Leukemia Research 31S3 (2007) S7–S9www.elsevier.com/locate/leukres

Improving clinical outcome in patients with myelodysplastic syndromeand iron overload using iron chelation therapy

Heather A. Leitch*Department of Hematology, St. Paul’s Hospital, University of British Columbia, Vancouver, BC, Canada

Abstract

Until recently, little information on the benefits of iron chelation therapy (ICT) in patients with myelodysplastic syndrome (MDS) andiron overload was known. A recent retrospective study showed improved survival in transfusion-dependent patients with MDS (Low orIntermediate-1 risk IPSS) receiving ICT, compared with those not receiving ICT; median overall survival was not reached at 160 monthsversus 40 months, respectively. Significantly more patients receiving ICT survived to 4 years (80% versus 44%; p< 0.03), suggesting thatMDS patients with iron overload might benefit from ICT. Prospective studies to confirm the benefit of ICT in MDS are warranted.© 2007 Elsevier Ltd. All rights reserved.

Keywords: Myelodysplastic syndrome; Iron overload; Iron chelation therapy

1. Introduction

Myelodysplastic syndromes (MDS) are a group of bone mar-row disorders characterized by ineffective hematopoiesisand an increased risk of progression to acute myeloidleukemia [1,2]. Survival and the risk of progression toleukemia can be predicted using the International Prog-nostic Scoring System (IPSS) developed by Greenberget al. [1], which assesses risk based on: cytogenetics; thepercentage of blasts present in the bone marrow; and thenumber of cytopenias. More than 90% of patients withMDS will eventually require red blood cell transfusionsto correct anemia [1], and over time transfusion-dependentpatients accumulate iron, and the risk of hemosiderosis-associated organ dysfunction increases. Clinical evidenceof iron overload can occur after transfusion of 10−20 unitsof red blood cells, and without iron chelation therapy theaccumulation of iron results in progressive dysfunctionin the heart, liver, and endocrine system [3,4]. When thestorage capacity of the body for iron is exceeded, ironis deposited in organs including the liver, pituitary gland,gonads, heart, and pancreas, leading to organ dysfunctionand clinical sequelae.

*Department of Hematology, St Paul’s Hospital, University of BritishColumbia, 440−1144 Burrard Street, Vancouver, BC V6Z 2A5, Canada.Tel.: +1 604 684 5794; fax: +1 604 684 5705.E-mail address: hleitch@providencehematology.com (H.A. Leitch).

2. Principles of iron chelation therapy

Iron-induced damage can occur by two mechanisms. First,insoluble iron complexes are deposited in the tissues andorgans, leading to toxicity. Second, when the capacity oftransferrin to carry iron is exceeded, the presence of non-transferrin-bound iron in the plasma leads to the formationof labile plasma iron [5], which in turn generates reactiveoxygen species that damage cell membranes, proteins, andnucleic acids [6,7]. Iron chelation therapy involves the useof a drug that binds with iron to form what is called achelate (Fig. 1); as a result, the metal loses its toxic effectand is more readily removed from the body. Iron chelationtherapy is generally reserved for forms of iron overload inwhich phlebotomy cannot mobilize iron stores adequatelyor cannot be tolerated because of concurrent anemia.The effectiveness of iron chelation therapy has been

clearly demonstrated in patients with thalassemia who aredependent on red blood cell transfusion. For example,serum ferritin levels fell in 2 patients with homozygousb-thalassemia treated with continuous intravenous deferox-amine (Fig. 2); at the same time cardiac arrhythmias were

Toxic Non-toxic

Metal+ Chelator

Outside

theMetalChelatorChelator ChelatorChelator+ body

“Chelate”

Metal

Fig. 1. The principle of iron chelation therapy.

0145-2126/ $ – see front matter © 2007 Elsevier Ltd. All rights reserved.

S8 H.A. Leitch / Leukemia Research 31S3 (2007) S7–S9

8000

6000

4000

mfe

rrit

in(µ

g/l)

2000Seru

m

0

0 6 12 18 24 30 36 42 48

Months of intravenous treatment with deferoxamine

Fig. 2. Decline in serum ferritin levels in response to continuousintravenous infusion of deferoxamine in two iron-overloaded patients withhomozygous b-thalassemia. Redrawn with permission from Davis andPorter [8].

reversed and left ventricular ejection fraction improved [8].Other studies have shown that iron chelation therapy withdeferoxamine can arrest the progression of iron overload,improve hepatic laboratory abnormalities and arrest liverfibrosis, and reduce the risk of diabetes and glucoseintolerance [3]. Ten-year overall survival was significantlybetter in transfusion-dependent patients with thalassemiawho were well chelated than in those who were poorlychelated [9].Until recently, however, there has been little information

on iron overload in patients with MDS. Patients withMDS, in comparison to patients with thalassemia, areolder (median age at diagnosis 65−75 years) and mayhave comorbidities that make them more sensitive tothe effects of iron overload [10]. A post-mortem studyshowed that two-thirds of patients with MDS and ahigh transfusion requirement showed evidence of hepaticiron overload [11]. Many of these patients had arrhythmias,congestive heart failure, and impaired pituitary function,and all of them had impaired glucose tolerance; all canbe secondary to the effects of iron overload. In a study of37 patients with refractory anemia with ringed sideroblasts(RARS) subgroup of MDS (by the French–American–British [FAB] classification), a high transfusion requirementwas associated with poor prognosis. Of the 15 deaths, heartfailure was the cause of death in 7 patients, all of whom hadclinical and biochemical evidence of iron overload [12]. Inanother study of 46 patients with MDS, congestive heartfailure was seen in more than 40% of highly transfusedpatients, and was frequently the cause of death [13].Although it has been shown that overall survival de-

creases with increasing transfusion burden and increasingiron overload [14], and that elevated pre-transplant serumferritin levels adversely affect survival in patients with MDSundergoing hematopoietic stem-cell transplantation [15],there is little information in the literature on clinicaloutcomes in patients with MDS receiving iron chelationtherapy.

3. Clinical outcomes of transfusion-dependentMDS patients treated with iron chelation therapy

Several guidelines on when to initiate iron chelation therapyin patients with MDS have been published [16–19]. Thecriteria used historically in British Columbia, Canada, forinitiating iron chelation therapy were: low-risk disease (Lowor Intermediate-1 [Int-1] risk IPSS) with a life expectancyof 5 years, and either a serum ferritin level over 2000mg/lor a transfusion intake of at least 20 units of packedred blood cells, or clinical, biopsy or imaging evidenceof iron overload. A retrospective review was performedto determine the impact of iron overload on the clinicaloutcomes of patients with MDS, and whether iron chelationtherapy improved these outcomes [20]. This review included178 patients with bone marrow biopsy-confirmed MDS.Clinical data were collected from the practice database,the Home Hemosiderosis Program of British Columbiadatabase, and by chart review.The baseline characteristics of the patients were typical

of patients with MDS; over half were over 65 years in age,there was a predominance of male patients, and most had anEastern Cooperative Oncology Group (ECOG) performancestatus of 0 or 1. Approximately half of the patients hadneutropenia, anemia, or thrombocytopenia as defined by theIPSS, and just under half of the patients had two to threecytopenias. Two-thirds of patients had less than 5% blastsin the bone marrow. Karyotype was favourable risk in 60%,and nearly 60% fell into the IPSS categories of Low or Int-1risk. Nearly half of the patients had a serum ferritin levelof 1000mg/l or less early in their course (within 3 yearsof diagnosis), and nearly half of the patients received morethan 20 units of red blood cells in total. MDS-directedtreatment was predominantly supportive care (71%).Iron chelation therapy with subcutaneous deferoxamine

was given to 18 patients for a median of 15 months; itwas initiated for an elevated serum ferritin (over 1000mg/l)in 13 patients, clinical suspicion and biochemical evidenceof iron overload in 3 patients, and number of transfusionsgiven alone (over 20 units total) in 2. Factors significantfor overall survival in a univariate analysis were: age atdiagnosis; IPSS risk; MDS subtype; a history of at leastone serious infection; progression to acute leukemia; typeof treatment for MDS; elevated serum ferritin; clinicalevidence of iron overload; receiving iron chelation therapy;and the number of transfusions received ( p< 0.05 for all).In a multivariate analysis the only factors that remainedsignificant for overall survival were IPSS risk (p< 0.008)and having received iron chelation therapy (p< 0.02).In patients with Low or Int-1 risk IPSS MDS, overall

survival was significantly improved in those who receivediron chelation therapy compared to those who did not;median overall survival was not reached at 160 monthsand 40 months, respectively ( p< 0.03) [20]. Significantlymore patients who received iron chelation therapy survivedto 4 years (80% versus 44%; p< 0.03). Finally, serumferritin levels fell significantly in patients who received iron

H.A. Leitch / Leukemia Research 31S3 (2007) S7–S9 S9

chelation therapy, whereas they increased significantly inthose who did not.

4. Discussion

This study provides the first data showing improvedsurvival in transfusion-dependent MDS patients receivingiron chelation therapy. Due to the retrospective nature ofthe study, it was not possible to show a decrease in organdysfunction with iron chelation therapy, however the findingof improved survival in transfusion-dependent patients withMDS receiving iron chelation therapy is encouraging.Because the study is subject to the potential biases of allretrospective analyses, these findings need to be confirmedin prospective trials. Such trials would ideally evaluate theimpact of iron chelation therapy on morbidity, mortality,quality of life, transfusion requirements, cytopenias, andprogression to acute leukemia. They should include objec-tive measures of body iron such as serum ferritin level,transferrin saturation and liver iron concentration by biopsy,in addition to newer technology such as measurements ofnon-transferrin-bound iron, labile plasma iron and reactiveoxygen species, as well as cardiac and hepatic magneticresonance imaging.

Acknowledgment

This study was supported by a grant from NovartisCanada.

Conflict of interest statement

All data collection, analysis, and compilation for presenta-tion were performed independently.

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