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

Abstract

PURPOSE Myelodysplastic 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. METHODS A total of 2,876 patients with primary MDS from the GenoMed4All consortium were retrospectively analyzed. RESULTS IPSS-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. CONCLUSION IPSS-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.

Subclones with variants of uncertain clinical significance might contribute to ineffective hemopoiesis and leukemia predisposition

“…AML and MDS are heterogenous groups of hematologic clonal malignancies characterized by a wide range of clinical, biological, phenotypic, and molecular abnormalities, that differently affect clinical outcomes 23 . Risk stratification is currently performed using the European LeukemiaNet (ELN) guidelines for AML and the International Prognostic Scoring System‐Revised (IPSS‐R) or the novel Molecular‐IPSS (IPSS‐M) for MDS risk stratification 25,26 . Introduction of molecular alterations in MDS prognostic scoring system has represented a breakthrough in risk stratification, as molecular markers are essential disease prognosticators and can be also pharmacologically targeted 27 .…”

“…TET2, a member of the Ten‐eleven‐translocation (TET) family, deeply affects cell fate by regulating gene methylation through establishing novel 5‐hydroxymethylcytosine‐enriched genomic regions, 45 and by modifying RNA stability through 5‐methylcytosine oxidation 46,47 . Despite being frequently mutated in myeloid neoplasms, prognostic role of TET2 mutations is still controversial, as demonstrated by its absence in the novel IPSS‐M score 26 . Moreover, high genetic heterogeneity of TET2 in MDS has already been described, as a small proportion of MDS and CMML patients (1.1%) could have multiple simultaneous pathogenic mutations, that could be related to independent clones or to alternate alleles, suggestive of clonal evolution 48 .…”

Novel precision medicine approaches and treatment strategies in hematological malignancies

“…It also incorporates a strategy to handle potential missing genetic data and comes with a dynamic web interface accessible to both clinicians and patients (https://mds-risk-model.com/). The IPSS‐M was rapidly validated by several groups following its release, highlighting the importance of sharing data, methods, and algorithms in clinical hematology [45, 46]. The IPSS‐M was further observed to be predictive of relapse following stem‐cell transplantation (SCT), but not of response to hypomethylating agents [46].…”

“…The IPSS‐M was rapidly validated by several groups following its release, highlighting the importance of sharing data, methods, and algorithms in clinical hematology [45, 46]. The IPSS‐M was further observed to be predictive of relapse following stem‐cell transplantation (SCT), but not of response to hypomethylating agents [46]. Further studies are needed to identify clinically relevant predictive markers of response to such agents.…”

Performance of IPSS‐M in patients with myelodysplastic syndrome after hypomethylating agent failure

“…2 The IPSS-M has been externally validated by independent cohorts. 3 However, IPSS-M did not accurately prognosticate whether certain risk groups would preferentially respond to HMA therapy. Dynamic prognostic models remain elusive in MDS.…”