Is Iron-Chelation Therapy Useful in Persons with Myelodysplastic Syndrome Receive?

doi:10.4236/ojbd.2011.11002

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Open Journal of Bloo d Di seases, 2011, 1, 3-7

doi:10.4236/ojbd.2011.11002 Published Online September 2011 (http://www.SciRP.org/journal/ojbd)

Is Iron-Chelation Therapy Useful in Persons with

Myelodysplastic Syndrome?

Chaim Hershko1,*, Robert Peter Gale2

1Department of Hematology, Shaare Zedek Medical Center, Jerusalem, Israel; 2Haematology Section, Division of Experimental

Medicine, Department of Medicine, Imperial College, London, UK.

Email: *[email protected]

Received July 28th, 2011; revised August 29th, 2011; accepted September 6th, 2011.

ABSTRACT

Iron overload in myelodysplastic syndrome (MDS) results from multiple RBC-trans fusions and inap propriate increased

iron absoption associated with ineffective erythropoiesis. Data from hereditary iron-loading anemias indicate long-

term consequences of iron toxicity are preventable and potentially reversible by effective iron-chelation therapy (ICT).

There is increasing interest in using ICT in persons with MDS because of the recent introduction of orally effective

iron-chelators which are suitable for older persons. Ideally, opinions supporting the benefit of ICT in MDS should be

evidenced-based, especially data from randomized trials showing better survival and, in exceptional cases, improved

heart function. Such data are lacking. Nevertheless, it is possible to rely on the extensive data from trials of ICT in per-

sons with thalassemia and to use well-d efined predictors of increased risks of life-th reatening complicatio ns to identify

persons with MDS most likely to benefit from ICT.

Keywords: Myelodyspla stic Syndrome, MDS, Iron-Chelation, NTBI, Deferoxamine, Deferiprone, Deferasirox,

Transfusion Siderosis

1. Selection of Persons with MDS for

Iron-Chelating Therapy

The choice of persons with MDS who may benefit from

ICT is of continued interest and controversy [1-5]. De-

spite some differences, principles underlying recom-

mendations are remarkably similar for persons with MDS

and those with thalassemia. First, it is recognized that

life-threatening RBC-transfusion-induced iron overload

is only relevant to persons with MDS with a favorable

prognosis. Second, magnitude and rate of iron-accumu-

lation are critical. Substantial heart iron-accumulation is

expected only after about 100 units (U) of RBCs [6-11;

Table 1]. A person receiving 2 - 4 U RBCs monthly will

only be at risk after about 2 - 4 years. Thus, recommend-

dations to start ICT after 20 U RBCs are too liberal and

merits consideration only if the rate of RBC-transfusions

predicts ≥100 U RBCs in ≤4 years. Lastly, because se-

rum ferritin in persons with MDS is affected by inflam-

mation, infection and leukemia burden, it is an unreliable

indicator of iron-overload [12,13]. Hence, currently pro-

posed threshold ferritin levels of 1000 - 2500 ng/dL

should be supplemented or replaced by estimates of iron-

overload based on state-of-the-art MRI methodology which

directly assesses tissue iron-accumulation. When such

technology is unavailable, the RBC-transfusion threshold

of ≥100 U is a practical way to identify persons with

MDS at high-risk of life-threatening iron-accumulation.

The importance of ICT in MDS is not universally ac-

cepted [14]. Although favorable effects of ICT in thalas-

semia include reversal of arrhythmias, improvement in

left ventricular ejection-fraction, arrest of hepatic fibrosis

and decreased glucose tolerance are well-documented, it

is uncertain whether these outcomes apply to persons

with MDS receiving ICT.

2. Choice of Iron-Chelators in Persons with

MDS

A comparison of the 3 leading chelators is presented in

Table 2.

Deferox amin e: Because of its proved efficacy and the

extensive experience in persons with thalassemia, defer-

oxamine (DFO) is considered the gold-standard for ICT

[15]. However, compliance with the rigorous require-

ments of daily subcutaneous DFO infusions is a serious

limiting-factor. In practice, elderly persons with MDS are

not reasonable candidates to receive DFO.

Is Iron-Chelation Therapy Useful in Persons with Myelodysplastic Syndrome?

Table 1. Relation of heart iron-accumulation to RBC-transfusion volume in transfused adults without thalassemia.

Buja et al. (1971) Diverse diseases. Clinically-important heart iron accumulation in 60% of subjects after 101 - 200 and 100% of subjects after

201 - 300 U RBCs [6];

Schafer et al. (1981) Anemias. After 60 - 210 U RBCs left ventricular function was impaired in only the most heavily RBC-transfused subjects

[7];

Jensen et al. (2003) Diverse diseases. Abnormal heart iron-accumulation in subjects with liver iron concentration >22.3 mg/g dry weight equal to

89 U RBCs * [8];

DiTucci et al. (2008) Anemias. Heart T2* correlated with RBC-transfusions. No subject receiving <290 mL/Kg of PRBCs (equal to 101 U RBCs)

had an abnormal T2* value (< 20 ms) [9];

Chacko J. et al. (2007) MDS. Median RBC-transfusions of 63 and 112 U in persons not receiving or receiving ICT T2* was normal (90%) or

borderline-normal (10%) [10];

Konen E. et al. (2007) MDS. Median RBC-transfusions of 90 U RBCs. All subjects had normal T2 [11].

*Calculated by the Angelucci formula [26] assuming a mean body weight of 75 kg each U RBC representing 200 mg iron.

Table 2. Comparison of iron-chelating drugs [15].

Deferasirox Deferiprone Deferoxamine

373 139 657 MW (Da)

Tridentate Bidentate Hexadentate Chelating property

22.5 19.9 26.6 Iron-binding affinity (pM)

27 7 13 Chelating efficiency (%)

20 - 40 75 - 100 30 - 50 Dose mg/kg/d

Oral, once daily Oral 3 times daily s.c. or i.v. 8 - 12 hours, 5 days/week Route

12 - 16 h 3 - 4 h 20 - 30 min Half-life

High Intermediate Low Lipid solubility

Fecal Urine Urine/fecal Excretion

80 90 - 450 5 - 10 Peak plasma levels (pM)

GI, rash, ocular, auditory, kidneyGI, arthralgia, ↓PMN Ocular, auditory growth, local reactions, allergyAdverse effects

Deferiprone: Because of its smaller size and higher

lipophilicity compared with DFO, deferiprone (DFP)

readily enters cells and may access intracellular chelat-

able iron more effectively than DFO. The cardio-protec-

tive effect of DFP is the most remarkable advantage of

this compound. Weekly WBCs are recommended be-

cause of the risk of drug-induced agranulocytosis. This

complicates the management of ICT in persons with

MDS with disease or treatment-related granulocytopenia.

Deferasirox: DFS is a synthetic iron-chelator with a

plasma half-life of 11-19 hours which allows once-daily

oral dosing. DFS is highly-efficient in removing non-

transferrin bound iron from the blood [16] and is usually

well-tolerated. and is particularly suitable in older per-

sons with MDS. It is premature to conclude whether DFS

improves survival of persons with MDS. Recommended

monitoring includes monthly creatinine and liver func-

tion tests.

Combined Iron-Chelating Drugs: Persons failing

single-drug ICT may respond to a combination of iron-

chelators. There are considerable data on combined drugs

in persons with thalassemia. However, there are insuf-

ficient data to recommend this strategy in persons with

MDS.

3. Impact of ICT on Survival in MDS

There are few uncontrolled studies reporting the impact

of ICT on survival of persons with MDS. Retrospective

analyses of small studies of persons with MDS receiving

or not receiving ICT suggest better survival amongst the

former [17,18]. The most recent and extensive non-ran-

domized study [19] included 53 subjects receiving ICT

Is Iron-Chelation Therapy Useful in Persons with Myelodysplastic Syndrome?5

Table 3. Controversies regarding ICT in MDS.

Claim Ambiguity

ICT should be started at serum ferritins ≥1000-2500 ng/dL. Feritin is an acute phase protein and is unreliable in MDS [12,13].

ICT is indicated when RBC-transfusions ≥20 U. Clinically-important heart iron-accumulation occurs only after ≥

RBC-transfusions ≥100 U RBCs in ≤2-4 years [6-11].

ICT improves survival and prevents leukemia

transformation.

Non-randomized trial data which may reflect selection biases

[17-19].

Prospective controlled tials of ICT in MDS are

needed.

Low compliance and high-rates of competing causes

of morbidity and death in older persons may obscure benefits.

and 44 controls. Median survivals were 124 and 53

months suggesting a benefit for ICT. However, several

potential selection biases and issues complicate this

analysis: 1) causes of death did not differ between the

cohorts; 2) end-of study serum ferritin levels were simi-

lar; 3) persons not receiving ICT were older and had

somewhat worse prognoses; and 4) a higher rate of pro-

gression to AML in the no ICT cohort could reflect a

worse prognosis independent of ICT.

The major limitation of retrospective and non-ran-

domized survival studies is subject selection biases. Per-

sons expected to live long enough to benefit from ICT

are more likely to receive ICT biasing the survival analy-

sis. Although the need for randomized studies is widely

accepted, it is unlikely these will resolve controversy

over using ICT in MDS. The high rate of competing

causes of morbidity and death in older persons with MDS

may obscure a possible benefit of ICT [19]. Conse-

quently, long-term use of ICT will likely rest on

thoughtful initial evaluation of each person considering

relevant clinical data including: 1) likelihood of suffi-

ciently long survival to receive ≥ 100 U RBCs within ≤ 2

- 4 years; and (2) periodic evaluation of the severity and

distribution of iron-accumulation using state-of-the-art

MRI techniques. Current claims and ambiguities regard-

ing ICT in MDS are summarized in Table 3.

4. Effects of ICT on Hematopoiesis

Improvement in RBC-production in MDS following ICT

was first reported by Jensen et al [20] and confirmed in

several subsequent reports in persons with MDS or

MPN-associated myelofibrosis [21]. This effect is unpre-

dictable and seen with several iron-chelators.

The mechanism responsible for the effect of iron che-

lation on hemoglobin production is unknown. In a person

with homozygous glutaredoxin-5 (GRLX5) mutation

with sideroblast-like microcytic anemia and iron-over-

load, deferoxamine treatment resulted in improved heme

synthesis and the partial correction of anemia [22]. Here,

the likely mechanism of improved hemoglobin synthesis

could be redistribution of mitochondrial iron into the

cytosol following ICT reversing repression of ALA-

synthase-2 translation. This effect may be expected in

only occasional persons with MDS and excessive mito-

chondrial iron deposition. Understanding the underlying

mechanism of this effect may have practical implica-

tions.

5. Other Benefits of ICT

A recent review suggested removal of NTBI by ICT may

protect against infection, leukemia transformation and

improve transplant outcomes [23]. These claims should

be interpreted cautiously. As discussed, lower risks of

leukemia transformation may reflect selection-biases [19].

Also, as discussed, increased pretransplant ferritin levels

may reflect co-morbidities adversely affecting transplant

outcome [24] unrelated to iron-overload. Using ICT to

prevent transplant-related infections is particularly haz-

ardous because iron chelators inhibit ribonucleotide re-

ductase and may delay or prevent engraftment [25]. Be-

cause of these considerations, we consider trials of ICT

in unselected persons with MDS ill-advised [23].

6. Conclusions

Development of oral effective iron-chelators suitable for

use in older persons has led to increasing interest in ICT

in persons with MDS. Appropriate selection of persons

with MDS who may benefit from ICT involves several

considerations: 1) RBC-tranfusion-related iron-overload

is only relevant to persons with a favourable prognosis; 2)

clinically-important heart iron-accumulation is expected

only after about ≥100 U RBCs given over ≤2 - 4 years;

and 3) serum ferritin is a poor indicator of iron-overload

and should be replaced by state-of-the-art MRI tech-

niques. Retrospective analyses of non-randomized and/or

uncontrolled trials of ICT in persons with MDS suggest

ICT results in a decrease in iron-accumulation-related

mortality and, sometimes, decreased RBC-transfusion

rates. However, important selection biases are likely to

operate in these studies. Randomized trials are needed to

determine if there is a survival benefit correlated with

ICT in persons with MDS.

Is Iron-Chelation Therapy Useful in Persons with Myelodysplastic Syndrome?

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Disclosure: C. H. received travel support and honoraria

from Novartis Basel Switzerland and Apotex Toronto

Canada. RPG is an employee of Celgene Corp, Summit,

NJ.