy, cirrhosis and diabetes [25,26].

.2. Impact of IO on survival

Several retrospective studies suggest a negative associa-ion between transfusion dependency in MDS and overallurvival (OS) [27–29]. Whether this is due to the transfu-ions themselves or to the fact that more severe diseasesequire more frequent transfusions is a matter of debate. Fur-hermore, the impact of IO on OS in MDS patients has alsoeen demonstrated. In a retrospective nationwide survey ofapanese patients, Takatoku et al. found that in 37 of 38atients who died of hepatic or cardiac failure had ferritinevels >1000 �g/L suggesting that IO resulted in increased

ortality [30]. On the other hand, in a retrospective analysisf a US database, complications potentially attributable toO in MDS such as cardiac events, diabetes and liver diseaseccurred at a higher frequency in MDS patients receiving


lood transfusions [31]. Also, Sanz et al. confirmed theseesults in a large series of 2994 patients where they showedhat IO is an independent prognostic variable of OS and alsoML transformation [32]. However, the results have never



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een published in definitive form. Transfusion dependencyoupled by increases in serum ferritin levels further exacer-ates OS [29].

.3. Impact of IO on cardiac, hepatic and endocrineunction

The risk of cardiac events is increased in MDS patients,articularly in those who are transfusion-dependent [33].hronic anemia remains a co-factor in the development ofardiac failure because it necessitates increased cardiac out-ut in order to compensate for impaired tissue oxygenationhereby leading to heart complications. MDS patients areeported to be at higher risk of cardiac events comparedo the general population (73.2% versus 54.5%; P < 0.01)ith transfused MDS patients having a higher risk than non-

ransfused ones (82.4%% versus 67.1%; P < 0.001) [33].nce again, this maybe attributable to cardiac remodeling

orrelated to anemia [34], which is there even in transfusedatients who suffer from fluctuating hemoglobin levels, ando subsequent myocardial hypoxia, as well as to IO. Somenconsistency in fact exists in results from studies employingardiac magnetic resonance imaging T2* (MRI) as measuref IO in MDS. These studies suggest that cardiac iron accu-ulation is not frequent in MDS patients [35–37].Although the majority of MDS patients do not live long

nough to manifest conditions of liver cirrhosis, hepatic com-lication nevertheless have been implicated in IO. In oneetrospective study of 4546 patients with MDS and otherematopoietic disorders, transfusion dependency was sig-ificantly associated with risk of potential complicationsf IO (liver disease P = 0.0008 and diabetes P = 0.0025)38]. Moreover, in another Japanese retrospective study, theuthors report 75 deaths, with cardiac failure noted in 24%f cases and liver failure noted in 6.7% of cases [30]. Ofhese, 97% had ferritin levels >1000 ng/ml. Moreover, a large,etrospective analysis from US Medicare database revealedhat diabetes occurs significantly more frequently in patientsith MDS. When MDS patients were compared based on

ransfusion dependency, those receiving transfusions had andditional increased risk of diabetes than those not receiv-ng transfusions; however, the difference was not statisticallyignificant (44.4% versus 37.1%; P = 0.1) [33].

.4. Diagnosis and evaluation of IO

Most data on modalities for the assessment of IO ineneral come from experience with transfusion-dependenthalassemia patients.

Ferritin: In the general population, IO is generally definedy a serum ferritin level >300 �g/L in men and >200 �g/L inomen. Serum ferritin thresholds of >1000 and >2500 �g/L


ave been classically used to flag patients with increased mor-idity risk and to tailor indications for chelation therapy inhe thalassemia population [39]. The aforementioned studiesvaluating the consequences of IO in MDS patients also relied

intf

gy/Hematology xxx (2014) xxx–xxx 3

n a serum ferritin level of >1000 �g/L. Elderly patientsith MDS present frequently with comorbidities, and chronic

nflammation is a common finding. In this group of patients,-reactive protein and other parameters are altered, and so is

erritin. It is thus a parameter which has some disadvantages,ut may help in following a patient, allowing repeated examsnd being rather costless and highly reproducible.

Liver iron: Assessment of liver iron concentration remainshe gold standard for quantification of total body iron [40],ith values up to 1.8 mg Fe/g dry weight considered normal,alues up to 7 mg Fe/g dry weight seen in some non-halassemic populations without apparent adverse effects andalues >15 mg Fe/g dry weight commonly associated withorse prognosis, liver fibrosis progression, or liver function

bnormalities [39].Liver biopsy enables pathologists to determine liver iron

oncentration as well as severity of liver disease in patientsho are at high risk of liver involvement. However, liveriopsy is contraindicated in almost the totality of MDSatients since there is an increased risk of bleeding due tohrombocytopenia and/or platelet dysfunction [7].

MRI: Magnetic resonance imaging using either R2 (1/T2)r R2* (1/T2*) pulse sequences are reliable, internationallyeproducible, and non-invasive methods for assessing liverron concentration, and have been validated against liveriopsy in several diseases complicated by IO [41–43]. Thepper limit to reliably estimate liver iron concentration byRI is approximately 30–40 mg Fe/g dry weight, depending

n the scanner specifications [43]. This method is expensive,equires a skilled radiologist, needs accurate software ands not readily available in all hematologic centers treating

DS patients. Moreover, not all MDS patients on chelationeally require this determination, unless ferritin is increasingr some cardiac failure signs have appeared, or transfusionistory prior to therapy is not clear [8]. Cardiac siderosiss measured using T2* MRI (normal: >20 ms) a functionalnalysis in the end, which correlates with subsequent risk ofeart failure. It is now validated as a true measure of cardiacron, correlating with chemical measurement on post-mortemardiac biopsies [42].

Hepcidin: Serum hepcidin measured by mass spectrom-try or ELISA (EIA-5258) revealed that highly transfusedatients were shown to have significantly higher hepcidin lev-ls while patients with low hepcidin levels had significantlyigher hemoglobin and transferrin, and lower serum ferritinnd transferrin saturation [8,10,44]. A correlation betweenepcidin and OS was seen with a hepcidin level accordingo EIA-5258 at or above the median of 17.5 ng/ml associatedith a significantly worse survival (P = 0.03) [44]. However,

he clinical reliability of hepcidin is still a subject of activeesearch.

Practically, the best approach should be to assess iron


ntake by registering all transfusions carefully, which isot frequently done in clinics. For patients with significantransfusion burden, cardiac function (by ultrasound), liverunction, and glucose tolerance test should be performed



4 S. Temraz et al. / Critical Reviews in Oncology/Hematology xxx (2014) xxx–xxx

Table 1Iron chelators available for the management of IO.

Agent Approval (US, FDA) Administration Schedule and dose Clearance Most common adverse events

Deferoxamine[46]

Chronic IO due totransfusion-dependentanemias

Subcutaneous,intravenous

20–40 mg/kg/d over8–24 h 5–7 d/wk

RenalHepatic

Hypersensitivity reactions,tachycardia, gastrointestinal events,increased transaminases

Deferasirox [50] Chronic IO due toblood transfusions ornon-transfusion-dependentthalassemia

Oral 20–40 mg/kg/d Hepatobiliary Gastrointestinal events involvingdiarrhea, nausea, constipation andabdominal pain; skin rashes andincreased serum creatinine level

Deferiprone [51] Transfusional IO dueto thalassemia

Oral 25–33 mg/kg 3×/d fora total daily dose of

g/kg

Renal Gastrointestinal symptoms,granulocytosis, agranulocytosis and

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very three months. In case of increasing ferritin levels with-ut specific inflammatory or infective causes during ironhelation therapy (ICT), as well as in case of cardiac or liverysfunction, more accurate exams, like cardiac MRI (T2*)hould be performed.

. Iron chelation therapy

.1. Chelation therapy

The rationale behind using ICT is removing the increasedron burden specifically LCI to minimize production of ROShereby decreasing cellular and organ damage. Patients mostikely to benefit from chelation therapy include those withow or intermediate-1 IPSS risk MDS who have a long lifexpectancy and are anticipated to receive more than 20 redlood cell transfusions and/or whose serum ferritin level is1000 �g/L [1,45]. Chelation therapy efficacy can be moni-

ored by monitoring trends and levels of serum ferritin.Multiple drugs have been developed to decrease iron bur-

en from IO states. The three iron chelators approved forse include deferoxamine (DFO, Desferal®, Novartis PharmaG, Basel, Switzerland), deferasirox (Exjade®, Novartisharma AG, Basel, Switzerland) and recently deferiproneFerriprox®, Apotex Inc., Toronto, ON, Canada) (Table 1).FO binds to NTBI or to iron that is found in ferritin andemosiderin but not transferrin forming the ferrioxamineolecule which is later excreted via the kidneys [46] (Fig. 1).errioxamine renders iron unavailable to chemical reactionsnd hence prevents formation of ROS. DFO promotes ferritinegradation in lysosomes by inducing autophagy [47]. Botheferiprone and deferasirox are likely to chelate cytosolic ironnd iron which is extracted from ferritin prior to ferritin degra-ation by proteosomes [47] (Fig. 1). Besides its efficacy as anron chelator, deferasirox administration has been associatedith increased levels of hepcidin that results in the removal


f ferroportin from the enterocyte membrane and its subse-uent degradation by lysosomes [48]. Lately, Deferasirox haseen used frequently in the treatment of IO in MDS patients.he oral administration in fact allows higher compliance of

sf

elevation of liver enzymes

lderly patients who do not accept such prolonged infusionsnd may be subject to bleeding at the subcutaneous insertionite. Despite these positive characteristics, in a recent Italiantudy, the percentage of drop out from a chelation study inower risk MDS was pretty high and related to compliancend side effects, even if mild which impaired MDS patientsompliance [49]. Fig. 2 shows one suggested algorithm onhe management of IO in MDS patients with the use of theforementioned iron chelators.

.2. Effect of chelation therapy on survival in MDS

Evidence supporting the fact that IO causes severe compli-ations comes from the demonstration of prolonged survivaln MDS patients undergoing ICT. At present, all the evidenceomes from retrospective studies. These studies demon-trated that low risk MDS patients receiving chelation therapyad a better median OS compared to non-chelated ones52–55]. Recently, significant improvement in survival waseported in low risk MDS patients exhibiting non-RARS fea-ures but the same was not achieved for patients with RARS56]. Median OS in the RARS who received chelation ther-py was 134.4 months versus 99 months; however, it didot reach statistical significance. The retrospective nature ofhese trials does not exclude potential bias that arises from theossibility that patients with a better performance score had areater chance of being started on ICT. This bias can only bexcluded once a prospective randomized placebo controlledrial is undertaken. A large phase 3 trial (TELESTO, Clini-al trials.gov: NCT00940602) is currently recruiting patientsith low and intermediate-1 risk MDS patients to receive

ither deferasirox monotherapy or placebo. Although the ret-ospective studies consistently show a survival advantage ofhelation therapy, these results cannot be confirmed untilesults of this phase 3 trial are available.

.3. Efficacy of chelation therapy in MDS patients


Results on the efficacy of chelation therapy in decreasingerum ferritin levels, LPI and liver iron concentrations comerom prospective trials (Table 2). Most available data on the



S. Temraz et al. / Critical Reviews in Oncology/Hematology xxx (2014) xxx–xxx 5

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ig. 1. Mechanism of action of iron chelators in the management of iroon-transferrin bound iron; TFR-1: transferrin receptor-1; LPI: labile plasm

se of ICT in MDS patients come from deferasirox trials,ecause they are more recent and data were collected in anppropriate and complete manner. Few and relatively smalltudies have been conducted with other iron chelators inatients with MDS.


Decreases in liver iron concentration depended on the dosef deferasirox administered and transfusion requirements57,60]. Both Gatterman et al. and Breccia et al. reported

ert

able 2fficacy of the iron chelators deferasirox, deferoxamine and deferiprone in MDS p

tudy Patients Treatment Duration (m

orter et al. [57] 47 Deferasirox 12

etzegeroth et al. [58] 12 Deferasirox 12

reenberg et al. [59] 24 Deferasirox 613

PIC trial, Gattermanet al. [60]

341 Deferasirox 12

Xtend and eXjange,Gatterman et al. [61]

123 Chelationnaïve44 previouslychelated

Deferasirox 12

S03 trial, List et al. [62] 914933

Deferasirox 122436

reccia et al. [63] 40 Deferasirox 12

olte et al. [64] 40 Deferasirox 12

onzalez et al. [65] 28 DFO 12

ersten et al. [66] 18 Deferiprone 12

: significant; NR: not reported; NS: not significant; LPI: labile plasma iron; LIC: l

oad. TBI: transferrin bound iron; ROS: reactive oxygen species; NTBI:DMT1: divalent metal transporter 1.

significant decrease in serum ferritin regardless of chela-ion history [60,63] suggesting that deferasirox is effectiven patients receiving chelation therapy for the first time andn patients switching from other chelation therapies. How-ver, the same result was not achieved in the EXtend and


Xjange trials where a significant decrease in serum fer-itin was seen only in patients not receiving prior chelationherapy [61]. Also, the decrease in serum ferritin level was

atients.

onths) Decrease in LIC Decrease inferritin

Decrease in LPI

S S NRS S NRSNS

NSNS

SS

NR S S

NR SNS

NR

NR S S

S NR NRS NR SNS NR NRS NR NR

iver iron concentration; DFO: deferoxamine.



6 S. Temraz et al. / Critical Reviews in Oncology/Hematology xxx (2014) xxx–xxx

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ig. 2. Suggested algorithm for the use of iron chelators in MDS patients. *Creatinine more than twice the upper limit of normal, platelet counts <50 ×eferasirox. *Contraindications to deferoxamine include: severe renal failur

ssociated with a significant improvement in alanine transam-nase (P < 0.00001), which is an indicator of hepatocellularnjury that can lead to cirrhosis [60].


.4. Hematological improvement with iron chelation

Evidence of hematological improvement with the use ofron chelation was reported previously in a study by Jensen

t

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dications to deferasirox include: creatinine clearance < 40 ml/min or serum, severe hepatic impairment (Child–Pugh class C) and hypersensitivity toria, Clcr < 10 ml/min and hypersensitivity to deferoxamine.

t al. with the use of DFO. DFO was successful in decreasingransfusional requirements and 5/11 patients became transfu-ion independent [67]. Further improvement in platelet andeutrophil counts was also reported. In patients who showedmprovement in erythropoietic output, an increase in serum


ransferrin receptor was detected.Similarly, a post hoc analysis evaluated hematologic

esponse to deferasirox in a cohort of iron-overloaded



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atients with MDS enrolled in the EPIC trial. Erythroid,latelet and neutrophil responses were observed in 21.5%53/247), 13.0% (13/100) and 22.0% (11/50) of the patientsfter a median of 109, 169 and 226 days, respectively.edian serum ferritin reductions were greater in hemato-

ogic responders compared with non-responders at end oftudy, although these differences were not statistically sig-ificant [68]. In another retrospective Italian study, 42.7%f patients receiving chelation with DFO or deferasiroxchieved a hematologic response. Eighteen patients becameransfusion independent; 12 of which received deferasiroxnd the remainder DFO [69]. Median time to response was5 months for DFO and 3 months for deferasirox.

One proposed mechanism is the dynamic, bidirec-ional regulation between erythropoiesis and IO where notnly ineffective erythropoiesis leads to increased intesti-al iron absorption through the down-regulation of theepatic hormone hepcidin [70], but also treatment of IOffects erythropoietic capacity and leads to improvements inemoglobin level and red cell survival [71–73]. In a recenttudy from thalassemia patients, mobilization of hematopoi-tic peripheral progenitors (namely Erythroid Burst-Formingnits) was significantly higher in deferasirox-treated patients

han those receiving other chelators, irrespective or the degreef iron depletion; which may indicate that the observedffects of deferasirox on hematologic outcomes are mediatedy other factors [74]. In fact, it has been recently demon-trated that in MDS patients, IO suppresses the proliferationf erythroid progenitors cells (BFU-E), while the myeloidompartment (CFU-GM) is not affected and it was shownhat ICT may revert such phenomenon [75]. It is a sharedpinion that the ideal MDS patient to receive chelation is aatient with IPSS lower risk score (INT-1 and LOW), trans-usion dependent but with a reasonable expectance of life, sohat ICT may be effective and possibly make some differencen outcome. Nevertheless, it is becoming clearer that there is

subset of IPSS higher risk MDS patients which could ben-fit from ICT [45]. In particular, eligible MDS patients forhom a hematopoietic stem cell transplantation (HSCT) isrogrammed should be chelated because there is growingvidence that high ferritin levels before HSCT are corre-ated with worst outcome in patients receiving myeloablativeonditioning regimen [76,77]. Therefore, it is strongly advis-ble to properly chelate these patients, even shortly beforeSCT [78]. On the other hand, some higher risk patientsho received a therapy modifying their survival and diseaseistory could also take advantage from supportive ICT.

. Conclusion

IO is a reality for transfusion dependent MDS patients. It


s a matter of debate whether this overload has time to yieldrgan damage, but it is quite evident that cellular damage andNA genotoxic effect via ROS species are induced. Another

mportant point would be to verify the threshold of RBC


ransfusions leading to IO in MDS, and whether patients maye rescued by appropriate ICT [79].

The consequence of IO may be more relevant in patientsith low and intermediate-1 risk MDS who may survive long

nough. The causes of death in large MDS series may indicatehat IO may play a critical role in exacerbating pre-existing

orbidity or even unmask silent ones, especially because ofhe relative frailty of the large part of MDS patients. Theseonsiderations, together with the concept of “optimal” sup-ortive care, should indicate iron chelation as an integratedool in the management of MDS patients. Nevertheless, theres still ample skepticism in accepting this therapy, maybe dueo low familiarity with the problem of IO and its diverse con-equences. It is to be said that still little is known in ironomeostasis in MDS and that although MDS experts shouldearn the lesson from thalassemia experience, more evidencend data are required to clarify the role of iron in MDS dis-ase manifestation and outcome. A lively debate is going onmong MDS experts, and it seems as if the field was dividedn “a priori” believers in IO and non- believers [80]. Prospec-ive carefully planned randomized studies are the key to solvehis issue.

unding source

None declared.

onflicts of interest

Sally Temraz reported no conflicts of interest. Aliaher reported receiving research funding and honorariarom Novartis Pharmaceuticals; Khaled Musallam reportedeceiving research funding and honoraria from Novartisharmaceuticals and is currently (at the time of submission)n employee of Novartis Pharma AG, Basel, Switzerland;aleria Santini reported receiving honoraria as a speaker fromelegene, Novartis, Janssen and GSK.

eviewers

Photis Beris, Associate Professor, Faculté de Médecine,eneva University, Swiss Internal Medicine, 51 avenuelanc, CH-1202 Genève, Switzerland.

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iography

Dr Ali Taher is a Professor of Medicine at the Divi-ion of Hematology–Oncology of the American University


iate Chair for Research and the director of the Residencyesearch Program. In addition, he is a Consultant Hema-

ologist at the Thalassemia Department of the Chronic Care


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1 Oncolo

CloAAHbs�s

lst�itbophilia and bleeding disorders, as well the incidence and

0 S. Temraz et al. / Critical Reviews in

enter in Hazmieh, Lebanon and a fellow of the Royal Col-ege of Physicians and an Adjunct Professor at Emory Schoolf Medicine, Atlanta, USA. Also, he is a member of themerican Society of Hematology, the European Hematologyssociation, the International Society on Thrombosis andemostasis, the Mediterranean League against Thromboem-olic Diseases, and of Alpha Omega Alpha honorary medical


ociety. His research focuses on hemoglobinopathies, notably-thalassemia and sickle cell disease, as well as thrombo-is and hemostasis. Within thalassemia, his research interest

pi


ies in the detection of iron overload and the efficacy andafety of novel oral iron chelators. Moreover, he inves-igates the pathophysiology and clinical implications of-thalassemia intermedia and its associated complications

ncluding mostly iron overload and hypercoagulability. Inhrombosis and hemostasis, he investigates inherited throm-


rophylaxis of venous thromboembolism across several med-cal and surgical settings.


iron overload and chelation therapy in myelodysplastic syndromes

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