Review Of Published Survival Evidence For Iron Chelation Therapy (ICT) In Patients With Myelodysplastic Syndromes (MDS)
Authors: Tolley Keith , Vieira Joao , Foster Craig , Strickson Amanda , Kundishora Stephanie 
Published: October 2019

Abstract
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).ReferenceStudy objectiveStudy designTreatments/patient numbersKey resultFox 2009Neukirchen 2012Survival outcomes in MDS pts receiving ICTRetrospective matched-pair analysis N=188 low-int. MDS:N=94 ICTN=94 no ICTMedian survival = 74 mths in ICT pts vs. 49 mths in non-ICT pts (p=0.002)Raptis 2009Outcomes in low-risk MDS pts with/ without ICTRetrospective, single-arm analysis: 9 US institutionsN=78 low risk MDS:N=32 ICTN=46 no ICTMedian Overall Survival (OS) = 103 mths in chelated = pts vs. 55 mths in non-chelated pts; p=0.02; multivariate HR 0.372, p=0.03Rose 2010Analyse survival in transfusion-dependent, low-risk MDS pts pts with/ without ICTMultivariate prospective analysis in low/Int-1 IPSS MDS: 18 centers in FranceN=97 low-int. MDSN=44 no ICTN=53 ICTMedian 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 2011Survival outcomes in MDS pts receiving DFORetrospective chart review of 178 MDS pts in CanadaN=178 low-int. MDS receiving DFOIn MDS pts receiving ICT, there was a significant improvement in OS. Median OS for all MDS pts = 36 mthsLyons 2011Impact of chelation on clinical outcomes and OS in low-risk MDS ptsRetrospective analysis from MDS registry: 107 US centresN=600 low-int. MDSN=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<0.0001Komrokji 2011 Impact of ICT on OS, AML transformation in low-risk MDS ptsRetrospective pt chart review from a US centre N=97 low-int. MDS:N=45 ICT (N=35 DFX; N=10 DFO)N=52 no ICTMedian OS 59 mths for pts with ICT vs. 33.7 mths no ICT (p<0.013; HR 0.52). Leitch 2012Survival outcomes in lower risk/RARS pts with ICTRetrospective pt chart review in CanadaN=268 lower risk MDSLower 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
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.