Iron overload due to frequent blood transfusions in patients with myelodysplastic syndrome (MDS) is associated with complications, including a risk of cardiac disease and transformation to acute myeloid leukaemia (AML). Iron chelation therapy (ICT) with deferasirox and desferrioxamine is an essential part of the management of iron overload in low and intermediate prognostic risk MDS patients [NCCN Clinical Practice Guidelines in Oncology: Myelodysplastic Syndromes; Bennett 2008]. However, despite the risks of cardiac complications and AML, prior to 2009 there was little published evidence that ICT could improve survival outcomes in patients with MDS. A PubMed and ASH abstract search (conducted July 2013) has revealed a growing body of evidence indicating increased survival of a median of 2 – 6 years in transfusion-dependent MDS patients treated with ICT, relative to patients without ICT (see Table).

Reference Study objective Study design Treatments/patient numbers Key result 
Fox 2009
Neukirchen 2012 		Survival outcomes in MDS pts receiving ICT Retrospective matched-pair analysis  N=188 low-int. MDS:
N=94 ICTN=94 no ICT 		Median survival = 74 mths in ICT pts vs. 49 mths in non-ICT pts (p=0.002) 
Raptis 2009 Outcomes in low-risk MDS pts with/ without ICT Retrospective, single-arm analysis: 9 US institutions N=78 low risk MDS:
N=32 ICTN=46 no ICT 		Median Overall Survival (OS) = 103 mths in chelated = pts vs. 55 mths in non-chelated pts; p=0.02; multivariate HR 0.372, p=0.03 
Rose 2010 Analyse survival in transfusion-dependent, low-risk MDS pts pts with/ without ICT Multivariate prospective analysis in low/Int-1 IPSS MDS: 18 centers in France N=97 low-int. MDS
N=44 no ICTN=53 ICT 		Median OS 53 mths in non-ICT pts, 124 mths in ICT pts (p=<0.0003). In multivariate analysis ICT significantly associated with improved OS (HR of 0.386, CI: 0.196-0.757, p=0.005).  
Leitch 2011 Survival outcomes in MDS pts receiving DFO Retrospective chart review of 178 MDS pts in Canada N=178 low-int. MDS receiving DFO In MDS pts receiving ICT, there was a significant improvement in OS. Median OS for all MDS pts = 36 mths 
Lyons 2011 Impact of chelation on clinical outcomes and OS in low-risk MDS pts Retrospective analysis from MDS registry: 107 US centres N=600 low-int. MDS
N=263 received ICT, (191 received ≥6 mths) 		Mean time to AML transformation was 27.3 mths in non-ICT pts vs. 40.6 mths in ICT pts. Median survival 52.2 (with ICT) vs.99.3 mths (no ICT); p<0.0001 
Komrokji 2011  Impact of ICT on OS, AML transformation in low-risk MDS pts Retrospective pt chart review from a US centre  N=97 low-int. MDS:
N=45 ICT (N=35 DFX; N=10 DFO)N=52 no ICT 		Median OS 59 mths for pts with ICT vs. 33.7 mths no ICT (p<0.013; HR 0.52).  
Leitch 2012 Survival outcomes in lower risk/RARS pts with ICT Retrospective pt chart review in Canada N=268 lower risk MDS Lower IPSS /Non-RARS diagnosis associated with improved survival. Median OS for non-RARS without ICT =44 mths and with ICT, OS was not reached (p<0.0001). No significant difference between RARS with ICT (134.4 mths) or without ICT treatment (99 mths). 
Reference Study objective Study design Treatments/patient numbers Key result 
Fox 2009
Neukirchen 2012 		Survival outcomes in MDS pts receiving ICT Retrospective matched-pair analysis  N=188 low-int. MDS:
N=94 ICTN=94 no ICT 		Median survival = 74 mths in ICT pts vs. 49 mths in non-ICT pts (p=0.002) 
Raptis 2009 Outcomes in low-risk MDS pts with/ without ICT Retrospective, single-arm analysis: 9 US institutions N=78 low risk MDS:
N=32 ICTN=46 no ICT 		Median Overall Survival (OS) = 103 mths in chelated = pts vs. 55 mths in non-chelated pts; p=0.02; multivariate HR 0.372, p=0.03 
Rose 2010 Analyse survival in transfusion-dependent, low-risk MDS pts pts with/ without ICT Multivariate prospective analysis in low/Int-1 IPSS MDS: 18 centers in France N=97 low-int. MDS
N=44 no ICTN=53 ICT 		Median OS 53 mths in non-ICT pts, 124 mths in ICT pts (p=<0.0003). In multivariate analysis ICT significantly associated with improved OS (HR of 0.386, CI: 0.196-0.757, p=0.005).  
Leitch 2011 Survival outcomes in MDS pts receiving DFO Retrospective chart review of 178 MDS pts in Canada N=178 low-int. MDS receiving DFO In MDS pts receiving ICT, there was a significant improvement in OS. Median OS for all MDS pts = 36 mths 
Lyons 2011 Impact of chelation on clinical outcomes and OS in low-risk MDS pts Retrospective analysis from MDS registry: 107 US centres N=600 low-int. MDS
N=263 received ICT, (191 received ≥6 mths) 		Mean time to AML transformation was 27.3 mths in non-ICT pts vs. 40.6 mths in ICT pts. Median survival 52.2 (with ICT) vs.99.3 mths (no ICT); p<0.0001 
Komrokji 2011  Impact of ICT on OS, AML transformation in low-risk MDS pts Retrospective pt chart review from a US centre  N=97 low-int. MDS:
N=45 ICT (N=35 DFX; N=10 DFO)N=52 no ICT 		Median OS 59 mths for pts with ICT vs. 33.7 mths no ICT (p<0.013; HR 0.52).  
Leitch 2012 Survival outcomes in lower risk/RARS pts with ICT Retrospective pt chart review in Canada N=268 lower risk MDS Lower IPSS /Non-RARS diagnosis associated with improved survival. Median OS for non-RARS without ICT =44 mths and with ICT, OS was not reached (p<0.0001). No significant difference between RARS with ICT (134.4 mths) or without ICT treatment (99 mths). 

Pts: patients; ICT: iron chelating therapy; MDS: myelodysplastic syndrome; SC: Subcutaneous infusion; RA: Refractory anaemia; AML: acute myeloid leukaemia; OS: overall survival; IPSS: International Prognostic Scoring System; HR: hazard ratio; INT-1: intermediate-1; DFX: deferasirox; DFO: desferrioxamine; RARS: ring sideroblasts; SF: Serum ferritin; mths: months

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All the published evidence for survival benefit is in lower IPSS risk MDS patients, with a significant survival benefit seen in the sub-group of patients with non-RARS (Leitch 2012). The main limitation of the studies is that they are all based on retrospective or prospective observational study designs; hence have a risk of selection bias, although many utilize multivariate techniques to control for confounding factors. Furthermore, none of the studies assess survival associated with type of ICT although there is an ongoing RCT (TELESTO) addressing the impact of deferasirox on OS in low risk MDS patients. In addition, it would be useful to explore whether the observational data from each study could be pooled to assess OS outcomes in transfusion-dependent lower risk MDS, by MDS sub-group and by type of ICT. In conclusion, there is now extensive evidence of an association between ICT and survival improvement in transfusion-dependent lower prognostic risk MDS patients.

Disclosures:

Tolley:Tolley Health Economics: Consultancy. Off Label Use: ICT for patients with iron overload due to blood transfusion in patients with MDS. Vieira:Novartis: Employment. Strickson:Tolley Health Economics: Consultancy. Kundishora:Novartis: Employment.

Topics:
iron chelation therapy, myelodysplastic syndrome, brachial plexus neuritis, refractory anemia with sideroblasts, prostatic hypertrophy risk score, transfusion, deferasirox, iron overload, risk reduction, blood transfusion

Author notes

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Asterisk with author names denotes non-ASH members.

© 2013 by The American Society of Hematology
2013
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