Real-World Validation of Molecular International Prognostic Scoring System for Myelodysplastic Syndromes

The study was conducted by GenoMed4All consortium and supported by EuroBloodNET, the European Reference Network on rare hematologic diseases. The Humanitas Ethics Committee approved the study. Written informed consent was obtained from each participant. This study was registered at ClinicalTrials.gov (ClinicalTrials.gov identifier: NCT04889729).European Union (GenoMed4All project No. 101017549 to M.G.D.P., C.D.G., T.H., U.P., P.F., M.D.C.; Transcan 7 Horizon 2020-EuroMDS project No. 20180424 to M.G.D.P., F.S., U.P., P.F.; HARMONY project No. 116026 to GC); AIRC Foundation (Associazione Italiana per la Ricerca contro il Cancro, Milan Italy-Project No. 22053 to M.G.D.P. and No. 26216 to G.C.); PRIN 2017 (Ministry of University & Research, Italy-Project 2017WXR7ZT to M.G.D.P.); Ricerca Finalizzata 2016 and 2018 (Italian Ministry of Health, Italy-Project RF2016-02364918 to M.G.D.P. and Project NET-2018-12,365,935 to M.G.D.P., F.P., M.T.V.); Cariplo Foundation (Milan Italy-Project No. 2016-0860 to M.G.D.P.); Beat Leukemia Foundation, Milan Italy (to M.G.D.P.)PURPOSEMyelodysplastic syndromes (MDS) are heterogeneous myeloid neoplasms in which a risk-adapted treatment strategy is needed. Recently, a new clinical-molecular prognostic model, the Molecular International Prognostic Scoring System (IPSS-M) was proposed to improve the prediction of clinical outcome of the currently available tool (Revised International Prognostic Scoring System [IPSS-R]). We aimed to provide an extensive validation of IPSS-M.METHODSA total of 2,876 patients with primary MDS from the GenoMed4All consortium were retrospectively analyzed.RESULTSIPSS-M improved prognostic discrimination across all clinical end points with respect to IPSS-R (concordance was 0.81 v 0.74 for overall survival and 0.89 v 0.76 for leukemia-free survival, respectively). This was true even in those patients without detectable gene mutations. Compared with the IPSS-R based stratification, the IPSS-M risk group changed in 46% of patients (23.6% and 22.4% of subjects were upstaged and downstaged, respectively).In patients treated with hematopoietic stem cell transplantation (HSCT), IPSS-M significantly improved the prediction of the risk of disease relapse and the probability of post-transplantation survival versus IPSS-R (concordance was 0.76 v 0.60 for overall survival and 0.89 v 0.70 for probability of relapse, respectively). In high-risk patients treated with hypomethylating agents (HMA), IPSS-M failed to stratify individual probability of response; response duration and probability of survival were inversely related to IPSS-M risk.Finally, we tested the accuracy in predicting IPSS-M when molecular information was missed and we defined a minimum set of 15 relevant genes associated with high performance of the score.CONCLUSIONIPSS-M improves MDS prognostication and might result in a more effective selection of candidates to HSCT. Additional factors other than gene mutations can be involved in determining HMA sensitivity. The definition of a minimum set of relevant genes may facilitate the clinical implementation of the score