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T. de Witte et al.
dependent patients, whereas iron chelation therapy nor- malizes LPI levels. These findings suggest that NTBI and LPI may serve as early indicators of iron toxicity and a means to measure the effectiveness of iron chelation ther- apy in patients with LR-MDS. However, qualified NTBI and LPI are only currently available in specialized labora- tories.44
Large observational cohorts with detailed clinical and laboratory data, like the EUMDS cohort, are the ideal framework in which to identify well defined MDS sub- types that may benefit from novel targeted treatments. An example of such a subtype is MDS with loss of parts of chromosome 5, namely del5q; these patients have a rela- tively favorable outcome on lenalidomide treatment. In order to identify homogeneous subsets of patients within MDS, preliminary evidence has suggested that recently identified mutations in splicing factors may recognize dis- tinct disease entities within myeloid neoplasms.45 Splicing modulators are now in pre-clinical testing, and are very likely to lead to the introduction of effective drugs for spe- cific groups of MDS patients. Luspatercept, a specific inhibitor of growth and differentiation factor-11, a mem- ber of the transforming growth factor β superfamily, induced substantial improvement of anemia, especially in patients with ring sideroblasts.46 Characterization of indi- vidual cases by new genetic markers (one of the main objectives of the MDS-RIGHT project) will allow refined classification of patients into biological subgroups that are expected to respond differently to therapeutic interven- tions to guide discontinuation of those interventions that are less effective or less cost-effective.
The main question is whether RCT data and retrospective cohort data in selected tertiary care centers are representa- tive of the 'real world' data of the older patients with LR- MDS in the general population. A careful comparison of the 'real world' data and the RCT data will be needed in order to provide a clear answer to these questions. Meanwhile, the current analyses of data collected over 10 years in the EUMDS Registry provides relevant and important informa- tion which could help assess prognosis and response to stan- dard interventions in this older patient group.
Acknowledgments
The authors would like to thank all local investigators (full list in Annex 1), operational team members, data managers, research nurses and patients for their contribution to the EUMDS Registry; Nicole Blijlevens, Jackie Droste and the research group at Radboud University Medical Center, Nijmegen for administrative, logistical and practical support; Dorine Swinkels, Rian Roelofs, and Erwin Wiegerinck of the Radboudumc expertise center for iron disorders for the measure- ment of LPI, NTBI and hepcidin-25; Jan Verhagen for his con- tribution in the measurement of the iron parameters; Margot Rekers, Karin van der Linden, and Siem Klaver for sample han- dling; Elise van Pinxten-van Orsouw and Linda van der Landen for data entry of all iron parameters; Erica Travaglino, and Chiara Elena for accruing patients and validation of the Pavia Registry data; and Tim Bagguley, W. Thomas Johnston, Louise de Swart for their contribution to the analyses. We would like to express specific thanks to Odile Beyne-Rauzy, Fabio Efficace, Otilia Georgescu, Njetoc^ka Gredelj-Šimec, Agnes Guerci-Bresler, Gerwin Huls, Karin A. Koinig, Marian van Kraaij, Marta Krejci, Elisa Luño, Mac Macheta, Marius MacKenzie, Slobodanka Ostojić-Kolonić, Panagiotis Panagiotidis, Sophie Park, Chloé Reiniers, Borhane Slama, and Michail Spanoudakis for their contribution to the studies described, and Rosalie Lubber for the design of Figure 4.
Funding
The work of the EUMDS Registry is supported by an educa- tional grant from Novartis Pharmacy B.V. Oncology Europe, Amgen Limited, and Celgene. This work is part of the MDS- RIGHT activities, which has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement n. 634789 - “Providing the right care to the right patient with MyeloDysplastic Syndrome at the right time”. The Pavia Registry is supported by a grant from Associazione Italiana per la Ricerca sul Cancro (IG 20125). Part of the work is supported by Translational Implementation of genetic evidence in the management of MDS (TRIAGE-MDS) (TRIAGE-MDS, Austrian Science Found I 1576) within the TRANSCAN - Primary and secondary prevention of cancer call (ERA Net).
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