DISEASE MANAGEMENT

Use chelation therapy to reduce iron overload and improvesurvival in patients with myelodysplastic syndromes

Most patients with myelodysplastic syndromes require

red blood cell transfusions to treat their chronic anaemia.

This leads to an increased risk of transfusional iron over-

load, which has been associated with adverse effects on

survival. Based on limited data, iron chelation therapy ap-

pears to have beneficial effects in these patients.

Syndromes have serious risks

Myelodysplastic syndromes (MDS) are clonal disorders

of haematopoietic progenitor cells, which are characterized

by ineffective haematopoiesis and the risk of transformation

from MDS to acute myeloid leukaemia (AML). Lower-risk

MDS is associated with increased apoptosis, which can lead

to peripheral blood cytopenias,[1] while clonal evolution is

the predominant feature of higher-risk MDS, predisposing

the patient to AML progression.[2]

This article summarizes a review on treating iron over-

load in patients with MDS by Leitch.[3]

Usual approach is supportive care

The majority of patients with MDS are elderly, with

>85% presenting at age ‡70 years, making them ineligible

for aggressive therapies such as curative haematopoietic

stem cell transplantation (SCT).[3] Although effective alter-

native treatment options have recently become available

(e.g. decitabine, lenolidamide and azacitidine), these are not

always suitable for some patients. Therefore, supportive care

is the usual treatment approach in MDS, with the aim of

minimizing the impact of cytopenias and to maintain health-

related quality of life (HR-QOL), although these interven-

tions do not generally alter the course of disease.[3]

Dependence on transfusion increasing

Many patients with MDS are dependent on red blood cell

(RBC) transfusions to manage their chronic anaemia from

the time they present with the disease, with the proportion

increasing with time, progressive bone marrow failure and

patient age.[3] In fact, most patients eventually require trans-

fusion for anaemia. New treatment options offer an alter-

native to transfusions, although they may not be appropriate

for all patients; »40% of MDS patients currently receive

RBC transfusion as the only intervention.[3]

Dependence on RBC transfusion can place MDS patients

at an increased risk of iron overload and, ultimately, may

adversely affect survival.[3-5] For example, in a study in 426

MDS patients,[5] transfusion-dependent patients had in-

creased iron levels (assessed by ferritin levels), and inferior

overall and leukaemia-free survival relative to non-transfusion

dependent patients. Moreover, overall and leukaemia-free

survival progressively decreased by the degree of trans-

fusion dependence (hazard ratio 1.36 and 1.40, respectively,

for each additional RBC unit transfused every 4 weeks).[5]

Iron overload linked to several factors

As there is no mechanism for excreting iron from the

body, the reticuloendothelial system can be readily over-

whelmed in patients who are regularly transfused.[3] The

following factors, all of which increase transferrin satura-

tion, may contribute to iron overload in MDS:[3]

� RBC transfusion (leads to increased macrophage iron);� ineffective erythropoiesis (leads to increased absorption

of iron by the gastrointestinal tract via hepcidin and

ferroportin);� myelosupressive therapy (leads to decreased iron utiliza-

tion through decreased erythropoiesis).

Outcome is oxidative stress and organdamage

Significant parenchymal iron loading can result in

transferrin saturation and the generation of non-transferrin

bound iron, which can participate in oxidative reactions and

cause cellular damage, with mitochondrial DNA thought to

be particularly susceptible.[3]

In patients with b-thalassaemia, it is well established that

iron overload can induce organ damage and may contribute

to early death.[1] Similar, albeit more indirect, data are be-

ginning to emerge in patients with MDS. Transfusion-

dependent patients with MDS have a high incidence of

arrhythmia, chronic heart failure (CHF), hepatic dysfunc-

tion, hepatic fibrosis and glucose intolerance, which were

the cause of death in many patients.[3] In a recent retro-

spective study in patients with MDS or other haemopoietic

disorders, transfusion therapy significantly (p £ 0.0025) in-creased the risk of conduction/rhythm disorders (odds ratio

Drugs Ther Perspect 2011; Vol. 27, No. 9

14

[OR] 4.18), liver disease (OR 0.31) and diabetes mellitus

(OR 5.05).[6]

Cardiac disease appears to the main cause of non-

leukemic death in MDS (incidence >50%) and has been

correlated with serum ferritin level.[3] Over 3 years in a US

Medicare population, 74% of MDS patients experienced

cardiac events, including arrhythmia, CHF and infarction,

with these events predominantly occurring in transfused pa-

tients (79% vs 54% for non-transfused patients; p< 0.0001).[7]

However, cardiac tissue iron deposits do not appear to in-

crease in transfusional patients with MDS, suggesting other

mechanisms, such as oxidative stress or anaemia, may ac-

count for this effect. Death related to hepatic dysfunction is

also associated with transfusion frequency and increased

ferritin level.[8] Further studies are required with regard to

the effects of iron overload on endocrine and cardiac func-

tion in MDS patients.

Poorer outcomes for higher-risk patients

In higher-risk MDS patients and in the intensive chemo-

therapy and SCT settings, iron overload may be predictive of

poorer outcomes (i.e. decreased overall survival and higher

mortality rates), as a result of increased transplant-related

mortality, infections and leukaemic progression.[9] Toxicity

from iron overload in these settings may be related to oxi-

dative stress (presence of non-transferrin bound iron) and

infection risk (bacterial and fungal utilization of iron).[3]

There is also preclinical evidence to suggest progression to

AML is via iron-mediated dysregulation of cellular growth

and differentiation, with these effects ameliorated when iron

levels were reduced.[3]

Many methods for monitoring iron

Serum ferritin level is the simplest and most widely used

measure for monitoring iron load; however, values may be

affected by many variables, such as inflammation, tissue

damage and abnormal hepatic function.[3] Serum ferritin

levels of <300 mg/L are considered normal, levels of >1000to <2500 mg/L indicate mild and moderate iron overload,

and levels of >2500 mg/L indicate severe iron overload.

Normal values are 20–50% for transferrin saturation and

0–0.4 mmol/L labile plasma iron, with higher values in-

dicating iron overload.

Assessing liver iron concentration by liver biopsy is limited

in MDS due to thrombocytopenia and neutropenia, which may

predispose patients to bleeding and infections. More recently,

noninvasive methods have become available, including T2*

MRI for hepatic and cardiac tissue, although measurements

generated by this technique have not yet been correlated to

clinical outcomes in MDS.[3] Although a number of techniques

for quantifying non-transferrin bound iron have recently been

developed, their use remains investigational.[3]

Chelation can correct iron balance ...

Chelators are agents that bind iron, rendering it non-toxic

and in a form that is amenable to excretion outside the

body.[3] The goal of chelation therapy in MDS is to maintain

iron balance and safe tissue iron levels by preventing

transfusion-associated accumulation of excess iron and as-

sociated end-organ dysfunction. Guidelines for chelation in

MDS generally recommend chelation in lower-risk patients

with an otherwise reasonable life expectancy (e.g. >1 year)

and evidence of transfusional iron overload.[3] MDS patients

who would benefit most from iron chelation therapy include

patients requiring transfusion of ‡2 RBC units/month for

‡1 year; patients with ferritin level >1000 ng/mL; patients

without co-morbidities that would limit prognosis; patients

who are candidates for allograft; patients in whom there is a

need to preserve organ function; patients who are unresponsive

to or ineligible for primary therapy (e.g. immunomodulatory or

hypomethylating agents).[10,11]

Chelation is also an option in some patients with higher-

risk MDS (i.e. recommended in patients who are candidates

for SCT and may be considered in patients who are re-

sponding to therapies that are able to modify life expectancy,

including SCT).[11,12]

These guidelines are limited, however, by the fact that

they have been extrapolated from experience in patients with

thalassaemia. This has generated uncertainty among clinicians

regarding treatment, which appears to be reflected in the low

proportion of patients receiving chelation therapy.[3] Rea-

sons for non-chelation in MDS include short life expectancy,

advanced patient age, co-morbidity, noncompliance and

high-risk MDS; however, the development of more convenient

formulations of deferoxamine may lead to more prompt,

widespread and persistent treatment with chelators.[3]

y and appears to be beneficial

In lower-risk transfusion-dependent MDS patients, iron

chelation therapy may lower ferritin levels, and has been

associated with improved survival according to data from

retrospective studies.[3] A prospective randomized con-

trolled trial is currently underway to further evaluate surviv-

al benefits of iron chelation.[13] Although there is evidence

to suggest that iron-chelation therapy can reverse organ

toxicity in patients with thalassaemia, data for MDS patients

are limited.[3] Preliminary data have shown a beneficial ef-

fect of chelation on hepatic function, with deferasirox

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therapy for 12 months in MDS patients (n = 341) providing

significant reductions from baseline in median ferritin

(p = 0.002) and mean ALT (p < 0.0001) levels.[14]

Furthermore, after beginning chelation, some lower-risk

MDS patients may have improvements in cells counts, with

some becoming RBC transfusion independent and others

having in a decrease in RBC transfusion requirements.[3]

Although further investigation is required, it has been pro-

posed that chelation improves marrow function by reducing

oxidative stress, altering intracellular levels of nuclear factor-

kB and increasing erythropoietin levels.[3]

Growing evidence suggests that lowering iron may be

beneficial in higher-risk MDS patients around SCT or chemo-

therapy without transplant. According to a number of small

studies of interventions to manage iron overload, phle-

botomy, chelation and antioxidant administration had a

number of beneficial outcomes (e.g. normalization of ferritin

levels, resolution of liver disease and CHF, reduced trans-

plant-related mortality, and improved event-free survival and

overall survival) in SCT patients.[3] However, chelation in

higher-risk MDS is currently only recommended for patients

who are candidates for SCT. Phlebotomy following SCT may

be a simpler intervention than chelation around SCT.[3]

Features of available chelators vary

Currently available chelators include deferoxamine, defer-

iprone and deferasirox (table I). Deferoxamine has a relatively

short half-life, and as such, must be administered as a con-

tinuous parenteral infusion in order to effectively reduce iron

levels.[3] Many patients find this route of administration cum-

bersome and access to alternative oral agents (deferiprone and

deferasirox) may be limited in some countries for regulatory

or financial reasons. An alternative twice-daily subcutaneous

Table I. Features of currently available iron chelation agents[3,10,11,16]

Deferoxamine Deferiprone Deferasirox

Approved indications in the EU

Chronic iron overload from transfusion-

dependent anaemias

Acute iron intoxication

Iron overload in pts with b-thalassaemia

when deferoxamine is contraindicated

or inadequate

Chronic iron overload due to frequent RBC

transfusions in pts with b-thalassaemia aged ‡6 y

Chronic iron overload due to RBC transfusions when

deferoxamine is contraindicated or inadequate in the

following pt groups: pts with other anaemias; pts aged

2–5 y; pts with b-thalassaemia with iron overload due

to infrequent blood transfusion

Available formulations

Injection (powder for reconstitution)

[subcutaneous or intravenous infusion]

Oral tablet or solution Oral dispersible tablets (disperse in water, or orange

or apple juice before administration)

Suggested dosage in pts with myelodysplastic syndromes[10]a

20–60mg/kg/day infused over ‡8–12 h for

‡5 day/wkb75–100mg/kg/day in three divided

doses

20–30mg/kg once daily

Elimination half-life (excretion route)

20–30 min (urinary, faecal) 3–4 h (urinary) 8–16 h (faecal)

Potentially serious adverse effects

Injection-site reaction

Ocular and/or otic toxicity

Blood dyscrasias, particularly

agranulocytosis (rare)

Renal insufficiency (usually reversible or non-

progressive) occurs in up to one-third of pts (may

require dose adjustments or interruptions)

Gastrointestinal disturbances (including ulceration

and fatal haemorrhage)

Monitoring requirements

Pts should be monitored as per recommendations in each agent’s prescribing information

Monitor iron levels (e.g. based on serum ferritin levels and transferrin saturation, and, where available, hepatic and/or cardiac T2* MRI, and

non-transferrin bound iron, labile plasma iron and reactive oxygen species levels) at least every 3 mo in pts receiving transfusions

Monitor organ function (cardiac, hepatic, endocrine) where indicated

Monitor for iron-chelation agent-related adverse events (e.g. ocular, otic or renal toxicity, gastrointestinal ulceration or bleeding, blood disorders,

delayed development in children) where indicated

a Starting dosage is adjusted according to transfusion requirements, the goal of therapy (i.e to maintain or reduce body iron) and adverse effects.

Treatment should be continued for as long as transfusion therapy continues and/or as long as iron overload remains clinically relevant.

b Therapeutic index (mean daily dose [mg/kg]/serum ferritin [ng/mL]) should be kept <0.025 at all times to avoid audiometric, retinal and skeletal

toxicity.

RBC = red blood cells; pts = patients.

16

Drugs Ther Perspect 2011; Vol. 27, No. 9

bolus formulation of deferoxamine has shown promising re-

sults with a good safety profile in a limited number of patients,

although rebound non-transferrin bound iron can occur with

this treatment. An extended-release formulation of deferox-

amine is currently in preclinical stage of development.[15]

Tailor chelator choice?

Different chelators are thought to act on different in-

tracellular iron pools (e.g. cytosol, nucleus and mitochon-

dria), which may have an impact on clinical endpoints,

although the reasons for these differences are not yet clear.[3]

For example, detoxification of liver iron by deferoxamine

may be related to its uptake in macrophages, the major site

of transfusional iron accumulation, while in preclinical

models, deferiprone or deferoxamine therapy resulted in

partial extraction of radiolabelled iron from cardiomyocytes,

with restoration of contractility of these cells. Further un-

derstanding of iron distribution and its relationship to clin-

ical outcomes may allow for improved chelator selection

that can be tailored to clinical circumstances.[3]

Research is currently underway that may contribute to the

development of new and improved chelators, with a focus

on the following areas:[3]

� Understanding how chelators clear iron and from which

cellular or extracellular compartments.� Elucidation of the as yet poorly defined mechanism by

which non-transferrin bound iron enters some cellular

compartments (such as mitochondria).� Developing chelators based on the structure of ferritin;

it may be possible to manipulate iron exit pores in the

ferritin cage and thus facilitate iron extraction.� Developing chelators with greater antiproliferative activ-

ity, and investigating their mechanism of action at the

molecular level.

Future studies of MDS interventions should incorporate

measures of HR-QOL and the impact of co-morbidities. In

available studies in transfusion-dependent MDS patients, HR-

QOL was impaired and many patients had co-morbidities (e.g.

diabetes and CHF) that are associated an increased risk of

death.[3] A co-morbidity index specific to MDS has been de-

veloped to predict the impact of extra-haematological co-mor-

bidities on outcome, including cardiac and hepatic disease, and

takes into account patient risk (low, medium or high risk).[17]

Disclosure

This review was adapted from Drugs 2011; 71 (2): 155-77[3] by Adis

editors and medical writers. The preparation of these articles was not

supported by any external funding.

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1172-0360/11/0009-0017/$19.95 ª 2011 Adis Data Information BV. All rights reserved.