The Role of Iron Chelation Therapy for Patients With Myelodysplastic Syndromes

The appropriate role of iron chelation therapy in the management of patients with myelodysplastic syndromes (MDS) is currently controversial. Some investigators interpret data to indicate that careful attention to iron parameters, with early initiation of iron chelation in patients with evidence suggesting transfusion-associated iron overload, is an important component of high-quality MDS patient care. Other physicians are more skeptical, noting that chelation can be cumbersome or costly, has associated risks, and has not yet been shown to reduce morbidity or mortality in the MDS setting. This article reviews the extent to which iron chelation therapy might be either an important clinical intervention in MDS or a distraction from more pressing clinical concerns.

Abstract

The appropriate role of iron chelation therapy in the management of patients with myelodysplastic syndromes (MDS) is currently controversial. Some investigators interpret data to indicate that careful attention to iron parameters, with early initiation of iron chelation in patients with evidence suggesting transfusion-associated iron overload, is an important component of high-quality MDS patient care. Other physicians are more skeptical, noting that chelation can be cumbersome or costly, has associated risks, and has not yet been shown to reduce morbidity or mortality in the MDS setting. This article reviews the extent to which iron chelation therapy might be either an important clinical intervention in MDS or a distraction from more pressing clinical concerns.

Medscape: Continuing Medical Education Online

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Release date: January 6, 2011; Expiration date: January 6, 2012

Learning Objectives

Upon completion of this activity, participants will be able to:

  • Describe the association between MDS and anemia
  • Evaluate iron overload in patients with MDS
  • Distinguish benefits of iron chelation therapy among patients with iron overload in MDS
  • Identify adverse events associated with oral iron chelation therapy

More than 90% of patients with myelodysplastic syndromes (MDS) are anemic at the time of diagnosis,1 and most patients will require red blood cell (RBC) transfusions at some point during the course of their illness. Patients with MDS who require RBC transfusions experience worse outcomes than transfusion-independent patients, even when the cohorts are matched for other known disease-associated prognostic markers.2,3

The specific reasons why patients with MDS requiring transfusions experience more rapid disease progression and shorter overall survival are currently unclear. RBC transfusion dependence might mark patients who have intrinsically more severe marrow failure and more dangerous disease, but the RBC transfusions themselves also likely confer risks. Several recent investigations have focused on the specific risk of transfusion-associated iron overload (hemosiderosis) in MDS, because each RBC unit contains approximately 200 to 250 mg of elemental iron, and humans lack a physiologic excretion mechanism for excess iron. Iron overload from increased gut iron absorption in the setting of ineffective erythropoiesis, exacerbated by RBC transfusions, has proven to be a leading cause of death in several congenital forms of anemia, such as severe β-thalassemia.4

The risk of iron overload in chronic acquired anemic states, such as MDS, could be clinically relevant, because this risk is potentially modifiable with iron chelation therapy (ICT). However, which patients with MDS should be offered ICT is currently an area of uncertainty in clinical practice.5 Although the advent of an effective orally bioavailable iron chelator, deferasirox (Exjade, approved by the FDA in 2005; deferiprone [L1], another orally administered iron chelator, is available in many countries but not in the United States) promised increased convenience for patients compared with injectable deferoxamine (Desferal, FDA-approved in 1968), ICT is costly and confers risks, and thus far no completed randomized clinical trials have shown that patients with MDS benefit from ICT. This article discusses the evidence supporting the concept that iron overload is harmful to patients with MDS, benefits and risks of ICT, preliminary data from phase II deferasirox clinical trials, and the various consensus guidelines on management of excess iron in patients with MDS.

Evidence of Possible Harm From Iron Overload in MDS

Correlation Between High Serum Ferritin Levels and Poor Outcomes

In a retrospective multivariable analysis of prognostic factors in 467 Italian patients with MDS treated between 1992 and 2002, Malcovati et al.6 observed that a serum ferritin level of greater than 1000 μg/L was associated with inferior survival, with a hazard ratio of 1.36 for every 500 μg/L of increase over 1000 μg/L—an effect that persisted even after controlling for the known risk of transfusion burden. Serum ferritin levels were normal (i.e., < 350 μg/L) or only modestly elevated at diagnosis for most patients in the Italian series. Patients exceeded a ferritin threshold of 1000 μg/L after they received a median of 21 RBC units over 10.8 months of transfusion dependency. The adverse effects of high ferritin were only significant in patients with the lower-risk MDS subtypes, refractory anemia (RA) or RA with ring sideroblasts. In contrast, an elevated ferritin did not significantly alter survival in patients with refractory cytopenias with multilineage dysplasia or RA with excess blasts, presumably because of the shorter overall life expectancy of these patients because of higher-risk intrinsic disease factors. After the Italian results were published in 2005, Japanese and Spanish investigators confirmed the finding of increased mortality associated with an elevated serum ferritin level in patients with MDS.7,8 In contrast to serum ferritin, serum transferrin saturation measurements have been less useful as a measure of degree of iron overload or effectiveness of ICT in patients with MDS.9

Medicare Data: MDS-Associated Comorbidities

Serum ferritin levels correlate generally with total body iron stores, but ferritin is a nonspecific biomarker that is sensitive to inflammatory status and other non–iron-related influences. To further explore correlations between MDS and potential iron toxicity, Goldberg et al.10 reviewed 2253 patients aged 65 years or older who were coded in a Medicare database during 2003 as newly diagnosed with MDS. When compared with more than 1.3 million patients without MDS who were enrolled in Medicare in 2003, the 512 patients with MDS from whom 3-year follow-up data were available had a higher risk of cardiac events during the follow-up period (73.2% vs. 54.5%) and an increased rate of diabetes (40.0% vs. 33.1%), hepatic disease (0.8% vs. 0.2%), and infections such as sepsis (22.5% vs. 6.1%). The subset of patients with MDS who received RBC transfusions (n = 205) were at even greater risk for cardiac events than nontransfused patients with MDS (n = 307) and people without MDS (82.4% vs. 67.1% vs. 54.5%, respectively), and at increased risk of fungal infections (14.6% vs. 6.2% vs. < 1%, respectively).

In view of the well-recognized association between iron overload and specific complications in the transfused congenital anemia population, including hepatic complications, such as liver fibrosis and cirrhosis; endocrinopathies, such as hypopituitarism and diabetes; and cardiac disorders, such as cardiomyopathy and conduction system abnormalities, the Medicare data suggest several potential mechanisms for the association between transfusion dependence and worse outcomes in MDS. However, the presence of chronic anemia, biologic aspects of MDS unrelated to iron, or other indirect factors may also be important contributors to some of these complications. Similar results to those in the study by Goldberg et al.10 emerged from a nested case-control analysis that used claims data from a health insurance group.11

High Serum Ferritin and Increased Risk of Complications of Allogeneic Stem Cell Transplantation

Armand et al.12 at the Dana-Farber Cancer Institute in Boston showed that among patients with MDS or acute leukemia who underwent myeloablative allogeneic stem cell transplantation (SCT), outcomes were poorer and transplant-related mortality was higher in those with elevated pretransplant serum ferritin levels compared with those with normal levels. An association between high ferritin and worse posttransplant outcomes was then confirmed by SCT teams from the Cleveland Clinic,13 City of Hope Medical Center,14 and the Fred Hutchinson Cancer Research Center.15 Excess SCT-related mortality associated with high serum ferritin seems to be caused by various causes, including increased rates of infection with siderophoric (i.e., iron-avid) microorganisms and hepatic veno-occlusive disease. In one study, elevated ferritin was associated with reduced rates of acute and chronic graft-versus-host disease, yet non–relapse-related mortality was still increased.13 Whether elevated ferritin might influence a graft-versus-leukemia effect is unknown. Although autologous SCT is rarely used as an MDS treatment in the United States, Korean and European groups found that high serum ferritin levels were associated with difficulty mobilizing stem cells from patients with MDS (possibly also because these patients have more advanced disease), and transplant outcomes were poorer in patients with elevated ferritin levels.16

Other Data Suggest the Risk of Complications of Iron Overload in MDS is Small

Some conflicting data have been published that suggest iron overload may not be a major clinical concern for many patients with MDS. For example, in an analysis of 126 patients with acquired sideroblastic anemia, Chee et al.17 showed that transfusion dependence was associated with modestly poorer outcomes, but no correlation was seen between overall survival and serum ferritin levels. Ferritin also did not predict poor outcomes in a Mayo Clinic series of 88 patients with del(5q) MDS.18

In addition, several recent studies have used MRI to assess cardiac iron accumulation in transfused patients with MDS, using the T2* (R2*) gradient echo technique. Cardiac iron accumulation, which is of particular concern given the advanced age of most patients and the high prevalence of cardiac comorbidities and risk factors for heart disease, seems to be uncommon in MDS. In 3 studies of patients with MDS who had received an average of 50 to 125 RBC units, only 5 of 32 had a T2* signal of less than 20 ms indicating increased cardiac iron.1921 Cellular iron processing is complex, and variables such as HFE genotype and other polymorphisms in genes encoding iron regulatory proteins are likely to modify the risk for accumulation of toxic iron species in individual patients.22

Patients with MDS who have excess blasts or a complex karyotype continue to have poor outcomes, with a life expectancy often measured in months rather than years, and no evidence shows that a high ferritin influences the clinical course for these higher-risk patients. Several investigators have argued that although a subset of patients with MDS have an indolent natural history for whom a focus on iron overload is appropriate, excessive concern about iron overload may distract patients and clinicians from considerations regarding disease-modifying therapy that are of higher priority.5,23

Potential Benefits from ICT

Although the benefit usually cited for ICT is removal of excess iron from body organs in which inappropriate deposits of reactive iron molecules are present and inhibiting normal tissue function and causing injury, ICT might also have favorable effects through other mechanisms. Reduction of labile plasma iron (LPI), a toxic redox-active form of non–transferrin-bound iron (NTBI) that appears in the plasma when the capacity of plasma transferrin to bind iron released from macrophages and gut epithelium is exceeded, could be just as important for ICT outcomes as achievement of net negative iron balance. The potential beneficial effects of reducing LPI include reduction of infections, improved survival after allogeneic SCT, and delayed disease progression.24 Notably, in the US03 clinical trial of deferasirox in MDS, LPI rapidly disappeared with ICT in all patients in whom LPI was measurable at study enrollment (41% of 176 patients had elevated LPI levels).25

LPI is of concern partly because LPI-induced reactive oxygen species (ROS) can catalyze oxidative damage to intracellular lipids, proteins, and nucleic acids, which can lead to genomic instability. Genomic instability might promote disease progression through accumulation of new somatic mutations.26 In a Spanish series of 2994 patients with MDS, elevated serum ferritin levels and high transfusion requirements correlated with progression to acute myeloid leukemia.27 NTBI, including LPI, also has been shown to augment growth of several microorganisms in vitro, including Candida albicans and Staphylococcus epidermidis, and might also cause hepatocyte injury, predisposing patients to veno-occlusive disease.24,28 Like LPI, ROS can be reduced through deferasirox therapy.29

Concerns about the harmful effects of LPI are particularly applicable in the allogeneic SCT setting. Usually not enough time is available between identification of a patient as a transplant candidate and the transplant procedure for ICT to be administered to achieve a net negative iron balance, yet LPI can be eliminated relatively quickly. Several clinical studies are currently addressing whether short-term peritransplant administration of deferasirox or other iron chelators can reduce LPI levels and transplant-related mortality.

Reducing LPI through ICT might also improve hematopoiesis, because cell damage from increased ROS contributes to ineffective erythropoiesis,30 and deferasirox has additional ROS-independent effects on apoptosis through its effects on nuclear factor kappa B (NF-κB).31 Although there are case reports of patients with MDS who have become free of RBC transfusions after initiating effective ICT,32 clinical experience and preliminary results from the US03 study25 suggest this is uncommon, occurring in less than 5% of treated patients.

Currently, other than anecdotes of treatment-emergent transfusion independence, no clinical evidence supports any of the above theoretical benefits of ICT in patients with MDS. In several retrospective comparison studies, including a Canadian study of 18 chelated patients and another analysis of 55 chelated patients from 18 Francophone centers, patients who received ICT were noted to have lived markedly longer than cohorts who did not receive ICT (226 vs. 41 months median survival in the Canadian study, 124 vs. 53 months in the French study).33,34 The role of selection bias in these retrospectively obtained results is problematic, because clinicians likely administered ICT preferentially to patients with the most favorable disease features. The reported 15-year survival advantage in the Canadian study is difficult to explain, for instance, based solely on ICT. Additionally, the ICT protocols used in both studies were nonuniform. Well-controlled prospective clinical trial data will be essential to definitively establish a role for ICT in MDS.

Clinical Trial Results and Plans

In small series of patients, ICT with parenteral deferoxamine has been reported to reduce the total body iron burden in patients with MDS,35 but chronic deferoxamine infusions are cumbersome, and therefore most ICT clinical data in MDS have emerged in the oral deferasirox era. In addition to small single-center studies,9,36 the 24-patient multicenter US02 study showed that deferasirox can effectively reduce hepatic iron concentration, LPI, and serum ferritin levels despite ongoing RBC transfusions.37 In addtion, larger prospective, open-label, phase II multicenter clinical trials of once-daily oral deferasirox have now been completed. One multicenter trial was conducted in North America (US03 study), whereas the other trial enrolled patients in Europe, Asia, Australia, and Africa (the Evaluation of Patients' Iron Chelation with Exjade [EPIC] study).38,39 Additionally, an important placebo-controlled study (TELESTO) of deferasirox ICT in patients with lower-risk MDS was recently initiated. Combination therapy with deferoxamine plus either deferasirox or deferiprone might mobilize iron stores more rapidly than single-agent therapy, but limited data are available on patients with MDS treated with combination ICT.40

US03 Trial

The US03 deferasirox clinical trial included a 1-year core treatment phase and a 2-year extension phase. Eligible patients were those with International Prognostic Scoring System low or intermediate-1 risk MDS who had a ferritin levels of 1000 μg/L or more, a serum creatinine twice the upper limit of the normal range or less, and received greater than 20 units of RBCs. The initial deferasirox dose in the US03 study was 20 mg/kg per day, which could be increased up to 40 mg/kg per day if the ferritin did not drop appropriately. US03 trial 1- and 2-year interim results were presented at the American Society of Hematology annual meetings in 2007, 2008, and 2009, but have not yet been published in full.25,38,41

The 173 eligible patients from 45 centers who enrolled in the US03 trial had a median baseline ferritin of 2771 μg/L, mean pre-enrollment transfusion duration of 3.5 years (mean, 69 RBC units), and a median age of 70 years. The 91 patients who completed 1 year of deferasirox therapy experienced a 23% reduction in the median ferritin, and LPI had returned to normal levels in all of the 68 patients with elevated baseline LPI who completed 3 months of therapy. The deferasirox dose had to be increased to at least 30 mg/kg per day in greater than 40% of patients because of persistent serum ferritin elevation.

Rates of study withdrawal were high: 45% of patients could not complete 12 months of therapy either because of adverse events (54 patients, 31%), death (17 deaths, all considered not related to drug therapy), disease progression, withdrawal of consent, or administrative reasons. Only 83 patients (i.e., 47% of those enrolled in the core phase) entered the extension study, and 35 patients (42%) of these dropped out during year 2,41 so that less than one third of the original 173 patients were still receiving ICT 2 years later. Serum creatinine levels increased to more than 33% above baseline values and above the upper limit of normal in 33% of patients. Adverse events are discussed in further detail later. During the second year of the trial, the mean serum ferritin of patients still enrolled in the study continued to decline (Figure 1).

EPIC Trial

The EPIC trial enrolled 1744 patients with transfusion-dependent anemia from diverse causes, including 341 patients with MDS.39 Entry criteria for patients with MDS were similar to those used in the US03 trial, except that patients with ferritin levels less than 1000 μg/L were eligible if liver MRI indicated 2 mg or more of iron per gram dry weight. Patients receiving 2 to 4 RBC units per month were treated at an initial dose of 20 mg/kg per day of deferasirox, whereas those with lower or higher transfusion needs started at 10 or 30 mg/kg per day, respectively.

Figure 1
Figure 1

Trend in mean serum ferritin levels in patients with MDS over 2 years during treatment with deferasirox in the US03 open-label North American clinical trial. Data are limited to the 54 patients who completed 2 years of therapy; 173 eligible patients entered the study, whereas 83 patients completed at least 1 year of therapy and entered the extension study.

From: List AF, Baer MR, Steensma DP, et al. Two-year analysis of efficacy and safety of deferasirox (Exjade) treatment in myelodysplastic syndrome patients enrolled in the US03 study. Available at: http://ash.confex.com/ash/2009/webprogram/Paper18472.html. Accessed November 5, 2010. With permission from the American Society of Hematology.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 9, 1; 10.6004/jnccn.2011.0007

Figure 2
Figure 2

Design of the ongoing TELESTO prospective, randomized clinical trial (NCT00940602), designed to evaluate the efficacy of iron chelation in patients with MDS. TELESTO is not an acronym; the trial is instead named after Telesto, the daughter of the Greek mythological Titaness and sea goddess Tethys and the Titan Oceanus. Telesto in Greek (Tελεστϖ) can be translated as “success” in English.

Abbreviations: IPSS, International Prognostic Scoring System; MDS, myelodysplastic syndromes; RBC, red blood cell.

Data from www.clinicaltrials.gov.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 9, 1; 10.6004/jnccn.2011.0007

The median age of patients with MDS enrolled in the EPIC study was 68 years, and 52% had previously received ICT; their baseline median ferritin, 2730 μg/L, was almost identical to that in US03 trial participants. The reduction in median serum ferritin during the 1-year EPIC study was 35% in chelation-naïve patients and 22% in previously chelated patients, whereas LPI was reduced in a sustained fashion in patients in whom it was elevated at enrollment.

As in the US03 trial, the rate of study withdrawal was also high in the EPIC trial, with 166 (48.7%) patients dropping out from adverse events (78 patients; adverse events were considered drug-related in 44 patients), withdrawal of consent (33 patients), death (26 deaths, none considered by investigators to be study drug-related), or other causes. Renal insufficiency was again common: 24.9% of patients had 2 consecutive serum creatinine increases greater than 33% above baseline that also exceeded the upper limit of the normal range. One patient with normal pretreatment liver tests experienced an elevation in alanine aminotransferase to greater than 10 times the upper limit of normal. A quality of life (QOL) analysis indicated improvement in QOL with ICT.

TELESTO Trial

The TELESTO clinical study is an ambitious industry-sponsored, randomized, prospective, placebo-controlled trial of deferasirox ICT in transfusion-requiring patients who have lower-risk MDS, an elevated serum ferritin level, and preserved renal and hepatic function. The TELESTO study is projected to enroll 630 patients, who will be treated with either placebo or deferasirox for up to 5 years. The study schema is depicted in Figure 2. Although convincing patients to commit to a lengthy placebo-controlled trial may be challenging, legitimate clinical equipoise exists about the role of ICT in MDS, and the data obtained will be critical for answering questions about the potential benefits and risks of ICT in MDS.

Risks of ICT

Adverse events with ICT may result from either perturbation of iron trafficking or the chelating drug itself, and distinguishing these is often difficult. Adverse events associated with deferasirox overlap somewhat with those reported during deferoxamine ICT, but exceptions do exist.42 For instance, the iron–deferoxamine siderophore complex promotes growth of Mucor species, but deferasirox seems to be fungicidal for Mucorales, and ongoing clinical trials are evaluating deferasirox as an adjuvant antifungal agent for patients with life-threatening zygomycoses.43 Gastrointestinal adverse events are much more frequent with the orally administered deferasirox than with the injectable deferoxamine.

Table 1

Adverse Effects of Deferasirox in the EPIC Study*

Table 1

Adverse events in patients with MDS reported in the US03 and EPIC trials are summarized in Tables 1 and 2. Regardless of the patient population, gastrointestinal effects such as nausea, diarrhea, and abdominal bloating are by far the most common side effects associated with deferasirox treatment. Although usually mild and manageable with supportive care measures, these effects may lead some patients to discontinue therapy. A maculopapular skin rash is the most common nongastrointestinal side effect, and is often self-limited.

Renal insufficiency, which may be a consequence of excessively rapid chelation, with passage of high concentrations of harmful iron molecules through the kidney, is the most common serious adverse event associated with deferasirox. Renal injury is a particular concern in elderly patients with MDS, who have risk factors for reduced kidney function more often than younger patients with congenital forms of anemia. Several reports have been made of other serious adverse events during deferasirox therapy, including hepatic failure, gastrointestinal hemorrhage, renal tubular acidosis, alopecia, agranulocytosis, otic or ocular toxicity, and anaphylaxis.42 The frequency of these idiosyncratic serious events is as yet unclear, but their possibility must be considered when deciding whether ICT is worthwhile for individual patients with MDS.

Table 2

Adverse Effects of Deferasirox in the US03 Trial*

Table 2
Table 3

Representative Clinical Guidelines Concerning Iron Chelation Therapy for Patients with MDS

Table 3

In early 2010, the FDA required a black box warning and other updates to the prescribing information for deferasirox because of postmarketing adverse event reports, including renal impairment and renal failure, hepatic impairment and hepatic failure, and gastrointestinal hemorrhage (http://www.fda.gov/Safety/MedWatch/SafetyInformation/Safety-AlertsforHumanMedicalProducts/ucm200850.htm).

Guidelines

Several organizations and expert panels, including NCCN, have published guidelines for the management of iron overload in patients with MDS, including parameters for ICT initiation and treatment monitoring (Table 3).44,45 Because of the lack of prospective trials of ICT in the MDS setting, considerable variation exists between these guidelines with respect to specific recommendations.44 In general, however, existing guidelines recommend consideration of assessment of iron status in lower-risk patients with MDS who have a life expectancy of at least several years and have received at least 20 RBC units over 1 year or more; intervention is suggested if the serum ferritin is persistently 1000 μg/L or greater, if other evidence suggests clinically relevant iron overload (e.g., abnormal MRI results or elevated LPI), or if allogeneic SCT is planned. Serial serum ferritin levels are the easiest and least costly way to monitor candidates for ICT and track efficacy of ICT in patients undergoing therapy, but serum ferritin levels may be increasingly supplemented by hepatic and cardiac T2* MRI monitoring, where available.

Conclusions

Increasing evidence suggests that iron overload and elevated LPI may contribute to poor outcomes in some patients with MDS. However, patients with MDS face serious competing risks from peripheral blood cytopenias and disease progression, and the magnitude of the independent effect of iron overload on morbidity and mortality is currently uncertain and probably small. Although a fraction of patients with MDS may exist for whom iron toxicity is clinically relevant and results in reduced life expectancy, the risk to individual patients will likely depend critically on non-MDS factors, such as HFE genotype or other variations affecting iron processing. ICT may offer benefit to carefully selected patients with MDS, but ICT is costly (e.g., the deferasirox United States retail price for an adult may exceed $5000 per month) and carries risks, and treatment discontinuation rates were high among carefully screened patients enrolled in recent multicenter phase II studies. Prospective, well-controlled, randomized trials are essential to better define the risk–benefit ratio and specific groups of patients with MDS for whom ICT might be indicated.

EDITORKerrin M. Green, MA, Assistant Managing Editor, Journal of the National Comprehensive Cancer NetworkDisclosure: Kerrin M. Green, MA, has disclosed no relevant financial relationships.
CME AUTHOR
Charles P. Vega, MD, Associate Professor; Residency Director, Department of Family Medicine, University of California, Irvine
Disclosure: Charles P. Vega, MD, has disclosed no relevant financial relationships.

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Correspondence: David P. Steensma, MD, Division of Hematologic Malignancies, Dana-Farber Cancer Institute, 44 Binney Street, Suite D1B30 (Mayer 1B21), Boston, MA 02115. E-mail: david_steensma@dfci.harvard.eduDisclosure: David P. Steensma, MD, has disclosed the following relevant financial relationships:Served on the advisory board for: Novartis Pharmaceuticals Corporation

Supplementary Materials

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    Trend in mean serum ferritin levels in patients with MDS over 2 years during treatment with deferasirox in the US03 open-label North American clinical trial. Data are limited to the 54 patients who completed 2 years of therapy; 173 eligible patients entered the study, whereas 83 patients completed at least 1 year of therapy and entered the extension study.

    From: List AF, Baer MR, Steensma DP, et al. Two-year analysis of efficacy and safety of deferasirox (Exjade) treatment in myelodysplastic syndrome patients enrolled in the US03 study. Available at: http://ash.confex.com/ash/2009/webprogram/Paper18472.html. Accessed November 5, 2010. With permission from the American Society of Hematology.

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    Design of the ongoing TELESTO prospective, randomized clinical trial (NCT00940602), designed to evaluate the efficacy of iron chelation in patients with MDS. TELESTO is not an acronym; the trial is instead named after Telesto, the daughter of the Greek mythological Titaness and sea goddess Tethys and the Titan Oceanus. Telesto in Greek (Tελεστϖ) can be translated as “success” in English.

    Abbreviations: IPSS, International Prognostic Scoring System; MDS, myelodysplastic syndromes; RBC, red blood cell.

    Data from www.clinicaltrials.gov.

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