Improved survival in MDS patients receiving iron chelation therapy – A matched pair analysis of 188 patients from the Düsseldorf MDS registry

doi:10.1016/j.leukres.2012.04.006

Leukemia Research

Volume 36, Issue 8, August 2012, Pages 1067-1070

https://doi.org/10.1016/j.leukres.2012.04.006 Get rights and content

Abstract

MDS patients are prone to develop transfusional iron overload. Iron overload may partly explain why transfusion dependency is associated with a decreased likelihood of survival. Our matched-pair analysis included 94 patients on long-term chelation therapy and 94 matched patients without it. All patients had iron overload, defined as serum ferritin (SF) above 1000 ng/ml or a history of multiple transfusions and SF ≥ 500 ng/ml. Median SF was 1954 ng/ml in chelated and 875 ng/ml in non-chelated patients. The difference in median survival (74 vs. 49 months, respectively; p = 0.002) supports the idea that iron chelation therapy is beneficial for MDS patients.

Introduction

Patients with myelodysplastic syndromes (MDS) suffer from peripheral blood cytopenias as a result of bone marrow failure. Besides medullary blast count and karyotype, transfusion dependency has been identified as an important prognostic factor [1], [2] and has therefore been integrated into the WHO-classification based prognostic scoring system (WPSS) [3].

Despite new treatment options, many MDS patients rely on red blood cell transfusions. Chronic transfusion therapy causes iron overload. Recently, a large retrospective analysis showed that iron overload, defined as a serum ferritin >1000 ng/ml, was a significant prognostic factor for OS and leukemia-free survival in MDS [1]. On multivariate analysis, the influence of iron overload was independent of transfusion requirement.

If iron overload shortens the survival of patients with MDS, iron chelation (IC) should do the opposite. This view is supported by a partly retrospective and partly prospective observational study by Rose et al. [4] showing that patients with an IPSS low or intermediate-1 risk profile who received iron chelation therapy lived longer than patients who did not. However, there are as yet no results available from randomized clinical trials to confirm such a survival benefit. We performed a retrospective matched-pair analysis drawing on the data base of the Düsseldorf MDS registry.

Section snippets

Methods

At the time of patient selection the Düsseldorf MDS registry included 3552 patients, diagnosed between 1975 and 2008. For matched-pair analysis [5] we identified 94 polytransfused MDS patients who had been receiving long-term chelation therapy. The registry was then searched for matching partners who received supportive care, including growth factors, but neither iron chelators nor disease-modifying drugs. The following characteristics were used for matching: age at diagnosis (±5 years),

Results

Patient characteristics are shown in Table 1a, Table 1b. All 188 patients showed iron overload, defined as a serum ferritin ≥1000 ng/ml, or a history of multiple transfusions and a serum ferritin ≥500 ng/ml. All ferritin levels were measured at the time of referral to our center, which was usually early after diagnosis. The proportion of heavily transfusion-dependent patients was largest among patients with del(5q), RCMD, and refractory anemia with excess blasts (RAEB-I and -II). At least 50% of

Discussion

In the field of thalassemia, it is well established that transfusional iron overload limits life expectancy due to toxic effects on heart, liver and other organs. In patients with MDS, the situation is more difficult to understand. Chronic transfusion therapy is clearly associated with a decreased likelihood of overall survival and leukemia-free survival [1], [2]. There is a dose-dependent effect of transfusion requirement, and a similar dose-dependent effect of serum ferritin levels, on

Funding source

This work was supported by Novartis Pharma AG. The sponsor was not involved in collection, analysis and interpretation of data; in the writing of the manuscript; and in the decision to submit the manuscript for publication. Part of the data have been presented at ASH 2009, Abstract 1747.

Conflict of interest

U.G. and N.G. received speakers honorary and research support from Novartis Pharma AG. F.F. and A.K. received speakers honorary from Novartis Pharma AG.

Acknowledgments

Contributions. U.G. and N.G. made the conception and design of the study. J.N., U.G. and N.G. were responsible for analysis and interpretation of the data, and J.N. wrote the manuscript. F.F., A.K., N.K. and C.S. acquired the data, U.G. and N.G. revised the article critically and R.H. revised the article critically and gave the final approval.

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Citation Excerpt :
However, the organs of patients with MDS are also older, possibly making them more susceptible to a deleterious effect of iron. A number of studies indicate that ICT in patients with MDS may have beneficial effects on organ function and OS; however, these data are from non-randomized studies and the results are therefore debated, pending full results from the prospective, randomized controlled trial of ICT with deferasirox (DFX) in MDS (NCT00940602) (Abraham et al., 2017; Angelucci et al., 2018; Chee et al., 2008; ClinicalTrials.gov, 2016; Gattermann et al., 2010b; Guariglia et al., 2011; Hoeks et al., 2017; Leitch, 2007; Leitch et al., 2008, 2017b; Lyons et al., 2017; Mainous et al., 2014; Neukirchen et al., 2012; Remacha et al., 2015; Rose et al., 2010; Steensma, 2009; Tefferi and Stone, 2009; Wong and Leitch, 2018; Zeidan et al., 2015). A consistent, and initially surprising observation in clinical studies of ICT in MDS is hematologic improvement (HI) in a significant minority of patients, including a reduction in RBC transfusion requirements and even transfusion independence (Angelucci et al., 2014; Gattermann et al., 2012; Nolte et al., 2013).
Myelodysplastic syndromes (MDS) are clonal hematopoietic stem cell disorders characterized by cytopenias and progression to acute myeloid leukemia (AML). Although several treatments for MDS are available, the mainstay of therapy for most patients remains supportive care. This includes red blood cell (RBC) transfusion to correct anemia, which leads to iron overload. RBC transfusion dependence and iron overload portend inferior overall survival. Some studies indicate that iron chelation therapy (ICT) may have beneficial effects on clinical endpoints in MDS; however, these data are from non-randomized trials and the validity of the results is vigorously debated. A consistent observation in clinical studies of ICT in MDS has been hematologic improvement (HI) in some patients, including a reduction in RBC transfusion requirements and even transfusion independence. Here, we review data on HI with ICT in lower risk MDS, preclinical data examining mechanisms by which HI may occur, and identify areas for future investigation.
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Transfused MDS patients are at risk for iron overload (IOL). IOL may exacerbate congestive heart failure (CHF), coronary artery disease (CAD) and arrythmias (ARR). We retrospectively examined cardiac events (CE) in red blood cell (RBC) transfusion dependent (TD) lower IPSS risk MDS patients. Patients were censored at death or MDS progression. 151 MDS patients were lower IPSS risk and RBC TD. Median number of cardiac risk factors (RF) per patient was 1 (1–4). CE following RBC TD occurred in 48 (32%) and were: CHF, n = 20; CAD, n = 15; ARR, n = 11. In univariate analysis factors significant for time to (TT) CE were: age at 1st RBC transfusion; number of RBCU transfused while lower IPSS risk; received iron chelation therapy (ICT); MDS treatment received; and number of cardiac RF/patient (p ≤ 0.02). Receiving ICT remained significant for TTCE in multivariate analysis (p = 0.03). Median TTCE in patients not receiving and receiving ICT was 7.0 (0.1–65.0) and 20.0 (0.1–148.6) months, respectively (p = 0.02). For lower IPSS risk RBC transfusion dependent MDS patients, time to first cardiac event following RBC TD was significantly longer in patients receiving ICT. These results suggest ICT may delay cardiac events in transfused patients. The results should be confirmed in larger numbers in prospective analyses.

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